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.

[Myths and evidence on the use of botulinum toxin: spasticity in adults and in children with cerebral palsy]. / Mitos y evidencias en el empleo de la toxina botulinica: espasticidad del adulto y del nintilde;o con paralisis cerebral.

INTRODUCTION: Spasticity is a medical problem with a high incidence that significantly impact on the quality of life of patients and their families. AIM: To analyze and to answer different questions about the use of botulinum toxin type A (BTA) in our clinical practice. DEVELOPMENT: A group of experts in neurology develop a list of topics related with the use of BTA. Two big groups were considered: spasticity in adults and in children with cerebral palsy. A literature search at PubMed for English, French, and Spanish language articles published up to June 2016 was performed. The manuscript was structured as a questionnaire that includes those questions that, according to the panel opinion, could generate more controversy or doubt. The initial draft was reviewed by the expert panel members to allow for modifications, and after subsequent revisions for achieving the highest degree of consensus, the final text was then validated. Different questions about diverse aspects of spasticity in adults, such as methods for evaluating spasticity, infiltration techniques, doses, number of infiltration points, etc. Regarding spasticity in children with cerebral palsy, the document included questions about minimum age of infiltration, methods of analgesia, etc. CONCLUSIONS: This review is a tool for continuous training for neurologist and rehabilitation specialist and residents of both specialties, about different specific areas of the management of BTA.

TITLE: Mitos y evidencias en el empleo de la toxina botulinica: espasticidad del adulto y del nintilde;o con paralisis cerebral.Introduccion. La espasticidad es un problema medico frecuente que impacta de forma significativa en la calidad de vida de los pacientes y sus familias. Objetivo. Analizar y dar respuesta a diferentes cuestiones en el uso de la toxina botulinica tipo A (TBA) en nuestra practica clinica habitual. Desarrollo. Un grupo de expertos en neurologia elaboro una lista de temas relacionados con el uso de la TBA. Se consideraron dos grandes bloques: espasticidad del adulto y del nintilde;o con paralisis cerebral. Se realizo una revision de la bibliografia que incluyo los diferentes articulos publicados en espantilde;ol, ingles y frances hasta junio de 2016. El documento se estructuro como un cuestionario que incluyo las preguntas que, segun el criterio del panel, podrian generar mayor controversia o duda. El borrador inicial del documento fue revisado por los miembros del panel y se realizaron las modificaciones necesarias hasta alcanzar el mayor grado de consenso. A continuacion, el texto final fue validado. Se incluyeron diferentes preguntas sobre diferentes aspectos de la espasticidad en adultos: evaluacion de la espasticidad, tecnicas de infiltracion, dosis, numero de puntos, etc. En cuanto a la espasticidad en los nintilde;os con paralisis cerebral, se analizaron preguntas como: edad minima de infiltracion, metodos de sedoanalgesia, etc. Conclusiones. Esta revision constituye una herramienta para neurologos, medicos rehabilitadores y residentes de ambas especialidades, dentro de diferentes ambitos especificos del manejo de la TBA.

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.

[Adult-onset metabolic diseases]. / Enfermedades metabólicas de aparición en la edad adulta.

Inborn errors of metabolism (IEM) can have their onset in adolescence or in adulthood. Although it is difficult to contribute exact data on prevalence -because there are few studies in this respect, and IEM are regarded as infrequent- their detection is important due to the possibilities for therapy and family genetic counselling. The main symptoms of IEM in the adult are neurological, followed by hepatic. Two basic modes of onset can be established. One is acute, normally taking the form of consciousness alteration, lethargy, coma of unknown etiology in a previously healthy patient (urea cycle deficits, homocysteine remethylation disorders and porphyries are the most frequent causes). The other is an insidious, often progressive, chronic symptomathology that can involve complex clinical features, and more rarely a symptom that is isolated in a persistent way (Wilson's disease, mitochondrial diseases, lysosomal storage disorders, Refsum's disease and glycogenosis are some examples of this group). It is especially important to determine the forms of acute onset as these can present situations of extreme emergency where appropriate conduct can prevent the death of the patient. In this case, simple laboratory examinations, such as determination of ammonia, homocysteine, lactate, acylcarnitines, amino acids, organic and porfirines, can guide the diagnosis and enable the start of intensive treatment. This article provides a practical approach that deals with the general characteristics and the clinical keys for suspecting the most usual IEMs in the adult.

[Effectiveness and safety of levetiracetam in 133 children with medication resistant epileptic seizures]. / Eficacia y tolerabilidad del levetiracetam en 133 niños con crisis epilépticas farmacorresistentes.

INTRODUCTION: Levetiracetam (LEV) is the latest drug approved in the European Union for use in polytherapy in children over 4 years of age with partial epileptic seizures that are resistant to other antiepileptic drugs. AIM. To report our experience of associating LEV in children with medication resistant epileptic seizures. PATIENTS AND METHODS: We conducted an open, observational, respective study involving 133 children with refractory epilepsies: 106 with focal seizures and 27 with other types of seizures. LEV was associated over a period of more than 6 months and we evaluated its repercussion on the frequency of the seizures and the side effects related to the drug. RESULTS: With average doses of LEV of 1,192 +/- 749 mg/day the frequency of the seizures was reduced by over 50% in 58.6% of cases and seizures were quelled in 15.8% of patients. Side effects were produced in 27.8% of cases, and were usually transient or tolerable; these effects led to withdrawal of LEV in only eight cases (6.02%). In 37 children (27.8%), their relatives noted an improvement in their social behaviour and cognitive abilities. CONCLUSIONS: a) LEV is an effective drug that is well tolerated in children with refractory epilepsy; b) Its effectiveness in different types of seizures indicates a broad therapeutic spectrum; and c) LEV can even condition favourable secondary effects, a circumstance that has been reported only exceptionally in the case of other antiepileptic drugs.

[Acute onset ataxia in infancy: its aetiology, treatment and follow-up]. / Ataxia de aparición aguda en la infancia: etiología, tratamiento y seguimiento.

INTRODUCTION: Acute childhood ataxia is a cause of referency to the pediatric emergency room. AIM. To characterize the etiology, clinical picture, management, and outcome of acute ataxia in our hospital. PATIENTS AND METHODS: A prospective study was undertaken including 39 children with acute ataxia who were admitted between January 1, 2001 and December 31, 2003. RESULTS: During the study period 159,002 episodes were evaluated, 39 children (0.024%) with acute ataxia. The most common diagnoses were post-infectious ataxia (51.2%) and toxic exposure (25.6%). The mean age at presentation in post-infectious ataxia was 55 +/- 27.61 months, 60% females. A prodromal febrile illness was noted in 95%: varicella (10), nonspecific viral infection (6), mycoplasma, enterovirus, and Epstein-Barr virus. The latency from the prodromal illness to the onset of ataxia was 5.86 +/- 3.78 days. Lumbar punctures were altered in 11/17. All computed tomography scans performed were normal. At follow up, one boy presented asymmetric signs of cerebellar dysfunction secondary to hemicerebellitis. The media of the patient who showed full-gait recovery was 18 days, and was complete in all children, except one boy who presented hemophagocytic lymphohistiocytosis. Toxic ingestion was the second most common cause. Boys less than 6 years were more commonly affected. CONCLUSIONS: Acute childhood ataxia are an uncommon cause of presentation to our pediatric emergency room. Postinfectious ataxia and drug ingestion are the most common diagnosis, with a usually benign and self-limited process. A thorough history and neurology examination should be guided to etiology. Neuroimaging studies and hospitalization are needed only if atypical presentation, asymmetric neurologic examination and prolonged ataxia.

[Apraxia of gait: an acquired sequela with a poor prognosis]. / Apraxia de la marcha: una secuela adquirida de evolución desfavorable.

INTRODUCTION: Gait apraxia is not used to be considered as a diagnostic entity in Pediatric Neurology. CASE REPORTS: We present two pediatric patients that, after to have acquired normal gait and in consequence of a acute process, they lost the capacity to walk. In spite of intensive rehabilitation treatment hold along various years, they had not been able to help them. Both injury were very dissimilar; in one of them was affected the precentral and paracentral cortex in consequence of an encephalitic process. In the other, the basal ganglia and the hippocampus after a situation of near-drowning at the age of 15 months. CONCLUSION: The mechanism of this disorder is discussed and emphasis is done in its badly long-term prognosis.

[Idiopathic catastrophic epileptic encephalopathy: an untreatable convulsive malady in infancy]. / Encefalopatía epiléptica catastrófica idiopática: una forma intratable de estado de mal convulsivo en la infancia.

AIM: To present a case of catastrophic childhood epileptic syndrome with multifocal status epilepticus. CASE REPORT: A 4 years old boy with a multifocal status epilepticus of unknown origin which could only be controlled along some days with thiopentone enough to cause electrical suppression, and relapsed again after having stopped it. CONCLUSION: But for very high doses of barbiturates, any antiepileptic drug could control or improve the convulsions. MRI, initially normal, was followed by a progressive cerebral and cerebellar atrophy and the boy survived with heavy neurological secuelae.

[Idiopathic epilepsies: some therapeutic aspects]. / Epilepsias idiopáticas: aspectos terapéuticos.

AIMS: The purpose of this study was to determine the therapeutic approach to be used in localisation-related and generalised epilepsies and idiopathic epileptic syndromes. DEVELOPMENT: Recent literature on the subject was reviewed, as were the records on a total of 118 patients from two paediatric neurology units between the years 2000 and 2003. With regard to the localisation-related cases, the following recommendations are made: 1. Treatment with monotherapy; 2. Low doses, since any antiepileptic drug can make epilepsy worse, and more so in the case of RBEI; 3. If the seizures get worse with treatment, the doses must be reduced instead of increased; 4) Carbamazepine (CBZ) and oxcarbazepine (OXC) are first choice drugs; clobazam (CLB) is indicated in OBEI and in some atypical BPEI, in which steroids in monotherapy can occasionally prove useful; valproate (VPA) is an alternative for cases of intolerance and exacerbation, and 5. Two-year treatment and electroencephalogram (EEG) monitoring for exacerbation. As regards idiopathic generalised epilepsies: 1. VPA in monotherapy is recommended in all the forms, 48% were controlled; 18% were controlled with VPA + lamotrigine (LTG); 2. Childhood absence epilepsy is controlled up to 50% with VPA and 85% with VPA + ethosuximide (ESM); 3. LTG, CLB, topiramate (TPM) and Rivotril (CLN) are alternatives to be considered in all types of epilepsies and syndromes that are resistant to medication, and 4. In GCTS, VPA should be chosen in low doses in juvenile myoclonic epilepsy of Janz.

[Factors related to the short term remission of tics in children with Tourette syndrome]. / Factores que influyen en la remisión a corto plazo de los tics en niños con síndrome de Gilles de la Tourette.

INTRODUCTION: Tourette syndrome shows a fluctuating evolution, often masked by its comorbidity. OBJECTIVE: To study the clinical factors predicting the initial remission of tics in children with Tourette syndrome. Patients and methods. All patients attended during the last 5 years at a Child Neurology hospital based out patient clinic, with the diagnosis of Tourette syndrome according to DSM IV criteria, were selected. OUTCOME MEASURE: total remission of tics during at least 3 months, evaluated during the patient s second visit to our clinic. Demographic, clinic and therapeutic variables were studied. Statistical analysis was based on the Student t test or non parametric tests, as necessary. RESULTS: 53 patients, 44 males and 9 females. Age at starting tics: 6.9 2.2 years, time of evolution: 2 years (range: 1 9.4). Comorbidity in 51%: 34% with attention deficit hyperactivity disorder (ADHD), 17% with obsessive compulsive disorder (OCD) and school underachievement: 26%. Familial antecedents of tics, OCD, or ADHD: 49%. Tics remission at second visit to our clinic: 41.5%. Patients without remission were those with an earlier onset of tics (p=0.085), longer time of evolution (p< 0.05), or school underachievement (p= 0.024). Remission was not statistically associated with treatment. OCD and ADHD were associated with school failure but were not related to the tics evolution. CONCLUSION: The short term (at second visit), temporal (minimum 3 months) total remission of Tourette syndrome was not related to treatment but to previous duration of the syndrome and to factors (other than OCD and ADHD) that lead to school failure.

[Disturbances of neuroblast migration and amniocentesis. An under diagnosed problem?]. / Trastornos de la migración neuroblástica y amniocentesis. Un problema infradiagnosticado?

INTRODUCTION: Performing amniocentesis between the fourth and sixth months of gestation is a widespread practice. However, it can entail serious consequences, apart from the loss of the foetus, such as injuries to the developing central nervous system. CASE REPORTS: Over the past few years we have dealt with four patients who were carriers of a focal disturbance of neuroblast migration, which could have its origins in amniocentesis. Two patients displayed mental retardation and difficult to treat epilepsy, while the other two only presented hemiparesis. In two cases the right hemisphere of the brain was affected. One of them also presented extracranial brain tissue, which was possibly extruded during the accidental puncture of the skull. CONCLUSIONS: Despite its being rarely mentioned in the literature, a direct or indirect attack on the brain during diagnostic amniocentesis is a possibility that must be borne in mind when considering the use of this technique

[Use of a hospital pediatric emergency department during the night]. / Utilización nocturna de una unidad de urgencias pediátrica hospitalaria.

OBJECTIVE: To determine the characteristics of children younger than 14 years visiting our pediatric emergency department between 0:00 and 8:00 hours. PATIENTS AND METHODS: Retrospective review of 300 children visiting our emergency department at night. RESULTS: Between March 1 and 22 1999 we recorded 300 episodes from 0:00-8:00 hours (1.7 patients/hour) and 2350 episodes from 8:00-24:00 hours (6. 6 patients/hour). Of the 300 episodes registered at night, 132 children (44%) came between 0:00 and 2:00. The most common complaints were: respiratory symptoms in 116 patients (38.6%), fever in 61 (20.3%) and digestive symptoms in 61 (20.3%). We carried out at least one complementary test in 111 patients (37.0%). Five children (1.7%) were admitted to the hospital (80 between 8:00 and 24:00, 3.4%, p = 0.15) and 25 (8.3%) were admitted for a few hours to the observation ward (123 of the 2350 who came between 8:00 and 24:00, 5.2%, p = 0.06). Final diagnoses were: ear nose and throat infection in 91 (30.3%), fever without source in 38 (12.6%), asthma in 29 (9.6%), acute gastroenteritis in 27 (9%), croup in 22 (7.3%), vomiting in 14 (4.6%), abdominal pain in 13 (4.3%), febrile convulsion in 6 (2%), pneumonia in 5 (1.6%), bronchiolitis in 5 (1. 6%), bacteremia in 1 (0.3%), and other diagnoses in 46 (16.3%). CONCLUSIONS: The number of visits to our emergency department diminished at night, particularly between 0:00 and 2:00. The night-time admission rate was less than the daytime rate, although this difference was not statistically significant. Admission for a few hours to the observation ward was more common at night. The percentage of patients with respiratory illnesses was higher during the night.

[Gram stain and dipstick as diagnostic methods for urinary tract infection in febrile infants]. / Tinción de Gram y tira reactiva como métodos diagnósticos de la infección del tracto urinario del lactante con fiebre.

AIM: To compare urinary gram staining and dipstick for the detection of urinary tract infection (UTI)in febrile infants. METHODS: Prospective study of 175 febrile infants aged 124 months. In all infants, a urine specimen was analyzed to detect UTI. The dipstick test was used to detect leukocytes and nitrites and samples were taken for gram staining and urine culture. Urine was obtained by urethral catheterization. Positive urine results were defined as 50.000 colony forming units per millimeter of urinary tract pathogen. RESULTS: The mean age was 9.8 months (SD: 6.64). Urine culture was positive in 87 patients (49.5%). Diagnosis of UTI was confirmed in 91 patients (51.9%), of whom 74 were admitted for clinically suspected pyelonephritis (81.3%). Gram stain had the highest specificity (98.9%) and pyuria the highest sensitivity (90.8%). Better results were obtained using the combination of dipstick and Gram stain with a sensitivity of 93.1%, specificity of 98.4%, positive predictive value of 98.5% and negative predictive value of 92.5%. CONCLUSIONS: Urinary Gram stain appears to be more reliable than dipstick in detecting UTI in febrile infants but the results of both tests should be interpreted together.