[Hemicerebellitis due to chikungunya associated with refractory status epilepticus in the paediatric age]. / Hemicerebelitis por chikungunya asociado a estado epiléptico refractario en edad pediátrica.

TITLE: Hemicerebelitis por chikungunya asociado a estado epiléptico refractario en edad pediátrica.

Salbutamol tolerability and efficacy in patients with spinal muscular atrophy type II.

Spinal muscular atrophy (SMA) is an autosomal recessive disease caused by homozygous deletions or loss-of-function mutations in SMN1, which result in a degeneration of motor neurons in the spinal cord and brain stem. Even without a randomized placebo-controlled trial, salbutamol has been offered to patients with SMA in the neuromuscular clinics of most of hospitals for many years. We describe the response to salbutamol in 48 patients with SMA type II who were not taking any other medication. We investigate the changes over an eighteen-month period in motor functional scales and we analyze side effects and subjective response to treatment. Our results suggest that oral administration of salbutamol might be helpful in the maintenance of motor function in patients with SMA type II. An apparent beneficial effect was observed in functional scales of children under the age of 6, especially during the first 6 months of therapy. The majority of patients of all ages referred some kind of subjective positive effect associated with therapy intake. Salbutamol seemed safe and was well tolerated without serious side effects.

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.

Outbreak of brainstem encephalitis associated with enterovirus-A71 in Catalonia, Spain (2016): a clinical observational study in a children's reference centre in Catalonia.

OBJECTIVES: To describe the characteristics of an outbreak of brainstem encephalitis and encephalomyelitis related to enterovirus (EV) infection in Catalonia (Spain), a setting in which these manifestations were uncommon. METHODS: Clinical and microbiological data were analysed from patients with neurological symptoms associated with EV detection admitted to a reference paediatric hospital between April and June 2016. RESULTS: Fifty-seven patients were included. Median age was 27.7 months (p25-p75 17.1-37.6). Forty-one (72%) were diagnosed with brainstem encephalitis, seven (12%) with aseptic meningitis, six (11%) with encephalitis, and three (5%) with encephalomyelitis (two out of three with cardiopulmonary failure). Fever, lethargy, and myoclonic jerks were the most common symptoms. Age younger than 12 months, higher white-blood-cell count, and higher procalcitonin levels were associated with cardiopulmonary failure. Using a PAN-EV real-time PCR, EV was detected in faeces and/or nasopharyngeal aspirate in all the patients, but it was found in cerebrospinal fluid only in patients with aseptic meningitis. EV was genotyped in 47 out of 57 and EV-A71 was identified in 40 out of 47, being the only EV type found in patients with brainstem symptoms. Most of the detected EV-A71 strains were subgenogroup C1. Intravenous immunoglobulins were used in 34 patients. Eight cases (14%) were admitted to the intensive care unit. All the patients but three, those with encephalomyelitis, showed a good clinical course and had no significant sequelae. No deaths occurred. CONCLUSIONS: The 2016 outbreak of brainstem encephalitis in Catalonia was associated with EV-A71 subgenogroup C1. Despite the clinical manifestations of serious disease, a favourable outcome was observed in the majority of patients.

Phenotypic heterogeneity in two large Roma families with a congenital myasthenic syndrome due to CHRNE 1267delG mutation. A long-term follow-up.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders. Mutations in CHRNE are one of the most common cause of them and the ɛ1267delG frameshifting mutation is described to be present on at least one allele of 60% of patients with CHRNE mutations. We present a comprehensive description of the heterogeneous clinical features of the CMS caused by the homozygous 1267delG mutation in the AChR Ɛ subunit in nine members of two large Gipsy kindreds. Our observations indicate that founder Roma mutation 1267delG leads to a phenotype further characterized by ophthalmoplegia, bilateral ptosis, and good response to pyridostigmine and 3,4-DAP; but also by facial weakness, bulbar symptoms, neck muscle weakness, and proximal limb weakness that sometimes entails the loss of ambulation. Interestingly, we found in our series a remarkable proportion of patients with a progressive or fluctuating course of the disease. This finding is in some contrast with previous idea that considered this form of CMS as benign, non progressive, and with a low impact on the capacity of ambulation.

Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations.

Rapsyn (RAPSN) mutations are a common cause of postsynaptic congenital myasthenic syndromes. We present a comprehensive description of the clinical and molecular findings of ten patients with CMS due to mutations in RAPSN, mostly with a long-term follow-up. Two patients were homozygous and eight were heterozygous for the common p.Asn88Lys mutation. In three of the heterozygous patients we have identified three novel mutations (c.869T > C; p.Leu290Pro, c.1185delG; p.Thr396Profs*12, and c.358delC; p.Gln120Serfs*8). In our cohort, the RAPSN mutations lead to a relatively homogeneous phenotype, characterized by fluctuating ptosis, occasional bulbar symptoms, neck muscle weakness, and mild proximal muscle weakness with exacerbations precipitated by minor infections. Interestingly, episodic exacerbations continue to occur during adulthood. These were characterized by proximal limb girdle weakness and ptosis, and not so much by respiratory insufficiency after age 6. All patients presented during neonatal period and responded to cholinergic agonists. In most of the affected patients, additional use of 3,4-diaminopyridine resulted in significant clinical benefit. The disease course is stable except for intermittent worsening.

KLHL40-related nemaline myopathy with a sustained, positive response to treatment with acetylcholinesterase inhibitors.

Congenital myopathies are a group of inherited muscle disorders characterized by hypotonia, weakness and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. Neuromuscular transmission defects have recently been reported in several patients with congenital myopathies (CM). Mutations in KLHL40 are among the most common causes of severe forms of nemaline myopathy. Clinical features of affected individuals include fetal akinesia or hypokinesia, respiratory failure, and swallowing difficulties at birth. Muscle weakness is usually severe and nearly half of the individuals have no spontaneous antigravity movement. The average age of death has been reported to be 5 months in a recent case series. Herein we present a case of a patient with a nemaline myopathy due to KLHL40 mutations (c.604delG, p.Ala202Argfs*56 and c.1513G>C, p.Ala505Pro) with an impressive and prolonged beneficial response to treatment with high-dose pyridostigmine. Myasthenic features or response to ACEI have not previously been reported as a characteristic of nemaline myopathy or KLHL40-related myopathy.

Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency.

Tyrosine hydroxylase (TH) deficiency is an inborn error of dopamine biosynthesis and a cause of early parkinsonism. Two clinical phenotypes have been described. Type "B": early onset severe encephalopathy; type "A": later onset, less severe and better response to L-dopa. We aimed to study the expression of several key dopaminergic and gabaergic synaptic proteins in the cerebrospinal fluid (CSF) of a series of patients with TH deficiency and their possible relation with the clinical phenotype and response to L-DOPA. Dopamine transporter (DAT), D2-receptor and vesicular monoamine transporter (VMAT2) were measured in the CSF of 10 subjects with TH deficiency by Western blot analysis. In 3 patients, data of pre- and post-treatment with L-DOPA were available, and in one of them, GABA vesicular transporter was determined. Results were compared to an age-matched control population. The concentration of D2-receptors in CSF was significantly higher in patients with TH deficiency than in controls. Similarly, DAT and vesicular monoamine transporter type 2 were up-regulated. Studies performed before L-DOPA, and on L-DOPA therapy showed a paradoxical response with D2 receptor expression increase as L-Dopa doses and homovanillic concentration gradually raised in a B phenotype patient. The opposite results were found in two patients with A phenotype. However, this is a very small sample, and further studies are needed to conclude robust differences between phenotypes. Synaptic proteins are detectable in the CSF and their quantification can be useful for understanding the pathophysiology of neurotransmitter defects and potentially to adjust and personalize treatments in the future.

Síndrome de Down y epilepsia / Down’s syndrome and epilepsy

El síndrome de Down (SD) es la primera causa genética de retraso mental: afecta aproximadamente a uno de cada 660 nacimientos. Se asocia con numerosas complicaciones eurológicas, como la demencia de inicio precoz (similar a la enfermedad de Alzheimer), a enfermedad de moyamoya, la laxitud de ligamentos espinales y la epilepsia. La prevalencia de epilepsia en individuos con SD es mayor que en la población en general, con tasas que varían entre el 1% y el 13% y una media del 5,5%. La mayor propensión de estos pacientes a desarrollar epilepsia está relacionada con anomalías estructurales y moleculares del cerebro y con complicaciones secundarias. También se sabe que poseen menos células que contienen gránulos de ácido γ-aminobutírico y una concentración mayor de glutamato que favorece un estado hiperexcitatorio. El síndrome de West, con espasmos infantiles (EI), es el síndrome epiléptico más común en los niños con SD. Hay muchas anomalías en el electroencefalograma (EEG) asociadas con el SD, pero sin que se haya establecido ningún patrón específico. El esquema terapéutico de elección para los EI suele incluir hormona adrenocorticotropa, valproato y vigabatrina, pero no se ha demostrado que exista una diferencia significativa entre los distintos esquemas terapéuticos. Diversos estudios ponen de manifiesto que la población infantil con SD tiene un mejor control de la epilepsia cuando se compara con la de niños con EI asociados a otras causas. En adultos con SD se han descrito convulsiones focales, crisis reflejas y epilepsia mioclónica de inicio tardío asociada con demencia. En este artículo se presenta una revisión de la epilepsia en el SD (AU)

Down syndrome (DS) is the most common genetic cause of mental retardation affecting approximately one in 660 births. DS is associated with many neurological complications, including early-onset dementia that resembles Alzheimer’s disease, Moyamoya disease, strokes, spinal ligamentous laxity and epilepsy. The prevalence of epilepsy in individuals with DS is higher than in the general population, with rates ranging from 1 to 13%, with a media of 5.5%. The increased seizure susceptibility in DS has been attributed to inherent structural and molecular anomalies of the brain and to secondary complications. Among other facts patients with DS have less inhibitory γ-aminobutiric acid containing granule cells and an increased level of glutamate, which favours a hyperexcitable state. West syndrome, with infantile spasms, is the most common epilepsy syndrome in children with DS. There are many electroencephalographic (EEG) anomalies associated with DS but no specific pattern has been established. The primary drug choices for infantile spasms are adrenocorticotropic hormone, valproate and vigabatrine, but no significant difference has been demonstrated with different treatment options. Studies have shown that children with DS have better seizure control compared to other children with symptomatic infantile spasms. Other seizure types have been described in adult patients with DS including focal crisis, reflex seizures, and late-onset myoclonic epilepsy associated with dementia. This article provides an overview of epilepsy in DS (AU)

Infantile parkinsonism and GABAergic hypotransmission in a patient with pyruvate carboxylase deficiency.

Pyruvate carboxylase deficiency is a rare metabolic disorder, with three different phenotypes. We aim to report the case of a newborn presenting the severe neonatal form of this deficiency (the B or "French" phenotype, hypokinesia and rigidity being the main features) and the results of the study of classic neurotransmitters involved in movement control. Hyperdopaminergic transmission (both in the cerebrospinal fluid and in the substantia nigra) and hypoGABAergic transmission (in the substantia nigra) were found. Both gamma-aminobutyric acid and dopamine markers were found coexisting in individual neurons of the substantia nigra. This is the first time this phenomenon has been reported in the literature. We discuss the possible role of GABAergic deficiency, its interaction with other neurotransmitters and its implication in neurotransmitter homeostasis. A better comprehension of that field would increase understanding of the pathophysiology of neurological symptoms and neurotransmitter plasticity.

Hypokinetic-rigid syndrome in children and inborn errors of metabolism.

Hypokinetic-rigid syndrome (HRS) or "parkinsonism" is rare in children. From a clinical point of view it is characterised by a group of signs in which hypokinesia (decreased number of movements), bradykinesia (slowness of movements), rigidity and rest tremor are the fundamental traits. Nervous system infections, immunomediated encephalitis, hypoxia and some drugs have been described as acquired or secondary causes of HRS in the paediatric age. Inborn errors of metabolism (IEM) comprise and important group regarding genetic causes. Main diseases causing HRS in children are neurotransmitter (biogenic amines) defects, metal storage diseases, energy metabolism disorders and lysosomal diseases. In general, in IEM, the HRS is associated to other neurological signs such as dykinesias, pyramidal signs, and psychomotor delay, is very rare in the neonatal period, tends to be more frequent in advanced stages of progressive diseases, and may respond to specific therapies. In particular, l-dopa + carbidopa can be a very effective treatment in neurotransmitter defects, whereas other disorders such as Wilson disease and some particular lysosomal disorders have different therapeutic possibilities. Furthermore, other genetic conditions in dopa-responsive and non-responsive HRS should be also considered, especially in juvenile parkinsonism. Through this review, a practical orientation for paediatric neurologists concerning clinical clues, diagnostic procedure and treatment of metabolic HRS will be provided.