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1.
Clin Genet ; 74(6): 502-12, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18700894

RESUMEN

Congenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-alpha2. We describe the molecular study of 26 patients with clinical presentation, magnetic resonance imaging and/or laminin-alpha2 expression in muscle, compatible with MDC1A. The combination of full genomic sequencing and complementary DNA analysis led to the particularly high mutation detection rate of 96% (50/52 disease alleles). Besides 22 undocumented polymorphisms, 18 different mutations were identified in the course of this work, 14 of which were novel. In particular, we describe the first fully characterized gross deletion in the LAMA2 gene, encompassing exon 56 (c.7750-1713_7899-2153del), detected in 31% of the patients. The only two missense mutations detected were found in heterozygosity with nonsense or truncating mutations in the two patients with the milder clinical presentation and a partial reduction in muscle laminin-alpha2. Our results corroborate the previous few genotype/phenotype correlations in MDC1A and illustrate the importance of screening for gross rearrangements in the LAMA2 gene, which may be underestimated in the literature.


Asunto(s)
Laminina/genética , Distrofias Musculares/congénito , Distrofias Musculares/genética , Polimorfismo Genético , Adolescente , Adulto , Niño , Preescolar , Femenino , Eliminación de Gen , Humanos , Lactante , Masculino , Mutación , Adulto Joven
2.
Hum Mutat ; 26(4): 395-6, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16134148

RESUMEN

We studied 21 patients, from 18 families, with L-2-hydroxyglutaric aciduria (L-2-HGA), a rare neurometabolic disorder with a homogeneous presentation: progressive neurodegeneration with extrapyramidal and cerebellar signs, seizures, and subcortical leukoencephalopathy. Increased levels of L-2-hydroxyglutaric acid in body fluids proved the diagnosis of L-2-HGA in all 21 patients. We analyzed the L-2-HGA gene (L2HGDH), recently found to be mutated in consanguineous families with L-2-HGA, and identified seven novel mutations in 15 families. Three mutations appeared to be particularly prevalent in this Portuguese panel: a frameshift mutation (c.529delC) was detected in 12 out of 30 mutant alleles (40%), a nonsense mutation (c.208C>T; p.Arg70X) in 7/30 alleles (23%), and a missense mutation (c.293A>G; p.His98Arg) in four out of 30 mutant alleles (13%), suggesting that common origin may exist. Furthermore, two novel missense (c.169G>A; p.Gly57Arg, c.1301A>C; p.His434Pro) and two splice error (c.257-2A>G, c.907-2A>G) mutations were found. All the mutations presumably lead to loss-of-function with no relationship between clinical signs, progression of the disease, levels of L-2-HGA and site of the mutation. In the three remaining families, no pathogenic mutations in the L-2-HGA were found, which suggests either alterations in regulatory regions of the gene or of its intervening sequences, compound heterozygosity for large genomic deletion and, or further genetic heterogeneity.


Asunto(s)
Oxidorreductasas de Alcohol/genética , Glutaratos/orina , Mutación , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Niño , Preescolar , Estudios de Cohortes , Consanguinidad , Salud de la Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Portugal , Alineación de Secuencia , Análisis de Secuencia de ADN
3.
Arch Neurol ; 58(2): 201-5, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11176957

RESUMEN

BACKGROUND: The recessive ataxias are a heterogeneous group of neurodegenerative disorders characterized by cerebellar ataxia associated with a number of different neurologic, ophthalmologic, or general signs. They are often difficult to classify in clinical terms, except for Friedreich ataxia, ataxia-telangiectasia, and a relatively small group of rare conditions for which the molecular basis has already been defined. OBJECTIVES: To study the clinical presentation and to define diagnostic criteria in a group of Portuguese patients with ataxia and ocular apraxia, an autosomal recessive form without the essential clinical and laboratory features of ataxia-telangiectasia. PATIENTS AND METHODS: We reviewed 22 patients in 11 kindreds, identified through a systematic survey of hereditary ataxias being conducted in Portugal. RESULTS: Age at onset ranged from 1 to 15 years, with a mean of 4.7 years. The duration of symptoms at the time of last examination varied from 5 to 58 years. All patients presented with progressive cerebellar ataxia, the characteristic ocular apraxia, and a peripheral neuropathy. Associated neurologic signs included dystonia, scoliosis, and pes cavus. Magnetic resonance imaging was performed in 16 patients, all of whom showed cerebellar atrophy. CONCLUSIONS: Ataxia with ocular apraxia may be more frequent than postulated before, and may be identified clinically using the following criteria: (1) autosomal recessive transmission; (2) early onset (for most patients in early childhood); (3) combination of cerebellar ataxia, ocular apraxia, and early areflexia, with later appearance of the full picture of peripheral neuropathy; (4) absence of mental retardation, telangiectasia, and immunodeficiency; and (5) the possibility of a long survival, although with severe motor handicap.


Asunto(s)
Apraxias/diagnóstico , Trastornos de la Motilidad Ocular/diagnóstico , Degeneraciones Espinocerebelosas/diagnóstico , Adolescente , Adulto , Edad de Inicio , Apraxias/complicaciones , Apraxias/epidemiología , Atrofia , Cerebelo/patología , Niño , Distonía/complicaciones , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos de la Motilidad Ocular/complicaciones , Trastornos de la Motilidad Ocular/epidemiología , Linaje , Enfermedades del Sistema Nervioso Periférico/complicaciones , Portugal , Estudios Retrospectivos , Degeneraciones Espinocerebelosas/complicaciones , Degeneraciones Espinocerebelosas/epidemiología
4.
Brain Dev ; 19(4): 268-73, 1997 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9187477

RESUMEN

We present clinical, biochemical and cranial magnetic resonance imaging data of six pediatric patients with L-2-hydroxyglutaric aciduria. All the children have the same ethic origin and lived in the northern area of Portugal. Our findings reinforce the described phenotype of this rare metabolic disease with mental deficiency, severe cerebellar dysfunction, mild extrapyramidal and pyramidal symptoms, progressive macrocephaly and seizures. Magnetic resonance imaging revealed subcortical leukoencephalopathy, cerebellar atrophy and signal changes in the putamina and dentate nuclei. These were similar to those of the previous reports in all patients. The urinary excretion of L-2-hydroxyglutaric acid was variably increased in all patients. The other persistent biochemical abnormality was hyperlysinemia. We have found a strong correlation between the severity of the clinical manifestations and the extension of the lesions in the neuroimaging studies. There was no correlation between the clinical findings and the amount of urinary excretion of L-2-hydroxyglutaric acid. We report the second case in the literature of a cerebral thalamic tumor in L-2-hydroxyglutaric aciduria; neuropathological examination of the surgical biopsy demonstrated a diffuse fibrillary astrocytoma.


Asunto(s)
Glutaratos/orina , Discapacidad Intelectual/complicaciones , Errores Innatos del Metabolismo/complicaciones , Aminoacidurias Renales/complicaciones , Adolescente , Ataxia/complicaciones , Ataxia/diagnóstico por imagen , Ataxia/patología , Biopsia , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Niño , Preescolar , Femenino , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/patología , Imagen por Resonancia Magnética , Masculino , Errores Innatos del Metabolismo/patología , Errores Innatos del Metabolismo/orina , Portugal , Aminoacidurias Renales/patología , Aminoacidurias Renales/orina , Tomografía Computarizada por Rayos X
5.
Neuromuscul Disord ; 23(7): 557-61, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23582336

RESUMEN

Fukuyama congenital muscular dystrophy (FCMD) is one of the most common autosomal recessive diseases among the Japanese population, due to a founder mutation of the fukutin gene (FKTN). Mutations in FKTN are now being described in an increasing number of non-Japanese patients. We report a Portuguese child with FCMD. The diagnosis was supported by clinical, histological, magnetic resonance imaging (MRI) and genetic studies. Genetic analysis of FKTN by Multiplex Ligation Probe Amplification (MLPA) revealed a homozygous duplication from exon 4 to exon 7. This in-frame duplication was confirmed by cDNA analysis. To our knowledge this is the first report of a FCMD case caused by an intragenic gross exonic duplication in the FKTN gene. This report widens the clinical and mutational spectrum in FCMD and corroborates the importance of screening for large deletions and duplications in CMD patients.


Asunto(s)
Duplicación de Gen , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Mutación/genética , Síndrome de Walker-Warburg/genética , Exones , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética/métodos , Fenotipo , Síndrome de Walker-Warburg/diagnóstico
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