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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.

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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.

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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.

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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.

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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.

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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.

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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%).

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PURPOSE: To report the cyclosporine-induced complications of optic neuropathy, partial external ophthalmoplegia, and other neurologic abnormalities. METHODS: Case report. A 22-year-old man with severe active Crohn disease developed bilateral optic neuropathy, nystagmus, external ophthalmoplegia, and ataxia on the fifth day of cyclosporine A (CyA) parenteral therapy. RESULTS: Cyclosporine therapy was discontinued as soon as toxic clinical manifestations appeared. Cyclosporine blood level detected then was 1,290 ng/ml (therapeutic level: 150 to 300 ng/ml). Partial external ophthalmoplegia improved dramatically; however, the patient's optic neuropathy progressed to optic atrophy, leaving the patient visually impaired. Various possible mechanisms for cyclosporine-induced neurotoxicity are discussed. CONCLUSION: It is important to closely monitor neuro-ophthalmologic and neurologic signs of patients treated with cyclosporine.

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Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark. We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.

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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.

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Foix-Chavany-Marie syndrome (FCMS) is characterized by facio-linguo-masticatory diplegia in the absence of limb weakness. The most common cause is a cortical lesion resulting from a stroke but a congenital form has been reported. We present the case of a 53-year-old man who was admitted to hospital with worsening dysphagia which was know to have been present together with anarthria and facial palsy, since birth. He demonstrated features of FCMS with pseudobulbar palsy and unaffected reflexes and automatic responses. Cranial CT and MRI scans showed bilateral opercular lesions of CSF intensity in continuity with the lateral ventricles. We conclude that this case of static FCMS for over 50 years may represent a 'pure' form of congenital FCMS with motor symptomatology and unaccompanied by mental retardation or epilepsy.

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Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic disorder with late-onset progressive myopathy affecting mainly head and neck striated muscles. It is more common in certain ethnic communities. Dysphagia was usually attributed to the malfunction of striated pharyngeal muscles. We studied a group of Bukharan immigrants affected by this disorder (N = 13). Esophageal studies, including endoscopy, manometry, and scintigraphic emptying were performed. Very low pharyngeal pressures were measured. Upper esophageal pressures (UEP) were in the normal range in eight patients, and above normal in three patients. Four also had low lower esophageal sphincter pressure. Esophageal body peristaltic activity was grossly impaired in all patients: mainly nonpropulsive, simultaneous, retrograde, and failed activity was recorded. Marked retention of isotopic material was demonstrated in all patients studied, usually in the middle and lower parts of the body, ranging from 17 to 100% retention. The dysphagia in OPMD is due not only to dysfunction of pharyngeal and upper esophageal striated muscle, but also has a significant smooth muscle component.

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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.

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Intravascular malignant lymphomatosis (IML) is a rare disease characterized by proliferation of neoplastic cells of lymphoid origin within small blood vessels. The median survival of IML patients is only 6 months. Any organ can be affected, with or without clinical expression. Although skin lesions are classic, they are relatively uncommon (28%). Neurological symptomatology (which evolves over a few weeks) is the most common clinical expression (83%). Dementia is the most common neurological symptom that occurs in about half of the patients with central nervous system pathology, and is associated with poorer prognosis. The diagnosis is confirmed by histology but, except for lung, biopsies are not sensitive and are helpful only when performed in the symptomatic organs; furthermore, when associated with anesthesia, they can be followed by dramatic worsening of the patient's condition. Elevated LDH is a good indicator of IML in patients with subacute neurological symptomatology, especially if associated with signs suggestive of other organ involvement.

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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.

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In an attempt to evaluate EEG changes associated with dementia in Parkinson's disease (PD), we performed frequency analysis in three groups of 10 subjects each; two with PD, and one normal control group. The PD patient groups were matched for age, sex, severity and duration of disease, but were discordant for the existence of dementia. Normals were age- and sex-matched healthy volunteers. The relative alpha amplitude was significantly decreased in the demented PD patients, unrelated to motor disability. There was a nonsignificant but consistent trend of increased amplitude in the delta and theta range in the demented PD patients as compared to nondemented PD subjects and normal controls, as well as increased amplitude in the theta and delta range with more severe motor disability in the nondemented PD patients.

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