Charcot-Marie-Tooth (CMT) is a heterogeneous group of progressive disorders, characterized by chronic motor and sensory polyneuropathy. This hereditary disorder is related to numerous genes and varying inheritance patterns. Thus, many patients do not reach a final genetic diagnosis. We describe a 13-year-old girl presenting with progressive bilateral leg weakness and gait instability. Extensive laboratory studies and spinal magnetic resonance imaging scan were normal. Nerve conduction studies revealed severe lower limb peripheral neuropathy with prominent demyelinative component. Following presumptive diagnosis of chronic inflammatory demyelinating polyneuropathy, the patient received treatment with steroids and intravenous immunoglobulins courses for several months, with no apparent improvement. Whole-exome sequencing revealed a novel heterozygous c.2209C>T (p.Arg737Trp) mutation in the MARS gene (OMIM 156560). This gene has recently been related to CMT type 2U. In-silico prediction programs classified this mutation as a probable cause for protein malfunction. Allele frequency data reported this variant in 0.003% of representative Caucasian population. Family segregation analysis study revealed that the patient had inherited the variant from her 60-years old mother, reported as healthy. Neurologic examination of the mother demonstrated decreased tendon reflexes, while nerve conduction studies were consistent with demyelinative and axonal sensory-motor polyneuropathy. Our report highlights the importance of next-generation sequencing approach to facilitate the proper molecular diagnosis of highly heterogeneous neurologic disorders. Amongst other numerous benefits, this approach might prevent unnecessary diagnostic testing and potentially harmful medical treatment.
The aims of this study were to (1) characterize the clinical phenotype, (2) define the causative mutation, and (3) correlate the clinical phenotype with genotype in a large consanguineous Arab family with myotonia congenita. Twenty-four family members from three generations were interviewed and examined. Genomic DNA was extracted from peripheral blood samples for sequencing the exons of the CLCN1 gene. Twelve individuals with myotonia congenita transmitted the condition in an autosomal dominant manner with incomplete penetrance. A novel missense mutation [568GG>TC (G190S)] was found in a dose-dependent clinical phenotype. Although heterozygous individuals were asymptomatic or mildly affected, the homozygous individuals were severely affected. The mutation is a glycine-to-serine residue substitution in a well-conserved motif in helix D of the CLC-1 chloride channel in the skeletal muscle plasmalemma. A novel mutation, 568GG>TC (G190S) in the CLCN1 gene, is responsible for autosomal dominant myotonia congenita with a variable phenotypic spectrum.
BRCA mutation carriers were reported to display a skewed distribution of FMR1 genotypes, predominantly within the low normal range (CGG repeat number o26). This observation led to the interpretation that BRCA1/2 mutations are embryo-lethal, unless rescued by 'low FMR1 alleles'. We undertook to re-explore the distribution of FMR1 alleles subdivided into low, normal and high (o26, 26-34, and 434 CGG repeats, respectively) subgenotypes, on a cohort of 125 Ashkenazi women, carriers of a BRCA1/2 founder mutation. Ashkenazi healthy females (n ¼ 368), tested in the frame of the Israeli screening population program, served as controls. BRCA1/2 carriers and controls demonstrated a comparable and non-skewed FMR1 subgenotype distribution. Taken together, using a homogeneous ethnic group of Ashkenazi BRCA1/2 mutation carriers, we could not confirm the reported association between FMR1 low genotypes and BRCA1/2 mutations. The notion that BRCA1/2 mutations are embryo-lethal unless rescued by the low FMR1 subgenotypes is hereby refuted. European Journal of Human Genetics ( Expansion of the CGG segment to the so-called pre-mutation range (approximately g.5061CGG (55_200)) is associated with neuropsychiatric risks and primary ovarian insufficiency. 1 The full mutation range g.5061CGG(4200) instigates gene inactivation and loss of FMR1 protein, thereby causing fragile X syndrome, an X-linked condition, the leading cause of inherited intellectual disability in humans. 2,3 Gleicher et al 4-6 have constructed a 'private' classification of subgenotypes within the normal FMR1 range (up to 55 repeats). As such, they labeled alleles of 26-34 CGG repeats g.5061CGG(26_34) as 'normal' , alleles of less than 26 repeats as 'low range' g.5061CGG(5_25) and those of more than 34 repeats as 'high range' g.5061CGG(35_55). Repeats within the median range g.5061CGG(29_30) correspond allegedly with the switching point between positive and negative message and peak translation of the gene product of FMR1. [4][5][6][7] Individuals were then defined as 'normal' if both alleles were in the 'normal' range, as 'heterozygous' if one allele was outside the 'normal' range and as homozygous if both alleles were outside of the range. These genotypes were further subdivided based on whether FMR1 alleles were above (high) or below (low) the normal range. [4][5][6][7]
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