Rapid Molecular Diagnosis of Genetically Inherited Neuromuscular Disorders Using Next-Generation Sequencing Technologies.

Neuromuscular diseases are genetically highly heterogeneous, and differential diagnosis can be challenging. Over a 3-year period, we prospectively analyzed 268 pediatric and adult patients with a suspected diagnosis of inherited neuromuscular disorder (INMD) using comprehensive gene-panel analysis and next-generation sequencing. The rate of diagnosis increased exponentially with the addition of genes to successive versions of the INMD panel, from 31% for the first iteration (278 genes) to 40% for the last (324 genes). The global mean diagnostic rate was 36% (97/268 patients), with a diagnostic turnaround time of 4-6 weeks. Most diagnoses corresponded to muscular dystrophies/myopathies (68.37%) and peripheral nerve diseases (22.45%). The most common causative genes, TTN, RYR1, and ANO5, accounted for almost 30% of the diagnosed cases. Finally, we evaluated the utility of the differential diagnosis tool Phenomizer, which established a correlation between the phenotype and molecular findings in 21% of the diagnosed patients. In summary, comprehensive gene-panel analysis of all genes implicated in neuromuscular diseases facilitates a rapid diagnosis and provides a high diagnostic yield.

Impact of COVID-19 in Immunosuppressed Children With Neuroimmunologic Disorders.

BACKGROUND AND OBJECTIVES: To investigate whether children receiving immunosuppressive therapies for neuroimmunologic disorders had (1) increased susceptibility to SARS-CoV2 infection or to develop more severe forms of COVID-19; (2) increased relapses or autoimmune complications if infected; and (3) changes in health care delivery during the pandemic. METHODS: Patients with and without immunosuppressive treatment were recruited to participate in a retrospective survey evaluating the period from March 14, 2020, to March 30, 2021. Demographics, clinical features, type of immunosuppressive treatment, suspected or confirmed COVID-19 in the patients or cohabitants, and changes in care delivery were recorded. RESULTS: One hundred fifty-three children were included: 84 (55%) female, median age 13 years (interquartile range [8-16] years), 79 (52%) on immunosuppressive treatment. COVID-19 was suspected or confirmed in 17 (11%) (all mild), with a frequency similar in patients with and without immunosuppressive treatment (11/79 [14%] vs 6/74 [8%], p = 0.3085). The frequency of neurologic relapses was similar in patients with (18%) and without (21%) COVID-19. Factors associated with COVID-19 included having cohabitants with COVID-19 (p < 0.001) and lower blood levels of vitamin D (p = 0.039). Return to face-to-face schooling or mask type did not influence the risk of infection, although 43(28%) children had contact with a classmate with COVID-19. Clinic visits changed from face to face to remote for 120 (79%) patients; 110 (92%) were satisfied with the change. DISCUSSION: In this cohort of children with neuroimmunologic disorders, the frequency of COVID-19 was low and not affected by immunosuppressive therapies. The main risk factors for developing COVID-19 were having cohabitants with COVID-19 and low vitamin D levels.

First female with Allan-Herndon-Dudley syndrome and partial deletion of X-inactivation center.

Allan-Herndon-Dudley is an X-linked recessive syndrome caused by pathogenic variants in the SLC16A2 gene. Clinical manifestations are a consequence of impaired thyroid metabolism and aberrant transport of thyroid hormones to the brain. Carrier females are generally asymptomatic and may show subtle symptoms of the disease. We describe a female with a complete Allan-Herndon-Dudley phenotype, carrying a de novo 543-kb deletion of the X chromosome. The deletion encompasses exon 1 of the SLC16A2 gene and JPX and FTX genes; it is known that the latter two genes participate in the X-inactivation process upregulating XIST gene expression. Subsequent studies in the patient demonstrated the preferential expression of the X chromosome with the JPX and FTX deletion.

New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy.

Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3-6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.

Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert / Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease

Antecedentes y objetivos: La enfermedad de Steinert o distrofia miotónica tipo 1 (DM1), (OMIM 160900) es la miopatía más prevalente en el adulto. Es una enfermedad multisistémica con alteración de prácticamente todos los órganos y tejidos y una variabilidad fenotípica muy amplia, lo que implica que deba ser atendida por diferentes especialistas que dominen las alteraciones más importantes. En los últimos años se ha avanzado de manera exponencial en el conocimiento de la enfermedad y en su manejo. El objetivo de la guía es establecer recomendaciones para el diagnóstico, el pronóstico, el seguimiento y el tratamiento de las diferentes alteraciones de la DM1. Material y métodos: Esta guía de consenso se ha realizado de manera multidisciplinar. Se ha contado con neurólogos, neumólogos, cardiólogos, endocrinólogos, neuropediatras y genetistas que han realizado una revisión sistemática de la literatura. Recomendaciones: Se recomienda realizar un diagnóstico genético con cuantificación precisa de tripletes CTG. Los pacientes con DM1 deben seguir control cardiológico y neumológico de por vida. Antes de cualquier cirugía con anestesia general debe realizarse una evaluación respiratoria. Debe monitorizarse la presencia de síntomas de disfagia periódicamente. Debe ofrecerse consejo genético a los pacientes con DM1 y a sus familiares. Conclusión: La DM1 es una enfermedad multisistémica que requiere un seguimiento en unidades especializadas multidisciplinares

Background and objectives: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. Material and methods: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. Recommendations: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. Conclusion: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up

Autosomal dominant distal myopathy with nemaline rods due to p.Glu197Asp mutation in ACTA1.

In a previous report of a new phenotype with predominant scapulo-humeral-peroneal-distal myopathy associated with the Glu197Asp mutation in ACTA1, muscle biopsies did not show nemaline rods, nor could nemaline rods formation be demonstrated in an exhaustive functional in vivo or in vitro study. However, muscle biopsy in members of our family, carrying a similar clinical phenotype of some members of the original family and the same ACTA1 mutation, revealed the presence of numerous nemaline rods, suggesting that there must be other factors that explain the absence of nemaline rods.

Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert's disease. / Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert.

BACKGROUND AND OBJECTIVES: Steinert's disease or myotonic dystrophy type 1 (MD1), (OMIM 160900), is the most prevalent myopathy in adults. It is a multisystemic disorder with dysfunction of virtually all organs and tissues and a great phenotypical variability, which implies that it has to be addressed by different specialities with experience in the disease. The knowledge of the disease and its management has changed dramatically in recent years. This guide tries to establish recommendations for the diagnosis, prognosis, follow-up and treatment of the complications of MD1. MATERIAL AND METHODS: Consensus guide developed through a multidisciplinary approach with a systematic literature review. Neurologists, pulmonologists, cardiologists, endocrinologists, neuropaediatricians and geneticists have participated in the guide. RECOMMENDATIONS: The genetic diagnosis should quantify the number of CTG repetitions. MD1 patients need cardiac and respiratory lifetime follow-up. Before any surgery under general anaesthesia, a respiratory evaluation must be done. Dysphagia must be screened periodically. Genetic counselling must be offered to patients and relatives. CONCLUSION: MD1 is a multisystemic disease that requires specialised multidisciplinary follow-up.

Hydrocephalus in pyridoxine-dependent epilepsy: New case and literature review.

INTRODUCTION: Pyridoxine-dependent epilepsy (PDE) is a rare disorder of the lysine metabolism, characterized by a pharmacoresistant epileptic encephalopathy that usually begins in the neonatal period. However, its phenotypic spectrum is wide and not limited to seizures. We report a new case of PDE who developed hydrocephalus, along with an exhaustive review of the literature. CASE REPORT: Our patient presented with seizures at 13 h of life. Antiepileptic drugs, vitamins and cofactors were required to achieve seizure control. Laboratory tests were congruent with PDE. She remained seizure-free until age five months, when seizures reappeared in the context of increasing head size and irritability. A cranial ultrasound showed hydrocephalus, for which she underwent ventriculoperitoneal shunting. DISCUSSION: Seven other patients with same features have been previously reported. Seizure onset occurred within the first 7 days in all patients. Most of the children developed hydrocephalus at 6-7 months of age. In 4 out of 7 a genetic mutation was identified, despite the accurate etiology of hydrocephalus was unknown in most of them. The case we report behaved similarly to the others previously described. We postulate that the pathogenesis of this complication could be related to the high expression of antiquitin in choroid plexus epithelium, where the cerebrospinal fluid is produced. CONCLUSIONS: patients with PDE should be closely monitored, since they may present severe complications. We highlight the development of hydrocephalus, an uncommon but potentially life-threatening problem reported in 8 patients up to present time.

Parálisis braquial obstétrica: incidencia, seguimiento evolutivo y factores pronósticos / Obstetric brachial plexus palsy: incidence, monitoring of progress and prognostic factors

Introducción. La parálisis braquial obstétrica se relaciona con la distocia de hombros, y su principal factor de riesgo es la macrosomía. Su incidencia se estima entre 0,1 y 6,3 casos por 1.000 recién nacidos vivos. La mayoría de los casos se resuelve, pero puede provocar déficit funcional permanente, por lo que es de interés identificar posibles factores pronósticos. Pacientes y métodos. Estudio descriptivo de los recién nacidos con parálisis del plexo braquial obstétrica nacidos en el hospital entre los años 2011 y 2015. Se han recogido variables maternas, perinatales, obstétricas y del tipo de lesión, y se han relacionado con la posibilidad de la recuperación a los seis meses. Resultados. Se diagnosticaron 32 casos, lo que supone una incidencia del 1,44‰ de recién nacidos vivos. El 59% fueron varones, y el 37,5%, macrosómicos. La afectación más frecuente fue la lesión del plexo a nivel proximal (94%). El 44% sufrió distocia de hombros, y el 47% permaneció con secuelas al sexto mes. El antecedente de distocia de hombros se relacionó con mal pronóstico de recuperación. Conclusiones. La incidencia de parálisis braquial obstétrica se mantiene estable en los últimos años. El porcentaje de niños que presentan secuelas a los seis meses es relevante. Son necesarios estudios prospectivos para poder establecer los factores pronósticos a largo plazo de esta patología (AU)

Introduction. Obstetric brachial plexus palsy is related with shoulder dystocia, and its main risk factor is macrosomia. Its incidence is estimated to be between 0.1 and 6.3 cases per 1,000 live newborn infants. Most cases are resolved but can give rise to permanent functional deficiency, which means that there is an interest to identify possible prognostic factors. Patients and methods. We conducted a descriptive study of newborn infants with obstetric brachial plexus palsy born in our hospital between the years 2011 and 2015. Maternal, perinatal and obstetric variables, as well as the type of lesion, were collected and were related with the possibility of recovery at six months. Results. Altogether 32 cases were diagnosed, which represents an incidence of 1.44‰ of live newborn infants. 59% were males and 37.5% of them were macrosomic. The most frequent disorder was injury to the plexus at the proximal level (94%). 44% suffered from shoulder dystocia, and 47% still had sequelae at the sixth month. The antecedent of shoulder dystocia was related with a poor prognosis for recovery. Conclusions. The incidence of obstetric brachial plexus palsy has remained stable in recent years. The percentage of children who present sequelae at six months is significant. Prospective studies are needed to be able to establish the longterm prognostic factors of this pathology (AU)

Parálisis bilateral delVI par craneal como manifestación inicial de la meningitis meningocócica / Bilateral abducens nerve palsy as the initial clinical manifestation of meningococcal meningitis

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Ictus isquémico presumiblemente perinatal: factores de riesgo, hallazgos clínicos y radiológicos / Presumed perinatal ischemic stroke: risk factors and clinical and radiological findings

Introducción. El ictus isquémico presumiblemente perinatal es una causa frecuente de secuelas neurológicas importantes. Los objetivos del estudio son describir las características clínicas y los factores de riesgo implicados, y analizar las diferencias según su origen vascular. Pacientes y métodos. Estudio descriptivo retrospectivo que incluye pacientes con diagnóstico de ictus isquémico presumiblemente perinatal atendidos en un hospital terciario entre 1990-2015. Resultados. Se incluyeron 44 pacientes: 24 (55%) fueron de origen arterial, frente a 20 (45%) de origen venoso. El diagnóstico fue significativamente más tardío en los de origen venoso que en los de origen arterial (14 y 8 meses respectivamente; p = 0,025). La mayoría comenzó con un déficit motor (90%), y las crisis epilépticas y el retraso psicomotor global fueron menos frecuentes en ambos grupos (< 5%). La prevalencia de epilepsia posterior fue significativamente más frecuente entre los de origen arterial (p = 0,020). Se analizaron los factores de riesgo teóricamente implicados en su patogenia: prenatales, obstétricos, perinatales, protrombóticos y cardíacos, sin hallarse diferencias significativas en la presencia de éstos entre los infartos arteriales y los venosos. Encontramos la presencia de al menos una alteración en el estudio de hipercoagulabilidad en el 48,3% de los pacientes. Conclusión. Es preciso investigar el papel que desempeñan los factores de riesgo implicados en el ictus isquémico presumiblemente perinatal para establecer medidas preventivas. Su diagnóstico es más tardío si el origen es venoso (AU)

Introduction. Presumed perinatal ischemic stroke is a frequent cause of neurological sequelae. We aimed to describe the different clinical findings and risk factors and to analyse the differences according the vascular origin. Patients and methods. Retrospective, descriptive study of patients diagnosed with presumed perinatal ischemic stroke attended at a tertiary pediatric hospital from 1990 to 2015. Results. 44 patients were included. A total of 24 patients (55%) had arterial ischemic stroke and 20 (45%) had periventricular venous infarction. Delay in diagnosis was significantly higher in patients with periventricular venous infarction compared to those with arterial ischemic stroke (14 and 8 months respectively; p = 0.025). Most patients presented with asymmetrical motor development (90%), only < 5% with seizures or non motor delays. Subsequent epilepsy at follow-up was significantly more prevalent in arterial ischemic stroke group (p = 0.020). We determined risk factors theoretically involved in the pathogenesis of presumed perinatal ischemic stroke: prenatal, obstetrical, perinatal, prothrombotic and cardiac. No significant differences between risk factors and vascular origin were found. Prothrombotic abnormalities were common (48.3%). Conclusions. Investigation in risk factors implicated in presumed perinatal ischemic stroke is required to develop prevention strategies. Delay in diagnosis is higher in periventricular venous infarction group (AU)

Alteraciones del lenguaje en la cerebelitis aguda: más allá de la disartria / Language disorders in acute cerebellitis: beyond dysarthria

Introducción. La cerebelitis aguda es una de las principales causas de síndrome cerebeloso en la infancia. Entre un amplio elenco de manifestaciones, en el que predominan la cefalea y la ataxia, podemos encontrar otras menos habituales, aunque interesantes, como las alteraciones del lenguaje, más allá de la bien conocida disartria cerebelosa. Las diferentes combinaciones en que pueden aparecer los síntomas, especialmente cuando no se acompañan de ataxia, hacen de este cuadro un verdadero reto para el clínico. Casos clínicos. Se presentan dos pacientes, de 2 y 4 años, con clínica, pruebas de laboratorio y neuroimagen compatibles con cerebelitis aguda parainfecciosa, que asociaron una llamativa alteración del lenguaje, uno en forma de mutismo cerebeloso y otro en forma de hipofluencia y agramatismo, y este último cursaba además en ausencia de ataxia. La evolución de ambos casos fue buena, y persistieron leves alteraciones del habla en el seguimiento posterior. Conclusiones. Casos como éstos amplían el espectro de manifestaciones clínicas de la cerebelitis aguda. Cada vez cobra mayor importancia la participación del cerebelo en procesos neurocognitivos como el lenguaje y, aunque muchos aspectos son aún especulativos, alcanzar a definir su verdadero papel tendrá una repercusión en el diagnóstico, el tratamiento y el pronóstico a largo plazo de estos pacientes (AU)

Introduction. Acute cerebellitis is one of the main causes of cerebellar syndrome in infancy. Among the wide range of manifestations, headache and ataxia being the most predominant, we can find other less frequent, although nonetheless interesting, ones, such as language disorders, which go beyond the well-known cerebellar dysarthria. The different combinations in which the symptoms can appear, especially when not accompanied by ataxia, make the condition a real challenge for the clinician. Case reports. Two patients, aged 2 and 4 years, with clinical features, lab tests and neuroimaging results consistent with parainfectious acute cerebellitis. Both of them also presented a striking language disorder, one in the form of cerebellar mutism and the other in the form of hypofluency and agrammatism, the latter also developing in the absence of ataxia. Both cases progressed favourably, and mild speech alterations persisted in the follow-up visits. Conclusions. Cases such as these expand the range of clinical manifestations of acute cerebellitis. The involvement of the cerebellum in neurocognitive processes like language is becoming increasingly more important and, although many aspects are still only speculations, managing to define its true role will have important repercussions on the diagnosis, treatment and long-term prognosis of these patients (AU)

Hipotensión intracraneal idiopática asociada a disrafismo espinal oculto / Idiopathic intracranial hypotension associated with occult spinal dysraphism

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Disección carotídea como causa de ictus perinatal / Carotid dissection as the cause of perinatal strokes

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