RESUMEN
BACKGROUND: Hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM 201300) is a rare recessive neuropathy typically diagnosed in the first decade. The 1973 study of a French Canadian family led to the definition of HSAN2. OBJECTIVES: To demonstrate that the apparent higher prevalence of HSAN2 in Quebec is due to the presence of two HSN2 mutations and that carriers of different mutations appear to have a similar phenotype. METHODS: Through attending physicians, the authors recruited French Canadian patients with HSAN2. Exclusion of linkage to the known HSAN loci and linkage to the HSAN2 was performed using standard methods. Sequencing of the HSN2 gene was used to uncover the causal mutations. RESULTS: A large cluster of HSAN2 patients comprising 16 affected individuals belonging to 13 families was identified. The mode of inheritance is clearly autosomal recessive. All patients originated from southern Quebec, and 75% are from the Lanaudière region. Whereas linkage to the HSAN1, 3, and 4 loci was excluded, linkage to the 12p13.33 HSAN2 locus was confirmed. Sequencing of the HSN2 gene uncovered two French Canadian mutations and a novel nonsense mutation in a patient of Lebanese origin, all predicted to lead to truncations of the HSN2 protein. The comparison of clinical variables between patients with different genotypes does not suggest any difference in phenotype. CONCLUSIONS: Two founder mutations are responsible for the apparently higher prevalence of HSAN2 in French Canadians. Genotype-phenotype correlation does not suggest any significant clinical variability.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Neuropatías Hereditarias Sensoriales y Autónomas/epidemiología , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Adulto , Anciano , Secuencia de Bases/genética , Niño , Preescolar , Mapeo Cromosómico , Cromosomas Humanos Par 12/genética , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas , Genotipo , Humanos , Lactante , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Antígenos de Histocompatibilidad Menor , Linaje , Nervios Periféricos/patología , Nervios Periféricos/fisiopatología , Fenotipo , Prevalencia , Proteínas Serina-Treonina Quinasas , Quebec/epidemiología , Proteína Quinasa Deficiente en Lisina WNK 1RESUMEN
A previously healthy girl died suddenly and unexpectedly at three months of age in her sleep and an autopsy failed to reveal an adequate cause of death. As the father was known to have myophosphorylase (PPL) deficiency (McArdle's disease), we performed molecular genetic analysis of the PPL gene in autopsy muscle of the proposita. The girl was homozygous for the nonsense mutation at codon 49 most commonly associated with typical McArdle's disease. This report suggests that among children presenting as Sudden Infant Death Syndrome (SIDS) there may be cases associated with myophosphorylase deficiency.
Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo V/genética , Muerte Súbita del Lactante/genética , Adulto , Femenino , Humanos , Lactante , MasculinoRESUMEN
We describe two unrelated Spanish families with isolated sensorineural hearing loss. In both pedigrees, the deafness was transmitted maternally, which suggested a mitochondrial, DNA (mtDNA) defect. Within the same pedigree, some relatives showed aminoglycoside-induced deafness, whereas others were not exposed to aminoglycosides before the onset of hearing loss. Molecular genetic analysis in both families showed the A-to-G transition at nt 1555 (A1555G) in the mitochondrial 12S rRNA gene. In one pedigree, the mutation was homoplasmic; in the other, it was heteroplasmic. To assess the frequency of this mutation, we screened 42 patients of various ethnic backgrounds with isolated sensorineural hearing loss; none harbored the A1555G mutation. This is the first report of heteroplasmy in a family with isolated sensorineural deafness associated with the A1555G mutation.