RESUMEN
Giant axonal neuropathy (GAN) is a rare autosomal recessive disorder that affects both the peripheral nerves and central nervous system. Since the discovery in 2000 of the gigaxonin gene on chromosome 16q24.1 to be causative, more than 40 GAN mutations have been reported from different racial backgrounds. We report the clinicogenetic findings of a 24-year-old Japanese man with GAN. He had consanguineous parents and showed the phenotype of classical severe GAN. We found a novel homozygous nonsense mutation (p.R162X) in the GAN gene. This is the first genetically-determined Japanese case of GAN, with a follow-up period of more than 15 years. In addition, this mutation is novel. We also reviewed previous reports of GAN to see whether there is any genotype-phenotype correlation.
Asunto(s)
Proteínas del Citoesqueleto/genética , Neuropatía Axonal Gigante/genética , Neuropatía Axonal Gigante/patología , Mutación/genética , Preescolar , Análisis Mutacional de ADN , Salud de la Familia , Humanos , Japón , Imagen por Resonancia Magnética , Masculino , Tomografía Computarizada por Rayos XRESUMEN
We report here an autopsy case of sporadic adult-onset Hallervorden-Spatz syndrome, also known as neurodegeneration with brain iron accumulation type 1 (NBIA1), without hereditary burden. A 49-year-old woman died after a 27-year disease course. At the age of 22, she suffered from akinesia, resting tremor, and rigidity. At the age of 28, she was admitted to our hospital because of worsening parkinsonism and dementia. Within several years, she developed akinetic mutism. At the age of 49, she died of bleeding from a tracheostomy. Autopsy revealed a severely atrophic brain weighing 460 g. Histologically, there were iron deposits in the globus pallidus and substantia nigra pars reticulata, and numerous axonal spheroids in the subthalamic nuclei. Neurofibrillary tangles were abundant in the hippocampus, cerebral neocortex, basal ganglia, and brain stem. Neuritic plaques and amyloid deposits were absent. Lewy bodies and Lewy neurites, which are immunolabeled by anti-α-synuclein, were absent. We also observed the presence of TDP-43-positive neuronal perinuclear cytoplasmic inclusions, with variable frequency in the dentate gyrus granular cells, frontal and temporal cortices, and basal ganglia. TDP-43-positive glial cytoplasmic inclusions were also found with variable frequency in the frontal and temporal lobes and basal ganglia. The present case was diagnosed with adult-onset NBIA-1 with typical histological findings in the basal ganglia and brainstem. However, in this case, tau and TDP-43 pathology was exceedingly more abundant than α-synuclein pathology. This case contributes to the increasing evidence for the heterogeneity of NBIA-1.
Asunto(s)
Encéfalo/patología , Proteínas de Unión al ADN/metabolismo , Hierro/metabolismo , Neurodegeneración Asociada a Pantotenato Quinasa/metabolismo , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Proteínas tau/metabolismo , Atrofia , Encéfalo/metabolismo , Resultado Fatal , Femenino , Humanos , Persona de Mediana Edad , Enfermedades Neurodegenerativas/clasificación , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neurodegeneración Asociada a Pantotenato Quinasa/patología , Fosfotransferasas (Aceptor de Grupo Alcohol)/biosíntesis , Proteínas tau/biosíntesisRESUMEN
We report the mutation analysis of a Japanese patient diagnosed with infantile-type Alexander disease. The genetic analysis revealed a new missense mutation, an A to G transition at nucleotide position 1026 in exon 6, leading to the substitution of glycine for glutamic acid at amino acid position 371(E371G). This mutation was not detected in 50 Japanese controls using denaturing high-performance liquid chromatography.
Asunto(s)
Enfermedad de Alexander/genética , Proteína Ácida Fibrilar de la Glía/genética , Mutación , Enfermedad de Alexander/patología , Encéfalo/patología , Niño , Cromatografía Líquida de Alta Presión/métodos , Análisis Mutacional de ADN/métodos , Femenino , Ácido Glutámico/genética , Glicina/genética , Humanos , Japón , Imagen por Resonancia Magnética/métodosRESUMEN
Hypokalemic metabolic tubulopathy, such as in Bartter syndrome and Gitelman syndrome, is caused by the dysfunction of renal electrolyte transporters. Despite advances in molecular genetics with regard to hypokalemic metabolic tubulopathy, recent reports have suggested that the phenotype-genotype correlation is still confusing, especially in classic Bartter and Gitelman syndromes. We report here two Japanese patients who suffered from clinically diagnosed classic Bartter syndrome but who presented hypocalciuria. Hypocalciuria is generally believed to be a pathognomonic finding of NCCT malfunction. To better understand the genotype-phenotype correlation in these two cases, we screened four renal electrolyte transporter genes [Na-K-2Cl cotransporter (NKCC2), renal outer medullary K channel (ROMK), Cl channel Kb (ClC-Kb), and Na-Cl cotransporter (NCCT)] by the PCR direct sequencing method. We identified three ClC-Kb allelic variants, including two new mutations (L27R and W610X in patient 1 and a G to C substitution of a 3' splice site of intron 2 and W610X in patient 2). We did not find any mutations in the other three genes. Our present data suggest that some ClC-Kb mutations may affect calcium handling in renal tubular cells.
Asunto(s)
Proteínas de Transporte de Anión/genética , Síndrome de Bartter/genética , Calcio/orina , Canales de Cloruro/genética , Proteínas de la Membrana/genética , Mutación , Adolescente , Síndrome de Bartter/orina , Niño , Humanos , MasculinoRESUMEN
A T-to-G transition at nucleotide 9176 (T9176G) in the mitochondrial adenosine triphosphate 6 gene (MTATP6) was detected in two siblings with Leigh syndrome. Heteroplasmy was observed in the mother's leukocytes. The T9176G mutation changes a highly conserved leucine residue to an arginine in subunit 6 of ATPase and is maternally inherited like mutations in the other mitochondrial genes. Another mutation in the same codon (T9176C) has been previously reported in Leigh syndrome. This gives strong support to the relevance of MTATP6 dysfunction in Leigh syndrome and the importance of leucine at that position.