RESUMEN
Defects of O-linked glycosylation of alpha-dystroglycan cause a wide spectrum of muscular dystrophies ranging from severe congenital muscular dystrophy associated with abnormal brain and eye development to mild limb girdle muscular dystrophy. We report a female patient who developed isolated pelvic girdle muscle weakness and wasting, which became symptomatic at age 42. Exome sequencing uncovered a homozygous c.131T > G (p.Leu44Pro) substitution in DPM3, encoding dolichol-P-mannose (DPM) synthase subunit 3, leading to a 50% reduction of enzymatic activity. Decreased availability of DPM as an essential donor substrate for protein O-mannosyltransferase (POMT) 1 and 2 explains defective skeletal muscle alpha-dystroglycan O-glycosylation. Our findings show that DPM3 mutations may lead to an isolated and mild limb girdle muscular dystrophy phenotype without cardiomyopathy.
Asunto(s)
Manosiltransferasas/genética , Proteínas de la Membrana/genética , Distrofia Muscular de Cinturas/genética , Mutación , Distroglicanos/metabolismo , Femenino , Homocigoto , Humanos , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/diagnóstico por imagen , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/patología , FenotipoRESUMEN
BACKGROUND AND PURPOSE: Pompe disease is a rare inheritable muscle disorder for which enzyme replacement therapy (ERT) has been available since 2006. Uniform criteria for starting and stopping ERT in adult patients were developed and reported here. METHODS: Three consensus meetings were organized through the European Pompe Consortium, a network of experts from 11 European countries in the field of Pompe disease. A systematic review of the literature was undertaken to determine the effectiveness of ERT in adult patients on a range of clinical outcome measures and quality of life. A narrative synthesis is presented. RESULTS: Consensus was reached on how the diagnosis of Pompe disease should be confirmed, when treatment should be started, reasons for stopping treatment and the use of ERT during pregnancy. This was based on expert opinion and supported by the literature. One clinical trial and 43 observational studies, covering a total of 586 individual adult patients, provided evidence of a beneficial effect of ERT at group level. At individual patient level, the response to treatment varied, but factors associated with a patient's response to ERT were not described in many studies. Eleven observational studies focused on more severely affected patients, suggesting that ERT can also be beneficial in these patients. There are no studies on the effects of ERT in pre-symptomatic patients. CONCLUSIONS: This is the first European consensus recommendation for starting and stopping ERT in adult patients with Pompe disease, based on the extensive experience of experts from different countries.
Asunto(s)
Terapia de Reemplazo Enzimático , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Calidad de Vida , Adulto , Consenso , Esquema de Medicación , Europa (Continente) , Humanos , Guías de Práctica Clínica como AsuntoRESUMEN
We report the first Belgian family with Laing early-onset distal myopathy (MPD1). The proposita started limping at age 7. Later, there was severe weakness of proximal and distal muscles, including neck flexors. Her daughter developed foot drop at age 4. Progressive weakness of distal limb extensor muscles and mild weakness of the neck flexor and proximal muscles were noted. In both patients, CK and nerve conductions were normal, but EMG showed a brief, small amplitude, abundant, polyphasic potential pattern. Heart and respiration were normal. Several muscle biopsies have been performed in each with various diagnoses, including aspecific myopathic changes, congenital fibre type disproportion, and denervation-reinnervation. Analysis of MYH7 revealed a c.4522_4524del mutation (p.Glu1508del). This appears to be a de novo mutation, which has been reported in French, Norwegian, and Finnish patients.
Asunto(s)
Miopatías Distales/genética , Miopatías Distales/patología , Salud de la Familia , Anciano , Bélgica , Miosinas Cardíacas/genética , Femenino , Humanos , Músculo Esquelético , Mutación/genética , Cadenas Pesadas de Miosina/genéticaRESUMEN
BACKGROUND: Consensus guidelines on the definition, investigation, and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been previously published in European Journal of Neurology and Journal of the Peripheral Nervous System. OBJECTIVES: To revise these guidelines. METHODS: Disease experts, including a representative of patients, considered references retrieved from MEDLINE and Cochrane Systematic Reviews published between August 2004 and July 2009 and prepared statements that were agreed in an iterative fashion. RECOMMENDATIONS: The Task Force agreed on Good Practice Points to define clinical and electrophysiological diagnostic criteria for CIDP with or without concomitant diseases and investigations to be considered. The principal treatment recommendations were: (i) intravenous immunoglobulin (IVIg) (Recommendation Level A) or corticosteroids (Recommendation Level C) should be considered in sensory and motor CIDP; (ii) IVIg should be considered as the initial treatment in pure motor CIDP (Good Practice Point); (iii) if IVIg and corticosteroids are ineffective, plasma exchange (PE) should be considered (Recommendation Level A); (iv) if the response is inadequate or the maintenance doses of the initial treatment are high, combination treatments or adding an immunosuppressant or immunomodulatory drug should be considered (Good Practice Point); (v) symptomatic treatment and multidisciplinary management should be considered (Good Practice Point).
Asunto(s)
Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/terapia , Corticoesteroides/uso terapéutico , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Factores Inmunológicos/uso terapéutico , Intercambio PlasmáticoRESUMEN
BACKGROUND: Diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) have variable sensitivity and specificity. Newly published criteria by Koski et al combine clinical and electrophysiological components, either of which suffices to establish the diagnosis. European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria require mandatory electrophysiology, as do other sets of criteria. METHODS: The value of the two above-mentioned sets of criteria, on 151 patients with CIDP, and 162 controls with axonal neuropathy, from four European centres was assessed. Results were compared with Van den Bergh and Piéret's criteria and those of the American Academy of Neurology (AAN). The utility of more extensive nerve-conduction studies was ascertained. RESULTS: Koski et al's criteria had a sensitivity of 63% and specificity of 99.3%. With unilateral, right-sided, forearm/foreleg, four-nerve studies, EFNS/PNS criteria offered a sensitivity of 81.3% and specificity of 96.2% for "definite/probable" CIDP. Van den Bergh and Piéret's criteria had a sensitivity of 79.5% and specificity of 96.9%. AAN criteria were poorly sensitive (45.7%) but highly specific (100%). "Possible" electrophysiological CIDP as per EFNS/PNS criteria were poorly specific (69.2%). More extensive studies increased the diagnostic sensitivity of EFNS/PNS criteria (96.7%) but reduced the specificity (79.3%). CONCLUSIONS: In our patient populations, the EFNS/PNS criteria were the most sensitive and allowed identification of a highly significantly greater number of patients than Koski et al's criteria. The latter were comparable in specificity with the "definite/probable" EFNS/PNS electrodiagnostic subcategories. More extensive nerve-conduction studies improved diagnostic yield but resulted in loss of specificity.
Asunto(s)
Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Bélgica , Errores Diagnósticos , Electrofisiología , Inglaterra , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiología , Nervios Periféricos/fisiopatología , Guías de Práctica Clínica como Asunto/normas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
AIM: The strength and nature of the relationships between motor impairments and activity limitations assessed by the ACTIVLIM questionnaire were investigated in 245 patients with neuromuscular disorders. METHODS: Measures of motor impairments consisted of: (1) a grip strength test using a Jamar dynamometer, (2) a Manual Muscle Testing bilaterally performed in 18 muscle groups and (3) a gait speed spontaneously adopted by the patients using the 10 m timed walking test. RESULTS: Activity limitations were poorly correlated with grip strength in both hands (r = 0.3 and 0.36) and moderately correlated with gait speed (r = 0.53). Spearman's coefficients of correlation between the manual muscle testing and activity limitations were moderate to very poor (rho = 0.5 to 0.17). CONCLUSION: The relationships between motor impairments and activity limitations are not straightforward in patients with neuromuscular disorders, indicating that the activity limitations should be separately assessed and cannot be simply inferred from motor impairment measures.
Asunto(s)
Actividades Cotidianas/clasificación , Evaluación de la Discapacidad , Limitación de la Movilidad , Enfermedades Neuromusculares/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Marcha , Fuerza de la Mano , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular , Grupo de Atención al Paciente , Estadística como Asunto , Encuestas y Cuestionarios , Adulto JovenAsunto(s)
Síndrome de Guillain-Barré/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Ácido Micofenólico/análogos & derivados , Adulto , Anciano , Antiinflamatorios/administración & dosificación , Quimioterapia Combinada , Femenino , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Masculino , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Proyectos PilotoRESUMEN
BACKGROUND: Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance, often associated with CNS and ocular involvement. They are characterized by the abnormal glycosylation of alpha-dystroglycan, and caused by mutations in at least six genes encoding enzymes: FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE. POMT2 mutations have recently been identified in Walker-Warburg syndrome and in a milder muscle-eye-brain disease-like form. METHODS: We studied mentally retarded patients with CMD, analyzed POMT2 by sequencing the coding regions, and also performed a haplotype analysis in all patients and their family members carrying the new POMT2 mutation. RESULTS: We report three novel POMT2 mutations. One of these, p.Tyr666Cys, was homozygous in two unrelated patients and in a compound heterozygous state in others. All patients showed severe diffuse muscle weakness, microcephaly, severe mental retardation, and marked lordoscoliosis with hyperextended head. Elevated CK levels, cerebral cortical atrophy, and cerebellar vermis hypoplasia were constant findings. Mild cardiac abnormalities, focal white matter abnormalities, or partial corpus callosum hypoplasia were detected in single cases. Eye involvement was absent or mild. By genotype analysis, we defined a distinct 170kb haplotype encompassing POMT2 and shared by all the subjects harboring the mutation p.Tyr666Cys. CONCLUSIONS: Our results broaden the clinical spectrum associated with POMT2 mutations, which should be considered in patients with CMD associated with microcephaly, and severe mental retardation with or without ocular involvement.
Asunto(s)
Efecto Fundador , Discapacidad Intelectual/genética , Manosiltransferasas/genética , Distrofias Musculares/congénito , Distrofias Musculares/genética , Mutación/genética , Adolescente , Adulto , Atrofia/etiología , Atrofia/patología , Atrofia/fisiopatología , Encéfalo/anomalías , Encéfalo/patología , Encéfalo/fisiopatología , Niño , Análisis Mutacional de ADN , Distroglicanos/metabolismo , Femenino , Frecuencia de los Genes , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Haplotipos/genética , Humanos , Discapacidad Intelectual/patología , Masculino , Microcefalia/genética , Microcefalia/patología , Debilidad Muscular/genética , Debilidad Muscular/patología , Debilidad Muscular/fisiopatología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Distrofias Musculares/fisiopatologíaRESUMEN
Rippling muscle disease (RMD) is a rare muscle disorder characterised by muscle stiffness, exercise induced myalgia, and cramp-like sensations. It is genetically heterogeneous and can be acquired, but most cases show autosomal dominant inheritance due to mutations in the caveolin-3 (CAV3) gene. We report a novel heterozygous missense mutation in CAV3 in a Belgian family with autosomal dominant RMD. A 40 year old woman complained of fatigue, exercise induced muscle pain, and muscle cramps since the age of 35. Neurological examination revealed percussion induced rapid muscle contractions (PIRCs) and localised muscle mounding on percussion; muscle rippling was not observed. Creatine kinase (CK) was elevated but electromyography and nerve conduction studies were normal. Fluorescence immunohistochemistry revealed reduced caveolin-3 and dysferlin staining in a quadriceps muscle biopsy. Western blot analysis confirmed severely reduced caveolin-3 levels, whereas dysferlin was normal. Sequence analysis of the two coding exons of CAV3 revealed a hitherto unreported heterozygous C82A transversion in the first exon, predicting a Pro28Thr amino acid exchange. Thr patient's first degree relatives did not present with neuromuscular complaints, but PIRCs, muscle mounding, and muscle rippling were found in the mother, who also carried the CAV3 mutation.
Asunto(s)
Caveolinas/genética , Enfermedades Musculares/genética , Mutación Missense , Adulto , Bélgica , Caveolina 3 , Ejercicio Físico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular , Calambre Muscular/etiología , Proteínas Musculares/genética , Dolor , LinajeRESUMEN
BACKGROUND: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot-Marie-Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis. METHODS: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1. RESULTS: A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C). CONCLUSIONS: Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.
Asunto(s)
Axones/patología , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedades Desmielinizantes/genética , Genes Recesivos/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Edad de Inicio , Enfermedad de Charcot-Marie-Tooth/patología , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Niño , Preescolar , Cromosomas Humanos Par 8/genética , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/fisiopatología , Electrofisiología , Familia , Femenino , Ligamiento Genético/genética , Pruebas Genéticas , Humanos , Lactante , Masculino , Conducción Nerviosa/fisiología , Linaje , Nervio Sural/patología , TurquíaAsunto(s)
Síndrome de Isaacs/diagnóstico , Síndrome de Isaacs/etiología , Miastenia Gravis/complicaciones , Miastenia Gravis/diagnóstico , Timoma/diagnóstico , Diagnóstico Diferencial , Humanos , Síndrome de Isaacs/fisiopatología , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiologíaRESUMEN
Intramuscular botulinum toxin type A (BT-A) has been shown to reduce spasticity and to improve gait in children with cerebral palsy. To determine whether the efficacy of BT-A may be enhanced by electrical stimulation, as suggested in focal dystonia or in adult spastic patients, 12 children with dynamic foot equinus deformity were randomly assigned to two groups in a blinded, clinically controlled trial. Intramuscular BT-A into calf muscles was followed by adjuvant electrical stimulation in Group A (n = 6) but not in Group B (n = 6). Clinical assessment and instrumented gait analysis were performed before and 1, 3, and 6 months after treatment. The combined treatment of BT-A and electrical stimulation was not superior to BT-A alone. For all patients, improvement of the clinical and gait variables occurred at 1 and 3 months after BT-A injection.