Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.

Miyoshi myopathy (MM) is an adult onset, recessive inherited distal muscular dystrophy that we have mapped to human chromosome 2p13. We recently constructed a 3-Mb P1-derived artificial chromosome (PAC) contig spanning the MM candidate region. This clarified the order of genetic markers across the MM locus, provided five new polymorphic markers within it and narrowed the locus to approximately 2 Mb. Five skeletal muscle expressed sequence tags (ESTs) map in this region. We report that one of these is located in a novel, full-length 6.9-kb muscle cDNA, and we designate the corresponding protein 'dysferlin'. We describe nine mutations in the dysferlin gene in nine families; five are predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce more than one myopathy phenotype (MM, limb girdle dystrophy, distal myopathy with anterior tibial onset).

Giant axonal neuropathy locus refinement to a < 590 kb critical interval.

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder, characterised clinically by the development of chronic distal polyneuropathy during childhood, mental retardation, kinky or curly hair, skeletal abnormalities and, ultrastructurally, by axons in the central and peripheral nervous systems distended by masses of tightly woven neurofilaments. We recently localised the GAN locus in 16q24.1 to a 5-cM interval between the D16S507 and D16S511 markers by homozygosity mapping in three consanguineous Tunisian families. We have now established a contig-based physical map of the region comprising YACs and BACs where we have placed four genes, ten ESTs, three STSs and two additional microsatellite markers, and where we have identified six new SSCP polymorphisms and six new microsatellite markers. Using these markers, we have refined the position of our previous flanking recombinants. We also identified a shared haplotype between two Tunisian families and a small region of homozygosity in a Turkish family with distant consanguinity, both suggesting the occurrence of historic recombinations and supporting the conclusions based on the phase-known recombinations. Taken together, these results allow us to establish a transcription map of the region, and to narrow down the GAN position to a < 590 kb critical interval, an important step toward the identification of the defective gene.

Clinical and genetic study of familial Parkinson's disease in Tunisia.

OBJECTIVE: To determine inheritance patterns and clinical characteristics of familial PD (F-PD) in Tunisia. METHODS: Twenty-one index patients were selected on the basis of typical PD and a family history of PD. The 21 families of the index patients were visited at home, and clinical assessment of all available relatives, a total of 133 individuals, was made. Extensive pedigree data detected 67 additional cases. We ascertained medical history, age, age at onset, first sign at onset, course of the disease, dosage and duration of levodopa (LD) treatment, and associated diseases. One patient from each family was hospitalized to confirm response to LD by evaluation of untreated and treated Unified Parkinson's Disease Rating Scale scores. The sex ratio, transmission pattern, ancestral secondary cases, and segregation ratio (SR) were determined by pedigree analysis. RESULTS: Eighty-eight patients were analyzed (44 men and 44 women; mean age at onset, 39.8 +/- 14.4 years). Pedigree analysis showed 10 single-generation (SG) families (i.e., all affected members belonging to 1 generation) and 11 multigenerational (MG) families (i.e., affected members spanning >1 generation). Parental consanguinity was more frequent in SG families than in MG families. The SR in SG families was 0.23 +/- 0.05, compatible with autosomal recessive (AR) inheritance. Analysis of MG pedigrees showed autosomal dominant (AD) inheritance with reduced penetrance in 9 of 10 families. Age at onset was younger than in sporadic PD. Intrafamilial variability of age at onset, symptom of onset, and clinical course was observed. There was no difference in clinical characteristics between SG and MG families apart from dystonic foot at onset, which was more frequent in SG families. CONCLUSIONS: First, F-PD is clinically similar to sporadic PD apart from younger age at onset. Second, there is intrafamilial and interfamilial variability of all clinical features. Third, F-PD in Tunisia is genetically heterogenous with at least two inheritance patterns: AD and AR.

Linkage to chromosome 13q11-12 of an autosomal recessive cerebellar ataxia in a Tunisian family.

OBJECTIVE: To report the clinical findings and the genetic linkage mapping of an autosomal recessive cerebellar ataxia associated to peripheral neuropathy, showing an early onset cerebellar ataxia with retained tendon reflexes (EOCA) phenotype. BACKGROUND: EOCA is a clinical syndrome delimited by Harding distinguished from Friedreich's ataxia (FA) mainly by the preservation of tendon reflexes. Molecular genetic study of patients with EOCA has demonstrated genetic heterogeneity. A form of autosomal recessive spastic ataxia has been described in Charlevoix Saguenay area in Quebec (ARSACS); the gene responsible has been mapped to chromosome 13q. METHODS: Genetic linkage analysis was performed on 18 members of a large family including 8 of 9 members with EOCA. After exclusion of FA and ataxia with vitamin E deficiency loci as well as loci of autosomal dominant cerebellar ataxias, we performed a linkage analysis to markers of 13q11-12 region. RESULTS: The 9 affected members of this family showed stereotyped clinical features with cerebellar ataxia, pyramidal syndrome, and a variable degree of axonal peripheral neuropathy. Linkage was detected between the disease locus and the microsatellite marker D13S232. Surrounding markers to D13S232 confirmed the linkage and showed the homozygosity of the affected members. CONCLUSION: The family reported here showed the same locus as autosomal recessive spastic ataxia Charlevoix Saguenay disease.

LGMD 2E in Tunisia is caused by a homozygous missense mutation in beta-sarcoglycan exon 3.

Four of the currently recognized autosomal recessive limb-girdle muscular dystrophies (LGMD type 2C-F) are caused by mutations in the genes encoding components of the sarcoglycan complex. LGMD 2C, caused by mutations in gamma-sarcoglycan, is prevalent in northern Africa, especially in Tunisia, where this type of muscular dystrophy was originally described. Although the disease initially was assumed to be genetically homogeneous in this region, linkage to the alpha-sarcoglycan locus (LGMD 2D) has also been found. We have now identified the first Tunisian family with beta-sarcoglycanopathy (LGMD 2E), further adding to the genetic heterogeneity of autosomal recessive LGMD in this population. Direct sequencing of the beta-sarcoglycan gene revealed a homozygous mutation (G272-->T, Arg91Leu) in exon 3. This change affects the same arginine residue in the immediate extracellular domain of the protein that was mutated to a proline (G272-->C, Arg91Pro) in a Brazilian family with a severe form of the disease. Immunohistochemical analysis for the sarcoglycan complex demonstrates absence of the known components of the complex in both of these families. We postulate that the immediate extracellular domain of beta-sarcoglycan may be important for the assembly and/or maintenance of this complex, potentially mediated by disulfide-bond formation to another sarcoglycan via the single cysteine residue in that domain.

[Multiple sclerosis in Tunisia. Clinical study of 100 cases]. / La sclêrose en plaques en Tunisie. Etude clinifue de 100 observations

One hundred cases of patients suffering from disseminated sclerosis (52 female and 48 male) were studied clinically and classified into four groups: typical, probable, possible and of acute onset. The present average age was 35.8 years and the age of onset of the disease 31.2 years. The mode of onset was progressive in 48 cases. The signs at onset were motor (44 p. 100), sensory (47 p. 100), ocular or visual (14 p. 100), vestibular (9 p. 100) and cerebellar (9 p. 100). An electronystagmogram was carried out in 74 cases: 44 were irritative in type, 22 deficitary and 8 normal. Electrophoresis of the cerebrospinal fluid revealed an increase in gamma globulins in 47 out of the 62 cases examined. Study of the geographic distribution of the place of birth and residence of the patients showed only a predominance in the northern part of Tunisia, probably related to easier communication from these regions with the Neurology Centre in Tunis.

[Multiple sclerosis in Tunisia: cochleo-vestibular study (author's transl)]. / Sclérose en plaques en Tunisie: étude cochléo-vestibulaire.

The authors undertook in Tunisia a cochleo-vestibular study of multiple sclerosis. 94 cases were included, with the following results:--67 patients had spontaneous nystagmus in the dark.--With provocation studies: - 52 cases showed signs of an irritative-type central vestibular syndrome, - 25 cases had a deficiency-type central vestibular syndrome. All of the patients underwent audition studies but the results showed that only 5 patients had a bilateral and symetrical retro-labyrinthine type perception deafness.

Identification of a new locus for autosomal recessive Charcot-Marie-Tooth disease with focally folded myelin on chromosome 11p15.

Autosomal recessive Charcot-Marie-Tooth disease type 4B (CMT4B) is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. A locus for CMT4B has previously been mapped to chromosome 11q23 in a southern Italian pedigree. We initially excluded linkage in two Tunisian families with CMT4B to chromosome 11q23, demonstrating genetic heterogeneity within the CMT4B phenotype. Subsequently, using homozygosity mapping and linkage analysis in the largest Tunisian pedigree, we mapped a new locus to chromosome 11p15. A maximum two-point lod score of 6.05 was obtained with the marker D11S1329. Recombination events refined the CMT4B locus region to a 5.6-cM interval between markers D11S1331 and D11S4194. The second Tunisian CMT4B family was excluded from linkage to the new locus, demonstrating the existence of at least a third locus for the CMT4B phenotype.

Refined mapping and characterization of the recessive familial amyotrophic lateral sclerosis locus (ALS2) on chromosome 2q33.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative neuromuscular disease that shows familial, autosomal dominant inheritance in 10%-15% of cases. Previous genetic analysis of one large family linked a recessive form of familial ALS (FALS-AR type 3) to the chromosome 2q33-35 region. Using additional polymorphic markers, we have narrowed the size of the linked region to approximately 1.7 cM by linkage and haplotype analysis. We have also established a yeast artificial chromosome contig across the locus that covers an approximate physical distance of 3 million bases. Based on this contig, genes and expressed sequences that map near the 2q33 region have been examined to determine whether they are located within this ALS2 candidate locus. Five identified genes and 34 expressed sequence tags map within the region defined by crossover analysis and merit further consideration as candidate genes for this disease.