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http://www.ncbi.nlm.nih.gov/pubmed/27709644 | 1. Andrologia. 2017 Oct;49(8). doi: 10.1111/and.12711. Epub 2016 Oct 6.
A case of hypopituitarism accompanying Kearns-Sayre syndrome treated with human
chorionic gonadotropin: A case report and literature review.
Kang YX(1), Wang YJ(1), Zhang Q(1), Pang XH(1), Gu W(1).
Author information:
(1)Department of Endocrinology, Zhejiang University School of Medicine Second
Affiliated Hospital, Hangzhou, China.
Comment in
Andrologia. 2017 Dec;49(10). doi: 10.1111/and.12810.
Kearns-Sayre syndrome (KSS) is a disorder caused by mutations in mitochondrial
DNA. Here, we report an unusual case of Kearns-Sayre syndrome accompanied by
hypopituitarism (deficiencies in reproductive and growth hormones). A
20-year-old male presented with growth retardation for the last 8 years, as well
as the following findings: short stature, delayed puberty, myasthenia, an
extraocular movement deficit, drooping eyelids, pectus carinatum and scoliosis.
Cerebral enhanced magnetic resonance imaging revealed dysplasias of the
pituitary, white matter and cerebellum. Laboratory work-up showed subnormal
testosterone and growth hormone levels, a subnormal testicular volume,
sensorineural deafness, pigmentary retinopathy, complete right bundle branch
block and left anterior bundle branch block. Pathological examination revealed
ragged red muscle fibres. Thus, this rare case involved the coexistence of
Kearns-Sayre syndrome and hypopituitarism in a patient. Administration of
coenzyme Q10 for the KSS and hormone replacement therapy for the
endocrinopathies were performed for treatment of this patient.
© 2016 Blackwell Verlag GmbH.
DOI: 10.1111/and.12711
PMID: 27709644 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22231766 | 1. RETRACTED ARTICLE
Indian J Pediatr. 2012 May;79(5):650-4. doi: 10.1007/s12098-011-0618-3. Epub
2012 Jan 10.
Kearns Sayre Syndrome--case report with review of literature.
Phadke M(1), Lokeshwar MR, Bhutada S, Tampi C, Saxena R, Kohli S, Shah KN.
Author information:
(1)Department of Pediatrics, Lilavati Hospital and Research Center, Mumbai,
India.
Retraction in
Indian J Pediatr. 2013 Nov;80(11):982. doi: 10.1007/s12098-013-1123-7.
Kearns-Sayre Syndrome is form of rare mitochondrial cytopathy, first described
by Thomas P. Kearns and George Pomeroy Sayre in 1958 and is characterized by
progressive external opthalmoplegia, cardiac conduction block, pigmentary
retinal degeneration, variable number of red ragged fibers on muscle biopsy. It
presents before the child reaches the age of twenty. Kearns-Sayre syndrome may
affect many organ systems and additional features may include myopathy,
dystonia, bulbar symptoms in the form of dysarthria and nasal regurgitation and
bilateral facial weakness. Endocrine abnormalities (e.g., diabetes, growth
retardation/short stature, and hypoparathyroidism), bilateral sensorineural
deafness, dementia, cataracts, and proximal renal tubular acidosis, skeletal
muscle weakness (proximal more than distal) and exercise intolerance are
additional features. Kearns Sayre Syndrome occurs as a result of large-scale
single deletions (or rearrangements) of mitochondrial DNA (mtDNA), which is
usually not inherited but occurs spontaneously, probably at the germ-cell level
or very early in embryonic development. No disease-modifying therapy is
available for Kearns-Sayre syndrome (KSS). Management is supportive vigilance
for detection of associated problems. In the future, potential treatment in
patients with Kearns-Sayre syndrome may attempt to inhibit mutant mtDNA
replication or encourage replication of wild-type mtDNA.
DOI: 10.1007/s12098-011-0618-3
PMID: 22231766 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/26884075 | 1. BMJ Case Rep. 2016 Feb 16;2016:bcr2015213813. doi: 10.1136/bcr-2015-213813.
Dilated cardiomyopathy with cardiogenic shock in a child with Kearns-Sayre
syndrome.
Sehgal S(1), Choudhry S(2), Debelenko L(3), L'Ecuyer T(1).
Author information:
(1)Department of Pediatric Cardiology, Children's Hospital of Michigan, Detroit
Medical Center, Detroit, Michigan, USA.
(2)Children's Hospital of Michigan, Detroit Medical Center and Washington
University School of Medicine, St Louis, Missouri.
(3)Department of Pathology, Children's Hospital of Michigan, Detroit Medical
Center, Detroit, Michigan.
Kearns-Sayre syndrome (KSS) is a mitochondrial myopathy resulting from
mitochondrial DNA deletion. This syndrome primarily involves the central nervous
system, eyes, skeletal muscles and the heart. The most well-known cardiac
complications involve the conduction system; however, there have been case
reports describing cardiomyopathy. We describe a case of a child with KSS who
presented with decompensated cardiac failure from dilated cardiomyopathy
representing cardiomyocyte involvement of KSS. Our patient had a rapidly
progressing course, despite maximal medical management, requiring emergent
institution of extracorporeal membrane oxygenation and transition to a
ventricular assist device. To the best of our knowledge, this is the youngest
patient in the literature to have dilated cardiomyopathy in KSS.
2016 BMJ Publishing Group Ltd.
DOI: 10.1136/bcr-2015-213813
PMCID: PMC5483557
PMID: 26884075 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35477912 | 1. Neurosciences (Riyadh). 2022 Apr;27(2):111-115. doi:
10.17712/nsj.2022.2.20210123.
Kearns-Sayre syndrome with rare imaging finding of SLC25A4 Mutation.
Zhao H(1), Shi M(1), Yang F(1), Yang X(1).
Author information:
(1)From the Department of Neurology, Hospital of Chengdu University of
Traditional Chinese Medicine, Chengdu, Sichuan Province, People's Republic of
China.
Kearns-Sayre Syndrome (KSS) is a subtype of chronic progressive external
ophthalmoplegia (CPEO). In this case, A 21-year-old man diagnosed with KSS, and
presented with chronic progressive blepharoptosis (ptosis) and external
ophthalmoplegia, diffuse depigmentation of the retinal pigment epithelium, and
cerebellar ataxia, with a cerebrospinal fluid protein of 254 mg/dL, was
reported. Genetic screening revealed a novel mutated gene in SLC25A4 in the
patient as well as in his mother: NM_001151:c.170G>C in exon 2. Its imaging
finding is a characteristic progressive atrophy of the right cerebellar
hemisphere. In conclusion, we found a case of KSS with a novel mutated gene in
SLC25A4: NM_001151:c.170G>C in exon 2 as the pathogenic mechanism, and found
that KSS can be caused only when the proportion of mutations in the SLC25A4 gene
reach a certain degree, and the patient with KSS showed a unique cranial imaging
feature of unilateral progressive cerebellar atrophy.
Copyright: © Neurosciences.
DOI: 10.17712/nsj.2022.2.20210123
PMCID: PMC9257918
PMID: 35477912 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16735969 | 1. Diabetes Metab. 2006 Apr;32(2):182-6. doi: 10.1016/s1262-3636(07)70267-7.
Kearns Sayre syndrome: an unusual form of mitochondrial diabetes.
Laloi-Michelin M(1), Virally M, Jardel C, Meas T, Ingster-Moati I, Lombès A,
Massin P, Chabriat H, Tielmans A, Mikol J, Guillausseau PJ.
Author information:
(1)Department of Internal Medicine-Diabetes and Metabolic Diseases, Hôpital
Lariboisière, Paris, France. [email protected]
Kearns Sayre syndrome (KSS) is a mitochondrial disorder characterized by the
emergence before age 20 of progressive external ophthalmoplegia, pigmentary
retinopathy, together with other heterogeneous clinical manifestations,
including cardiac conduction defects, muscle abnormalities and endocrinopathies.
KSS is associated with large heteroplasmic deletions in mitochondrial DNA. We
report the case of a 43-year-old woman, with diabetes mellitus as a first
manifestation at age 19. Later, she exhibited bilateral ptosis and external
ophthalmoplegia with progressive worsening. DNA analysis identified a large
mitochondrial DNA (mtDNA) deletion, which confirmed the diagnosis of KSS. By
reporting this case with diabetes mellitus as first manifestation, we aim at
emphasizing problems of diagnosis in these subtypes of mitochondrial diabetes.
DOI: 10.1016/s1262-3636(07)70267-7
PMID: 16735969 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35031921 | 1. Neurol Sci. 2022 Mar;43(3):2081-2084. doi: 10.1007/s10072-022-05881-8. Epub
2022 Jan 14.
Kearns-Sayre syndrome: expanding spectrum of a "novel" mitochondrial
leukomyeloencephalopathy.
Moscatelli M(#)(1), Ardissone A(#)(2), Lamantea E(3), Zorzi G(2), Bruno C(4),
Moroni I(2), Erbetta A(5), Chiapparini L(5).
Author information:
(1)Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta,
Milan, Italy. [email protected].
(2)Child Neurology Unit, Department of Pediatric Neuroscience, Fondazione IRCCS
Istituto Neurologico Carlo Besta, Milan, Italy.
(3)Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto
Neurologico Carlo Besta, Milan, Italy.
(4)Center of Translational and Experimental Myology, IRCCS Istituto Giannina
Gaslini, Genova, Italy.
(5)Neuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta,
Milan, Italy.
(#)Contributed equally
Erratum in
Neurol Sci. 2022 Nov;43(11):6607. doi: 10.1007/s10072-022-05950-y.
Kearns-Sayre syndrome (KSS) is a rare mitochondrial disease associated to a
widespread cerebral leukodystrophy. MRI shows a typical centripetal pattern
where U-fibers are mainly affected with a relative spare of periventricular
white matter. Recently, different patterns of spinal cord involvement have been
described in KSS. Here we report 4 new cases with typical cerebral
leukodystrophy associated with spinal cord lesions. A pattern characterized by
abnormal signal intensity in the H gray matter and posterior columns was found
in 2 patients, while the remaining 2 presented a peculiar involvement of the
spinal trigeminal nuclei at the junction of low medulla and cervical cord. MRI
spinal cord involvement in KSS is probably an underestimated finding and should
be evaluated in the diagnostic work up of these patients.
© 2022. Fondazione Società Italiana di Neurologia.
DOI: 10.1007/s10072-022-05881-8
PMID: 35031921 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25061332 | 1. Int J Gen Med. 2014 Jul 3;7:325-32. doi: 10.2147/IJGM.S65560. eCollection
2014.
Kearns-Sayre syndrome: a case series of 35 adults and children.
Khambatta S(1), Nguyen DL(1), Beckman TJ(1), Wittich CM(1).
Author information:
(1)Division of General Internal Medicine, Mayo Clinic, Rochester, MN, USA.
BACKGROUND: Kearns-Sayre syndrome (KSS) is a rare mitochondrial cytopathy, first
described at Mayo Clinic in 1958.
AIMS: We aimed to define patient and disease characteristics in a large group of
adult and pediatric patients with KSS.
METHODS: We retrospectively searched the Mayo Clinic medical index patient
database for the records of patients with KSS between 1976 and 2009. The 35
patients identified with KSS were analyzed in terms of demographic
characteristics, presenting signs and symptoms, diagnostic features, clinical
evolution, and associations between disease features and the development of
disability.
RESULTS: The mean (standard [SD]) age at KSS presentation was 17 (10) years, but
the mean age at diagnosis was 26 (15) years. Ophthalmologic symptoms developed
in all patients, and neurologic and cardiac involvement was common. Only four
patients (11%) in the series died, but all deaths were from sudden cardiac
events. The development of physical disability was significantly associated with
cognitive decline (P=0.004) but not with other clinical features, such as sex or
sudden cardiac death.
CONCLUSION: We report the largest case series to date of patients with KSS from
a single institution. In addition to the conduction system abnormalities
identified in previous series, our cohort included patients with syncope and
sudden cardiac death. This underscores the need to consider formal
electrophysiologic studies and prophylactic defibrillators in patients with KSS.
DOI: 10.2147/IJGM.S65560
PMCID: PMC4086664
PMID: 25061332 |
http://www.ncbi.nlm.nih.gov/pubmed/33030289 | 1. Mol Genet Genomic Med. 2020 Nov;8(11):e1509. doi: 10.1002/mgg3.1509. Epub 2020
Oct 8.
Mitochondrial DNA deletion and duplication in Kearns-Sayre Syndrome (KSS) with
initial presentation as Pearson Marrow-Pancreas Syndrome (PMPS): Two case
reports in Barranquilla, Colombia.
Sabella-Jiménez V(1), Otero-Herrera C(1), Silvera-Redondo C(2), Garavito-Galofre
P(2).
Author information:
(1)Genetics and Molecular Medicine Research Group, Universidad del Norte,
Barranquilla, Colombia.
(2)Genetics, Department of Medicine, Genetics and Molecular Medicine Research
Group, Universidad del Norte, Barranquilla, Colombia.
BACKGROUND: Kearns-Sayre Syndrome (KSS) and Pearson Marrow-Pancreas Syndrome
(PMPS) are among the classic phenotypes caused by mitochondrial DNA (mtDNA)
deletions. KSS is a rare mitochondrial disease defined by a classic triad of
progressive external ophthalmoplegia, atypical pigmentary retinopathy, and onset
before 20 years. PMPS presents in the first year of life with bone marrow
failure and exocrine pancreatic dysfunction, and can evolve into KSS later in
life. Even though an mtDNA deletion is the most frequent mutation in KSS and
PMPS, cases of duplications and molecular rearrangements have also been
described. In Colombia, few case reports of KSS and PMPS have been published in
indexed journals or have been registered in scientific events.
METHODS: We discuss clinical and genetic aspects of two case reports of
pediatric female patients, with initial clinical diagnosis of PMPS who later
evolved into KSS, with confirmatory molecular studies of an mtDNA deletion
and an mtDNA duplication.
RESULTS: A large-scale mtDNA deletion, NC_012920.1:m.8286_14416del, was
confirmed by Southern Blot in patient 1. An mtDNA duplication of 7.9 kb was
confirmed by MLPA in patient 2.
CONCLUSIONS: Our findings are compatible with the phenotypic and genetic
presentation of PMPS and KSS. We present the first molecularly confirmed case
reports of Colombian patients, diagnosed initially with PMPS, who later evolved
to KSS.
© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley
Periodicals LLC.
DOI: 10.1002/mgg3.1509
PMCID: PMC7667363
PMID: 33030289 [Indexed for MEDLINE]
Conflict of interest statement: The authors have no conflicts of interests to
declare. |
http://www.ncbi.nlm.nih.gov/pubmed/16977556 | 1. Neurologia. 2006 Sep;21(7):357-64.
[Mitochondrial DNA deletions in Kearns-Sayre syndrome].
[Article in Spanish]
Carod-Artal FJ(1), Lopez Gallardo E, Solano A, Dahmani Y, Herrero MD, Montoya J.
Author information:
(1)Servicio de Neurología, Hospital Sarah.
INTRODUCTION: Kearns-Sayre syndrome (KSS) is a mitochondrial disorder
characterized by progressive external ophthalmoplegia, pigmentary retinopathy,
onset before 20 years, and ragged-red fibers on muscle biopsy. KSS has been
associated to mitochondrial DNA (mtDNA) mutations. We report neurological
manifestations and mtDNA deletions in KSS.
METHODS: Six KSS patients underwent neurological examination, biochemical
analysis (muscle enzymes, lactate, cerebrospinal fluid analysis),
electromicrography, muscle biopsy (Gomori stain, electronic microscopy),
electrocardiogram, echocardiography, MRI/CT scan. MtDNA deletions were studied
in blood and muscle samples using Southern blotting and long polymerase chain
reaction.
RESULTS: Four males and two females (mean age: 27.7 years; range: 17-42; mean
age at onset: 8.2 years) were studied. Initial symptoms were ptosis and gaze
restriction, fatigue, exercise intolerance and proximal limb weakness. Syncope
and neurosensory hypoacusia were initial symptoms in two patients. All of them
presented a unique deletion in the mitochondrial genome, in heteroplasmy, and
their size was in the range of 4,420 and 9,437 basis pairs. Three of these
deletions are reported for the first time in this article. Most of the deletions
are flanked by small direct repeats elements.
CONCLUSIONS: Proximal muscle weakness and fatigue appear frequently in KSS
patients during follow up. The syndrome in these patients has been caused by
mtDNA deletions.
PMID: 16977556 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9832255 | 1. Clin Neuropathol. 1998 Nov-Dec;17(6):291-6.
Mitochondrial cytochrome b gene deletion in Kearns-Sayre syndrome associated
with a subclinical type of peripheral neuropathy.
Zanssen S(1), Molnar M, Buse G, Schröder JM.
Author information:
(1)Institut für Biochemie, Universitätsklinikum, RWTH, Aachen, Germany.
Kearns-Sayre syndrome (KSS) is a progressive neuromuscular disease characterized
by ophthalmoplegia, cardiac conduction block, and pigmentary retinopathy
associated with abnormal mitochondrial structure and function. Usually
mitochondrial DNA (mtDNA) deletions have been associated with Kearns-Sayre
syndrome and chronic progressive external ophthalmoplegia. Size and position of
the deletions differ markedly among these patients. The present study confirms
this observation for a patient with KSS by a muscle and nerve biopsy in which we
detected a 1.2 kb mtDNA deletion. The location of the deletion, however, is
unusual in this case: its position comprises nucleotides 14952 to 15739. The
defect is heteroplasmic and concerns the cytochrome b and tRNA genes. Complex I
and IV of the respiratory chain were intact in this case, indicating that below
a threshold of tRNA formation, the impaired biosynthesis and membrane
integration of one respiratory complex may cause the phenotypical appearance of
the KSS syndrome associated with a subclinical neuropathy.
PMID: 9832255 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31158487 | 1. J AAPOS. 2019 Oct;23(5):295-297. doi: 10.1016/j.jaapos.2019.05.005. Epub 2019
May 31.
Exophthalmos in Kearns-Sayre syndrome.
Tauber J(1), Polla DJ(2), Park S(3).
Author information:
(1)New York University School of Medicine, New York, New York.
(2)Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New
York.
(3)Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New
York. Electronic address: [email protected].
Kearns-Sayre syndrome (KSS) is a rare mitochondrial DNA (mtDNA) deletion
syndrome that typically presents before 20 years of age and is characterized by
chronic progressive external ophthalmoplegia, pigmentary retinopathy, and a
combination of cardiac conduction defects, cerebellar ataxia, and elevated
cerebrospinal fluid protein levels. The mtDNA defects interfere with oxidative
phosphorylation and can affect a number of cellular energy processes in various
organs. We report the case of a 15-year-old girl with KSS that was uniquely
associated with bilateral, symmetrical exophthalmos.
Copyright © 2019 American Association for Pediatric Ophthalmology and
Strabismus. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.jaapos.2019.05.005
PMID: 31158487 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23102393 | 1. Indian Heart J. 2012 Sep-Oct;64(5):515-7. doi: 10.1016/j.ihj.2012.07.010. Epub
2012 Jul 27.
Symptomatic complete heart block leading to a diagnosis of Kearns-Sayre
syndrome.
Puri A(1), Pradhan A, Chaudhary G, Singh V, Sethi R, Narain VS.
Author information:
(1)Chhatrapati Shahuji Maharaj Medical University, Lucknow, India.
[email protected]
Kearns-Sayre syndrome (KSS) is a rare syndrome characterized by the triad of
progressive external ophthalmoplegia, pigmentary retinopathy and cardiac
conduction system disturbances; it is a mitochondrial encephalomyopathy with
which usually presents before the patient reaches the age of 20. Here we present
a case report of a patient with KSS who presented with symptomatic complete
heart block.
Copyright © 2012 Cardiological Society of India. Published by Elsevier B.V. All
rights reserved.
DOI: 10.1016/j.ihj.2012.07.010
PMCID: PMC3860714
PMID: 23102393 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27442316 | 1. Cornea. 2016 Sep;35(9):1250-4. doi: 10.1097/ICO.0000000000000927.
Coenzyme Q10 in the Treatment of Corneal Edema in Kearns-Sayre: Is There an
Application in Fuchs Endothelial Corneal Dystrophy?
Kim J(1), Medsinge A, Chauhan B, Wiest C, Scanga H, Monaghan R, Moore WH,
Nischal KK.
Author information:
(1)*University of Pittsburgh School of Medicine, Pittsburgh, PA; †Pediatric
Ophthalmology, Strabismus and Adult Motility, UPMC Eye Center, Children's
Hospital of Pittsburgh, Pittsburgh, PA; ‡Drexel University College of Medicine,
Philadelphia, PA; §Clinical and Academic Department of Ophthalmology, Great
Ormond Street Hospital for Children, London, United Kingdom; and ¶UPMC Eye
Center, Pittsburgh, PA.
Comment in
Cornea. 2016 Dec;35(12):e39. doi: 10.1097/ICO.0000000000001043.
PURPOSE: Corneal involvement in mitochondrial disease is seldom described.
Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterized by
retinitis pigmentosa, external ophthalmoplegia, and heart block. We report 2
patients with KSS with corneal lesions involving the endothelium, which improved
with Coenzyme Q10 (CoQ10). Based on recent research regarding the role of
dysfunctional oxidative metabolism in Fuchs Endothelial Corneal Dystrophy
(FECD), we propose that mitochondrial diseases and FECD share a final pathway.
METHODS: A chart review was performed and a review of the literature was
completed with a PubMed search using the terms "Kearns-Sayre Syndrome",
"mitochondria", "endothelium", "Fuchs endothelial corneal dystrophy", and
"cornea".
RESULTS: There are 19 reports of corneal involvement in clinical phenotypes of
mitochondrial disease. Nine of these 19 cases had findings consistent with KSS.
Our patients with KSS had microcystic changes throughout the cornea and
excrescences on the endothelial surface seen with ultrasound biomicroscopy,
similar to the clinical findings in FECD. CoQ10 improved corneal disease in both
children. CoQ10 deficiency has been reported in a variety of mitochondrial
diseases, and efficacy of supplementation has been demonstrated. It may be
beneficial in these patients because of its antioxidant properties and role in
oxidative phosphorylation.
CONCLUSIONS: The common deletion found in patients with KSS has recently been
implicated in FECD, which has recently been shown to be a disease related to
dysfunctional oxidative metabolism. Future research should explore the use of
antioxidants, such as CoQ10 in patients with FECD.
DOI: 10.1097/ICO.0000000000000927
PMID: 27442316 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16773512 | 1. Neuropediatrics. 2006 Apr;37(2):110-3. doi: 10.1055/s-2006-924226.
Atypical MRI findings in Kearns-Sayre syndrome: T2 radial stripes.
Hourani RG(1), Barada WM, Al-Kutoubi AM, Hourani MH.
Author information:
(1)Department of Diagnostic Radiology, The American University of Beirut Medical
Center, Riad El Solh 1107, 2020 Beirut, Lebanon. [email protected]
Kearns-Sayre syndrome (KSS) is a mitochondrial disorder consisting of external
ophthalmoplegia, retinitis pigmentosa, ataxia and heart block. Magnetic
resonance imaging (MRI) shows abnormal T2 high signal intensity in the deep gray
matter nuclei, the cerebellar and the subcortical white matter. We report an
unusual MR pattern of KSS, where the T2 images revealed radially oriented,
hypointense stripes in hyperintense white matter, a characteristic MRI pattern
of lysosomal disease not previously reported in KSS.
DOI: 10.1055/s-2006-924226
PMID: 16773512 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32787478 | 1. Ophthalmic Genet. 2020 Oct;41(5):497-500. doi: 10.1080/13816810.2020.1799416.
Epub 2020 Aug 13.
Retinoschisis associated with Kearns-Sayre syndrome.
Chertkof J(1), Hufnagel RB(1), Blain D(1), Gropman AL(2), Brooks BP(1).
Author information:
(1)Ophthalmic Genetics & Visual Function Branch, National Eye Institute,
National Institutes of Health , Bethesda, Maryland, USA.
(2)Department of Neurology, Children's National Medical Center , Washington,
District of Columbia, USA.
Comment in
Ophthalmic Genet. 2021 Feb;42(1):99. doi: 10.1080/13816810.2020.1827444.
Ophthalmic Genet. 2021 Feb;42(1):100. doi: 10.1080/13816810.2020.1832295.
BACKGROUND: Kearns-Sayre Syndrome (KSS) is characterized by pigmentary
retinopathy, external ophthalmoplegia and heart block. We report on a now
24-year-old male with clinical retinoschisis and molecularly confirmed KSS.
MATERIALS AND METHODS: Physical and complete ophthalmic examination, molecular
diagnosis.
RESULTS: Over nine years of follow-up, the subject manifested progressive signs
and symptoms of KSS, including external ophthalmoplegia/strabismus, ptosis,
pigmentary retinopathy, corneal edema, Type I diabetes mellitus, gut
dysmotility, sensorineural deafness and heart block. At age 21 he was
incidentally found to have retinoschisis on optical coherence tomography that
remained stable over three years follow-up. Sequencing of the RS1 gene revealed
no pathogenic variants, effectively ruling out co-existing X-linked
retinoschisis.
CONCLUSIONS: These findings suggest retinoschisis may be a rare manifestation of
KSS. A trial of a carbonic anhydrase inhibitor was frustrated by coexisting
corneal edema associated with the condition.
DOI: 10.1080/13816810.2020.1799416
PMCID: PMC8127726
PMID: 32787478 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interest The authors report no
conflicts of interest. The authors alone are responsible for the content and
writing of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/9677732 | 1. Turk J Pediatr. 1998 Apr-Jun;40(2):255-9.
Kearns-Sayre syndrome. A case report.
Altunbaşak S(1), Bingöl G, Ozbarlas N, Akçören Z, Hergüner O.
Author information:
(1)Department of Pediatric Neurology, Cukurova University Faculty of Medicine,
Adana, Turkey.
Kearns-Sayre syndrome (KSS) is a mitochondrial disorder. There is a large-scale
mitochondrial DNA (mtDNA) deletion in most of the case. In this article, a case
of KSS who has progressive external ophthalmoplegia (PEO), retinitis pigmentosa
(RP), complete heart block, encephalopathy attacks, type-1 diabetes mellitus,
ragged-red fiber (RRF) and lactic acidosis is presented and discussed in light
of the literature available on this subjects. Diagnosis is confirmed by
determination of mtDNA deletion.
PMID: 9677732 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1424198 | 1. Clin Endocrinol (Oxf). 1992 Jul;37(1):97-103. doi:
10.1111/j.1365-2265.1992.tb02289.x.
Endocrine dysfunction in Kearns-Sayre syndrome.
Harvey JN(1), Barnett D.
Author information:
(1)St. James University Hospital, Leeds, UK.
Kearns-Sayre syndrome (KSS) is a form of mitochondrial myopathy in which
specific clinical features, namely progressive external ophthalmoplegia,
pigmentary retinal degeneration and cardiac conduction defects, occur. KSS has
also been associated with a variety of endocrine and metabolic disorders, in
particular short stature, gonadal failure, diabetes mellitus, thyroid disease,
hyperaldosteronism, hypomagnesaemia, and bone, tooth and calcification
abnormalities. A case is described exhibiting all of these features. A survey of
the literature was conducted to determine the prevalence of these conditions
among reported cases. Cases with hypoparathyroidism were considered separately
to see if they constituted a distinct subgroup with multiple endocrine
dysfunction. Short stature was common, being documented in 38% of cases. Gonadal
dysfunction before or after puberty was also common (20% of cases) and affected
both sexes equally. Diabetes mellitus was recorded in 13% of cases, half of
which required insulin. Thyroid disease, hyperaldosteronism and hypomagnesaemia
were uncommon but were probably not looked for in many cases. Bone or tooth
abnormalities and calcification of the basal ganglia were found both in those
with and without hypoparathyroidism. While endocrine and metabolic dysfunction
was found more commonly in those with hypoparathyroidism this is likely to be
due to increased recognition rather than increased prevalence. No evidence of an
autoimmune polyendocrine syndrome including hypoparathyroidism was found.
DOI: 10.1111/j.1365-2265.1992.tb02289.x
PMID: 1424198 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/572507 | 1. Neurology. 1979 Aug;29(8):1172-4. doi: 10.1212/wnl.29.8.1172.
Familial Kearns-Sayre syndrome.
Schnitzler ER, Robertson WC Jr.
The Kearns-Sayre syndrome (KSS) is a distinctive type of progressive external
ophthalmoplegia, characterized by pigmentary degeneration of the retina, heart
block, elevated concentration of cerebrospinal fluid protein, and abnormal
muscle mitochondria. Previously described cases have all been sporadic.
Consequently, viral infections and autoimmune disorders have been proposed as
etiologies. The occurrence of KSS in two brothers suggests that genetic factors
may play a role in the pathogenesis of some cases.
DOI: 10.1212/wnl.29.8.1172
PMID: 572507 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16735000 | 1. Funct Neurol. 2006 Jan-Mar;21(1):39-41.
Unusual clinical presentation of a patient carrying a novel single 1.8 kb
deletion of mitochondrial DNA.
Zoccolella S(1), Torraco A, Amati A, Lamberti P, Serlenga L, Papa S, Petruzzella
V.
Author information:
(1)Department of Neurological Sciences, University of Bari, Italy.
Kearns-Sayre syndrome (KSS) is a mitochondrial encephalomyopathy characterized
by progressive external ophthalmoplegia (PEO), pigmentary retinopathy and onset
before the age of 20 years. Cerebellar ataxia, as well as short stature and
increased protein content in the cerebrospinal fluid, are frequent additional
symptoms. A single large mitochondrial (mt) DNA deletion of 4,977 bp is the most
common molecular defect in KSS. Recently, different mutations have also been
associated with incomplete, KSS-like phenotypes. We describe the unusual
clinical presentation of a patient carrying a novel 1,814-bp deletion of mtDNA.
In contrast with typical KSS, the clinical picture of this patient did not
include either palpebral ptosis or PEO and was dominated by an ataxic syndrome.
PMID: 16735000 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17763890 | 1. Pediatr Cardiol. 2008 May;29(3):659-62. doi: 10.1007/s00246-007-9040-z. Epub
2007 Aug 29.
Kearns-Sayre syndrome presenting as complete heart block.
Chawla S(1), Coku J, Forbes T, Kannan S.
Author information:
(1)Pediatrics, Children's Hospital of Michigan, 3901 Beaubien Blvd., Detroit, MI
48201, USA.
Kearns-Sayre syndrome (KSS) is a rare mitochondrial disorder characterized by
large-scale deletions of mitochondrial DNA. Neuromuscular and cardiac conduction
systems are most commonly involved in these patients. Here, we discuss a
10-year-old patient with diabetes mellitus who presented in complete heart block
leading to the diagnosis of KSS. The cardiovascular complications of this
syndrome are reviewed and discussed.
DOI: 10.1007/s00246-007-9040-z
PMID: 17763890 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11018246 | 1. J Neurol Sci. 2000 Sep 1;178(1):29-36. doi: 10.1016/s0022-510x(00)00354-3.
Kearns-sayre syndrome: oncocytic transformation of choroid plexus epithelium.
Tanji K(1), Schon EA, DiMauro S, Bonilla E.
Author information:
(1)Department of Neurology, College of Physicians and Surgeons of Columbia
University, New York, NY 10032, USA.
Kearns-Sayre syndrome (KSS) is a sporadic multisystem disorder due to a defect
of oxidative phosphorylation and associated with clonally-expanded
rearrangements of mitochondrial DNA (mtDNA) deletions (Delta-mtDNAs) and/or
duplications (dup-mtDNAs). To gain further insight into the pathogenesis of CNS
dysfunction in KSS, we studied the choroid plexus from two autoptic cases using
in situ hybridization (ISH) of mtDNA, and immunohistochemistry to detect mtDNA
and nuclear DNA-encoded subunits of the respiratory chain. Neuropathological
examination of both cases showed oncocytic transformation of choroid plexus
epithelial cells. In the same cells, ISH demonstrated that the predominant
species of mtDNA were Delta-mtDNAs, and immunohistochemistry showed a decreased
expression of mtDNA-encoded proteins. We suggest that mitochondrial
abnormalities due to the presence of abundant Delta-mtDNAs in the choroid plexus
play an important role in causing the increased cerebrospinal fluid (CSF)
protein and reduced folic-acid levels that are characteristic of KSS.
DOI: 10.1016/s0022-510x(00)00354-3
PMID: 11018246 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22981519 | 1. J Fr Ophtalmol. 2012 Nov;35(9):718.e1-4. doi: 10.1016/j.jfo.2012.06.010. Epub
2012 Sep 12.
[Kearns-Sayre syndrome: a case report].
[Article in French]
Gaboune L(1), Baha Ali T, Benfdil N, Khoumiri R, Ouaggag B, Sayouti A,
Moutaouakil A.
Author information:
(1)Service d'ophtalmologie, hôpital Mère-Enfant, CHU Mohamed VI, BP 2360, avenue
Ibn Sina Ammerchich, Marrakech, Maroc. [email protected]
Kearns-Sayre syndrome (KSS), first described in 1958, is a multisystem disease
defined by a characteristic triad of progressive external ophthalmoplegia,
pigmentary retinopathy and atrioventricular block. These signs are frequently
associated with increased cerebrospinal fluid protein level and cerebellar
ataxia. This syndrome is caused by deletions in mitochondrial DNA, the age of
onset is generally below 20, and the degree of severity differs between
patients, as well as the prognosis, which may be fatal. The ocular
manifestations include: bilateral ptosis, progressive external ophthalmoplegia
and atypical pigmentary retinopathy. By way of this case report, the authors
discuss the epidemiologic, clinical and therapeutic aspects of KSS, including
the difficulty in managing ptosis in these cases.
Copyright © 2012. Published by Elsevier Masson SAS.
DOI: 10.1016/j.jfo.2012.06.010
PMID: 22981519 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12007693 | 1. Int J Cardiol. 2002 May;83(2):179-81. doi: 10.1016/s0167-5273(02)00040-2.
Alarming atrioventricular block and mitral valve prolapse in the Kearns-Sayre
syndrome.
Katsanos KH, Pappas CJ, Patsouras D, Michalis LK, Kitsios G, Elisaf M, Tsianos
EV.
Kearns-Sayre syndrome (KSS) is a multisystem mitochondrial disorder
characterized by the invariant triad: onset before 20, progressive external
ophthalmoplegia and pigmentary retinal degeneration, plus at least one of the
following: complete (or not) heart block, cereberal dysfunction and CSF protein
above 100 mg/dl. Autopsies from patients with KSS revealed widespread tissue
distribution mtDNA deletions. These deletions result in significantly lower
activities of the enzymes of the respiratory chain. The same deletion of
mitochondrial DNA present in skeletal muscle is found in myocardial tissue. An
18-year-old girl diagnosed with the KSS was admitted to our hospital because of
an upper respiratory tract infection and dysphagia. ECG showed cardiac
conduction defects. The patient had no history of syncope. At her surface ECG
there was a complete RBBB (QRS duration approximately 130 ms), a clockwise
rotation with an axis of approximately 90 degrees and a slight QT prolongation
(420 ms). Echocardiography showed prolapse with thickening and degeneration of
both mitral valve leaflets but without mitral regurgitation. The patient was
started on a diet rich in potassium and pharmaceutical therapy with magnesium
oxide (240 mg of elemental Mg p.o. per day), 1 g of calcium carbonate t.i.d.,
vitamin D (calcitriol 0.25 microg p.o. per day) and coenzyme Q(10) 100 mg daily
and discharged 6 days later with slightly improved biochemical profile but
apparent clinical improvement. Urgent pacemaker implantation was decided but
unfortunately the patient died due to acute cardiac arrest 10 days later.
DOI: 10.1016/s0167-5273(02)00040-2
PMID: 12007693 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7630231 | 1. Med Clin (Barc). 1995 Jul 1;105(5):180-4.
[Progressive external ophthalmoplegia and the Kearns-Sayre syndrome: a clinical
and molecular study of 6 cases].
[Article in Spanish]
Barrientos A(1), Casademont J, Grau JM, Cardellach F, Montoya J, Estivill X,
Urbano-Márquez A, Nunes V.
Author information:
(1)Servei de Medicina Interna General, Hospital Clínic i Provincial, Universitat
de Barcelona.
The Kearns-Sayre syndrome (KSS) associates progressive external ophthalmoplegia
initiating prior to the age of 20 years and pigmentary retinitis with a series
of other heterogeneous clinical manifestations. The incomplete syndrome is
usually denominated progressive external ophthalmoplegia (PEO)-plus which is a
sporadically appearing mitochondrial cytopathy associated with large deletions
of a variable proportion of mitochondrial DNA (mtDNA) molecules. Six patients
with PEO-plus/KSS in whom muscle biopsy was performed following a complete
clinical study are described. The muscle was processed by conventional
histochemical techniques, electron microscopy, and genetic study (Southern
transference, polymerase chain reaction, restriction cartography and both manual
and automatic sequencing). The percentage of mutated mtDNA molecules for each
patient was obtained by densitometry. The 6 patients presented multiorganic
clinical manifestations characteristics of most mitochondrial diseases. The
presence of destructured red fibers were observed in all the biopsies. All the
patients presented a deletion in the mtDNA of a size between 4,861 to 7,437 base
pairs (bp). All the deletions appeared flanked by direct repetitions from 4 to
13 bp and one also presented inverse repetitions from 5 to 6 bp in the zone next
to the rupture point. In the 6 cases heteroplasmia was observed with a variable
percentage of deleted molecules from 23 to 56%. The molecular basis of
progressive external ophthalmoplegia-plus/Kearns-Sayre syndrome appears to be
the existence of sole, large deletions in the mitochondrial DNA with the varying
in location and percentage conditioning the appearance of different phenotypes
similar among themselves. The 7,437 base pair deletion was the most frequently
observed in the patients analyzed.
PMID: 7630231 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9286453 | 1. Am J Med Genet. 1997 Sep 5;71(4):443-52. doi:
10.1002/(sici)1096-8628(19970905)71:4<443::aid-ajmg14>3.0.co;2-g.
High proportions of mtDNA duplications in patients with Kearns-Sayre syndrome
occur in the heart.
Fromenty B(1), Carrozzo R, Shanske S, Schon EA.
Author information:
(1)Department of Neurology, College of Physicians and Surgeons, Columbia
University, New York, New York 10032, USA.
Kearns-Sayre syndrome (KSS) is a sporadic multisystem mitochondrial disorder
characterized by progressive external ophthalmoplegia, pigmentary retinopathy,
onset before age 20, and severe cardiac conduction defects that can lead to
death. KSS patients harbor partial deletions of mitochondrial DNA (delta-mtDNA),
sometimes associated with the corresponding mtDNA duplication (dup-mtDNA). As
reports on the distribution of dup-mtDNAs among KSS tissues are scarce, we
searched for the presence of dup-mtDNAs in different autopsy tissues of two such
patients, one of whom carried the so-called "common deletion." Using a newly
developed long polymerase chain reaction (PCR) protocol in conjunction with
Southern blot analyses, we found dup-mtDNAs in most of the examined tissues from
both patients. The proportion of dup-mtDNA in these tissues was much lower than
the proportion of delta-mtDNA, with one notable exception: in both patients, we
found an unusually high level of dup-mtDNA in the heart. These data suggest that
dup-mtDNAs may be more stable in heart tissue of KSS patients than in other
long-lived postmitotic tissues.
DOI: 10.1002/(sici)1096-8628(19970905)71:4<443::aid-ajmg14>3.0.co;2-g
PMID: 9286453 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17342029 | 1. Pediatr Endocrinol Rev. 2006 Dec-2007 Jan;4(2):117-37.
The clinical diagnosis and molecular genetics of kearns-sayre syndrome: a
complex mitochondrial encephalomyopathy.
Maceluch JA(1), Niedziela M.
Author information:
(1)Department of Pediatric Endocrinology and Diabetes, Poznan University of
Medical Sciences, Poznan, Poland.
From the first description by Kearns and Sayre in 1958, this syndrome has been
diagnosed in several hundred patients. However, the labile character of its
clinical manifestations makes diagnosis difficult and delayed. Only recently,
some thirty years from the first diagnosis, have we recognized mitochondrial DNA
rearrangements as the molecular basis of the disease. This has lead to
increasing interest in the contribution which mtDNA deletions make to
Kearns-Sayre Syndrome (KSS) and other disorders. Although the true prevalence of
this syndrome in the general population is unknown, a basic awareness of the KSS
phenotype, as well as of the essential elements of patient evaluation is
important for appropriate patient management. Although methods of assessing
patients for mtDNA rearrangements are well developed, ambiguity in patient
diagnosis often remains even after detailed, multisystem testing. Advances in
our understanding of the genetic background and the tissue specific effects of
mtDNA deletions, in addition to resolving the inheritance pattern, will also
increase our ability to diagnose, manage and counsel patients with this
disorder.
PMID: 17342029 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32609007 | 1. DNA Cell Biol. 2020 Aug;39(8):1449-1457. doi: 10.1089/dna.2019.5010. Epub 2020
Jun 29.
Clinical Phenotype and Genetic Features of a Pair of Chinese Twins with
Kearns-Sayre Syndrome.
Guo L(1)(2), Wang X(3)(4), Ji H(1)(2)(5).
Author information:
(1)State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for
Brain Science, ENT Institute and Otorhinolaryngology Department, Fudan
University Eye & ENT Hospital, Shanghai, People's Republic of China.
(2)NHC Key Laboratory of Hearing Medicine and Fudan University, Shanghai,
People's Republic of China.
(3)Institutes of Biomedical Sciences, Fudan University, Shanghai, People's
Republic of China.
(4)Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education,
Nantong University, Nantong, People's Republic of China.
(5)Department of Otorhinolaryngology, Affiliated Eye and ENT Hospital of Fudan
University, Shanghai, China.
Comment in
DNA Cell Biol. 2020 Oct;39(10):1907-1908. doi: 10.1089/dna.2020.5882.
Kearns-Sayre Syndrome (KSS) is a severe mitochondrial disorder involving the
central nervous system, eyes, ears, skeletal muscles, and heart. The
mitochondrial DNA (mtDNA) rearrangements, especially the deletions, are present
in almost all KSS patients and considered as the disease-causing factor.
However, the size and position of mtDNA deletions are distinct in different
individuals. In this study, we report the case of a pair of Chinese twins with
KSS. The twin patients revealed typical KSS clinical symptoms, including heart
block, bilateral sensorineural hearing loss, progressive external
ophthalmoplegia, exercise intolerance, proximal limb weakness, and endocrine
disorders. Using long-range polymerase chain reactions (long-range PCR) and
next-generation sequencing (NGS), the genetic features of the twin patients were
investigated. A large 6600 bp mtDNA deletion, ranging from position 8702 to
15,302, was detected in both patients. To our knowledge, this kind of mtDNA
deletion has never been described previously. Our study enriched the mutation
spectrum of KSS and showed that NGS is a powerful tool for detecting mtDNA large
variants.
DOI: 10.1089/dna.2019.5010
PMID: 32609007 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9727847 | 1. Eur J Pediatr. 1998 Aug;157(8):643-7. doi: 10.1007/s004310050902.
Mitochondrial DNA deletion with Kearns Sayre syndrome in a child with Addison
disease.
Boles RG(1), Roe T, Senadheera D, Mahnovski V, Wong LJ.
Author information:
(1)Medical Genetics, Children's Hospital Los Angeles, CA 90027, USA.
[email protected]
Kearns Sayre syndrome (KSS) is a multisystem disorder with a confounding variety
of clinical manifestations, including ocular myopathy, pigmentary retinopathy,
heart block and ataxia. Endocrinopathies are common in KSS, including growth
hormone deficiency, hypogonadism, diabetes mellitus and hypoparathyroidism. A
variety of deletions of mitochondrial DNA (mtDNA) are found in most cases. We
report on a 5-year-old boy with Addison disease in whom further investigation
revealed a 4.9 kilobase mtDNA deletion and KSS. Later he developed severe lactic
acidosis and expired.
CONCLUSION: The degree of mutant mtDNA heteroplasmy in various tissues on
autopsy did not correlate well with the clinical manifestations, although this
may be due at least in part to replacement with other tissue types. Our report
is the first of non-autoimmune Addison disease in KSS and patients with KSS
should be evaluated for adrenal insufficiency. Early recognition of adrenal
insufficiency is crucial to prevent mortality from this cause.
DOI: 10.1007/s004310050902
PMID: 9727847 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/15869681 | 1. Pacing Clin Electrophysiol. 2005 May;28(5):454-7. doi:
10.1111/j.1540-8159.2005.40049.x.
Kearns-Sayre syndrome: a case report and review of cardiovascular complications.
Young TJ(1), Shah AK, Lee MH, Hayes DL.
Author information:
(1)Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA.
[email protected]
Kearns-Sayre syndrome (KSS) is a rare genetic abnormality. Classified as a
mitochondrial cytopathy, the primary pathology of this syndrome is a disturbance
of mitochondrial DNA, which codes for the proteins required for the respiratory
chain reaction. Onset occurs before age 20, and is manifest as chronic
progressive external ophthalmoplegia and retinal degeneration. Management issues
of KSS include prophylactic cardiac pacing for conduction defects, which has
been shown to improve survival. Other clinical considerations relate to dietary
supplements to attempt to control the progressive effects of the disease.
DOI: 10.1111/j.1540-8159.2005.40049.x
PMID: 15869681 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25539952 | 1. Orphanet J Rare Dis. 2014 Dec 24;9:217. doi: 10.1186/s13023-014-0217-2.
Follow-up of folinic acid supplementation for patients with cerebral folate
deficiency and Kearns-Sayre syndrome.
Quijada-Fraile P(1), O'Callaghan M(2), Martín-Hernández E(3), Montero R(4)(5),
Garcia-Cazorla À(6)(7), de Aragón AM(8), Muchart J(9), Málaga I(10), Pardo
R(11), García-Gonzalez P(11), Jou C(12), Montoya J(13)(14), Emperador S(15),
Ruiz-Pesini E(16)(17), Arenas J(18)(19), Martin MA(20)(21), Ormazabal A(22)(23),
Pineda M(24)(25), García-Silva MT(26)(27), Artuch R(28)(29).
Author information:
(1)Unidad de Enfermedades Mitocondriales-Enfermedades Metabólicas Hereditarias.
Dpto. de Pediatría y Radiología, Hospital 12 de Octubre, Madrid, Spain.
[email protected].
(2)Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology
Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues,
Barcelona, 08950, Spain. [email protected].
(3)Unidad de Enfermedades Mitocondriales-Enfermedades Metabólicas Hereditarias.
Dpto. de Pediatría y Radiología, Hospital 12 de Octubre, Madrid, Spain.
[email protected].
(4)Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III,
Madrid, Spain. [email protected].
(5)Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology
Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues,
Barcelona, 08950, Spain. [email protected].
(6)Centre For research in rare diseases (CIBERER), Institut de Salud Carlos III,
Madrid, Spain. [email protected].
(7)Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology
Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues,
Barcelona, 08950, Spain. [email protected].
(8)Unidad de Enfermedades Mitocondriales-Enfermedades Metabólicas Hereditarias.
Dpto. de Pediatría y Radiología, Hospital 12 de Octubre, Madrid, Spain.
[email protected].
(9)Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology
Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues,
Barcelona, 08950, Spain. [email protected].
(10)Servicio de Pediatría, Hospital Universitario Central de Asturias, Oviedo,
Spain. [email protected].
(11)Servicios de Pediatría y Radiología, Hospital de Cabueñes, Asturias, Spain.
[email protected].
(12)Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology
Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues,
Barcelona, 08950, Spain. [email protected].
(13)Centre For research in rare diseases (CIBERER), Institut de Salud Carlos
III, Madrid, Spain. [email protected].
(14)Departamento de Bioquímica, Biología Molecular y Celular, Universidad de
Zaragoza, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.
[email protected].
(15)Departamento de Bioquímica, Biología Molecular y Celular, Universidad de
Zaragoza, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.
[email protected].
(16)Centre For research in rare diseases (CIBERER), Institut de Salud Carlos
III, Madrid, Spain. [email protected].
(17)Departamento de Bioquímica, Biología Molecular y Celular, Universidad de
Zaragoza, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain.
[email protected].
(18)Centre For research in rare diseases (CIBERER), Institut de Salud Carlos
III, Madrid, Spain. [email protected].
(19)Mitochondrial Diseases Laboratory, Hospital 12 de Octubre Research Institute
(i + 12), Madrid, Spain. [email protected].
(20)Centre For research in rare diseases (CIBERER), Institut de Salud Carlos
III, Madrid, Spain. [email protected].
(21)Mitochondrial Diseases Laboratory, Hospital 12 de Octubre Research Institute
(i + 12), Madrid, Spain. [email protected].
(22)Centre For research in rare diseases (CIBERER), Institut de Salud Carlos
III, Madrid, Spain. [email protected].
(23)Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology
Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues,
Barcelona, 08950, Spain. [email protected].
(24)Centre For research in rare diseases (CIBERER), Institut de Salud Carlos
III, Madrid, Spain. [email protected].
(25)Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology
Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues,
Barcelona, 08950, Spain. [email protected].
(26)Unidad de Enfermedades Mitocondriales-Enfermedades Metabólicas Hereditarias.
Dpto. de Pediatría y Radiología, Hospital 12 de Octubre, Madrid, Spain.
[email protected].
(27)Centre For research in rare diseases (CIBERER), Institut de Salud Carlos
III, Madrid, Spain. [email protected].
(28)Centre For research in rare diseases (CIBERER), Institut de Salud Carlos
III, Madrid, Spain. [email protected].
(29)Pediatric Neurology, Clinical Biochemistry, Histopathology and Radiology
Departments, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2., Esplugues,
Barcelona, 08950, Spain. [email protected].
BACKGROUND: Kearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome
that presents with profound cerebral folate deficiency and other features.
Preliminary data support the notion that folinic acid therapy might be useful in
the treatment of KSS patients. Our aim was to assess the clinical and
neuroimaging outcomes of KSS patients receiving folinic acid therapy.
PATIENTS: We recruited eight patients with diagnoses of KSS. Four cases were
treated at 12 de Octubre Hospital, and the other two cases were treated at Sant
Joan de Déu Hospital. Two patients refused to participate in the treatment
protocol.
METHODS: Clinical, biochemical and neuroimaging data (magnetic resonance imaging
or computed tomography scan) were collected in baseline conditions and at
different time points after the initiation of therapy. Cerebrospinal fluid
5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence
detection. Large-scale mitochondrial DNA deletions were analysed by Southern
blot.
TREATMENT PROTOCOL: The follow-up periods ranged from one to eight years. Cases
1-4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8
received 3 mg/kg/day.
RESULTS: No adverse effects of folinic acid treatment were observed. Cerebral
5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline
conditions. Moreover, all three patients who accepted lumbar puncture after
folinic acid therapy exhibited complete recoveries of their decreased basal
cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases
neurologically improved after folinic therapy. Disease worsened in the other
patients. Post-treatment neuroimaging was performed for the 6 cases that
received folinic acid therapy. One patient exhibited improvements in white
matter abnormalities. The remaining patients displayed progressions in
subcortical cerebral white matter, the cerebellum and cerebral atrophy.
CONCLUSIONS: Four patients exhibited clinical and radiological progression of
the disease following folinic acid treatment. Only one patient who was treated
in an early stage of the disease exhibited both neurological and radiological
improvements following elevated doses of folinic acid, and an additional patient
experienced neurological improvement. Early treatment with high-dose folinic
acid therapy seems to be advisable for the treatment of KSS.
TRIAL REGISTRATION: Eudrac T2007-00-6748-23.
DOI: 10.1186/s13023-014-0217-2
PMCID: PMC4302586
PMID: 25539952 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19344916 | 1. J Neurol Sci. 2009 Jun 15;281(1-2):110-2. doi: 10.1016/j.jns.2009.03.007. Epub
2009 Apr 2.
Diffusion tensor imaging in a case of Kearns-Sayre syndrome: striking brainstem
involvement as a possible cause of oculomotor symptoms.
Duning T(1), Deppe M, Keller S, Mohammadi S, Schiffbauer H, Marziniak M.
Author information:
(1)Department of Neurology, University Hospital Muenster, Germany.
[email protected]
Kearns-Sayre syndrome (KSS) is a rare autosomal dominant mitochondrial disorder
affecting the central nervous system. Progressive external ophthalmoplegia is an
early and characteristic clinical symptom of the disease. We describe a
22-year-old female patient with a typical KSS including early and severe
external ophthalmoplegia. Conventional MRI and diffusion tensor imaging (DTI)
was performed to investigate the early involvement of the central nervous system
(CNS). DTI revealed substantial white matter alterations that were primarily
confined to the brainstem. These early DTI changes support the hypothesis that
regional affection of the brainstem may play a role in the pathogenesis of the
early oculomotor symptoms. DTI might be helpful to detect an early involvement
of the CNS in KSS.
DOI: 10.1016/j.jns.2009.03.007
PMID: 19344916 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25368789 | 1. Korean J Anesthesiol. 2014 Oct;67(4):283-6. doi: 10.4097/kjae.2014.67.4.283.
Epub 2014 Oct 27.
Obstetric anesthesia considerations in Kearns-Sayre syndrome: a case report.
Faris AS(1), Tawfic QA(1), Jeyaraj L(1).
Author information:
(1)Department of Anesthesiology, The Ottawa Hospital and University of Ottawa,
Ottawa, Canada.
Kearns-Sayre syndrome (KSS) is a rare mitochondrial myopathy that usually
develops before 20 years of age. It demonstrates multisystemic involvement with
a triad of cardinal features: progressive ophthalmoplegia, pigmentary
retinopathy, and cardiac conduction abnormalities. In addition, patients might
have cerebellar ataxia, a high content of protein in the cerebrospinal fluid,
proximal myopathy, multiple endocrinopathies, and renal tubular acidosis. We
herein report the successful obstetric analgesic and anesthetic management of a
28-year-old parturient patient with KSS who required labor analgesia and
proceeded to deliver by cesarean section. We extrapolate that regional
analgesia/anesthesia might be beneficial for reducing the metabolic demands
associated with the stress and pain of labor in patients with KSS. Efficient
postoperative analgesia should be provided to decrease oxygen requirements.
DOI: 10.4097/kjae.2014.67.4.283
PMCID: PMC4216793
PMID: 25368789 |
http://www.ncbi.nlm.nih.gov/pubmed/32026421 | 1. Drugs. 2020 Feb;80(3):329-333. doi: 10.1007/s40265-020-01267-2.
Golodirsen: First Approval.
Heo YA(1).
Author information:
(1)Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New
Zealand. [email protected].
Golodirsen (Vyondys 53™), an antisense oligonucleotide of the phophorodiamidate
morpholino oligomer (PMO) subclass designed to induce exon 53 skipping, has been
developed by Sarepta Therapeutics for the treatment of Duchenne muscular
dystrophy (DMD). In December 2019, intravenous golodirsen received its first
global approval in the USA for the treatment of DMD in patients with a confirmed
mutation of the DMD gene that is amenable to exon 53 skipping, based on positive
results from a phase I/II clinical trial. Golodirsen is in phase III clinical
development for the treatment of DMD worldwide. This article summarizes the
milestones in the development of golodirsen leading to this first approval for
DMD.
DOI: 10.1007/s40265-020-01267-2
PMID: 32026421 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33025945 | 1. Drugs Today (Barc). 2020 Aug;56(8):491-504. doi:
10.1358/dot.2020.56.8.3159186.
Golodirsen for Duchenne muscular dystrophy.
Anwar S(1), Yokota T(2).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Alberta, Canada.
(2)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Alberta, Canada; The Friends of Garrett Cumming Research
and Muscular Dystrophy Canada, HM Toupin Neurological Science Research Chair,
Edmonton, Alberta, Canada. [email protected].
Duchenne muscular dystrophy (DMD) is a life-shortening X-linked genetic disorder
characterized by progressive wasting and weakening of muscles in boys.
Loss-of-function mutations in the DMD gene, which codes for dystrophin, lead to
this disease. The majority of mutations in this gene result in the exclusion of
one or more exons from the transcript, eventually causing the remaining exons
not to fit together correctly (i.e., out-of-frame mutations). Antisense
oligonucleotides, e.g., phosphorodiamidate morpholino oligomers (PMOs), can
induce therapeutic exon skipping during pre-mRNA processing to restore the
reading frame of the primary transcript of DMD. As a result, truncated but
partially functional dystrophin is produced, potentially slowing down the
disease progression. Golodirsen is a provisionally approved PMO-based drug for
approx. 8% of all DMD patients amenable to exon 53 skipping. This article
summarizes golodirsen's pharmacology, efficacy and safety information. It also
discusses some controversies that golodirsen met after the approval.
Copyright 2020 Clarivate Analytics.
DOI: 10.1358/dot.2020.56.8.3159186
PMID: 33025945 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36401027 | 1. Methods Mol Biol. 2023;2587:125-139. doi: 10.1007/978-1-0716-2772-3_7.
Restoring Dystrophin Expression with Exon 44 and 53 Skipping in the DMD Gene in
Immortalized Myotubes.
Echigoya Y(1)(2), Yokota T(3)(4).
Author information:
(1)Laboratory of Biomedical Science, Department of Veterinary Medicine, College
of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan.
[email protected].
(2)Nihon University Veterinary Research Center, Fujisawa, Kanagawa, Japan.
[email protected].
(3)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AB, Canada.
(4)The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM
Toupin Neurological Science Research Chair, Edmonton, AB, Canada.
Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is a
therapeutic approach that applies to many Duchenne muscular dystrophy (DMD)
patients harboring out-of-frame deletion mutations in the DMD gene. In
particular, PMOs for skipping exon 44 have been developing in clinical trials,
such as the drug NS-089/NCNP-02. Two exon 53 skipping PMOs, golodirsen and
viltolarsen, have received conditional approval for treating patients due to
their ability to restore dystrophin protein expression. Although promising,
further development of exon-skipping technology is needed for patients to have
more therapeutic benefit. This chapter describes evaluation methods of exon 44
and 53 skipping PMOs in immortalized DMD patient-derived skeletal muscle cells.
We introduce how to quantify exon-skipping efficiencies and dystrophin rescue
levels represented by RT-PCR and western blotting, respectively. The screening
methods using immortalized patient myotubes can serve to find exon-skipping PMO
drug candidates.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2772-3_7
PMID: 36401027 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35213020 | 1. Methods Mol Biol. 2022;2434:217-233. doi: 10.1007/978-1-0716-2010-6_14.
Evaluation of Exon Skipping and Dystrophin Restoration in In Vitro Models of
Duchenne Muscular Dystrophy.
López-Martínez A(1), Soblechero-Martín P(1)(2), Arechavala-Gomeza V(3)(4).
Author information:
(1)Neuromuscular Disorders, Biocruces Bizkaia Health Research Institute,
Barakaldo, Spain.
(2)Osakidetza Basque Health Service, Bilbao-Basurto Integrated Health
Organisation, Basurto University Hospital, Clinical Laboratory Service, Bilbao,
Spain.
(3)Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
[email protected].
(4)Neuromuscular Disorders Research Group, Biocruces Bizkaia Health Research
Institute, Barakaldo, Spain. [email protected].
Several exon skipping antisense oligonucleotides (eteplirsen, golodirsen,
viltolarsen, and casimersen) have been approved for the treatment of Duchenne
muscular dystrophy, but many more are in development targeting an array of
different DMD exons. Preclinical screening of the new oligonucleotide sequences
is routinely performed using patient-derived cell cultures, and evaluation of
their efficacy may be performed at RNA and/or protein level. While several
methods to assess exon skipping and dystrophin expression in cell culture have
been developed, the choice of methodology often depends on the availability of
specific research equipment.In this chapter, we describe and indicate the
relevant bibliography of all the methods that may be used in this evaluation and
describe in detail the protocols routinely followed at our institution, one to
evaluate the efficacy of skipping at RNA level (nested PCR) and the other the
restoration of protein expression (myoblot ), which provide good results using
equipment largely available to most research laboratories.
© 2022. The Author(s).
DOI: 10.1007/978-1-0716-2010-6_14
PMCID: PMC9703204
PMID: 35213020 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36031908 | 1. J Neuromuscul Dis. 2022;9(5):649-654. doi: 10.3233/JND-220823.
Muscle MRI as a Diagnostic Challenge in Emery-Dreifuss Muscular Dystrophy.
Pinto MJ(1)(2), Fromes Y(3)(4), Ackermann-Bonan I(3)(4), Leturcq F(5), Verebi
C(5), Romero NB(6)(7)(8), Stojkovic T(6)(7).
Author information:
(1)Department of Neurology, Centro Hospitalar Universitário de São João, E.P.E.,
Porto, Portugal.
(2)Department of Clinical Neurosciences and Mental Health, Faculty of Medicine,
University of Porto, Porto, Portugal.
(3)Nuclear Magnetic Resonance Laboratory, Neuromuscular Investigation Center,
Institute of Myology, Pitié-Salpêtrière Hospital, Paris, France.
(4)Nuclear Magnetic Resonance Laboratory, CEA, DRF, IBFJ, Molecular Imaging
Research Center, Paris, France.
(5)Department of Genomic Medicine and Systemic Diseases, APHP, University of
Paris, Cochin Hospital, Paris, France.
(6)Reference Center for Neuromuscular Disorders, APHP, Myology Institute,
Pitié-Salpêtrière Hospital, Paris, France.
(7)Centre de Recherche en Myologie, GH Pitié-Salpêtrière, Sorbonne
Université-Inserm UMRS974, Paris, France.
(8)Neuromuscular Morphology Unit, Institute of Myology, Pitié-Salpêtrière
Hospital, Paris, France.
Emery-Dreifuss Muscular Dystrophy (EDMD) is an early-onset, slowly-progressive
group of myopathies, presenting with joint contractures, muscle weakness and
cardiac abnormalities. Variants in the EMD gene cause an X-linked recessive form
(EDMD1). The scarce EDMD1 muscle MRI accounts in the literature describe fatty
replacement of posterior thigh and leg muscles.We report a 22-year-old patient
with early-onset bilateral joint contractures, slowly progressive muscle
weakness and minor cardiac rhythm abnormalities. A novel loss-of-function
variant of EMD was identified and deemed probably pathogenic in the absence of
emerin detection by immunofluorescence and Western Blot. MRI revealed fatty
replacement of the lumbar spinal erectors and the posterior compartment of lower
limbs. Interestingly, Short Tau Inversion Recovery (STIR) sequences showed a
heterogenous hyper signal on the vasti, hamstrings and left lateral
gastrocnemius muscles.Oedema-like abnormalities were previously reported in
early stages of other muscular dystrophies, preceding fatty replacement and
muscle atrophy, but not in EDMD1 patients. We hypothesize that these oedema-like
changes may be a marker of early muscle pathology in EDMD1. Further studies
focusing on these abnormalities in the early phase of EDMD1 are required to test
our hypothesis.
DOI: 10.3233/JND-220823
PMID: 36031908 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36250567 | 1. Orthop Surg. 2022 Dec;14(12):3448-3454. doi: 10.1111/os.13526. Epub 2022 Oct
17.
Surgical Treatment for Severe Cervical Hyperlordosis and Thoracolumar
Kyphoscoliosis with Emery-Dreifuss Muscular Dystrophy: A Case Report and
Literature Review.
Tang Z(1), Hu Z(2), Qin X(2), Zhu Z(1)(2), Liu Z(1)(2).
Author information:
(1)Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum
Tower Hospital, The Clinical College of Nanjing Medical University, Nanjing,
China.
(2)Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum
Tower Hospital, The Affiliated Hospital of Nanjing University Medical School,
Nanjing, China.
BACKGROUND: Emery-Dreifuss muscular dystrophy (EDMD) is an uncommon, gradually
progressive X-linked myopathy, and it could result in rigid spinal deformity.
Only a few case reports have described surgical treatment of cervical
hyperlordosis and thoracolumbar kyphoscoliosis secondary to EDMD. We report a
rare case of EDMD to present the surgical strategies of severe cervical
hyperlordosis and thoracolumbar kyphoscoliosis.
CASE PRESENTATION: The patient was a 22-year-old man with EDMD who had severe
cervical hyperlordosis and thoracolumbar kyphoscoliosis. A posterior spinal
fusion from T9-S2 was performed to correct the thoracolumbar kyphoscoliosis at
the age of 21 years. Six months later, with an anterior C7-T1 closing wedge
bone-disc-bone osteotomy and a posterior-anterior-posterior cervicothoracic
fusion from C4-T4, the cervical deformity was corrected, thus achieving a
horizontal gaze. During 1.5-year follow-up, no loss of correction was observed.
CONCLUSION: Cervical posterior-anterior-posterior closing-wedge osteotomy
combined with long fusion at thoracolumbar spine can be a reliable surgical
technique to correct severe spine deformity in EDMD. This two-stage revision
surgical strategy can help restore a horizontal gaze on the basis of a balanced
trunk. Cervical deformity in such patients should be corrected in the first
stage considering its role as a "driver" of the global spine deformity.
© 2022 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John
Wiley & Sons Australia, Ltd.
DOI: 10.1111/os.13526
PMCID: PMC9732636
PMID: 36250567 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36274837 | 1. Front Cell Dev Biol. 2022 Oct 6;10:1007120. doi: 10.3389/fcell.2022.1007120.
eCollection 2022.
Emerin interacts with histone methyltransferases to regulate repressive
chromatin at the nuclear periphery.
Marano N(1), Holaska JM(1).
Author information:
(1)Department of Biomedical Sciences, Cooper Medical School of Rowan University,
Camden, NJ, United States.
X-Linked Emery-Dreifuss muscular dystrophy is caused by mutations in the gene
encoding emerin. Emerin is an inner nuclear membrane protein important for
repressive chromatin organization at the nuclear periphery. Myogenic
differentiation is a tightly regulated process characterized by genomic
reorganization leading to coordinated temporal expression of key transcription
factors, including MyoD, Pax7, and Myf5. Emerin was shown to interact with
repressive histone modification machinery, including HDAC3 and EZH2. Using
emerin-null myogenic progenitor cells we established several EDMD-causing emerin
mutant lines in the effort to understand how the functional interaction of
emerin with HDAC3 regulates histone methyltransferase localization or function
to organize repressive chromatin at the nuclear periphery. We found that, in
addition to its interaction with HDAC3, emerin interacts with the histone
methyltransferases EZH2 and G9a in myogenic progenitor cells. Further, we show
enhanced binding of emerin HDAC3-binding mutants S54F and Q133H to EZH2 and G9a.
Treatment with small molecule inhibitors of EZH2 and G9a reduced H3K9me2 or
H3K27me3 throughout differentiation. EZH2 and G9a inhibitors impaired cell cycle
withdrawal, differentiation commitment, and myotube formation in wildtype
progenitors, while they had no effect on emerin-null progenitors. Interestingly,
these inhibitors exacerbated the impaired differentiation of emerin S54F and
Q133H mutant progenitors. Collectively, these results suggest the functional
interaction between emerin and HDAC3, EZH2, and G9a are important for myogenic
differentiation.
Copyright © 2022 Marano and Holaska.
DOI: 10.3389/fcell.2022.1007120
PMCID: PMC9583931
PMID: 36274837
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/27179216 | 1. Folia Neuropathol. 2016;54(1):1-8. doi: 10.5114/fn.2016.58910.
Emery-Dreifuss muscular dystrophy: the most recognizable laminopathy.
Madej-Pilarczyk A(1), Kochański A.
Author information:
(1)Dr Agnieszka Madej-Pilarczyk, Neuromuscular Unit, Mossakowski Medical
Research Centre, Polish Academy of Sciences, 5 Pawińskiego St., 02-106 Warsaw,
Poland, phone: +48 22 608 66 01, fax: +48 22 608 65 31, e-mail:
[email protected].
Emery-Dreifuss muscular dystrophy (EDMD), a rare inherited disease, is
characterized clinically by humero-peroneal muscle atrophy and weakness,
multijoint contractures, spine rigidity and cardiac insufficiency with
conduction defects. There are at least six types of EDMD known so far, of which
five have been associated with mutations in genes encoding nuclear proteins. The
majority of the EDMD cases described so far are of the emerinopathy (EDMD1)
kind, with a recessive X-linked mode of inheritance, or else laminopathy
(EDMD2), with an autosomal dominant mode of inheritance. In the work described
here, the authors have sought to describe the history by which EDMD came to be
distinguished as a separate entity, as well as the clinical and genetic
characteristics of the disease, the pathophysiology of lamin-related muscular
diseases and, finally, therapeutic issues, prevention and ethical aspects.
DOI: 10.5114/fn.2016.58910
PMID: 27179216 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10838246 | 1. Neuromuscul Disord. 2000 Jun;10(4-5):228-32. doi:
10.1016/s0960-8966(00)00105-x.
Emery-Dreifuss muscular dystrophy - a 40 year retrospective.
Emery AE(1).
Author information:
(1)Department of Neurology, Royal Devon & Exeter Hospital, EX2 5DW, Exeter, UK.
Emery-Dreifuss muscular dystrophy (EDMD) was delineated as a separate form of
muscular dystrophy nearly 40 years ago, based on the distinctive clinical
features of early contractures and humero-peroneal weakness, and cardiac
conduction defects. The gene, STA at Xq28, for the commoner X-linked EDMD
encodes a 34 kD nuclear membrane protein designated 'emerin', and in almost all
cases on immunostaining is absent in muscle, skin fibroblasts, leucocytes and
even exfoliative buccal cells, and a mosaic pattern in female carriers. The
gene, LMNA at 1q21, for the autosomal dominant Emery-Dreifuss muscular dystrophy
encodes other nuclear membrane proteins, lamins A/C. The diagnosis (at present)
depends on mutation analysis rather than protein immunohistochemistry. It is
still not at all clear how defects in these nuclear membrane proteins are
related to the phenotype, even less clear that LMNA mutations can also be
associated with familial dilated cardiomyopathy with no weakness, and even
familial partial lipodystrophy with diabetes mellitus and coronary heart
disease! What began as clinical studies in a relatively rare form of dystrophy
has progressed to detailed research into the functions of nuclear membrane
proteins particularly in regard to various forms of heart disease.
DOI: 10.1016/s0960-8966(00)00105-x
PMID: 10838246 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1998333 | 1. Am J Hum Genet. 1991 Mar;48(3):468-80.
Assignment of Emery-Dreifuss muscular dystrophy to the distal region of Xq28:
the results of a collaborative study.
Consalez GG(1), Thomas NS, Stayton CL, Knight SJ, Johnson M, Hopkins LC, Harper
PS, Elsas LJ, Warren ST.
Author information:
(1)Department of Biochemistry, Emory University School of Medicine, Atlanta, GA
30322.
Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked humeroperoneal dystrophy
associated with cardiomyopathy that is distinct from the Duchenne and Becker
forms of X-linked muscular dystrophy. Linkage analysis has assigned EDMD to the
terminal region of the human X chromosome long arm. We report here further
linkage analysis in two multigenerational EDMD families using seven Xq28 marker
loci. Cumulative lod scores suggest that EDMD is approximately 2 cM from DXS52
(lod = 15.67) and very close to the factor VIII (F8C) and the red/green color
pigment (R/GCP) loci, with respective lod scores of 9.62 and 10.77, without a
single recombinant. Several recombinations between EDMD and three proximal Xq28
markers suggest that the EDMD gene is located in distal Xq28. Multipoint linkage
analysis indicates that the odds are 2,000:1 that EDMD lies distal to DXS305.
These data substantially refine the ability to perform accurate carrier
detection, prenatal diagnosis, and the presymptomatic diagnosis of at-risk males
for EDMD by linkage analysis. The positioning of the EDMD locus close to the
loci for F8C and R/GCP will assist in future efforts to identify and isolate the
disease gene.
PMCID: PMC1682981
PMID: 1998333 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21496632 | 1. Handb Clin Neurol. 2011;101:155-66. doi: 10.1016/B978-0-08-045031-5.00012-8.
Emery-Dreifuss muscular dystrophy.
Puckelwartz M(1), McNally EM.
Author information:
(1)University of Chicago, Chicago, IL 60637, USA.
Emery-Dreifuss muscular dystrophy (EDMD) is a progressive muscle-wasting
disorder defined by early contractures of the Achilles tendon, spine, and
elbows. EDMD is also distinctive for its association with defects of the cardiac
conduction system that can result in sudden death. It can be inherited in an
X-linked, autosomal dominant, or autosomal recessive fashion and is caused by
mutations in proteins of the nuclear membrane. Mutations in the EMD gene, which
encodes emerin, a transmembrane protein found at the inner nuclear membrane, are
responsible for X-linked EDMD. The most common etiology of autosomal dominant
EDMD is an LMNA gene mutation; LMNA encodes the intermediate filament protein
lamins A and C, which constitute the major scaffolding protein of the inner
nuclear membrane. Murine models of LMNA gene mutations have helped to identify
different mechanisms of disease. Loss of LMNA function leads to nuclear
fragility as well as other defects, such as abnormal nuclear function.
Additional genes encoding nuclear membrane proteins such as SYNE1 and SYNE2 have
also been implicated in EDMD, and in some cases their importance for cardiac and
muscle function has been supported by animal modeling.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/B978-0-08-045031-5.00012-8
PMID: 21496632 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31840275 | 1. Muscle Nerve. 2020 Apr;61(4):436-448. doi: 10.1002/mus.26782. Epub 2019 Dec
28.
Emery-Dreifuss muscular dystrophy.
Heller SA(1), Shih R(2), Kalra R(3), Kang PB(1)(3)(4).
Author information:
(1)Department of Neurology, University of Florida College of Medicine,
Gainesville, Florida.
(2)Congenital Heart Center, University of Florida College of Medicine,
Gainesville, Florida.
(3)Division of Pediatric Neurology, Department of Pediatrics, University of
Florida College of Medicine, Gainesville, Florida.
(4)Genetics Institute and Myology Institute, University of Florida, Gainesville,
Florida.
Emery-Dreifuss muscular dystrophy (EDMD) is a rare muscular dystrophy, but is
particularly important to diagnose due to frequent life-threatening cardiac
complications. EDMD classically presents with muscle weakness, early
contractures, cardiac conduction abnormalities and cardiomyopathy, although the
presence and severity of these manifestations vary by subtype and individual.
Associated genes include EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and
TTN, encoding emerin, lamin A/C, nesprin-1, nesprin-2, FHL1, LUMA, SUN1, SUN2,
and titin, respectively. The Online Mendelian Inheritance in Man database
recognizes subtypes 1 through 7, which captures most but not all of the
associated genes. Genetic diagnosis is essential whenever available, but
traditional diagnostic tools can help steer the evaluation toward EDMD and
assist with interpretation of equivocal genetic test results. Management is
primarily supportive, but it is important to monitor patients closely,
especially for potential cardiac complications. There is a high potential for
progress in the treatment of EDMD in the coming years.
© 2019 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.
DOI: 10.1002/mus.26782
PMCID: PMC7154529
PMID: 31840275 [Indexed for MEDLINE]
Conflict of interest statement: Scott A. Heller has no conflicts of interest to
disclose. Peter B. Kang has served as a consultant for AveXis and ChromaDex. He
has served on an advisory board for Sarepta Therapeutics. He has received
honoraria from Wiley for serving as an associate editor for Muscle & Nerve and
from Wolters Kluwer for contributing material to UpToDate. |
http://www.ncbi.nlm.nih.gov/pubmed/16550925 | 1. Acta Myol. 2005 Oct;24(2):98-103.
X-linked form of Emery-Dreifuss muscular dystrophy.
Hayashi YK(1).
Author information:
(1)Department of Neuromuscular Research, National Institute of Neuroscience,
National Center of Neurology and Psychiatry, Tokyo, Japan. [email protected]
Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscular disorder
clinically characterized by slowly progressive weakness affecting
humero-peroneal muscles, early joint contractures and cardiomyopathy with
conduction defects. Autosomal dominant and recessive forms are caused by
mutations in lamin A/C gene. Lamin A/C is a major component of nuclear lamina,
and its gene mutations cause several human disorders including muscular
dystrophy, cardiomyopathy, lipodystrophy, neuropathy, and progeria syndrome.
X-linked recessive form of EDMD is caused by mutation in EMD (or STA) gene
encoding an integral protein of the inner nuclear membrane. Emerin expresses
ubiquitously, but its deficiency affects only limited tissues of skeletal and
cardiac muscles and joints. In this paper, I will focus on clinical and
pathological aspects of X-EDMD and possible functions of emerin.
PMID: 16550925 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9436433 | 1. Nihon Rinsho. 1997 Dec;55(12):3186-9.
[Emery-Dreifuss muscular dystrophy].
[Article in Japanese]
Kubo S(1), Tsukahara T, Arahata K.
Author information:
(1)Department of Neuromuscular Research, National Institute of Neuroscience,
National Center of Neurology and Psychiatry (NCNP).
Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscular disorder
characterized by the triad of progressive weakness in humero-peroneal muscles,
early onset contractures and cardiomyopathy with conduction block that shows a
high risk of sudden death. In 1994, the gene responsible for X-linked EDMD has
been identified to Xq28 (designated as STA), that encodes a serine-rich protein
of 254 amino acids, named emerin. In 1996, we discovered a nuclear membrane
localization of emerin in the normal skeletal, cardiac and smooth muscles, but
not in the tissues from patients with X-linked EDMD who had a nonsense mutation
in the gene. In conclusion, molecular and genetic analyses of emerin are
essential for accurate diagnosis of patients with EDMD.
PMID: 9436433 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10711990 | 1. Semin Neurol. 1999;19(1):67-79. doi: 10.1055/s-2008-1040827.
Emery-Dreifuss muscular dystrophy.
Zacharias AS(1), Wagener ME, Warren ST, Hopkins LC.
Author information:
(1)Department of Neurology, Emory University School of Medicine, Atlanta,
Georgia 30322, USA.
Emery-Dreifuss muscular dystrophy (EDMD) is the third most common X-linked
muscular dystrophy. This disorder is characterized by childhood onset of early
contractures, humeroperoneal muscle atrophy, and cardiac conduction
abnormalities. Weakness is slowly progressive, but there is a broad spectrum of
clinical severity. Patients and carriers are at risk of sudden death. Regular
cardiac evaluation is mandatory to assess the risk of cardiac arrhythmias.
Unique atrial pathology is seen at autopsy. The mutated gene in EDMD is
localized to the long arm of the X chromosome. Mutations in the gene lead to
abolished synthesis of the gene product, emerin. Emerin is localized to the
nuclear membrane of skeletal, cardiac, and smooth muscle. The term
Emery-Dreifuss syndrome describes patients who have the EDMD phenotype without
X-linked inheritance. There is no treatment for the underlying disease, but
early placement of pacemakers may be lifesaving.
DOI: 10.1055/s-2008-1040827
PMID: 10711990 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16804269 | 1. Neurol India. 2006 Jun;54(2):197-9.
Emery dreifuss muscular dystrophy: a clinico-pathological study.
Gayathri N(1), Taly AB, Sinha S, Suresh TG, Gorai D.
Author information:
(1)Department of Neuropathology, National Institute of Mental Health and
Neurosciences, Bangalore, India. [email protected]
Emery-Dreifuss muscular dystrophy (EDMD) is a rare and genetically heterogeneous
disorder. We report two patients with emerin deficient X-linked EDMD and two
probable patients with EDMD with typical early contractures, progressive muscle
weakness and cardiac involvement. Family history was noted in one case. Muscle
biopsy revealed features of dystrophy in all.
PMID: 16804269 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11973618 | 1. Eur J Hum Genet. 2002 Mar;10(3):157-61. doi: 10.1038/sj.ejhg.5200744.
Emery-Dreifuss muscular dystrophy.
Helbling-Leclerc A(1), Bonne G, Schwartz K.
Author information:
(1)Inserm U523, Institut de Myologie, GH Pitié-Salpétrière, Paris, France.
Emery-Dreifuss muscular dystrophy (EDMD) is characterised by early contractures,
slowly progressive muscle wasting and weakness with a distinctive
humero-peroneal distribution and cardiac conduction defects leading to dilated
cardiomyopathy. The genes known to be responsible for EDMD encode proteins
associated with the nuclear envelope: the emerin and the lamins A and C.
DOI: 10.1038/sj.ejhg.5200744
PMID: 11973618 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10080180 | 1. Nat Genet. 1999 Mar;21(3):285-8. doi: 10.1038/6799.
Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss
muscular dystrophy.
Bonne G(1), Di Barletta MR, Varnous S, Bécane HM, Hammouda EH, Merlini L,
Muntoni F, Greenberg CR, Gary F, Urtizberea JA, Duboc D, Fardeau M, Toniolo D,
Schwartz K.
Author information:
(1)INSERM UR153, GH Pitié-Salpétriêre, Paris,
[email protected]
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures
of elbows and Achilles tendons, slowly progressive muscle wasting and weakness,
and a cardiomyopathy with conduction blocks which is life-threatening. Two modes
of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD;
OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the
disease. Mutations in EMD, the gene encoding emerin, are responsible for the
X-linked form. We have mapped the locus for EDMD-AD to an 8-cM interval on
chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype
in four other small families was potentially linked to this locus. This region
contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of
the nuclear lamina, lamins A and C, produced by alternative splicing. We
identified four mutations in LMNA that co-segregate with the disease phenotype
in the five families: one nonsense mutation and three missense mutations. These
results are the first identification of mutations in a component of the nuclear
lamina as a cause of inherited muscle disorder. Together with mutations in EMD
(refs 5,6), they underscore the potential importance of the nuclear envelope
components in the pathogenesis of neuromuscular disorders.
DOI: 10.1038/6799
PMID: 10080180 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/7894480 | 1. Nat Genet. 1994 Dec;8(4):323-7. doi: 10.1038/ng1294-323.
Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular
dystrophy.
Bione S(1), Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, Toniolo D.
Author information:
(1)Istituto di Genetica Biochimica ed Evoluzionistica CNR, Pavia, Italy.
Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive disorder
characterized by slowly progressing contractures, wasting of skeletal muscle and
cardiomyopathy. Heart block is a frequent cause of death. The disease gene has
been mapped to distal Xq28. Among many genes in this region, we selected eight
transcripts expressed at high levels in skeletal muscle, heart and/or brain as
the best candidates for the disease. We now report, in all five patients
studied, unique mutations in one of the genes, STA: these mutations result in
the loss of all or part of the protein. The EDMD gene encodes a novel
serine-rich protein termed emerin, which contains a 20 amino acid hydrophobic
domain at the C terminus, similar to that described for many membrane proteins
of the secretory pathway involved in vesicular transport.
DOI: 10.1038/ng1294-323
PMID: 7894480 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10689937 | 1. Rinsho Shinkeigaku. 1999 Nov;39(11):1138-43.
[A novel splice-site mutation in the STA gene in a Japanese patient with
Emery-Dreifuss muscular dystrophy].
[Article in Japanese]
Hasegawa T(1), Kobayashi K, Arahata K, Itoyama Y.
Author information:
(1)Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.
Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked recessive or autosomal
dominant progressive muscular dystrophy characterized by progressive muscle
wasting and weakness with scapulo-humero-peroneal distribution, early
contracture and cardiomyopathy with conduction block. The responsible gene for
EDMD, designated as 'STA', has been mapped to Xq 28 and cloned. It encodes a
serine-rich protein of 254-amino-acid, called 'emerin', localized in the inner
nuclear rim. We performed genetic analysis of a 23-year-old male clinically
diagnosed as EDMD and found a novel point mutation. Total RNA was extracted from
skeletal muscle and reverse-transcription and polymerase chain reaction
amplification was performed using a set of oligonucleotide primers between
5'-flanking site of exon 1 and exon 4. Our patient gave a smaller PCR product
(about 30 bp) than normal control. The determined cDNA sequence revealed a
deletion of 29 bp, spanning position 164 to 192 in exon 1. To clarify the mutant
allele, we performed genomic DNA sequence. Genomic DNA sequence from the
initiation of exon 1 to the upstream lesion of exon 2 confirmed a novel point
mutation G to C, at nucleotide 197 in the donor splice site of intron 1. This
point mutation may interfere with the correct splicing of the mRNA and cause
frameshift, resulted in truncation of predicted protein by premature stop. We
report a novel point mutation G to C, at nucleotide 197 in the intron 1 of STA
gene corresponding the truncation of predicted protein, which differs from any
of the previously reported mutations.
PMID: 10689937 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/9361031 | 1. Hum Mol Genet. 1997 Dec;6(13):2257-64. doi: 10.1093/hmg/6.13.2257.
Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular
dystrophy.
Cartegni L(1), di Barletta MR, Barresi R, Squarzoni S, Sabatelli P, Maraldi N,
Mora M, Di Blasi C, Cornelio F, Merlini L, Villa A, Cobianchi F, Toniolo D.
Author information:
(1)Institute of Genetics, Biochemistry and Evolution CNR, Via Abbiategrasso 207,
27100 Pavia, Italy.
Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked inherited disease
characterized by early contracture of the elbows, Achilles tendons and
post-cervical muscles, slow progressive muscle wasting and weakness and
cardiomyopathy presenting with arrhythmia and atrial paralysis: heart block can
eventually lead to sudden death. The EDMD geneencodes a novel ubiquitous
protein, emerin, which decorates the nuclear rim of many cell types. Amino acid
sequence homology and cellular localization suggested that emerin is a member of
the nuclear lamina-associated protein family. These findings did not explain the
role of emerin nor account for the skeletal muscle- and heart-specific clinical
manifestations associated with the disorder. Now we report that emerin localizes
to the inner nuclear membrane, via its hydrophobic C-terminal domain, but that
in heart and cultured cardiomyocytes it is also associated with the intercalated
discs. We propose a general role for emerin in membrane anchorage to the
cytoskeleton. In the nuclear envelope emerin plays a ubiquitous and dispensable
role in association of the nuclear membrane with the lamina. In heart its
specific localization to desmosomes and fasciae adherentes could account for the
characteristic conduction defects described in patients.
DOI: 10.1093/hmg/6.13.2257
PMID: 9361031 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31645980 | 1. Hum Genome Var. 2019 Sep 3;6:42. doi: 10.1038/s41439-019-0072-8. eCollection
2019.
Targeted next-generation sequencing identified a known EMD mutation in a Chinese
patient with Emery-Dreifuss muscular dystrophy.
Dai X(1)(2), Zheng C(3), Chen X(2)(4), Tang Y(2), Zhang H(2), Yan C(1)(2), Ma
H(1)(2), Li X(1)(2).
Author information:
(1)1School of Medicine, University of Electronic Science and Technology of
China, 610072 Chengdu, Sichuan China.
(2)2Department of Cardiology, Sichuan Academy of Medical Sciences and Sichuan
Provincial People's Hospital, 610072 Chengdu, Sichuan China.
(3)Shenzhen RealOmics (Biotech) Co., Ltd., 518081 Shenzhen, China.
(4)4ZunYi Medical University, 563000 Zunyi, Guizhou China.
Emery-Dreifuss muscular dystrophy (EDMD) is a rare X-linked recessive disease
characterized by the clinical triad of early childhood joint contractures,
progressive weakness in muscles and cardiac involvement and can result in sudden
death. Targeted next-generation sequencing was performed for a Chinese patient
with EDMD and the previously reported mutation [NM_000117.2: c.251_255del
(p.Leu84Profs*7)] in exon 3 of the emerin gene (EMD) was identified.
© The Author(s) 2019.
DOI: 10.1038/s41439-019-0072-8
PMCID: PMC6804839
PMID: 31645980
Conflict of interest statement: Conflict of interestThe authors declare that
they have no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/23622360 | 1. Handb Clin Neurol. 2013;113:1367-76. doi: 10.1016/B978-0-444-59565-2.00007-1.
Emery-Dreifuss muscular dystrophy, laminopathies, and other nuclear
envelopathies.
Bonne G(1), Quijano-Roy S.
Author information:
(1)Inserm, U974; Université Pierre et Marie Curie - Paris 6, UM 76; CNRS, UMR
7215; Institut de Myologie, and AP-HP - U.F. Cardiogénétique et Myogénétique,
Groupe Hospitalier Pitié-Salpêtrière, Paris, France. Electronic address:
[email protected].
The nuclear envelopathies, more frequently known as laminopathies are a rapidly
expanding group of human hereditary diseases caused by mutations of genes that
encode proteins of the nuclear envelope. The most frequent and best known form
is Emery-Dreifuss muscular dystrophy (EDMD), a skeletal myopathy characterized
by progressive muscular weakness, joint contractures, and cardiac disease. EMD
gene, encoding emerin, causes the X-linked form of EDMD, while LMNA gene
encoding lamins A and C, is responsible for autosomal forms, usually with a
dominant transmission. In the last years, the spectrum of conditions has been
extraordinarily enlarged, from a congenital muscular dystrophy with severe
paralytic or rapidly progressive picture due to de novo mutations in LMNA
(L-CMD) to a limb-girdle muscular dystrophy with adult onset and much milder
weakness (LGMD1B). LMNA has also been involved in a form of isolated
cardiomyopathy associated with cardiac conduction disease and in an axonal form
of hereditary neuropathy. Identification of this gene has been reported also in
a number of non-neuromuscular disorders including lipodystrophy syndromes and a
wide spectrum of premature aging syndromes ranging from mandibuloacral dysplasia
to restrictive dermopathy. Mutations in other genes implicated in the processing
or maturation of nuclear lamins have also been found. The extraordinary
complexity of the molecular and pathophysiological mechanisms of these diseases
is still not well known and the occurrence of modifying factors or genes is
highly suspected. Identification of new genes and investigation of new
therapeutic approaches are in progress.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/B978-0-444-59565-2.00007-1
PMID: 23622360 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10220866 | 1. Neuromuscul Disord. 1999 Mar;9(2):108-14. doi: 10.1016/s0960-8966(98)00097-2.
Emerin and cardiomyopathy in Emery-Dreifuss muscular dystrophy.
Funakoshi M(1), Tsuchiya Y, Arahata K.
Author information:
(1)Department of Neuromuscular Research, National Institute of Neuroscience,
Tokyo, Japan.
Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder characterized
by the clinical triad of life-threatening progressive cardiomyopathy with
conduction defect, early onset joint contractures and slow progressive muscle
weakness in scapulo-humero-peroneal distribution. Cardiomyopathy in EDMD is
usually noticed after the second to third decade of life, and becomes worse with
age. Permanent auricular paralysis occurs frequently and is considered a
hallmark of EDMD cardiomyopathy. Cardiac involvement may also occur in female
carriers. In autopsy cases, enlargement of the atria with remarkable thinning
have been observed. Identification of the gene responsible for X-linked EDMD
(X-EDMD) and the protein product, emerin, provided a diagnostic clue for EDMD.
Since the emerin gene is rather small, the entire sequence can easily be
surveyed. Western blot and immunohistochemistry show an absence of emerin in
muscle and skin tissues and oral exfoliating cells in male patients with X-EDMD,
and a reduction of the protein content with a mosaic expression pattern in
female carriers. Emerin anchors at the inner nuclear membrane of cardiac,
skeletal and smooth muscles, and interacts with lamins and nucleoplasm, thereby
possibly maintaining the mechanical stability of the nuclear membrane of muscle
cells that shows rigorous contraction/relaxation. More recently, positive emerin
staining at the cardiac demosomes and fasciae adherentes was noticed in addition
to the specific localization at the inner nuclear membrane. This localization
implies a physiological role for the protein in cardiac conduction.
DOI: 10.1016/s0960-8966(98)00097-2
PMID: 10220866 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32304242 | 1. Muscle Nerve. 2020 Jul;62(1):128-136. doi: 10.1002/mus.26892. Epub 2020 May 6.
Histone acetyltransferase inhibition rescues differentiation of emerin-deficient
myogenic progenitors.
Bossone KA(1)(2), Ellis JA(2), Holaska JM(1)(2).
Author information:
(1)Department of Biomedical Sciences, Cooper Medical School of Rowan University,
Camden, New Jersey, United States.
(2)Department of Pharmaceutical Sciences, University of the Sciences,
Philadelphia, Pennsylvania, United States.
INTRODUCTION: Emery-Dreifuss muscular dystrophy (EDMD) is a disease
characterized by skeletal muscle wasting, major tendon contractures, and cardiac
conduction defects. Mutations in the gene encoding emerin cause EDMD1. Our
previous studies suggested that emerin activation of histone deacetylase 3
(HDAC3) to reduce histone 4-lysine 5 (H4K5) acetylation (ac) is important for
myogenic differentiation.
METHODS: Pharmacological inhibitors (Nu9056, L002) of histone acetyltransferases
targeting acetylated H4K5 were used to test whether increased acetylated H4K5
was responsible for the impaired differentiation seen in emerin-deficient
myogenic progenitors.
RESULTS: Nu9056 and L002 rescued impaired differentiation in emerin deficiency.
SRT1720, which inhibits the nicotinamide adenine dinucleotide (NAD)+ -dependent
deacetylase sirtuin 1 (SIRT1), failed to rescue myotube formation.
DISCUSSION: We conclude that emerin regulation of HDAC3 activity to affect H4K5
acetylation dynamics is important for myogenic differentiation. Targeting H4K5ac
dynamics represents a potential new strategy for ameliorating the skeletal
muscle wasting seen in EDMD1.
© 2020 Wiley Periodicals, Inc.
DOI: 10.1002/mus.26892
PMCID: PMC7382944
PMID: 32304242 [Indexed for MEDLINE]
Conflict of interest statement: CONFLICT OF INTEREST The authors declare no
potential conflicts of interest. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the National
Institutes of Health. |
http://www.ncbi.nlm.nih.gov/pubmed/10732816 | 1. Neurogenetics. 1997 Sep;1(2):135-40. doi: 10.1007/s100480050020.
Emerin, deficiency of which causes Emery-Dreifuss muscular dystrophy, is
localized at the inner nuclear membrane.
Yorifuji H(1), Tadano Y, Tsuchiya Y, Ogawa M, Goto K, Umetani A, Asaka Y,
Arahata K.
Author information:
(1)Department of Anatomy II, National Defense Medical College, Saitama, Japan.
X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD) is an inherited
muscle disorder characterized by the clinical triad of progressive wasting of
humero-peroneal muscles, early contractures of the elbows, Achilles tendons and
postcervical muscles, and cardiac conduction block with a high risk of sudden
death. The gene for EDMD on Xq28 encodes a novel protein named emerin that
localizes at the nuclear membrane of skeletal, cardiac and smooth muscles and
some other non-muscle tissues. To investigate a possible physiological role for
emerin, we examined the ultrastructural localization of the protein in human
skeletal muscle and HeLa cells, using ultrathin cryosections. We found that the
immune-labeled colloidal gold particles were localized on the nucleoplasmic
surface of the inner nuclear membrane, but not on the nuclear pore. Emerin
stayed on the cytoplasmic surface of the nuclear lamina, even after detergent
treatment that solubilizes membrane lipids and washes out membrane proteins.
These results suggest that emerin anchors at the inner nuclear membrane through
the hydrophobic stretch, and protrudes from the hydrophilic region to the
nucleoplasm where it interacts with the nuclear lamina. We speculate that emerin
contributes to maintain the nuclear structure and stability, as well as nuclear
functions, particularly in muscle tissues that have severe stress with rigorous
contraction-relaxation movements and calcium flux.
DOI: 10.1007/s100480050020
PMID: 10732816 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11385714 | 1. Hum Mutat. 2001 Jun;17(6):522. doi: 10.1002/humu.1139.
Novel mutations in the emerin gene in Israeli families.
Nevo Y(1), Ahituv S, Yaron Y, Kedmi M, Shomrat R, Legum C, Orr-Urtreger A.
Author information:
(1)Pediatric Neuromuscular Service, Dana Hospital, Tel Aviv Sourasky Medical
Center, Israel. [email protected]
Emery-Dreifuss Muscular Dystrophy (EMD or EDMD) is a rare X-linked recessive
disorder, characterized by progressive muscle wasting and weakness,
contractures, and cardiomyopathy, manifesting as heart block. Mutation analysis
at the EMD gene locus was performed in 4 unrelated Israeli families with
X-linked EMD and in one sporadic case. In the 4 families 4 different mutations
were found, 3 of which were novel. These included two frame shift mutations in
exon 2 (333delT and 412insA) and one base pair substitution at the consensus +1
donor splice in intron 5 (1429G-->A). The fourth mutation in exon 6
(1675-1678delTCCG) has been previously described. No mutations were identified
in the one sporadic case. Two of the three novel mutations were found in exon 2.
A summary of the previously published mutations described in the EMD Mutation
Database (http://www.path.cam.ac.uk/emd/) as well as the mutations described in
our study suggest that the distribution of mutations in EMD gene is not entirely
random and that exon 2 is prone to mutations. Hum Mutat 17:522, 2001.
Copyright 2001 Wiley-Liss, Inc.
DOI: 10.1002/humu.1139
PMID: 11385714 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21372459 | 1. Intern Med. 2011;50(5):459-62. doi: 10.2169/internalmedicine.50.4598. Epub
2011 Mar 1.
Ventricular arrhythmia in X-linked Emery-Dreifuss muscular dystrophy: a lesson
from an autopsy case.
Ishikawa K(1), Mimuro M, Tanaka T.
Author information:
(1)Department of Cardiology, Okazaki City Hospital, Japan.
[email protected]
Emery-Dreifuss muscular dystrophy (EDMD) is a distinctive form of muscular
dystrophy which is often associated with cardiac abnormalities. Conduction
disturbances are frequently observed, and may necessitate pacemaker implantation
to prevent sudden death. In this case report, we present an autopsy of a
31-year-old man with X-linked EDMD who developed only minimal skeletal muscle
symptoms, and who died from ventricular arrhythmia despite undergoing a previous
pacemaker implantation. Ventricular arrhythmias in X-linked EDMD patients are
also discussed.
DOI: 10.2169/internalmedicine.50.4598
PMID: 21372459 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/17042210 | 1. Tunis Med. 2006 Jun;84(6):361-4.
[Cardiac involvement in Emery-Dreifuss muscular dystrophy: a case report].
[Article in French]
Chabrak S(1), Ammar S, Ammar N, Ouali S, Mghaieth F, Larbi N, Kafsi N, Hentati
F, Mechmeche R.
Author information:
(1)Service des Explorations Fonctionnelles et de Réanimatin Cardiologique, La
Rabta, Tunis.
Emery Dreifuss muscular dystrophy (EDMD) is an uncommon hereditary myopathy
characterized by 3 symptoms: slow progressive muscular atrophy, muscular
contractures and cardiac disease which affect prognosis. We report a 22 year-old
patient with EDMD which shows the typical features of the associated dilated
cardiomyopathy, ventricular arrhythmia, atrio-ventricular block, atrial
standstill then atrial paralysis.
PMID: 17042210 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29633897 | 1. Nucleus. 2018 Jan 1;9(1):268-274. doi: 10.1080/19491034.2018.1462635.
Clinical aspects of Emery-Dreifuss muscular dystrophy.
Madej-Pilarczyk A(1).
Author information:
(1)a Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of
Sciences , Warsaw , Poland.
Emery-Dreifuss muscular dystrophy (EDMD), clinically characterized by
scapulo-humero-peroneal muscle atrophy and weakness, multi-joint contractures
with spine rigidity and cardiomyopathy with conduction defects, is associated
with structural/functional defect of genes that encode the proteins of nuclear
envelope, including lamin A and several lamin-interacting proteins. This paper
presents clinical aspects of EDMD in context to causative genes,
genotype-phenotype correlation and its emplacement within phenotypic spectrum of
skeletal muscle diseases associated with envelopathies.
DOI: 10.1080/19491034.2018.1462635
PMCID: PMC5973255
PMID: 29633897 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12075650 | 1. Anaesth Intensive Care. 2002 Jun;30(3):372-5. doi: 10.1177/0310057X0203000320.
Anaesthetic management of a patient with Emery-Dreifuss muscular dystrophy.
Shende D(1), Agarwal R.
Author information:
(1)Department of Anaesthesia and Intensive Care, All India Institute of Medical
Sciences, New Delhi.
Emery-Dreifuss muscular dystrophy is a rare form of muscular dystrophy
associated with cardiac implications such as cardiomyopathy and arrhythmias
leading to sudden death. We describe the anesthetic management of a patient with
Emery-Dreifuss muscular dystrophy who presented for orthopaedic surgery and
discuss the disorder and its potential anaesthetic implications.
DOI: 10.1177/0310057X0203000320
PMID: 12075650 [Indexed for MEDLINE] |