Linkage of a commoner form of recessive amyotrophic lateral sclerosis to chromosome 15q15-q22 markers

Autosomal recessive familial amyotrophic lateral sclerosis (RFALS) is a rare form of ALS that usually presents at an early age with slow progression of symptoms. RFALS is clinically and genetically heterogeneous and the locus of RFALS type 3 was mapped to 2q33 (ALS2) in a single family. We now report linkage of a more-common form of RFALS to chromosome 15q15-q22 markers (ALS5) and show further genetic locus heterogeneity in RFALS. ALS5 is the locus for most families with RFALS and appears to be present in both North African and European populations

Dihydropteridine reductase deficiency in a large consanguineous tunisian family: Clinical, biochemical, and neuropathologic findings

We report the case of a large consanguineous Tunisian family of seven siblings suffering from dihydropteridine reductase deficiency with either typical clinical, biochemical, or autopsy findings. Two cousins also were reported to have the same symptoms. This metabolic disorder is characterized by severe microcephaly, psychomotor regression, and progressive basal ganglia calcifications. Dihydropteridine reductase assay on samples collected from the two brothers still alive did not show measurable activity. The sister and four brothers died between the ages of 3 years and 7 years. A neuropathology study done on the sister showed diffuse demyelination throughout the white matter and spongy vacuolation in the subthalamic nuclei, the superior cerebellar peduncles and the tegmentum tracts of the brain stem. The anterointernal part of the putamen was completely necrotic with nearly total nerve cell loss. Abnormal vascular proliferation and calcification of the walls of small, medium, and large arteries and veins, as well as diffusely scattered pericapillary and isolated calcospherites, were seen in this necrotic region. We think that folate deficiency may be involved in the pathogenesis of the basal ganglia calcification

Study of large inbred Friedreich ataxia families reveals a recombination between D9S15 and the disease locus

Friedreich ataxia is a neurodegenerative disorder with autosomal recessive inheritance. Precise linkage mapping of the Friedreich ataxia locus (FRDA) in 9q13-q21 should lead to the isolation of the defective gene by positional cloning. The two closest DNA markers, D9S5 and D9S15, show very tight linkage to FRDA, making difficult the ordering of the three loci. We present a linkage study of three large Friedreich ataxia families of Tunisian origin, with several multiallelic markers around D9S5 and D9S15. Haplotype data were used to investigate genetic homogeneity of the disease in these geographically related families. A meiotic recombination was found in a nonaffected individual, which excludes a 150-kb segment, including D9S15, as a possible location for the Friedreich ataxia gene and which should orient the search in the D9S5 region

Correction: A Mutation Causes MuSK Reduced Sensitivity to Agrin and Congenital Myasthenia.

Congenital myasthenic syndromes (CMSs) are a heterogeneous group of genetic disorders affecting neuromuscular transmission. The agrin/muscle-specific kinase (MuSK) pathway is critical for proper development and maintenance of the neuromuscular junction (NMJ). We report here an Iranian patient in whom CMS was diagnosed since he presented with congenital and fluctuating bilateral symmetric ptosis, upward gaze palsy and slowly progressive muscle weakness leading to loss of ambulation. Genetic analysis of the patient revealed a homozygous missense mutation c.2503A>G in the coding sequence of MUSK leading to the p.Met835Val substitution. The mutation was inherited from the two parents who were heterozygous according to the notion of consanguinity. Immunocytochemical and electron microscopy studies of biopsied deltoid muscle showed dramatic changes in pre- and post-synaptic elements of the NMJs. These changes induced a process of denervation/reinnervation in native NMJs and the formation, by an adaptive mechanism, of newly formed and ectopic NMJs. Aberrant axonal outgrowth, decreased nerve terminal ramification and nodal axonal sprouting were also noted. In vivo electroporation of the mutated MuSK in a mouse model showed disorganized NMJs and aberrant axonal growth reproducing a phenotype similar to that observed in the patient’s biopsy specimen. In vitro experiments showed that the mutation alters agrin-dependent acetylcholine receptor aggregation, causes a constitutive activation of MuSK and a decrease in its agrin- and Dok-7-dependent phosphorylation