•Molecular genetic and clinical findings of 64 genetically confirmed CMS patients.•Overview on relative frequencies of different subtypes in Spanish population.•Thirty-six different mutations were ...identified, with 6 of them not reported so far.•Phenotypes associated with the different CMS genes are described.
Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations. Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124_1127dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management.
Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disease that affects one in 3500 live-born males. The total absence of dystrophin observed in DMD patients is generally ...caused by mutations that disrupt the reading frame of the DMD gene, and about 80% of cases harbour deletions or duplications of one or more exons.
We reviewed 284 cases of males with a genetic diagnosis of DMD between 2007 and 2014. These patients were selected from 8 Spanish reference hospitals representing most areas of Spain. Multiplex PCR, MLPA, and sequencing were performed to identify mutations.
Most of these DMD patients present large deletions (46.1%) or large duplications (19.7%) in the dystrophin gene. The remaining 34.2% correspond to point mutations, and half of these correspond to nonsense mutations. In this study we identified 23 new mutations in DMD: 7 large deletions and 16 point mutations.
The algorithm for genetic diagnosis applied by the participating centres is the most appropriate for genotyping patients with DMD. The genetic specificity of different therapies currently being developed emphasises the importance of identifying the mutation appearing in each patient; 38.7% of the cases in this series are eligible to participate in current clinical trials.
Resumen Introducción La distrofia muscular de Duchenne (DMD) es una enfermedad neuromuscular grave que afecta a uno de cada 3.500 varones nacidos y sigue un patrón de herencia ligada al cromosoma X . ...En esta enfermedad se observa una ausencia total de la distrofina, generalmente debida a mutaciones en el gen DMD, que altera la pauta de lectura y en torno al 80% de los casos son debidos a deleciones y duplicaciones de uno o más exones. Métodos Se han revisado 284 casos de varones diagnosticados genéticamente de DMD entre los años 2007 y 2014. Estos pacientes provienen de 8 hospitales españoles de referencia que cubren la mayor parte del territorio español. Para la identificación de las mutaciones se realizaron las técnicas de reacción en cadena de la polimerasa multiplex, MLPA y secuenciación. Resultados Los pacientes con DMD presentan en su mayoría grandes deleciones (46,1%) o grandes duplicaciones (19,7%) en el gen de la distrofina. El restante 34,2% corresponde al conjunto de mutaciones puntuales, destacando las sustituciones nucleotídicas tipo nonsense que aparecen en la mitad de los casos. Este estudio permitió identificar 23 nuevas mutaciones en DMD: 7 grandes deleciones y 16 mutaciones puntuales. Conclusiones El algoritmo de diagnóstico genético aplicado por los centros participantes es el más adecuado para genotipificar a los pacientes con DMD. La especificidad genética de las distintas terapias en desarrollo pone de manifiesto la importancia de conocer la mutación de cada paciente, siendo un 38,7% de ellos susceptibles de participar en los ensayos clínicos actuales.
Abstract We report two patients with a new phenotype of dysferlinopathy presenting as congenital muscular disease. Both patients showed weakness in proximal lower limbs and neck flexor muscles at ...birth. The presence of normal CK levels during the first years should be noted. Initial MRI showed no abnormalities but short-time-inversion-recovery (STIR) sequences revealed a striking myoedema in gastrocnemius and hamstring muscles at the age of 5. Muscle biopsy showed mild dystrophic features and the absence of dysferlin. Dysferlin gene ( DYSF ) analysis revealed a p.Ala927LeufsX21 mutation in a homozygous state in both siblings. This new phenotype widens the clinical spectrum of dysferlin myopathies.
Idiopathic cardiomyopathies (ICM) are a group of heterogeneous cardiac diseases that may predispose young patients to sudden cardiac death. They may occur isolated or as a manifestation of a skeletal ...myopathy, sometimes being the first manifestation of a neuromuscular disease. Involvement of cardiac muscle in patients suffering from ICM may be overlooked, or, sometimes remains poorly defined. We aimed to evaluate the involvement of skeletal muscle in patients diagnosed with ICM. Among a series of 90 patients with ICM we selected 60 patients (sporadic patients presenting before the age of 40, and all familial cases irrespective of the age at the disease onset). We determined serum CK levels, and performed a detailed clinical examination specially focused on the presence of muscle weakness and/or joint retractions. Muscle imaging studies were performed in 49 cases. In 17 cases a genetic analysis was performed using a panel that includes 150 genes involved in familial cardiomyopathies. Results: we have examined 37 patients with dilated CM, 17 with hypertrophic CM, 3 left ventricular noncompaction CM, 2 arrhythmogenic right ventricular dysplasia, and 1 restrictive CM. CK levels were normal in all patients. Mild joint retractions were observed in 10, two of whom also had muscle weakness; two additional patients had isolated muscle weakness. Muscle imaging studies did not show relevant findings except for one patient. Among the patients manifesting muscle weakness and/or joint retractions a pathogenic mutation was identified in 4: LMNA n = 1, DES n = 1, DSP n = 1 and TTN = 1. Molecular analysis in 3 patients is currently in course. No mutations were identified in one patient with Achilles tendon retraction. Conclusions: Skeletal muscle involvement in patients with idiopathic cardiomyopathy is rare and in most cases very subtle. A detailed neurological examination may reveal some abnormalities that not always help to reach a final diagnosis.
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