Diversity of ARSACS mutations in French-Canadians.

BACKGROUND: The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability. METHODS: Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin. RESULTS: A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin. CONCLUSIONS: The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.

A founder mutation causing a severe methylenetetrahydrofolate reductase (MTHFR) deficiency in Bukharian Jews.

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. A novel homozygous MTHFR c.474A>T (p.G158G) mutation was detected in two unrelated children of Jewish Bukharian origin. This mutation generates an abnormal splicing and early termination codon. A carrier frequency of 1:39 (5/196) was determined among unrelated healthy Bukharian Jews. Given the disease severity and allele frequency, a population screening for individuals of this ancestry is warranted in order to allow prenatal, or preimplantation diagnosis.

Discordance in informed consent response on the basis of demographic factors: brief report.

During an outcomes study of spasticity treatment at a developmental center for 62 residents with profound intellectual disabilities, either botulinum toxin A (BTX-A), intrathecal baclofen (ITB), or both were recommended with physical and occupational therapy. Conservators consented to BTX-A more than ITB (p = .021). Court-appointed conservators were more likely to provide consent for treatment than family members (p = .026). Nonparents consented more than parents (p = .009). Finally, Caucasian conservators were more likely to consent to treatment than African American conservators (p = .036), but ethnicity of the resident did not influence consent. Gender of resident or conservator did not influence rate of consent. This report highlights disparities in surrogate consent giving for individuals with intellectual disabilities and indicates a need for more research to ensure that this vulnerable population has access to appropriate treatments.

A novel SACS gene mutation in a Tunisian family.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a distinct form of hereditary early-onset spastic ataxia. In 2000, the causative gene, SACS, encoding the protein sacsin, was identified in Quebec patients. The open reading frame (ORF) of SACS was initially reported to contain 11,487 bp and to be encoded by a single gigantic exon. Recently, eight additional exons upstream of the original ORF were found (ENST00000382298). We report four Tunisian ARSACS patients homozygous for a novel mutation in SACS exon 9 gene, c.12846_12850delAGAG. This mutation is localized upstream from the DnaJ domain leading to the loss of this domain, suggesting that the disease is associated with loss of critical chaperone function of sacsin.

Hyperreflexia and spastic paralysis among New Caledonian leprosy patients

A survey on New Caledonia confirmed the occurrence of a previously reported syndrome of spastic paralysis among leprosy patients. Of 18 patients recorded as having frank spastic paraplegia, seven were examined neurologically, as well as 51 other patients with leprosy but not spastic paralysis, and 23 patients with tuberculosis. Significant hyperreflexia was fairly common among both Melanesian and European leprosy patients, but was totally absent among tuberculosis patients. This syndrome was clinically unrelated to foci of neurologic disease previously reported in the Pacific Basin on Guam, the Kii Peninsula of Japan, and New Guinea. It is probably more closely related to diseases reported in other parts of the world that are generally regarded as nutritional or toxic in origin. The syndrome is possibly related to sulfone treatment of leprosy, although this has not been reported in other areas of the world where sulfones are used in the treatment of leprosy.(AU)