Ralph L. Carasso

Autosomal-recessive juvenile parkinsonism in a Jewish Yemenite kindred: Mutation of Parkin gene

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.

A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32.

We updated the clinical features of a consanguineous Arab Israeli family, in which four of seven children were affected by spastic paraplegia complicated by skin pigmentary abnormalities. A genomewide linkage screen performed for the family identified a new locus (SPG23) for this form of hereditary spastic paraplegia, in an approximately 25cM region of chromosome 1q24‐q32, with a peak logarithm of odds score of 3.05. Ann Neurol 2003;54:796–803

A rare recessive distal hereditary motor neuropathy with HSJ1 chaperone mutation.

Distal hereditary motor neuropathies (dHMN) form a clinically and genetically heterogeneous group of disorders, characterized by muscle weakness and atrophy predominating at the distal part of the limbs, due to the progressive degeneration of motor neurons in the spinal cord. We report here a novel rare variant of dHMN with autosomal recessive inheritance in a large Jewish family originating from Morocco. The disease is characterized by a predominance of paralysis at the lower limbs and an early adulthood onset. We performed a genetic study in this family to identify and characterized the causing mutation.

Camptocormia, axial dystonia, and parkinsonism: phenotypic heterogeneity of a parkin mutation.

Autosomal recessive juvenile parkinsonism (AR-JP) is a young-onset parkinsonism caused by mutations in the parkin gene.1 Exonic deletions or multiplications and truncating and missense mutations have been described.2,3⇓ The phenotype encompasses juvenile-, early-, and late-onset patients.2 We describe a large kindred with different phenotypic expressions of a mutation in the parkin gene. The patients belonged to two branches of an Arabic Israeli family (figure). Patients in Branch A have been previously described.4 The consanguinity of the branches was established to the seventh ancestral generation. Figure. The pedigree. Square symbols = men, circles = women, diagonal lines = deceased persons, ✓ = genotyped. The consanguinity of the branches of the family was established to the seventh ancestral generation. Four brothers (black squares) in Branch A (right) and two first-degree cousins (black square and circle) in Branch B (middle) are affected. All patients showed homozygous one adenine deletion at nucleotide position 202. The horizontal shaded symbols represent patients with tremor only who were clinically examined. The patient with an asterisk was genotyped …

Respiratory Muscle Performance and the Perception of Dyspnea in Parkinson's Disease

BACKGROUND Pulmonary and respiratory muscle function impairment are common in patients with Parkinsons disease (PD). However, dyspnea is not a frequent complaint among these patients, although it is well documented that the intensity of dyspnea is related to the activity and the strength of the respiratory muscles. PATIENTS AND METHODS We studied pulmonary function, respiratory muscle strength and endurance and the perception of dyspnea (POD) in 20 patients with PD (stage II and III Hoehn and Yahr scale) before and after their first daily L-dopa dose. Respiratory muscle strength was assessed by measuring the maximal inspiratory and expiratory mouth pressures (PImax and PEmax), at residual volume (RV) and total lung capacity (TLC) respectively. The POD was measured while the subject breathed against progressive load and dyspnea was rated using a visual analog scale. RESULTS Respiratory muscle strength and endurance were decreased and the POD was increased during the off medication period compared to normal subjects. There was a nonsignificant trend to an increase in Plmax, PEmax and endurance after L-dopa intake. The POD of PD patients decreased (p<0.05) following medication, although, it remained increased (p<0.01) as compared to the normal subjects. Even if patients had spirometry data showing a mild restrictive pattern, before medication, both forced vital capacity (FVC) and forced expiratory volume (FEV)1 remained almost identical after L-dopa intake. CONCLUSIONS Patients with PD have higher POD, compared to normal subjects and this increased perception is attenuated when the patients are on dopaminergic medication. The change in the POD is not related to changes in respiratory muscle performance or pulmonary functions. A central effect or a correction of uncoordinated respiratory movements by L-dopa may contribute to the decrease in POD following L-dopa treatment.

Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis

Objective: To identify the genetic variant that causes autosomal dominantly inherited motor neuron disease in a 4-generation Israeli-Arab family using genetic linkage and whole exome sequencing. Methods: Genetic linkage analysis was performed in this family using Illumina single nucleotide polymorphism chips. Whole exome sequencing was then undertaken on DNA samples from 2 affected family members using an Illumina 2000 HiSeq platform in pursuit of potentially pathogenic genetic variants that comigrate with the disease in this pedigree. Variants meeting these criteria were then screened in all affected individuals. Results: A novel mutation (p.R191G) in the valosin-containing protein (VCP) gene was identified in the index family. Direct sequencing of the VCP gene in a panel of DNA from 274 unrelated individuals with familial amyotrophic lateral sclerosis (FALS) revealed 5 additional mutations. Among them, 2 were previously identified in pedigrees with a constellation of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) and in FALS, and 2 other mutations (p.R159C and p.R155C) in IBMPFD alone. We did not detect VCP gene mutations in DNA from 178 cases of sporadic amyotrophic lateral sclerosis. Conclusions: We report a novel VCP mutation identified in an amyotrophic lateral sclerosis family (p.R191G) with atypical clinical features. In our experience, VCP mutations arise in approximately 1.5% of FALS cases. Our study supports the view that motor neuron disease is part of the clinical spectrum of VCP-associated disease.

Parkin gene causing benign autosomal recessive juvenile parkinsonism

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.

Cognitive impairment and reduced life span of oculopharyngeal muscular dystrophy homozygotes

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.

A comparison of dopamine agonists and catechol-O-methyltransferase inhibitors in Parkinson's disease.

To compare the efficacy and tolerability of three dopamine agonists—pergolide (PRG), pramipexole (PRX), and ropinirole (ROP)—and two catechol-O-methyltranferase (COMT) inhibitors—tolcapone (TOL) and entacapone (ENT)—as add-on therapies to levodopa (L-Dopa) in Parkinsons disease, we analyzed randomized, double-blind, placebo-controlled, multicenter studies. To our knowledge, they had not yet been evaluated in comparison with each other. Statistical analyses used odds ratios, numbers needed to harm, and Fishers inverse &khgr;2 method. Seven studies meeting the inclusion criteria included treatment of 1,756 patients. The common efficacy measures were the reduction of L-Dopa dose and “off” duration. The reported reduction in L-Dopa dose was significant for all drugs in relation to placebo, but was most significant for PRX and ENT (p < 0.0001). The most significant reduction in “off” duration was with PRG, PRX, and ENT (p < 0.001). The common tolerability measures were the percentage of patients withdrawn because of side effects, because of any reason, and because of the development of dyskinesias. Ropinirole, PRX, and ENT caused fewer withdrawals related to side effects. Pergolide was better than other analyzed drugs concerning withdrawals for any reason. All drugs caused more dyskinesias than placebo (p < 0.0001), with overlapping confidence intervals, except for TOL 600 mg, which caused more dyskinesias than dopamine agonists and ENT. Pramipexole and ENT had the best efficacy and tolerability profile in this analysis.

Acute mania and hemichorea

A 61-year-old man suddenly became euphoric and talkative. Later the same day, he developed hemichoreic movements of the left limbs. The patient fulfilled the DSM-IV criteria for a manic episode by abnormally and persistently elevated mood, decreased need for sleep, high distractibility, pressured speech, increased goal-directed activity, and hypersexuality. The mood changes persisted for several weeks. Magnetic resonance imaging of the brain showed a right thalamic infarction. The co-occurrence of hemichorea and mania caused by focal thalamic lesion is very rare. It may be explained by dysfunction in basal ganglia thalamocortical circuitry.