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Pathogenic variants in HMGCR were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. The mechanism linking pathogenic variants in HMGCR with skeletal muscle dysfunction is unclear. We knocked down Hmgcr in mouse skeletal myoblasts, knocked down hmgcr in Drosophila, and expressed three pathogenic HMGCR variants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) in Hmgcr knockdown mouse myoblasts. Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown of hmgcr in Drosophila led to lethality. Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.
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OBJECTIVE: Duchenne and Becker muscular dystrophies (DMD and BMD) are dystrophinopathies caused by variants in DMD gene, resulting in reduced or absent dystrophin. These conditions, characterized by muscle weakness, also manifest central nervous system (CNS) comorbidities due to dystrophin expression in the CNS. Prior studies have indicated a higher prevalence of epilepsy in individuals with dystrophinopathy compared to the general population. Our research aimed to investigate epilepsy prevalence in dystrophinopathies and characterize associated electroencephalograms (EEGs) and seizures. METHODS: We reviewed 416 individuals with dystrophinopathy, followed up at three centers between 2010 and 2023, to investigate the lifetime epilepsy prevalence and characterize EEGs and seizures in those individuals diagnosed with epilepsy. Associations between epilepsy and type of dystrophinopathy, genotype, and cognitive involvement were studied. RESULTS: Our study revealed a higher epilepsy prevalence than the general population (1.4%; 95% confidence interval: 0.7-3.2%), but notably lower than previously reported in smaller dystrophinopathy cohorts. No significant differences were found in epilepsy prevalence between DMD and BMD or based on underlying genotypes. Cognitive impairment was not found to be linked to higher epilepsy rates. The most prevalent epilepsy types in dystrophinopathies resembled those observed in the broader pediatric population, with most individuals effectively controlled through monotherapy. INTERPRETATION: The actual epilepsy prevalence in dystrophinopathies may be markedly lower than previously estimated, possibly half or even less. Our study provides valuable insights into the epilepsy landscape in individuals with dystrophinopathy, impacting medical care, especially for those with concurrent epilepsy.
Asunto(s)
Epilepsia , Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/epidemiología , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/genética , Masculino , Epilepsia/epidemiología , Epilepsia/etiología , Adolescente , Femenino , Adulto , Adulto Joven , Niño , Prevalencia , Persona de Mediana Edad , Preescolar , Electroencefalografía , Comorbilidad , Distrofina/genéticaRESUMEN
INTRODUCTION: Hereditary spastic paraplegia (HSP) is a set of neurodegenerative clinical features characterised by a progressive loss of strength in the lower limbs together with spasticity. It is the result of an axonal lesion in the corticospinal tracts. Type 1, known as SPG1, is the most common form of X-linked HSP. This is produced by a mutation in the gene for the L1 cell adhesion molecule (L1CAM). SPG1 presents with CRASH syndrome (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus). CASE REPORTS: We report the cases of three males, two brothers and a cousin (on the mother's side), with clinical features including intellectual disability, spastic paraparesis, long tract signs, facial dysmorphism and adducted thumbs. Neuroimaging revealed agenesis of the corpus callosum and ventriculomegaly in all three of them. Neurophysiological and metabolic studies were normal. The genetic study evidenced a specific mutation of the L1CAM gene (Xq28) in all three cases. CONCLUSION: We describe the clinical-radiological findings in three males with CRASH syndrome due to mutation c.516G>A in exon 5 of the L1CAM gene. These seem to be the first cases reported in Spain, according to the current literature. We recommend suspecting this syndrome when spastic paraparesis, intellectual disability and adducted thumbs are associated.
TITLE: Paraplejia espastica hereditaria ligada al cromosoma X por mutacion en el gen L1CAM: presentacion de tres casos del sindrome CRASH.Introduccion. La paraplejia espastica hereditaria (PEH) representa un conjunto de cuadros clinicos neurodegenerativos que se caracteriza por perdida progresiva de fuerza en los miembros inferiores con espasticidad. Esto se debe a una lesion axonal en los haces corticoespinales. La de tipo 1, conocida como SPG1, es la forma mas comun de PEH ligada al cromosoma X. Esta se produce por una mutacion en el gen de la molecula de adhesion celular L1 (L1CAM). La SPG1 se manifiesta con el sindrome CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus). Casos clinicos. Tres varones, dos hermanos y un primo (materno), con un cuadro clinico de discapacidad intelectual, paraparesia espastica, piramidalismo, dismorfias faciales y pulgares en aduccion. La neuroimagen mostro agenesia del cuerpo calloso y ventriculomegalia en los tres. Los estudios neurofisiologico y metabolico fueron normales. El estudio genetico evidencio en todos ellos una mutacion concreta en el gen L1CAM (Xq28). Conclusion. Se describen los hallazgos clinicorradiologicos de tres varones afectos de sindrome CRASH por mutacion c.516G>A en el exon 5 del gen L1CAM. Estos parecen ser los primeros casos descritos en España segun la bibliografia actual. Recomendamos sospechar este sindrome cuando se asocian paraparesia espastica, discapacidad intelectual y pulgares aductos.
Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/genética , Discapacidad Intelectual/genética , Mutación , Molécula L1 de Adhesión de Célula Nerviosa/genética , Paraplejía Espástica Hereditaria/genética , Adolescente , Niño , Humanos , Masculino , Linaje , FenotipoRESUMEN
INTRODUCTION: Pallister-Killian syndrome is characterised by intellectual disability, hypotonia, motor disability and a characteristic phenotype in which notable features include a rugged-looking face, alterations affecting the pigmentation of the skin and bitemporal alopecia. It is often associated with seizures and malformations in other organs and systems. The main cause is mosaicism for tetrasomy of chromosome 12p. CASE REPORTS: We present three new paediatric cases of this rare entity, its clinical features are described and a literature review is carried out. CONCLUSIONS: It is important to be familiar with the syndrome so that it can be diagnosed, since what commonly happens is that, without performing a skin biopsy or buccal smear, the chromosomal abnormality goes undetected if the classic cytogenetic techniques are used. Nowadays, the diagnosis can be performed in blood by means of CGH-array or SNP-array, although the chances of finding the chromosomal anomaly depend on the percentage of mosaicism.
TITLE: Presentacion de tres casos de sindrome de Pallister-Killian.Introduccion. El sindrome de Pallister-Killian se caracteriza por discapacidad intelectual, hipotonia, retraso motor y un fenotipo caracteristico en el que destaca un aspecto facial tosco, alteraciones pigmentarias de la piel y alopecia bitemporal. Es frecuente que se asocie a crisis convulsivas y a malformaciones en otros organos y sistemas. Tiene como causa principal el mosaicismo para la tetrasomia del cromosoma 12p. Casos clinicos. Se presentan tres nuevos casos pediatricos afectos de esta rara entidad, se describen las caracteristicas clinicas y se realiza una revision de la bibliografia. Conclusiones. Debe resaltarse la importancia del conocimiento del sindrome para poder llevar a cabo su diagnostico, puesto que lo habitual es que, sin practicar la biopsia cutanea o el frotis de mucosa bucal, la anomalia cromosomica pasa desapercibida si se usan tecnicas citogeneticas clasicas. Hoy en dia, es posible realizar el diagnostico en sangre mediante array-CGH o array-SNP, si bien la posibilidad de encontrar la anomalia cromosomica depende del porcentaje de mosaicismo.
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Trastornos de los Cromosomas/genética , Alopecia/genética , Niño , Preescolar , Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 12/genética , Discapacidades del Desarrollo/genética , Epilepsia/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/genética , Isocromosomas , Masculino , Mosaicismo , Fenotipo , Trastornos de la Pigmentación/genética , TetrasomíaRESUMEN
INTRODUCTION: Familial hemiplegic migraine is a rare subtype of migraine with aura that includes, as it progresses, a motor defect together with visual or sensory symptoms or speech disorders. It may be associated to symptoms such as basilar migraine, coma and convulsions. Familial hemiplegic migraine type 2 accounts for 25% of them. CASE REPORTS: Two patients, who started at the age of 4 years with episodes of motor deficits or seizures, together with an important sensory disorder that lasted for hours, which were sometimes triggered by banal traumatic injuries. A detailed description of the clinical and developmental features, as well as the studies conducted, is provided. The genetic study revealed mutations in gene ATP1A2: in one case this consisted in a nucleotide substitution in exon 18 (G2501A) that had already been reported, while in the other case there was a previously unknown change (c.381+3 G>T) in intron 4. CONCLUSIONS: We recommend that this condition should be suspected when a disagreement between the duration or the severity of the seizures and the duration and characteristics of the ensuing stupor is detected.
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Migraña con Aura/fisiopatología , Adolescente , Preescolar , Humanos , Masculino , Migraña con Aura/complicaciones , Migraña con Aura/diagnóstico , Migraña con Aura/genética , Mutación , Convulsiones/etiología , Convulsiones/fisiopatología , ATPasa Intercambiadora de Sodio-Potasio/genética , Estupor/etiología , Estupor/fisiopatologíaRESUMEN
Introducción. La paraplejía espástica hereditaria (PEH) representa un conjunto de cuadros clínicos neurodegenerativos que se caracteriza por pérdida progresiva de fuerza en los miembros inferiores con espasticidad. Esto se debe a una lesión axonal en los haces corticoespinales. La de tipo 1, conocida como SPG1, es la forma más común de PEH ligada al cromosoma X. Ésta se produce por una mutación en el gen de la molécula de adhesión celular L1 (L1CAM). La SPG1 se manifiesta con el síndrome CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus). Casos clínicos. Tres varones, dos hermanos y un primo (materno), con un cuadro clínico de discapacidad intelectual, paraparesia espástica, piramidalismo, dismorfias faciales y pulgares en aducción. La neuroimagen mostró agenesia del cuerpo calloso y ventriculomegalia en los tres. Los estudios neurofisiológico y metabólico fueron normales. El estudio genético evidenció en todos ellos una mutación concreta en el gen L1CAM (Xq28). Conclusión. Se describen los hallazgos clinicorradiológicos de tres varones afectos de síndrome CRASH por mutación c.516G>A en el exón 5 del gen L1CAM. Éstos parecen ser los primeros casos descritos en España según la bibliografía actual. Recomendamos sospechar este síndrome cuando se asocian paraparesia espástica, discapacidad intelectual y pulgares aductos
Introduction. Hereditary spastic paraplegia (HSP) is a set of neurodegenerative clinical features characterised by a progressive loss of strength in the lower limbs together with spasticity. It is the result of an axonal lesion in the corticospinal tracts. Type 1, known as SPG1, is the most common form of X-linked HSP. This is produced by a mutation in the gene for the L1 cell adhesion molecule (L1CAM). SPG1 presents with CRASH syndrome (corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus). Case reports. We report the cases of three males, two brothers and a cousin (on the mothers side), with clinical features including intellectual disability, spastic paraparesis, long tract signs, facial dysmorphism and adducted thumbs. Neuroimaging revealed agenesis of the corpus callosum and ventriculomegaly in all three of them. Neurophysiological and metabolic studies were normal. The genetic study evidenced a specific mutation of the L1CAM gene (Xq28) in all three cases. Conclusion. We describe the clinical-radiological findings in three males with CRASH syndrome due to mutation c.516G>A in exon 5 of the L1CAM gene. These seem to be the first cases reported in Spain, according to the current literature. We recommend suspecting this syndrome when spastic paraparesis, intellectual disability and adducted thumbs are associated
Asunto(s)
Humanos , Masculino , Niño , Adolescente , Moléculas de Adhesión de Célula Nerviosa , Enfermedades Genéticas Ligadas al Cromosoma X , Discapacidad Intelectual/genética , Mutación , Paraplejía Espástica Hereditaria/genética , Fenotipo , LinajeRESUMEN
Introducción. El síndrome de Aicardi-Goutières es una rara encefalopatía subaguda progresiva de inicio precoz -generalmente en el primer año de vida- caracterizada por retraso psicomotor, microcefalia, alteraciones en la sustancia blanca cerebral, calcificaciones intracraneales, pleocitosis y niveles elevados de interferón alfa en el líquido cefalorraquídeo. Asocia un incremento en la expresión de los genes estimulados por interferón en la sangre periférica, hecho conocido como interferon signature. Los niveles de genes estimulados por interferón se han postulado como un buen biomarcador, pues se mantienen elevados en la sangre periférica en el tiempo y son más sensibles, en comparación con las determinaciones de interferón alfa y neopterinas en el líquido cefalorraquídeo, las cuales descienden a partir del año de vida. Hasta la fecha se han descrito mutaciones en siete genes que sobreestimulan la vía del interferón alfa, y el último en descubrirse ha sido el IFIH1 (interferon induced with helicase C domain 1), con un patrón de herencia autosómico dominante. Caso clínico. Se presenta el primer caso descrito en la bibliografía hispana debido a mutación de novo en el gen IFIH1. Se expone el cuadro clínico, los estudios realizados y la revisión de los aspectos clínicos, neurorradiológicos y genéticos. Conclusiones. La herencia de las mutaciones descritas para el síndrome de Aicardi-Goutières era clásicamente autosómica recesiva, pero estos hallazgos muestran que mutaciones autosómicas dominantes en el gen IFIH1 pueden causar la enfermedad. Como hallazgo de neuroimagen no descrito previamente, presenta una lesión de encefalomalacia quística en la protuberancia (AU)
Introduction. Aicardi-Goutières syndrome is a rare progressive subacute encephalopathy of early onset -generally in the first year of life- characterised by psychomotor retardation, microcephaly, alterations in the white matter of the brain, intracranial calcifications, pleocytosis and elevated levels of interferon alpha in the cerebrospinal fluid. It is associated to an increase in the expression of genes stimulated by interferon in peripheral blood, a fact known as the interferon signature. The levels of genes stimulated by interferon has been postulated as a good biomarker, as they remain high in peripheral blood over time and are more sensitive, in comparison to determinations of interferon alpha and neopterins in cerebrospinal fluid, which descend as of one year of life. To date, mutations have been reported in seven genes that overstimulate the interferon alpha pathway, and the last to be discovered is IFIH1 (interferon induced with helicase C domain 1), with a pattern of dominant autosomal inheritance. Case report. We present the first case reported in the Hispanic literature caused by a de novo mutation in the IFIH1 gene. The clinical features, studies conducted and review of the clinical, neuroradiological and genetic aspects are described. Conclusions. The inheritance of the mutations reported for Aicardi-Goutières syndrome was classically considered as being recessive autosomal, but these findings show that dominant autosomal mutations in the IFIH1 gene can cause the disease. As a previously unreported neuroimaging finding, it presents a lesion consisting in cystic encephalomalacia in the pons (AU)