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1.
Nat Commun ; 8: 14848, 2017 03 31.
Article in English | MEDLINE | ID: mdl-28361972

ABSTRACT

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment.


Subject(s)
Genetic Therapy/methods , Muscle Strength/genetics , Muscular Dystrophy, Oculopharyngeal/therapy , Myoblasts, Skeletal/metabolism , Poly(A)-Binding Protein I/genetics , Transcriptome/genetics , Animals , Disease Models, Animal , Gene Knockdown Techniques/methods , HEK293 Cells , Humans , In Vitro Techniques , Mice , Mice, Transgenic , Muscular Dystrophy, Oculopharyngeal/physiopathology , Trinucleotide Repeat Expansion
2.
J Neurol Sci ; 334(1-2): 102-5, 2013 Nov 15.
Article in English | MEDLINE | ID: mdl-23962698

ABSTRACT

UNLABELLED: Hirayama disease (HD) is a rare motor disorder mainly affecting young men, characterized by atrophy and weakness of forearm and hand muscles corresponding to a C7-T1 myotome distribution. The weakness is usually unilateral or asymmetric and progression usually stops within several years. The etiology of HD is not well understood. One hypothesis, mainly based on MRI findings, is that the weakness is a consequence of cervical flexion myelopathy. The aim of this study was to explore the function of corticospinal and ascending somatosensory pathways during neck flexion using evoked responses. MATERIALS AND METHODS: 15 men with HD and 7 age-matched control male subjects underwent somatosensory evoked potentials (SSEP) and motor evoked potentials (MEP) studies with the neck in neutral position and fully flexed. SSEP studies included electrical stimulation of median and ulnar nerves at the wrist, and tibial nerve at the ankle with recording over the ipsilateral Erb's point, cervical spine, and contralateral sensory cortex. MEP recordings were obtained by magnetic stimulation of the motor cortex and the cervical lower spinal roots; the evoked responses were recorded from the contralateral thenar and abductor hallucis muscles. RESULTS: MEP recordings demonstrated significant lower amplitudes, and slightly prolonged latencies in HD patients on cervical stimulation, compared to control subjects. During neck flexion, MEP studies also demonstrated a statistically significant drop in mean upper limb amplitude on cervical stimulation in HD patients, as well as in control subjects, although to a lesser degree. In contrast, no significant differences were found in SSEP studies in HD patients compared to control subjects, or between neutral and flexed position in these groups. CONCLUSION: The study shows a negative effect of cervical flexion on MEP amplitudes in HD patients as well as in control subjects, requiring more studies to investigate its significance. Neck flexion did not have an influence on any SSEP parameters in patients or controls.


Subject(s)
Evoked Potentials, Motor/physiology , Evoked Potentials, Somatosensory/physiology , Neck/physiology , Spinal Muscular Atrophies of Childhood/physiopathology , Adolescent , Adult , Case-Control Studies , Electric Stimulation , Humans , Male , Pyramidal Tracts/physiopathology
3.
Neurology ; 73(8): 596-601, 2009 Aug 25.
Article in English | MEDLINE | ID: mdl-19704078

ABSTRACT

OBJECTIVE: To assess the evolution and life expectancy in patients with oculopharyngeal muscular dystrophy (OPMD) who are homozygotes for two (GCN)13 expansions in the PABPN1 encoding gene. BACKGROUND: OPMD is particularly frequent among French Canadians (FCs) and Uzbek Jews (UJs), who carry a same size, (GCN)13, PABPN1 mutation. The high rate of consanguinity among UJs together with late disease onset and normal fertility results in homozygous cases. METHODS: For 15 to 20 years, we followed 4 FC and 6 UJ homozygotes with OPMD and compared them with their heterozygous parents and siblings. In addition to clinical evaluation, electrodiagnostic tests, psychological tests, and brain imaging studies were performed. RESULTS: In all (GCN)13-(GCN)13 patients, OPMD started before age 35 years, with bilateral ptosis and dysphagia; external ophthalmoparesis and dysphonia followed within a few years, as well as weakness in proximal limb muscles. All patients had recurrent aspirations and lost weight; 4 patients required surgical interventions to alleviate dysphagia, and 5 required feeding gastrostomies. Most patients were followed by psychiatrists due to cognitive decline, recurrent depression, or psychotic episodes. Six patients died at ages 50, 51, 53, 56, 56, and 57 years. The eldest patient is now 51 years old; she is cachectic and requires special diet and psychiatric care for paranoid psychosis and uninhibited behavior. CONCLUSIONS: Oculopharyngeal muscular dystrophy progresses faster in homozygote compared with heterozygote patients. It is not restricted to the muscles, but also involves the CNS with cognitive decline and psychotic manifestations and leads to a reduced life expectancy.


Subject(s)
Cognition Disorders/mortality , Life Expectancy , Muscular Dystrophy, Oculopharyngeal/mortality , Cognition Disorders/complications , Cognition Disorders/genetics , Female , Follow-Up Studies , Humans , Longevity/genetics , Male , Middle Aged , Muscular Dystrophy, Oculopharyngeal/complications , Muscular Dystrophy, Oculopharyngeal/genetics
6.
Neurology ; 56(11): 1573-5, 2001 Jun 12.
Article in English | MEDLINE | ID: mdl-11402119

ABSTRACT

Autosomal recessive juvenile parkinsonism (AR-JP) is an early-onset parkinsonism caused by exonic deletions or point mutations in the parkingene. The relationship between the type of the genetic defect and the clinical presentation, the response to therapy, and the evolution have not been yet determined. The authors describe a single-basepair deletion at nucleotide 202 in exon 2 of the parkin gene in a kindred with a benign clinical course.


Subject(s)
Gene Deletion , Ligases , Parkinsonian Disorders/genetics , Proteins/genetics , Ubiquitin-Protein Ligases , Adolescent , Adult , Age of Onset , Base Sequence , Disease Progression , Exons , Family Health , Female , Genotype , Humans , Male , Middle Aged , Molecular Sequence Data , Pedigree
7.
Neurology ; 55(9): 1267-70, 2000 Nov 14.
Article in English | MEDLINE | ID: mdl-11087766

ABSTRACT

OBJECTIVE: To determine whether all cases of oculopharyngeal muscular dystrophy (OPMD) among Bukhara Jews share the same founder mutation. BACKGROUND: Autosomal dominant OPMD is caused by a (GCG)8-13 repeat expansion in the polyadenylation binding protein 2 (PABP2) gene. The disease has a worldwide distribution but is particularly prevalent in Bukhara Jews and in French Canadians, in whom it was introduced by three sisters in 1648. METHODS: We established the size of the PABP2 mutation in 23 Bukhara Jewish patients belonging to eight unrelated families. In all families, we constructed haplotypes for the carrying chromosomes composed of the alleles for eight chromosome 14q polymorphic markers. RESULTS: All patients share a (GCG)9 PABP2 mutation and a four-marker haplotype. Furthermore, a shared intron single nucleotide polymorphism (SNP) in the PABP2 gene 2.6Kb from the mutation was not observed in 22 families with (GCG)9 mutations from nine different countries. The smaller size of the chromosomal region in linkage disequilibrium around the mutation in Bukhara Jews, as compared with French Canadians, suggests a founder effect that occurred more than 350 years ago. Based on the Luria-Delbrück corrected "genetic clock," we estimate that the mutation appeared or was introduced once in the Bukhara Jewish population between AD 872 and 1512 (mean, AD 1243). CONCLUSION: OPMD among Bukhara Jews is the result of a shared, historically distinct, PABP2 (GCG)9 mutation that likely arose or was introduced in this population at the time they first settled in Bukhara and Samarkand during the 13th or 14th centuries.


Subject(s)
Jews/genetics , Muscular Dystrophies/genetics , Mutation/genetics , RNA-Binding Proteins/genetics , Genetic Linkage/genetics , Genotype , Humans , Poly(A)-Binding Proteins , Uzbekistan/ethnology
10.
Neurology ; 53(7): 1602-4, 1999 Oct 22.
Article in English | MEDLINE | ID: mdl-10534280

ABSTRACT

We report a Jewish family of Yemenite origin in which three brothers born from a consanguineous marriage had juvenile parkinsonism. The DNA samples from three affected brothers and one healthy brother were analyzed for the linkage to markers covering the autosomal-recessive juvenile parkinsonism (AR-JP) locus. A perfect homozygous cosegregation to the markers was found, giving a maximal lod score of 3.11 at D6S1579, D6S305, and D6S411, all of which are 0 cm apart from each other (nonparametric linkage score, 8.041; p = 0.000977). Exon 3 of the Parkin gene was homozygously deleted in all patients. The AR-JP gene also exists in the Jewish population.


Subject(s)
Genes, Recessive , Jews/genetics , Ligases , Mutation/genetics , Parkinsonian Disorders/genetics , Proteins/genetics , Ubiquitin-Protein Ligases , DNA/genetics , Exons , Gene Deletion , Genetic Linkage , Haplotypes , Homozygote , Humans , Lod Score , Male , Middle Aged , Pedigree , Yemen/ethnology
11.
Ann Neurol ; 46(1): 115-8, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10401788

ABSTRACT

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) usually begins with ptosis or dysphagia during the fifth or sixth decade of life. We studied 7 patients with OPMD symptoms starting before the age of 36 years. All were found to be homozygotes for the dominant (GCG)9 OPMD mutation. On average, disease onset was 18 years earlier than in heterozygotes, and patients had a significantly larger number of muscle nuclei containing intranuclear inclusions (INIs) (9.4 vs 4.9%).


Subject(s)
Homozygote , Muscular Dystrophies/genetics , Adult , Age Distribution , Age of Onset , DNA Mutational Analysis , Female , Haplotypes , Humans , Male , Middle Aged , Oculomotor Muscles , Pedigree , Pharyngeal Muscles , Phenotype
12.
Neuromuscul Disord ; 7 Suppl 1: S38-40, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9392014

ABSTRACT

Oculopharyngeal muscular dystrophy (OPMD) is considered frequent among French Canadians. Our previous observations suggested it is common also among the Jews originating from Bukhara in Uzbekistan, many of whom are now living in Israel. One hundred and seventeen OPMD patients were identified in a population of 70,000 people of Bukharian descent, resulting in a calculated minimal prevalence of 1:600. In all but three families age dependent autosomal dominant inheritance was documented. There is some evidence for genetic anticipation. Three young, severely ill, patients from two different families may be homozygotes, their parents being both affected. Bukhara Jews present the second largest known cluster and the prevalence is the highest in the world. The existence of very large families, intermarriage among carriers and probably homozygote offspring may be useful for genetic studies. A 'founder effect' may explain the high prevalence of OPMD in this population.


Subject(s)
Muscular Dystrophies/epidemiology , Muscular Dystrophies/genetics , Oculomotor Muscles , Pharyngeal Muscles , Adult , Blepharoptosis/epidemiology , Blepharoptosis/etiology , Blepharoptosis/genetics , Family Health , Founder Effect , Humans , Israel/epidemiology , Male , Muscular Dystrophies/physiopathology
13.
Neurology ; 46(5): 1324-8, 1996 May.
Article in English | MEDLINE | ID: mdl-8628475

ABSTRACT

We studied, by electron microscopy, muscle biopsies from seven patients with autosomal dominant oculopharyngeal muscular dystrophy (OPMD) belonging to the recently described Bukhara-Jewish cluster. Typical tubulofilamentous intranuclear inclusions (INI) of 8.5 nm outer diameter were present in all cases. The INI were observed in 4.5 +/- 1.8% of the nuclei in five patients. In the other two, they occurred in 9.5 +/- 0.5% of the nuclei and often occupied a larger nuclear area. These two patients, offspring of intermarriage between affected cousins, had an unusually severe form of OPMD beginning in their early 30s, suggesting homozygote state. Our results confirm that INI are pathognomonic for OPMD and suggest that their frequency may be quantitatively related to the number of abnormal DNA copies.


Subject(s)
Cell Nucleus/pathology , Inclusion Bodies/pathology , Jews , Muscular Dystrophies/genetics , Muscular Dystrophies/pathology , Oculomotor Muscles/pathology , Pharyngeal Muscles/pathology , Adult , Aged , Aged, 80 and over , Biopsy , Cell Nucleus/ultrastructure , Female , France , Humans , Inclusion Bodies/ultrastructure , Male , Microscopy, Electron , Muscle Fibers, Skeletal/pathology , Muscle Fibers, Skeletal/ultrastructure , Oculomotor Muscles/ultrastructure , Pedigree , Pharyngeal Muscles/ultrastructure , Uzbekistan/ethnology
14.
Hum Mol Genet ; 4(3): 429-34, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7795598

ABSTRACT

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant muscular dystrophy which presents typically after the age of 50 with progressive eyelid drooping and an increasing difficulty in swallowing. Though OPMD has a world-wide incidence, it is more common in the French Canadian population. We have identified a homogeneous group of families and studied 166 polymorphic markers as part of a genome search before establishing linkage to chromosome 14. We determined that the OPMD locus maps to a less than 5 cM region of chromosome 14q11.2-q13. The maximum two-point lod score in three French Canadian families of 14.73 (theta = 0.03) was obtained for an intronic cardiac beta myosin heavy chain gene (MYH7) marker. The regional localization for the OPMD locus raises the intriguing possibility that either the cardiac alpha or beta myosin heavy chain genes may play a role in this disease.


Subject(s)
Blepharoptosis/genetics , Chromosomes, Human, Pair 14 , Deglutition Disorders/genetics , Muscular Dystrophies/genetics , Myosins/genetics , Base Sequence , Chromosome Mapping , Female , Genetic Linkage , Genetic Markers , Haplotypes , Humans , Inclusion Bodies/ultrastructure , Male , Molecular Sequence Data , Muscle, Skeletal/pathology , Muscular Dystrophies/pathology , Pedigree , Recombination, Genetic , White People
15.
Neuromuscul Disord ; 3(5-6): 575-7, 1993.
Article in English | MEDLINE | ID: mdl-8186715

ABSTRACT

Oculopharyngeal muscular dystrophy (OPMD), a late onset autosomal dominant myopathy, is common among the French-Canadians and the Jews from Bukhara (Uzbekistan); most clinical histologic and genetic data published until now, as well as the recently suggested diagnostic criteria, are based on studies among the former. We studied 79 patients with OPMD belonging to the newly described Jewish-Bukhara cluster. The disease began between the ages of 21 and 78 yr (median 53 yr). In 11 patients (15%) it began before the age of 40. Ptosis was the first symptom in 59 patients and dysphagia in the remaining 20. Eight patients (10%) were monosymptomatic (ptosis) after more than 7 yr from the start of the disease; however, other family members had additional signs/symptoms. The patients belong to 29 families; in 26 age-dependent autosomal dominant inheritance could be documented. Among them there is certain evidence for genetic anticipation. This clinical study is the largest published concerning patients other than French-Canadians.


Subject(s)
Muscular Dystrophies/physiopathology , Oculomotor Muscles , Pharyngeal Muscles , Adult , Age of Onset , Aged , Blepharoptosis , Canada , Family , Female , France/ethnology , Genes, Dominant , Humans , Jews , Male , Middle Aged , Muscular Dystrophies/genetics , Muscular Dystrophies/pathology , Uzbekistan/ethnology
16.
J Clin Neuroophthalmol ; 11(2): 92-4; discussion 95, 1991 Jun.
Article in English | MEDLINE | ID: mdl-1832691

ABSTRACT

We examined the pupillary cycle time (PCT) in eight elderly patients with isolated oculomotor nerve palsy (ONP) that was characterized by complete involvement of the extraocular muscles. In addition to advanced age, all patients had at least one other vasculopathic risk factor. Although in all cases the pupil was completely spared by clinical impression, the PCT was significantly prolonged compared with the other eye and well outside the normal range (mean 1590 +/- 212 msec on the involved side and 1076 +/- 110 on the uninvolved side). On re-examination, after an interval of 2-3 months, the PCT was either normal or markedly improved in all patients, paralleling the recovery of extraocular muscle function. These findings suggest that even in pure, noncompressive ONPs there is subclinical pupillary involvement. Repeated PCT examinations may provide an objective means to estimate recovery. Moreover, in the problematic subgroup of "pupil sparing" incomplete ONP, PCT monitoring during the first days may indicate possible progression of a compressive lesion.


Subject(s)
Oculomotor Nerve Diseases/physiopathology , Reflex, Pupillary , Aged , Aged, 80 and over , Autonomic Nervous System/physiopathology , Female , Humans , Male , Middle Aged , Parasympathetic Nervous System/physiopathology
17.
Epilepsia ; 29(1): 30-3, 1988.
Article in English | MEDLINE | ID: mdl-3338420

ABSTRACT

A 73-year-old patient with hyperglycemia and rheumatoid arthritis presented with attacks of involuntary lingual movements that were associated with pain at the base of the tongue, often followed by aversion of head and eyes to the left with clonic contractions of the left corner of the mouth. Seizures could be induced by a combination of specific movement and somesthetic stimuli. Ictal EEG recording revealed a focal epileptiform discharge in the right centrofrontal area, thus confirming that the patient had lingual seizures, an extremely unusual manifestation.


Subject(s)
Epilepsy/physiopathology , Tongue/physiopathology , Aged , Electroencephalography , Humans , Male , Movement , Pain
18.
J Clin Neuroophthalmol ; 6(4): 232-5, 1986 Dec.
Article in English | MEDLINE | ID: mdl-2947928

ABSTRACT

Edge-light pupil cycle time has been introduced recently as a simple method for examining parasympathetic pupillary innervation. Since the sympathetic system is not thought to be involved in the light reflex, it was assumed that edge-light pupil cycle time would be unimpaired in lesions of the sympathetic pathways. In 12 patients with unilateral Horner's syndrome of different etiologies, the edge-light pupil cycle time was determined in both eyes. In all cases the edge-light pupil cycle time was significantly prolonged on the abnormal side. Patients with central, preganglionic, or postganglionic lesions showed the differences consistently. These data support the notion that the sympathetic system plays a role in the pupillo-dilating phase of edge-light pupil cycle time, presumably by exerting a tonic mydriatic effect. Since this tonic effect is lost in Horner's syndrome, leading to slowed redilatation, the edge-light pupil cycle time becomes prolonged. Thus, edge-light pupil cycle time may prove to be a valuable diagnostic test for Horner's syndrome.


Subject(s)
Horner Syndrome/physiopathology , Reflex, Pupillary , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Sympathetic Nervous System/physiopathology
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