Delphi consensus on recommendations for the treatment of spinal muscular atrophy in Spain (RET-AME consensus).

INTRODUCTION: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a biallelic mutation of the SMN1 gene, located on the long arm of chromosome 5, and predominantly affects the motor neurons of the anterior horn of the spinal cord, causing progressive muscle weakness and atrophy. The development of disease-modifying treatments is significantly changing the natural history of SMA, but uncertainty remains about which patients can benefit from these treatments and how that benefit should be measured. METHODOLOGY: A group of experts specialised in neurology, neuropediatrics, and rehabilitation and representatives of the Spanish association of patients with SMA followed the Delphi method to reach a consensus on 5 issues related to the use of these new treatments: general aspects, treatment objectives, outcome assessment tools, requirements of the treating centres, and regulation of their use. Consensus was considered to be achieved when a response received at least 80% of votes. RESULTS: Treatment protocols are useful for regulating the use of high-impact medications and should guide treatment, but should be updated regularly to take into account the most recent evidence available, and their implementation should be assessed on an individual basis. Age, baseline functional status, and, in the case of children, the type of SMA and the number of copies of SMN2 are characteristics that should be considered when establishing therapeutic objectives, assessment tools, and the use of such treatments. The cost-effectiveness of these treatments in paediatric patients is mainly influenced by early treatment onset; therefore, the implementation of neonatal screening is recommended. CONCLUSIONS: The RET-AME consensus recommendations provide a frame of reference for the appropriate use of disease-modifying treatments in patients with SMA.

Molecular characterization of congenital myasthenic syndromes in Spain.

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.

Nueva mutación en el gen STXBP1 en un paciente con síndrome de Ohtahara no lesional / Novel mutation in STXBP1 gene in a patient with non-lesional Ohtahara syndrome

Introducción: El síndrome de Ohtahara (SO, OMIM#308350, ORPHA1934) es una encefalopatía epiléptica de inicio precoz (EEIP) caracterizada por espasmos, crisis epilépticas intratables, un trazado electroencefalográfico de brote-supresión y retraso psicomotor grave. En la mayoría de los pacientes con SO se han identificado mutaciones en el gen STXBP1, que codifica para la proteína de unión a sintaxina 1 y que está implicado en el mecanismo de exocitosis de las vesículas sinápticas. Paciente y resultados: Se presenta el caso clínico de un varón de 19 meses de edad diagnosticado de SO en el que se ha identificado una mutación no descrita (c.1249 + 2T > C, G417AfsX7) en el gen STXBP1. La mutación está localizada en uno de los sitios donadores implicados en el procesamiento del ARNm del gen, lo que produce la pérdida del exón 14 y el posterior truncamiento de la proteína que codifica. Conclusiones: Esta nueva mutación en el gen STXBP1, identificada en un paciente sin lesión cerebral estructural subyacente, amplía el espectro mutacional asociado a este devastador síndrome epiléptico

Introduction: Ohtahara syndrome (OS, OMIM#308350, ORPHA1934) is an early-onset epileptic encephalopathy (EOEE) characterised by spasms, intractable seizures, suppression-burst pattern on the electroencephalogram, and severe psychomotor retardation. Mutations in STXBP1 -a gene that codes for syntaxin binding protein 1 and is involved in synaptic vesicle exocytosis- has been identified in most patients with OS. Patient and results: We report the case of a 19-month-old child with OS who displays a previously unreported mutation in STXBP1 (c.1249 + 2T > C, G417AfsX7). This mutation is located in a donor splice site and eliminates exon 14, resulting in a truncated protein. Conclusion: This previously unreported STXBP1 mutation in a subject with Ohtahara syndrome and non-lesional magnetic resonance imaging (MRI) broadens the mutational spectrum associated with this devastating epileptic syndrome

Novel mutation in STXBP1 gene in a patient with non-lesional Ohtahara syndrome. / Nueva mutación en el gen STXBP1 en un paciente con síndrome de Ohtahara no lesional.

INTRODUCTION: Ohtahara syndrome (OS, OMIM#308350, ORPHA1934) is an early-onset epileptic encephalopathy (EOEE) characterised by spasms, intractable seizures, suppression-burst pattern on the electroencephalogram, and severe psychomotor retardation. Mutations in STXBP1 -a gene that codes for syntaxin binding protein 1 and is involved in synaptic vesicle exocytosis- has been identified in most patients with OS. PATIENT AND RESULTS: We report the case of a 19-month-old child with OS who displays a previously unreported mutation in STXBP1 (c.1249+2T>C, G417AfsX7). This mutation is located in a donor splice site and eliminates exon 14, resulting in a truncated protein. CONCLUSION: This previously unreported STXBP1 mutation in a subject with Ohtahara syndrome and non-lesional magnetic resonance imaging (MRI) broadens the mutational spectrum associated with this devastating epileptic syndrome.

Anomalías cromosómicas subteloméricas en pacientes con retraso mental criptogénico / Subtelomeric rearrangements in cryptogenic mental retardation

Introducción: El retraso mental afecta al 3% de la población. En el 50% no es posible determinar la etiología. Las alteraciones cromosómicas submicroscópicas subteloméricas, no detectables con técnicas citogenéticas convencionales, pueden explicar algunos casos de retraso mental criptogénicos. Pacientes y métodos: Cohorte de 200 pacientes, con edades comprendidas entre los 2,5 y los 15 años, y retraso psicomotor (< 6 años) o retraso mental (> 6 años) criptogénicos. Variables: grado de retraso, dismorfias (faciales, manuales, macrosomía/microsomía), crecimiento intrauterino retardado, epilepsia. Identificación de reordenamientos cromosómicos subteloméricos mediante MLPA (multiplex ligation dependent probe amplification), que detecta pérdidas o ganancias de material genético. Confirmación de los hallazgos patológicos mediante FISH (fluorescent in situ hybridization) y/o array de CGH (comparative genomic hybridization). Resultados: Se detectaron anomalías subteloméricas en 9 pacientes, lo que representa el 4,5% de los casos. El estudio de progenitores demostró en un caso una traslocación en equilibrio. El resto eran alteraciones «de novo». Existía asociación significativa con la presencia de más de un rasgo fenotípico dismórfico o el antecedente de crecimiento intrauterino retardado, pero no con el grado de retraso ni con la presencia de epilepsia. Conclusiones: Las alteraciones cromósomicas submicroscópicas subteloméricas explican el 4,5% de los retrasos mentales de causa desconocida en nuestra serie. En nuestra población se asocian a la presencia de más de un rasgo fenotípico anormal o al antecedente de crecimiento intrauterino retardado (AU)

Introduction: Mental retardation affects 3% of the population, the origin of which cannot be established in 50% of cases. Subtelomeric rearrangements, not detected by routine cytogenetic studies, might explain some cases of unknown cause. Patients and methods: A study was conducted on 200 subjects with unexplained mental retardations using multiplex ligation dependent probe amplification (MLPA). Abnormal findings were confirmed by fluorescent in situ hybridization (FISH) and/or comparative genomic hybridization technology (CGH-array). Results: A subtelomeric aberration was identified in 9 patients. Eight were «de novo»; one was inherited from a phenotypically normal parent. There was a statistically significant association with the presence of more than one dysmorphic feature or with intrauterine growth retardation, but not with the severity of retardation or epilepsy. Conclusions: Subtelomeric rearrangements explained 4.5% of cases of mental retardation in our series. The presence of more than one dysmorphic feature or intrauterine uterine growth retardation increases the probability of this type of chromosomal aberration (AU)

[Subtelomeric rearrangements in cryptogenic mental retardation]. / Anomalías cromosómicas subteloméricas en pacientes con retraso mental criptogénico.

INTRODUCTION: Mental retardation affects 3% of the population, the origin of which cannot be established in 50% of cases. Subtelomeric rearrangements, not detected by routine cytogenetic studies, might explain some cases of unknown cause. PATIENTS AND METHODS: A study was conducted on 200 subjects with unexplained mental retardations using multiplex ligation dependent probe amplification (MLPA). Abnormal findings were confirmed by fluorescent in situ hybridization (FISH) and/or comparative genomic hybridization technology (CGH-array). RESULTS: A subtelomeric aberration was identified in 9 patients. Eight were «de novo¼; one was inherited from a phenotypically normal parent. There was a statistically significant association with the presence of more than one dysmorphic feature or with intrauterine growth retardation, but not with the severity of retardation or epilepsy. CONCLUSIONS: Subtelomeric rearrangements explained 4.5% of cases of mental retardation in our series. The presence of more than one dysmorphic feature or intrauterine uterine growth retardation increases the probability of this type of chromosomal aberration.