RESUMEN
BACKGROUND: Congenital myasthenic syndrome (CMS) due to mutations in GMPPB has recently been reported confirming the importance of glycosylation for the integrity of neuromuscular transmission. METHODS: Review of case notes of patients with mutations in GMPPB to identify the associated clinical, neurophysiological, pathological and laboratory features. In addition, serum creatine kinase (CK) levels within the Oxford CMS cohort were retrospectively analysed to assess its usefulness in the differential diagnosis of this new entity. RESULTS: All patients had prominent limb-girdle weakness with minimal or absent craniobulbar manifestations. Presentation was delayed beyond infancy with proximal muscle weakness and most patients recall poor performance in sports during childhood. Neurophysiology showed abnormal neuromuscular transmission only in the affected muscles and myopathic changes. Muscle biopsy showed dystrophic features and reduced α-dystroglycan glycosylation. In addition, myopathic changes were present on muscle MRI. CK was significantly increased in serum compared to other CMS subtypes. Patients were responsive to pyridostigimine alone or combined with 3,4-diaminopyridine and/or salbutamol. CONCLUSIONS: Patients with GMPPB-CMS have phenotypic features aligned with CMS subtypes harbouring mutations within the early stages of the glycosylation pathway. Additional features shared with the dystroglycanopathies include myopathic features, raised CK levels and variable mild cognitive delay. This syndrome underlines that CMS can occur in the absence of classic myasthenic manifestations such as ptosis and ophthalmoplegia or facial weakness, and links myasthenic disorders with dystroglycanopathies. This report should facilitate the recognition of this disorder, which is likely to be underdiagnosed and can benefit from symptomatic treatment.
Asunto(s)
Síndromes Miasténicos Congénitos/diagnóstico , Síndromes Miasténicos Congénitos/genética , Nucleotidiltransferasas/genética , Adolescente , Adulto , Anciano , Disfunción Cognitiva/complicaciones , Creatina Quinasa/sangre , Distroglicanos/metabolismo , Femenino , Glicosilación , Humanos , Masculino , Persona de Mediana Edad , Mutación , Síndromes Miasténicos Congénitos/metabolismo , Síndromes Miasténicos Congénitos/fisiopatología , Adulto JovenRESUMEN
Congenital myasthenic syndromes are inherited disorders that arise from impaired signal transmission at the neuromuscular junction. Mutations in at least 20 genes are known to lead to the onset of these conditions. Four of these, ALG2, ALG14, DPAGT1 and GFPT1, are involved in glycosylation. Here we identify a fifth glycosylation gene, GMPPB, where mutations cause congenital myasthenic syndrome. First, we identified recessive mutations in seven cases from five kinships defined as congenital myasthenic syndrome using decrement of compound muscle action potentials on repetitive nerve stimulation on electromyography. The mutations were present through the length of the GMPPB, and segregation, in silico analysis, exon trapping, cell transfection followed by western blots and immunostaining were used to determine pathogenicity. GMPPB congenital myasthenic syndrome cases show clinical features characteristic of congenital myasthenic syndrome subtypes that are due to defective glycosylation, with variable weakness of proximal limb muscle groups while facial and eye muscles are largely spared. However, patients with GMPPB congenital myasthenic syndrome had more prominent myopathic features that were detectable on muscle biopsies, electromyography, muscle magnetic resonance imaging, and through elevated serum creatine kinase levels. Mutations in GMPPB have recently been reported to lead to the onset of muscular dystrophy dystroglycanopathy. Analysis of four additional GMPPB-associated muscular dystrophy dystroglycanopathy cases by electromyography found that a defective neuromuscular junction component is not always present. Thus, we find mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. Clinical recognition of GMPPB-associated congenital myasthenic syndrome may be complicated by the presence of myopathic features, but correct diagnosis is important because affected individuals can respond to appropriate treatments.
Asunto(s)
Distroglicanos/metabolismo , Mutación/genética , Síndromes Miasténicos Congénitos/genética , Unión Neuromuscular/fisiopatología , Nucleotidiltransferasas/genética , Adolescente , Adulto , Análisis Mutacional de ADN , Salud de la Familia , Femenino , Células HEK293 , Humanos , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/patología , Síndromes Miasténicos Congénitos/patología , Unión Neuromuscular/patología , Nucleotidiltransferasas/metabolismo , Transfección , Adulto JovenRESUMEN
Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed whole-exome sequencing to determine the underlying defect in a group of individuals with an inherited limb-girdle pattern of myasthenic weakness. We identify DPAGT1 as a gene in which mutations cause a congenital myasthenic syndrome. We describe seven different mutations found in five individuals with DPAGT1 mutations. The affected individuals share a number of common clinical features, including involvement of proximal limb muscles, response to treatment with cholinesterase inhibitors and 3,4-diaminopyridine, and the presence of tubular aggregates in muscle biopsies. Analyses of motor endplates from two of the individuals demonstrate a severe reduction of endplate acetylcholine receptors. DPAGT1 is an essential enzyme catalyzing the first committed step of N-linked protein glycosylation. Our findings underscore the importance of N-linked protein glycosylation for proper functioning of the neuromuscular junction. Using the DPAGT1-specific inhibitor tunicamycin, we show that DPAGT1 is required for efficient glycosylation of acetylcholine-receptor subunits and for efficient export of acetylcholine receptors to the cell surface. We suggest that the primary pathogenic mechanism of DPAGT1 mutations is reduced levels of acetylcholine receptors at the endplate region. These individuals share clinical features similar to those of congenital myasthenic syndrome due to GFPT1 mutations, and their disorder might be part of a larger subgroup comprising the congenital myasthenic syndromes that result from defects in the N-linked glycosylation pathway and that manifest through impaired neuromuscular transmission.
Asunto(s)
Síndromes Miasténicos Congénitos/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/farmacología , Adulto , Amifampridina , Inhibidores de la Colinesterasa/uso terapéutico , Femenino , Glicosilación , Humanos , Extremidad Inferior , Masculino , Persona de Mediana Edad , Placa Motora/metabolismo , Mutación , Síndromes Miasténicos Congénitos/patología , Unión Neuromuscular/metabolismo , Receptores Colinérgicos/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos)/antagonistas & inhibidores , Tunicamicina/farmacologíaRESUMEN
BACKGROUND: A newly defined congenital myasthenic syndrome (CMS) caused by DPAGT1 mutations has recently been reported. While many other CMS-associated proteins have discrete roles localised to the neuromuscular junction, DPAGT1 is ubiquitously expressed, modifying many proteins, and as such is an unexpected cause of isolated neuromuscular involvement. METHODS: We present detailed clinical characteristics of five patients with CMS caused by DPAGT1 mutations. RESULTS: Patients have prominent limb girdle weakness and minimal craniobulbar symptoms. Tubular aggregates on muscle biopsy are characteristic but may not be apparent on early biopsies. Typical myasthenic features such as pyridostigmine and 3, 4- diaminopyridine responsiveness, and decrement on repetitive nerve stimulation are present. CONCLUSIONS: These patients mimic myopathic disorders and are likely to be under-diagnosed. The descriptions here should facilitate recognition of this disorder. In particular minimal craniobulbar involvement and tubular aggregates on muscle biopsy help to distinguish DPAGT1 CMS from the majority of other forms of CMS. Patients with DPAGT1 CMS share similar clinical features with patients who have CMS caused by mutations in GFPT1, another recently identified CMS subtype.
Asunto(s)
Análisis Mutacional de ADN , Síndromes Miasténicos Congénitos/genética , N-Acetilglucosaminiltransferasas/genética , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2 , Adulto , Edad de Inicio , Albuterol/uso terapéutico , Amifampridina , Biopsia , Inhibidores de la Colinesterasa/uso terapéutico , Diagnóstico Diferencial , Exoma , Femenino , Pruebas Genéticas , Glicosilación , Humanos , Masculino , Persona de Mediana Edad , Neuronas Motoras/fisiología , Músculo Esquelético/inervación , Músculo Esquelético/patología , Síndromes Miasténicos Congénitos/diagnóstico , Síndromes Miasténicos Congénitos/patología , Síndromes Miasténicos Congénitos/fisiopatología , Examen Neurológico , Unión Neuromuscular/fisiología , Fenotipo , Bloqueadores de los Canales de Potasio/uso terapéutico , Bromuro de Piridostigmina/uso terapéuticoRESUMEN
OBJECTIVE: To determine the minimum prevalence of spinocerebellar ataxia type 17 (SCA17) in the north east of England. PATIENTS AND METHODS: A defined region containing 2,516,500 individuals with 192 families with undiagnosed ataxia, 90 patients with a Huntington's disease-like phenotype and 292 controls. The number of (CAG/CAA)(n) repeats in the SCA17/TBP gene was determined by fluorescent PCR and sequenced in affected individuals. RESULTS: The mean repeat size for 584 control alleles was 34 (S.D.=3.58), ranging from 25 to 40. Two index cases had larger alleles with repeat lengths greater than the control range. Affected family members presented in adult life with ataxia followed by extrapyramidal features and cognitive impairment. In one family 44 repeats were associated with a younger age of onset than has been previously described. CONCLUSIONS: The minimum prevalence of SCA17 in the north east of England was 0.16/100,000 (upper 95% confidence interval 0.31/100,000).
Asunto(s)
Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/genética , Adolescente , Adulto , Ataxina-1 , Ataxinas , Atrofia/genética , Atrofia/patología , Atrofia/fisiopatología , Enfermedades de los Ganglios Basales/epidemiología , Enfermedades de los Ganglios Basales/genética , Encéfalo/patología , Encéfalo/fisiopatología , Niño , Preescolar , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/genética , Estudios de Cohortes , Estudios Transversales , Análisis Mutacional de ADN , Inglaterra/epidemiología , Femenino , Frecuencia de los Genes/genética , Pruebas Genéticas , Genotipo , Humanos , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Fenotipo , Repeticiones de Trinucleótidos/genéticaRESUMEN
OBJECTIVE: Motor neuron disease (MND) is a common neurodegenerative condition for which the underlying cause is uncertain in many patients. We identified a patient with clinical features suggestive of MND but additional cardiac and metabolic symptoms. We wished to determine if the clinical features were due to a mitochondrial DNA mutation. METHODS: The brain and spinal cord were studied using neuropathological techniques and agenetic defect investigated in individual neurons. RESULTS: There were atypical neuropathological features and genetic studies identified a pathogenic, heteroplasmic mitochondria tRNA(Ile) (4274T>C) mutation. INTERPRETATION: This case adds to the phenotypic variation seen in mitochondrial DNA disease but also highlights the potential role of mitochondrial dysfunction in the cause of MND.
Asunto(s)
ADN Mitocondrial/genética , Enfermedad de la Neurona Motora/genética , Mutación , ARN de Transferencia de Isoleucina/genética , Anciano , Análisis Mutacional de ADN/métodos , Complejo IV de Transporte de Electrones/metabolismo , Humanos , Inmunohistoquímica/métodos , Masculino , Enfermedad de la Neurona Motora/metabolismo , Enfermedad de la Neurona Motora/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Succinato Deshidrogenasa/metabolismoRESUMEN
Neuroferritinopathy is a recently recognized, dominantly inherited movement disorder caused by a mutation of the ferritin light chain gene. We present video case reports of 4 individuals with neuroferritinopathy chosen to illustrate how this disorder can present and subsequently progress clinically. The clinical phenotype of this disorder is highly variable with symptoms beginning in the third to sixth decades. Chorea, dystonia, or an akinetic-rigid syndrome can predominate in different individuals. Neuroferritinopathy is not restricted to the UK and it has been described in apparently sporadic cases. The diagnosis should therefore be considered in patients with a wide variety of different movement disorders. Characteristic neuroimaging assists in identifying affected individuals.
Asunto(s)
Ferritinas/genética , Trastornos del Movimiento/genética , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/patología , Trastornos del Movimiento/fisiopatología , Mutación , Neostriado/patología , Grabación de Cinta de Video/métodosRESUMEN
Normokalemic periodic paralysis (normoKPP) is well established in the literature, but there are doubts as to whether it exists as a discrete entity. Retrospective clinical and molecular analysis has confirmed suspicions that most normoKPP families actually have a variant of hyperkalemic periodic paralysis (hyperKPP) due to a mutation of the muscle-specific sodium channel gene (SCN4A). However, the original normoKPP family described by Poskanzer and Kerr (Poskanzer DC, Kerr DNS. A third type of periodic paralysis, with normokalemia and favourable response to sodium chloride. Am J Med 1961;31:328-342) has remained unchallenged. We identified the Met1592Val mutation of SCN4A in an affected descendent of this original normoKPP family. This is the final piece in the puzzle: normoKPP is actually a variant of hyperKPP and is not a distinct disorder.