(1) Desmin gene mutations in desmin-related skeletal myopathy and cardiomyopathy. Fifteen patients from 8 families affected with myopathy characterized by the presence of desmin deposits in cardiac and/or skeletal muscle were tested for mutations in the Desmin gene on chromosome 2q. Previous studies excluded association of Desmin gene with these types of myopathy in several French families. We identified two separate mutations in the Desmin gene, 449 (Leu -> Met), responsible for skeletal myopathy in a single American family with three affected individuals, and 358 (Ala -> Pro), apparently associated with both, skeletal and cardiac myopathy. Screening of a larger number of families is necessary to make a reliable conclusion. (2) Mapping oculopharyngeal muscular dystrophy (OPMD) to chromosome 14q. A large family from Bukhara, Central Asia, that includes over 70 individuals affected with OPMD, was tested for genetic linkage. A similar disease in a French- Canadian family (Brais et al., 1995) was previously mapped to chromosome 14q11.2-q13. Using the same set of markers, we established linkage of OPMD in our Bukharian kindred to the same locus. (3) Genetic mapping of the gene for Essential tremor (ET). A genome-wide search has been performed in three large American families with 5 to 18 affected individuals. Linkage was established in two of these families showing a combination of ET with Focal dystonia in more than 50% of patients. This result suggests that a single gene may be responsible for both syndromes. Collaboration with other groups in the Essential Tremor Consortium allowed to identify two other American families with linkage to the same locus and to significantly increase the lod score. (4) Juvenile form of spinocerebellar ataxia type 1 (SCA1) in patients with a large number of CAG repeats. CAG triplet expansion in the SCA1 gene on chromosome 6p was identified in 6 families. In one of them, there was a large Siberian SCA1 kindred with over 200 cases per generation, 15 juvenile patients (age of onset between 15 and 24) had 54 to 72 CAG repeats, the largest seen in this population. Dysphagia, diffuse skeletal muscle atrophy with fasciculations and tongue atrophy were much more prevalent in these younger patients, severely complicating the course of illness and leading to early death from respiratory failure. Three symptomatic individuals had expanded CAG repeats on both chromosomes. The age of onset, rate of disease progression and clinical manifestations of SCA1 in these homozygous carriers of the expanded allele corresponded to the allele with a greater number of repeat units indicating that the larger allele controls the phenotype. (5) Partial phosphofructokinase (PFK) deficiency is associated with a transcription terminating point mutation in the PFK-M gene. A unique myopathy with late-onset muscle weakness, vacuoles, abnormal mitochondria, and absence of the commonly found exon 5/intron 5 junction point mutation in the PFK-M gene was described. A novel mutation at codon 95 of the PFK-M gene changing the predicted arginine to stop, resulted in partial phosphofructokinase deficiency in three patients from an Ashkenazi Jewish family. In addition to the disease-associated codon 95 mutation, a long insertion of 252 nucleotides was found in the PFK-M cDNA, between exons 10 and 11, totally homologous to the sequence of the 10th intron. We concluded that intron retention in this case was dependent on the presence of the upstream transcription-terminating mutation. (6) Genetic mapping of a disease that includes features of autosomal dominant distal spinal muscular atrophy (DSMA) and hereditary motor and sensory neuropathy (HMSN). This unique syndrome has been characterized in a 5- generation Mongolian family with 13 members having profound muscle wasting and weakness of the thenar and first interossei muscles of the hands and progressing to involve lower extremities. Sensory impairment was found in four older patients. A similar disease was previously characterized in two separate families under the names of """"""""DSMA with upper limb predominance"""""""" and """"""""Charcot-Marie-Tooth axonal neuropathy"""""""", and was in both cases mapped to a locus on chromosome 7p14. We found that the Mongolian family under study showing mixed features of DSMA and HMSN is linked to the same locus. This observation suggests that a single gene may be responsible for two distinct syndromes.
