RESUMO
We previously localized and fine-mapped Charcot Marie Tooth 4A (CMT4A), the autosomal recessive, demyelinating peripheral neuropathy, to chromosome 8. Through additional positional cloning, we have identified a good candidate gene, encoding ganglioside-induced differentiation-associated protein-1 (GDAP1). We found three different mutations in four different Tunisian families-two nonsense and one missense mutation. How mutations in GDAP1 lead to CMT4A remains to be understood.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 8/genética , Proteínas do Tecido Nervoso/genética , Substituição de Aminoácidos , Cauda Equina/metabolismo , Doença de Charcot-Marie-Tooth/classificação , Doença de Charcot-Marie-Tooth/epidemiologia , Códon sem Sentido , Análise Mutacional de DNA , Genes Recessivos , Haplótipos/genética , Humanos , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/fisiologia , Tunísia/epidemiologiaRESUMO
OBJECTIVES: To report clinical, pathological and genetic findings in a Tunisian kindred with autosomal recessive juvenile parkinsonism (AR-JP) linked to parkin gene. BACKGROUND: AR-JP has been mapped to chromosome 6q and is caused by several mutations of the parkin gene (Park 2). Pathological features in AR-JP are characterized by neuronal loss in substantia nigra (SN) without Lewy bodies (LB). PATIENTS AND METHODS: Three affected siblings with juvenile Parkinson's disease were studied. Pathological examination of the brain was performed in one of them. Linkage studies and mutation analysis of the parkin gene were performed. RESULTS: Clinical picture was characterized by the association of rest tremor, bradykinesia and rigidity. Parkinsonian signs markedly improved with levodopa treatment in the three siblings. Dystonia was observed in one patient and diurnal fluctuations of parkinsonian signs in another one. Linkage analysis showed homozygous haplotypes in patients as compared to unaffected individuals and mutation analysis of the parkin gene revealed a homozygous two-base AG deletion in exon 2 (101-102). Pathological examination of the brain in one patient showed marked loss of pigmented neurons with extraneuronal free melanin in the lateral and medial parts of the SN associated to a slight spongiosis and astrocytic gliosis. In the locus coeruleus, there was also loss of pigmented neurons without gliosis. No LB or neurofibrillary tangles were found neither by traditional nor by histo-immunological stainings. CONCLUSION: This Tunisian kindred with AR-JP linked to a micro-deletion of the parkin gene shows clinical similarities with the previously reported Japanese and European families. Pathological features of this kindred are compared to what has been reported in AR-JP families linked to large exonic deletions of this gene.