RESUMEN
Allogeneic hematopoietic SCT (HSCT) has been proposed as a treatment for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). HSCT has been performed in nine patients using different protocols with varying success. Based on this preliminary experience, participants of the first consensus conference propose a common approach to allogeneic HSCT in MNGIE. Standardization of the transplant protocol and the clinical and biochemical assessments will allow evaluation of the safety and efficacy of HSCT as well as optimization of therapy for patients with MNGIE.
Asunto(s)
Trasplante de Células Madre/normas , Humanos , Seudoobstrucción Intestinal/genética , Seudoobstrucción Intestinal/cirugía , Encefalomiopatías Mitocondriales/genética , Encefalomiopatías Mitocondriales/cirugía , Distrofia Muscular Oculofaríngea , Oftalmoplejía/congénitoRESUMEN
Mutations in the gene encoding muscle-specific calpain 3 protease cause limb girdle muscular dystrophy type 2A. Calpainopathy is characterised by progressive symmetrical atrophy of pelvic, scapular and trunk muscles with an elevated creatine kinase. Most patients develop symptoms in childhood and lose the ability to walk by the age of 40 years. We describe a man who presented with foot drop at the age of 41 years, together with neurophysiological, histopathological and genetic data. This is the first report of calpainopathy presenting as foot drop, and widens the phenotype associated with this disease.
Asunto(s)
Calpaína/genética , Enfermedades Neuromusculares/genética , Adulto , Western Blotting , Creatina Quinasa/metabolismo , ADN/genética , Electromiografía , Exones/genética , Pie/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Proteínas Musculares/genética , Debilidad Muscular/etiología , Debilidad Muscular/genética , Debilidad Muscular/patología , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Conducción Nerviosa/fisiología , Enfermedades Neuromusculares/patología , Enfermedades Neuromusculares/fisiopatología , Columna Vertebral/patologíaAsunto(s)
Predisposición Genética a la Enfermedad/genética , Proteínas de Choque Térmico/genética , Patrón de Herencia/genética , Espasticidad Muscular/genética , Degeneraciones Espinocerebelosas/genética , Adulto , Atrofia/genética , Atrofia/patología , Tronco Encefálico/patología , Tronco Encefálico/fisiopatología , Cerebelo/metabolismo , Cerebelo/patología , Cerebelo/fisiopatología , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Genes Dominantes/genética , Genes Recesivos/genética , Pruebas Genéticas , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple/genética , Espasticidad Muscular/fisiopatología , Mutación/genética , Fibras Nerviosas Mielínicas/patología , Linaje , Fenotipo , Degeneraciones Espinocerebelosas/fisiopatología , Adulto JovenRESUMEN
BACKGROUND: Episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are autosomal dominant disorders characterised by paroxysmal ataxia and migraine, respectively. Point mutations in CACNA1A, which encodes the neuronal P/Q-type calcium channel, have been detected in many cases of EA2 and FHM1. The genetic basis of typical cases without CACNA1A point mutations is not fully known. Standard DNA sequencing methods may miss large scale genetic rearrangements such as deletions and duplications. The authors investigated whether large scale genetic rearrangements in CACNA1A can cause EA2 and FHM1. METHODS: The authors used multiplex ligation dependent probe amplification (MLPA) to screen for intragenic CACNA1A rearrangements. RESULTS: The authors identified five previously unreported large scale deletions in CACNA1A in seven families with episodic ataxia and in one case with hemiplegic migraine. One of the deletions (exon 6 of CACNA1A) segregated with episodic ataxia in a four generation family with eight affected individuals previously mapped to 19p13. In addition, the authors identified the first pathogenic duplication in CACNA1A in an index case with isolated episodic diplopia without ataxia and in a first degree relative with episodic ataxia. CONCLUSIONS: Large scale deletions and duplications can cause CACNA1A associated channelopathies. Direct DNA sequencing alone is not sufficient as a diagnostic screening test.
Asunto(s)
Ataxia/genética , Canales de Calcio/genética , Reordenamiento Génico , Migraña con Aura/genética , Adolescente , Adulto , Ataxia/diagnóstico , Ataxia/fisiopatología , Niño , Preescolar , Familia , Femenino , Ligamiento Genético , Humanos , Masculino , Migraña con Aura/diagnóstico , Migraña con Aura/fisiopatología , Linaje , Reacción en Cadena de la PolimerasaRESUMEN
PURPOSE: Mutations in the 1A-subunit of the brain P/Q-type calcium channel gene CACNA1A are responsible for spinocerebellar ataxia type 6 (SCA6), familial haemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). Considerable clinical and genetic overlap exists between these 3 allelic disorders. Clinical findings are varied and may include nystagmus. OBJECTIVE: To study the clinical phenotype and identify a causative mutation in a family who presented when the youngest member was diagnosed with apparent isolated congenital nystagmus (age 3 months). PATIENTS AND METHODS: 8 patients from one family underwent detailed clinical phenotyping comprising; ophthalmic and neurological examination, nystagmology, electrodiagnostic tests and brain imaging. The CACNA1A gene was screened for mutations by direct sequencing in one patient. Co-segregation of the disease and an identified sequence variation was shown using direct sequencing. RESULTS: Phenotyping revealed isolated atypical nystagmus in 4 family members and nystagmus in addition to late onset ataxia in 1 family member. Direct sequencing of the CACNA1A gene identified a novel missense mutation; (c.4110T>G p.Phe1370Leu (NM_000068.3)). CONCLUSIONS: We have shown that a mutation in the intracellular domain between s4 and s5 of repeat 3 can cause atypical nystagmus/cerebellar phenotypes, including isolated nystagmus in an infant. We also illustrate the necessity for detailed examination of relatives in cases of apparent isolated congenital nystagmus.
Asunto(s)
Ataxia/genética , Canales de Calcio/genética , Predisposición Genética a la Enfermedad/genética , Mutación/genética , Nistagmo Congénito/genética , Adulto , Edad de Inicio , Cerebelo/patología , Niño , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Nistagmo Congénito/patología , Fenotipo , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late onset neuromuscular disease characterised by proximal muscle weakness, ptosis, and swallowing difficulty. The only causative mutation described to date is a triplet repeat expansion consisting of two to seven additional base triplets in a repeat sequence in exon 1 of the polyadenine binding protein nuclear 1 (PABPN1) gene. This results in an increase in length of a polyalanine tract in the PABPN1 protein from 10 to 12-17 residues. OBJECTIVE: Description of another mutation in a case of OPMD. METHODS: Sequence analysis of exon 1 of the PABPN1 gene was undertaken on 202 patients referred for a possible diagnosis of OPMD but negative for the triplet repeat expansion mutation. RESULTS: A case was identified with typical symptoms of OPMD, negative for the repeat expansion mutation but with a missense mutation in PABPN1 close to the 3' end of the normal polyalanine codon repeat sequence. CONCLUSIONS: The single base mutation changes a glycine codon to an alanine codon and results in an increase in the number of contiguous polyalanine codons. This mimics the effect of the common triplet repeat expansion mutation and represents a previously undescribed mechanism of mutation.
Asunto(s)
Distrofia Muscular Oculofaríngea/genética , Mutación Puntual , Proteína II de Unión a Poli(A)/genética , Anciano , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Humanos , Datos de Secuencia Molecular , Distrofia Muscular Oculofaríngea/diagnóstico , Linaje , Proteína II de Unión a Poli(A)/química , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
Allgrove's or "4 A" syndrome is a rare autosomal recessive condition with alacrima, achalasia, autonomic disturbance, and ACTH insensitivity among other features. Recent studies have identified mutations in the AAAS, a candidate gene on chromosome 12q13 in such patients. Manifestations in adult patients are rarely reported. The syndrome usually presents during the first decade of life with dysphagia or severe (occasionally fatal) hypoglycaemic or hypotensive attacks, related to adrenocortical insufficiency. Onset of adrenal insufficiency or other features may be delayed to adulthood. In contrast with paediatric patients, adult patients with Allgrove's syndrome may present with multisystem neurological disease; the childhood history of achalasia or alacrima may be overlooked. The authors describe two families with two affected siblings and a further unrelated patient with typical clinical features of Allgrove's syndrome, who exhibit signs of multisystem neurological disease including hyperreflexia, muscle wasting, dysarthria, ataxia, optic atrophy, and intellectual impairment. None of the cases have developed adrenal insufficiency but all have progressive neurological disability. Autonomic dysfunction was a significant cause of morbidity in two cases. The three index cases represent the longest described follow up of Allgrove's syndrome into adulthood. It is speculated that they represent a subgroup of patients who follow an often undiagnosed chronic neurological course. Recognition of the syndrome presenting in adult life permits treatment of unrecognised autonomic dysfunction, adrenal insufficiency and dysphagia, and appropriate genetic advice.
Asunto(s)
Enfermedades de la Corteza Suprarrenal/diagnóstico , Enfermedades de la Corteza Suprarrenal/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/diagnóstico , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Acalasia del Esófago/diagnóstico , Acalasia del Esófago/fisiopatología , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/fisiopatología , Enfermedades del Aparato Lagrimal/diagnóstico , Enfermedades del Aparato Lagrimal/fisiopatología , Enfermedades de la Corteza Suprarrenal/genética , Adulto , Enfermedades del Sistema Nervioso Autónomo/genética , Acalasia del Esófago/genética , Femenino , Enfermedades Genéticas Congénitas/genética , Humanos , Enfermedades del Aparato Lagrimal/genética , Masculino , Persona de Mediana Edad , SíndromeRESUMEN
Somatic mutation in the mitochondrial genome occurs much more rapidly than in the nuclear genome and is a feature, possibly contributory, of the aging of cells and tissues. Identifying mitochondrial sequence changes in blood DNA of elderly subjects may provide a maker for the epigenetic changes of mitochondrial DNA known to occur in tissues with lower cellular turnover, and would also have implications for immunosenescence. No large-scale epidemiological studies have been reported previously. In this study we have established long-PCR banks of the mitochondrial genome from peripheral lymphocytes for an elderly cohort of 716 individuals with a range of measured aging phenotypes, and we have established assays for three widely reported mutations: the 4977 bp and 8048 bp deletions and point mutation A3243G. No individuals were identified with detectable heteroplasmy for these changes. Implications for tissue and population prevalence are discussed. The mitochondrial long-PCR DNA banks established will be useful for a wide range of studies of somatic mutation and of germline haplotypes in relation to aging.
Asunto(s)
Envejecimiento/genética , ADN Mitocondrial/genética , Linfocitos , Mutación , Anciano , Estudios de Cohortes , Análisis Mutacional de ADN , Bases de Datos de Ácidos Nucleicos , Inglaterra , Femenino , Humanos , Masculino , FenotipoAsunto(s)
Dermatomiositis/complicaciones , Debilidad Muscular/etiología , Músculos Palatinos , Anciano , Femenino , HumanosRESUMEN
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disorder of late onset that commonly presents with ptosis and dysphagia. The genetic basis of the condition has been identified recently as a stable trinucleotide repeat expansion in exon 1 of the poly(A) binding protein 2 gene (PABP2), in which (GCG)(6) is the normal repeat length. The prevalence of OPMD is greatest in patients of French-Canadian origin. It is not clear if expansion repeat length is a reliable test in other populations. In this study, we analysed the phenotypic and genotypic characteristics of 31 patients with OPMD in the UK. Ptosis was the first reported symptom in two-thirds of the patients, and half of the subjects studied had evidence of ophthalmoplegia. All but one family had a pathological expansion in the PABP2 gene, ranging from (GCG)(8) to (GCG)(13). In contrast to the French-Canadian population, (GCG)(10) was almost as common as (GCG)(9), evidence against a strong founder effect in the UK population. There was a weak association between repeat length and age of disease onset. Patients with longer repeat lengths, such as (GCG)(13), developed severe limb weakness early in the disease. We were unable to detect the (GCG)(7) polymorphism in over 200 normal controls, suggesting that the frequency of this expansion is lower than that found in the French-Canadian population. One family was negative for the expansion. Affected members presented with the classical features of OPMD, namely ptosis, dysphagia and cytoplasmic inclusions on muscle biopsy, although with some atypical features, such as early age of onset, high serum levels of creatine kinase and a profound ophthalmoplegia. This family is an example of a GCG expansion-negative oculopharyngeal syndrome requiring further genetic investigation. We conclude that PABP2 analysis is a reliable non-invasive diagnostic test for OPMD in the UK population.
Asunto(s)
Distrofias Musculares/genética , Adolescente , Adulto , Anciano , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Proteínas de Unión a Poli(A) , Proteínas de Unión al ARN/genética , Expansión de Repetición de Trinucleótido/genética , Reino UnidoRESUMEN
OBJECTIVES: The syndrome of X-linked sideroblastic anaemia with ataxia is rare, described only twice in the literature. The aim was to obtain clinical neurological and haematological data about this rare syndrome throughout adult life. METHODS: A family is described with two affected brothers and two affected maternal uncles. The family was evaluated clinically. Haematological investigations included full blood count, blood film, iron studies, free erythrocyte protoporphyrin (FEP) concentrations and a bone marrow examination where possible. RESULTS: Core neurological features included motor delay, ataxia evident from early childhood, and dysarthria. Neurological features were non-progressive until the fifth decade when slow progression became evident. Some family members showed mild spasticity. Patients usually have a mild asymptomatic anaemia or a borderline decreased mean corpuscular volume. Blood film examination showed Pappenheimer bodies. Bone marrow examination showed ring sideroblasts, indicating raised erythrocyte iron. Free erythrocyte protoporphyrin (FEP) concentrations were raised. CONCLUSIONS: Haematological features are subtle and can be easily overlooked, and individual patients may not display all the abnormal features. X-linked ataxias are rare and incorrect genetic advice may be given if the diagnostic haematological features of X-linked sideroblastic anaemia are overlooked. Males with early onset ataxia should have a haematological evaluation including a blood film, with a bone marrow examination if abnormal blood count indices and measurement of FEP concentrations raise suspicion. The condition has parallels with Pearson's syndrome and Friedreich's ataxia. All three conditions are associated with mitochondrial iron handling defects and ataxia. The human ATP binding cassette gene (hABC7) is a candidate gene and requires further investigation.
Asunto(s)
Anemia Sideroblástica/genética , Ataxia/complicaciones , Ligamiento Genético/genética , Miopatías Mitocondriales/genética , Cromosoma X/genética , Anciano , Anemia Sideroblástica/complicaciones , Encéfalo/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Two brothers with X-linked ataxia (XLA) were found to have hypochromic red cells and increased erythrocyte protoporphyrin despite normal iron stores. The mother was unaffected by ataxia and had normal iron stores but showed evidence of some red cell hypochromia with heavy basophilic stippling that stained positive for iron. Bone marrow biopsy confirmed the presence of ring sideroblasts in one of the brothers. The absence of mutations in the ALAS2 gene and the predominance of zinc over free protoporphyrin led to a search using a combination of DNA and cDNA analysis for the presence of mutations in the ABC7 gene. ABC7 encodes a mitochondrial half-type ATP Binding Cassette transporter involved in iron homeostasis. The published cDNA sequence was used to search databases for the genomic sequence of which 12 exons spanning 23.4 kb were mapped leaving the most 5' nucleotides unaccounted for. The identified exons and their exon-intron boundaries were amplified from DNA while the most 5' sequence including the initiation codon was amplified from cDNA of peripheral blood cells. Direct sequencing revealed hemizygosity in the brothers and heterozygosity in the mother for a G-->C transversion at position 1299 of the published cDNA. This predicts a V411L substitution at the beginning of the last of six putative transmembrane regions of the protein. Restriction enzyme digestion confirmed the presence of this mutation in the three family members but could not detect it in 200 normal alleles. An uncle affected by ataxia also carried this mutation. This study supports the recently hypothesized involvement of the ABC7 gene in XLSA/A and highlights a protein structure region of importance to this syndrome.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Anemia Sideroblástica/genética , Ataxia Cerebelosa/genética , Ligamiento Genético , Mutación Missense , Cromosoma X , Anemia Sideroblástica/metabolismo , Ataxia Cerebelosa/metabolismo , Femenino , Humanos , Hierro/metabolismo , Leucina , Masculino , Mitocondrias/metabolismo , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , ValinaRESUMEN
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder defined clinically by severe gastrointestinal dysmotility; cachexia; ptosis, ophthalmoparesis, or both; peripheral neuropathy; leukoencephalopathy; and mitochondrial abnormalities. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. We identified 21 probands (35 patients) who fulfilled our clinical criteria for MNGIE. MNGIE has clinically homogeneous features but varies in age at onset and rate of progression. Gastrointestinal dysmotility is the most prominent manifestation, with recurrent diarrhea, borborygmi, and intestinal pseudo-obstruction. Patients usually die in early adulthood (mean, 37.6 years; range, 26-58 years). Cerebral leukodystrophy is characteristic. Mitochondrial DNA (mtDNA) has depletion, multiple deletions, or both. We have identified 16 TP mutations. Homozygous or compound heterozygous mutations were present in all patients tested. Leukocyte TP activity was reduced drastically in all patients tested, 0.009 +/- 0.021 micromol/hr/mg (mean +/- SD; n = 16), compared with controls, 0.67 +/- 0.21 micromol/hr/mg (n = 19). MNGIE is a recognizable clinical syndrome caused by mutations in thymidine phosphorylase. Severe reduction of TP activity in leukocytes is diagnostic. Altered mitochondrial nucleoside and nucleotide pools may impair mtDNA replication, repair, or both.
Asunto(s)
Enfermedades Gastrointestinales/genética , Seudoobstrucción Intestinal/genética , Encefalomiopatías Mitocondriales/genética , Mutación , Timidina Fosforilasa/genética , Adulto , Edad de Inicio , Blefaroptosis , Etnicidad , Exones , Femenino , Genes Recesivos , Humanos , Intrones , Masculino , Persona de Mediana Edad , Mitocondrias Musculares/metabolismo , Músculo Esquelético/patología , Núcleo Familiar , Sistemas de Lectura Abierta , Oftalmoplejía , Mutación Puntual , Eliminación de Secuencia , SíndromeRESUMEN
X-linked myotubular myopathy (XLMTM) characteristically causes severe or fatal muscle weakness in male infants. Mutations in the gene MTM1, encoding the protein myotubularin, can be identified in most families. Prior to this report, XLMTM was thought not to cause symptomatic manifestations in female carriers. We describe an adult female from a large family with typical XLMTM. The patient had progressive disabling muscle weakness of later onset and lesser severity than that observed in affected males. The distribution of weakness resembled typical XLMTM with facial weakness, marked limb-girdle weakness, respiratory muscle involvement and dysphagia. Analysis of the MTM1 gene identified a heterozygous missense mutation (G378R) within the highly conserved tyrosine phosphatase site of myotubularin. We did not identify significantly skewed X-inactivation. We conclude that XLMTM is capable of causing significant disability in heterozygotes.
Asunto(s)
Ligamiento Genético/genética , Heterocigoto , Miopatías Estructurales Congénitas/genética , Cromosoma X/genética , Femenino , Humanos , Persona de Mediana Edad , Mutación Missense/genética , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas no ReceptorasRESUMEN
Ataxia with vitamin E deficiency is an autosomal recessive condition associated with a defect in the a-tocopherol transfer protein. Clinically it manifests as a progressive ataxia with a phenotype resembling that of Friedreich's ataxia. There is some evidence that progression of neurological symptoms is prevented by vitamin E therapy. A patient is described who was given a clinical diagnosis of Friedreich's ataxia. Molecular genetic analysis showed the absence of the frataxin gene expansion. Subsequent vitamin E assay showed deficiency and a diagnosis of ataxia with vitamin E deficiency was made. It is recommended that all patients with ataxia of unknown cause should have vitamin E deficiency excluded. When a diagnosis of Friedreich's ataxia is considered patients should have frataxin analysis in addition. Further, neurologists should be aware that ataxia with vitamin E deficiency may present as "mutation negative" Friedreich's ataxia.
Asunto(s)
Ataxia/diagnóstico , Ataxia/genética , Proteínas Portadoras/genética , Errores Diagnósticos , Ataxia de Friedreich/diagnóstico , Proteínas de Unión a Hierro , Mutación/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Deficiencia de Vitamina E/diagnóstico , Deficiencia de Vitamina E/genética , Adolescente , Análisis Mutacional de ADN , Electrocardiografía , Femenino , Ataxia de Friedreich/genética , Humanos , Fenotipo , FrataxinaRESUMEN
Subacute necrotizing encephalomyelopathy (Leigh syndrome) is associated with a number of mitochondrial DNA (mtDNA) abnormalities. We studied a family with maternally inherited encephalomyelopathy. Two siblings developed adult-onset Leigh syndrome. Muscle biopsy specimens showed enhanced succinic dehydrogenase activity and cytochrome oxidase-negative fibers. We sequenced the ATPase- and transfer RNA (tRNA)-encoding genes of mtDNA and identified a novel mtDNA valine tRNA mutation at base pair 1644. This transversion was heteroplasmic in blood and muscle in all individuals studied, and the proportion of mutant mtDNA correlated with disease severity. This is the first heteroplasmic transversion within a mtDNA tRNA gene and the second pathogenic mtDNA tRNA(Val) mutation to be associated with human disease.