Brainstem dysgenesis: beyond Moebius syndrome. / Disgenesia troncoencefalica: mas alla del sindrome de Moebius.

Brainstem dysgenesis designates all those patients with congenital dysfunction of cranial nerves and muscle tone due to prenatal lesions or malformations of the brainstem. This generic term has the advantage over the eponyms Moebius 'expanded' or 'unrestricted', Robin, Cogan or Carey-Fineman-Ziter syndromes in that it has a less restrictive view and provides a frame work that enables a systematic approach to diagnosis and research of most developmental disorders involving the brainstem. The review of the literature and our experience shows that infants with a predominant rombencephalic involvement are due to brainstem prenatal disruptive vascular accidents, while cases with midbrain and cerebellar involvement and widespread malformative syndromes have most likely an underlying genetic cause. Due to phenotypic heterogeneity associated with brainstem dysgenesis, it is crucial to evaluate each case individually and to establish a specific therapeutic plan. Intervention programs should start soon after diagnosis and directed to improve functions needed for daily life activities. Even though the prognosis of patients with brainstem dysgenesis due to prenatal destructive lesions depends on the magnitude of the vascular territory involved, in most patients with brainstem dysgenesis, the prognosis is better than the initial clinical manifestations would indicate.

TITLE: Disgenesia troncoencefalica: mas alla del sindrome de Moebius.El termino 'disgenesia troncoencefalica' se aplica a los pacientes que presentan afectacion congenita de multiples pares craneales, hipotonia muscular y signos leves de afectacion de la via piramidal. Este termino es ventajoso respecto al uso de eponimos tales como Moebius, Robin, Cogan y Carey-Fineman-Ziter, ya que es menos restrictivo y ofrece un nuevo enfoque para comprender las causas y su patogenia, asi como para mejorar el tratamiento de este grupo de alteraciones del desarrollo que afectan exclusiva o predominantemente al tronco del encefalo. La revision de la bibliografia y nuestra experiencia muestran que la mayoria de los casos con afectacion selectiva del rombencefalo se deben a lesiones disruptivas prenatales, mientras que en los casos con afectacion del mesencefalo y el cerebelo, asi como en los sindromes polimalformativos con afectacion destacada del troncoencefalo, la topografia de las lesiones es mas difusa y menos especifica, y la causa hereditaria, mas probable. Debido a la amplia heterogeneidad fenotipica asociada a la disgenesia troncoencefalica, es esencial realizar una evaluacion individualizada y establecer un plan de tratamiento especifico. Los programas de rehabilitacion deben comenzar poco despues del diagnostico y centrarse en mejorar las habilidades motoras, dotando al paciente de las herramientas necesarias para afrontar las necesidades diarias en funcion de la morbilidad asociada. Aunque el pronostico de la disgenesia troncoencefalica secundaria a lesiones disruptivas depende de la localizacion y la extension del territorio vascular afectado, en general, el pronostico de los pacientes con disgenesia troncoencefalica es mejor de lo que las manifestaciones clinicas iniciales harian suponer.

Concordancia entre una función de crecimiento del perímetro cefálico y la discapacidad intelectual en relación con la etiología de la microcefalia / Concordance between a head circumference growth function and intellectual disability in relation with the cause of microcephaly

INTRODUCCIÓN: Nuestro objetivo fue investigar la correlación entre patrones de crecimiento cefálico y discapacidad intelectual entre distintas presentaciones etiológicas de microcefalia. PACIENTES Y MÉTODOS: Se revisaron 3.269 gráficas de perímetro cefálico (PC) de una unidad de neuropediatría terciaria, seleccionándose 136 participantes con microcefalia. Utilizando las puntuaciones Z de las medidas de PC registradas definimos las variables: PC mínimo, caída de PC y recuperación de PC. Los pacientes se clasificaron según la existencia o no de discapacidad intelectual (CI inferior a 71) y la causa de la microcefalia (idiopática, familiar, sindrómica, sintomática y mixta). RESULTADOS: El uso del análisis discriminante permitió definir una función C como C=PC mínimo + caída de PC con un nivel de corte de puntuación Z de C=-4,32. En nuestra muestra, el 95% de los pacientes con resultados por debajo de este nivel, microcefalia severa, presentaban discapacidad intelectual. La concordancia global entre la función de PC y la presencia de discapacidad intelectual fue del 66%. En el grupo de sintomáticas y mixtas, esta concordancia alcanzó el 82%, en contraste con solo el 54% del grupo de idiopáticas y sindrómicas (p = 0,0002). CONCLUSIONES: La utilización de una función de crecimiento del PC discrimina la discapacidad intelectual en pacientes con microcefalia mejor que mediciones aisladas de PC, especialmente en etiologías secundarias y mixtas

INTRODUCTION: Our aim was to investigate the correlations between patterns of head growth and intellectual disability among distinct ætiological presentations of microcephaly. PATIENTS AND METHODS: 3,269 head circumference (HC) charts of patients from a tertiary neuropædiatric unit were reviewed and 136 microcephalic participants selected. Using the Z-scores of registered HC measurements we defined the variables: HC Minimum, HC Drop and HC Catch-up. We classified patients according to the presence or absence of intellectual disability (IQ below 71) and according to the cause of microcephaly (idiopathic, familial, syndromic, symptomatic and mixed). RESULTS: Using Discriminant Analysis a C-function was defined as C=HC Minimum + HC Drop with a cut-off level of C=-4.32 Z-score. In our sample 95% of patients scoring below this level, severe microcephaly, were classified in the disabled group while the overall concordance was 66%. In the symptomatic-mixed group the concordance between HC function and outcome reached 82% in contrast to only 54% in the idiopathic-syndromic group (P-value=0.0002). CONCLUSIONS: We defined a HC growth function which discriminates intellecutal disability of microcephalic patients better than isolated HC measurements, especially for those with secondary and mixed ætiologies

[Concordance between a head circumference growth function and intellectual disability in relation with the cause of microcephaly]. / Concordancia entre una función de crecimiento del perímetro cefálico y la discapacidad intelectual en relación con la etiología de la microcefalia.

INTRODUCTION: Our aim was to investigate the correlations between patterns of head growth and intellectual disability among distinct aetiological presentations of microcephaly. PATIENTS AND METHODS: 3,269 head circumference (HC) charts of patients from a tertiary neuropediatric unit were reviewed and 136 microcephalic participants selected. Using the Z-scores of registered HC measurements we defined the variables: HC Minimum, HC Drop and HC Catch-up. We classified patients according to the presence or absence of intellectual disability (IQ below 71) and according to the cause of microcephaly (idiopathic, familial, syndromic, symptomatic and mixed). RESULTS: Using Discriminant Analysis a C-function was defined as C=HC Minimum + HC Drop with a cut-off level of C=-4.32 Z-score. In our sample 95% of patients scoring below this level, severe microcephaly, were classified in the disabled group while the overall concordance was 66%. In the symptomatic-mixed group the concordance between HC function and outcome reached 82% in contrast to only 54% in the idiopathic-syndromic group (P-value=0.0002). CONCLUSIONS: We defined a HC growth function which discriminates intellectual disability of microcephalic patients better than isolated HC measurements, especially for those with secondary and mixed aetiologies.

[Intracranial hypertension associated with cerebral venous sinus thrombosis and mastoiditis. Two paediatric case reports]. / Hipertensión intracraneal asociada a trombosis de senos venosos cerebrales y mastoiditis. A propósito de dos casos pediátricos.

INTRODUCTION: Cerebral venous sinus thrombosis is a rare condition that is generally associated with acute processes, one of the most important being mastoiditis. Associated prothrombotic disorders can be detected in approximately half of all cases, regardless of the aetiology. Patients usually present clinical symptoms like headache, convulsions and diminished level of awareness, this latter factor being linked to a poor prognosis. CASE REPORTS: We report the cases of two paediatric patients with a clinical picture of intracranial hypertension within a context of mastoiditis as a complication of an acute ear infection, in whom cerebral venous sinus thrombosis was identified. Both patients were treated with lumbar punctures to evacuate cerebrospinal fluid and diuretic therapy. Anticoagulant therapy was added in the case of the second patient. Nevertheless, because of the persistence of the symptoms of intracranial hypertension, a ventriculoperitoneal shunt had to be performed in this patient. CONCLUSIONS: The preferred diagnostic method is magnetic resonance imaging with venography, although in an emergency computerised tomography can help reach a diagnosis in a third of cases. In addition to treating the symptoms, anticoagulation is also accepted (degree of evidence 1B) to prevent further progression.

[Oromotor disorders in a paediatric neurology unit. Their classification and clinical course]. / Trastornos oromotores en una unidad de neurología pediátrica. Clasificación y evolución clínica.

INTRODUCTION: The term 'oro-motor disorders' refers to a group of diseases that predominantly affect sensory inputs, motor systems and movement organization involved in sucking, chewing, swallowing, speech articulation and facial non-verbal communication. Loss of any of the aforementioned functions results in poor social integration and significant quality of life reduction. PATIENTS AND METHODS: Retrospective, observational study of 64 patients with oro-motor disorders diagnosed and followed-up at the Child Neurology Service of Vall d'Hebron University Hospital. The oro-motor disorder cause, age at the beginning of symptoms, type of feeding difficulties, type of speech disorders and other associated clinical manifestations were investigated in all patients. Changes in clinical manifestations throughout the period of follow-up in this cohort were analyzed as well. RESULTS: Classification of oro-motor disorders in childhood can be achieved combining the etiology and the anatomical location of the underlying disease. Four main groups can be distinguished: due to dysmorphological syndromes; secondary to bilateral perisylvian cortical dysplasias; due to brainstem dysgenesis, and secondary to congenital muscular diseases. CONCLUSIONS: Establishing the origin, nervous system location and pathophysiology of diseases leading to oro-motor disorders provides clues to natural history and permits anticipation in terms of treatment and care provision.

Trastornos oromotores en una unidad de neurología pediátrica. Clasificación y evolución clínica / Oromotor disorders in a paediatric neurology unit their classification and clinical course

Introducción. El concepto ‘trastornos oromotores’ engloba al conjunto de enfermedades que afectan de forma predominante a las estructuras que intervienen en la movilidad facial y orofaríngea, y que son imprescindibles para una correcta mecánica de la alimentación y para la articulación del lenguaje y la expresividad facial. La alteración de estas funcionespuede afectar significativamente a la calidad de vida y a la integración social de estos pacientes. Pacientes y métodos. Estudio descriptivo retrospectivo de 64 pacientes diagnosticados de trastornos oromotores, controlados en el Servicio de Neurología Pediátrica del Hospital Universitari Vall d’Hebron. De cada uno de ellos, detallamos: etiología, edad de presentación, información acerca del trastorno de la alimentación, de la articulación del lenguaje y de posibles manifestaciones asociadas, y evolución durante el período de seguimiento de los diferentes aspectos clínicos. Resultados. La revisión de la casuística delservicio nos ha permitido clasificar a los enfermos afectos de trastornos oromotores en función de la localización de la lesión y su enfermedad de base, distribuyéndolos en cuatro grupos principales: pacientes con síndromes polimalformativos, con afectación cortical perisilviana, con disgenesia troncoencefálica y con afectación del sistema nervioso periférico. Conclusiones. La clasificación de los pacientes afectos de trastornos oromotores y el estudio de la evolución natural de cada uno de los grupos facilitan el abordaje y permiten optimizar el manejo y realizar una prevención adecuada de las posibles complicaciones de este tipo de pacientes

Introduction. The term ‘oro-motor disorders’ refers to a group of diseases that predominantly affect sensory inputs, motor systems and movement organization involved in sucking, chewing, swallowing, speech articulation and facial nonverbal communication. Loss of any of the aforementioned functions results in poor social integration and significant quality of life reduction. Patients and methods. Retrospective, observational study of 64 patients with oro-motor disorders diagnosed andfollowed-up at the Child Neurology Service of Vall d’Hebron University Hospital. The oro-motor disorder cause, age at the beginning of symptoms, type of feeding difficulties, type of speech disorders and other associated clinical manifestations were investigated in all patients. Changes in clinical manifestations throughout the period of follow-up in this cohort wereanalyzed as well. Results. Classification of oro-motor disorders in childhood can be achieved combining the etiology and the anatomical location of the underlying disease. Four main groups can be distinguished: due to dysmorphological syndromes; secondary to bilateral perisylvian cortical dysplasias; due to brainstem dysgenesis, and secondary to congenital musculardiseases. Conclusions. Establishing the origin, nervous system location and pathophysiology of diseases leading to oro-motor disorders provides clues to natural history and permits anticipation in terms of treatment and care provision

[Private mutations in the myophosphorylase gene: the first case in a patient of Latin American descent]. / Mutaciones privadas en el gen de la miofosforilasa: primer caso en un paciente de origen latinoamericano.

INTRODUCTION: McArdle's disease (glycogenoses type V) is a common metabolic myopathy caused by deficient myophosphorylase activity. The disease is due to mutations in the myophosphorylase (PYGM) gene and is present in a large number of countries. CASE REPORT: A 13-year-old male who suffered an episode of muscle pain and offered increased levels of creatinkinase in plasma, myoglobinuria and mild weakness of the proximal muscles, after short but vigorous exercise. The patient was born in Ecuador and was adopted by a Spanish family. The myophosphorylase gene was analysed completely and the patient was found to be a carrier of a missense mutation, a homozygous change where a G is replaced by an A in exon 11, changing a valine for a methionine in codon 456 (V456M). The mutation described above affects an amino acid that is conserved in the enzyme and which was not present in the control population that was studied. CONCLUSIONS: These findings show the presence of McArdle's disease in several ethnic groups and confirm that the ethnic origin of the patient is important when it comes to deciding what mutations should be analysed first in molecular diagnosis studies.

Mutaciones privadas en el gen de la miofosforilasa: primer caso en un paciente de origen latinoamericano / Private mutations in the myophosphorylase gene: The first case in a patient of latin american descent

La enfermedad de McArdle (glicogenosis tipo V) es una miopatía metabólica común causada por unadeficiencia de la actividad de la miofosforilasa. La enfermedad se debe a mutaciones en el gen de la miofosforilasa (PYGM) y está presente en un gran número de países. Caso clínico. Varón de 13 años de edad que sufrió un episodio de dolor muscular y presentó unos niveles elevados de creatincinasa en plasma, mioglobinuria y debilidad de la musculatura proximal moderada, después de un corto pero vigoroso ejercicio. El paciente nació en Ecuador y fue adoptado por una familia española.Se analizó completamente el gen de la miofosforilasa y se encontró que el paciente era portador de una mutación consistente en pérdida de sentido, un cambio homocigótico de una G por una A en el exón 11, cambiando una valina por una metionina en el codón 456 (V456M). La mutación previamente descrita afecta a un aminoácido conservado en la enzima y no estaba presenteen la población control estudiada. Conclusiones. Estos hallazgos demuestran la presencia de la enfermedad de McArdle en varios grupos étnicos y sugiere que el origen étnico del paciente es importante para decidir qué mutaciones deberían analizarse primero en los estudios diagnósticos moleculares (AU)

McArdle's disease (glycogenoses type V) is a common metabolic myopathy caused by deficientmyophosphorylase activity. The disease is due to mutations in the myophosphorylase (PYGM) gene and is present in a large number of countries. Case report. A 13-year-old male who suffered an episode of muscle pain and offered increased levels of creatinkinase in plasma, myoglobinuria and mild weakness of the proximal muscles, after short but vigorous exercise. The patient was born in Ecuador and was adopted by a Spanish family. The myophosphorylase gene was analysed completely andthe patient was found to be a carrier of a missense mutation, a homozygous change where a G is replaced by an A in exon 11, changing a valine for a methionine in codon 456 (V456M). The mutation described above affects an amino acid that is conserved in the enzyme and which was not present in the control population that was studied. Conclusions. These findings show thepresence of McArdle’s disease in several ethnic groups and confirm that the ethnic origin of the patient is important when it comes to deciding what mutations should be analysed first in molecular diagnosis studies (AU)

[Cerebellar atrophy following acute Mycoplasma pneumoniae cerebellitis]. / Atrofia cerebelosa secundaria a cerebelitis aguda por Mycoplasma pneumoniae.

INTRODUCTION: Acute cerebellitis is an uncommon complication following Mycoplasma pneumoniae infection. A benign and self-limited course has been described in the few reports found of this association. CASE REPORTS: We report two patients with an apparently M. pneumoniae-induced acute cerebellitis that resulted in cerebellar atrophy. Patients presented with a cerebellar syndrome including ataxia, hypotonia, dysarthric speech and dysmetria, which were preceded by signs of respiratory infection. Initial brain magnetic resonance imaging (MRI) in case 1 was normal but in case 2 it displayed striking cerebellar swelling, small fourth ventricle and supratentorial ventriculomegaly which was self-limited and did not require neurosurgical intervention. Serological studies confirmed a recent M. pneumoniae infection. Case 1 has followed an unfavourable clinical course, with incomplete resolution of cerebellar dysfunction, while case 2 has remained asymptomatic. Follow-up brain MRI have demonstrated prominent cerebellar atrophy in both patients. CONCLUSIONS: M. pneumoniae infection should be considered in those patients with acute cerebellitis showing an incomplete resolution of cerebellar dysfunction or those who develop early cerebellar atrophy. The presenting MRI findings do not seem to predict final neurological outcome.

Atrofia cerebelosa secundaria a cerebelitis aguda por Mycoplasma pneumoniae / Cerebellar atrophy following acute mycoplasma pneumoniae cerebellitis

Introducción. La cerebelitis aguda es una complicación infrecuente de la infección por Mycoplasma pneumoniae. Los pocos pacientes descritos han seguido un curso benigno y autolimitado de forma similar al de las cerebelitis relacionadas con otros gérmenes. Casos clínicos. Describimos dos pacientes con una cerebelitisaguda por M. pneumoniae que evoluciona en pocos meses hacia una marcada atrofia cerebelosa. Los pacientes presentaron un síndrome cerebeloso caracterizado por ataxia, hipotonía, disartria y dismetría de las cuatro extremidades, precedido por signos de infección respiratoria. La resonancia magnética (RM) cerebral practicada durante la fase aguda en el caso 1 resultó normal y e nel caso 2 demostró un llamativo edema del parénquima cerebeloso, con IV ventrículo pequeño y ventriculomegalia supratentorial, que se autolimitó y que no requirió de intervención neuroquirúrgica. Los estudios serológicos permitieron confirmar la infección reciente por M. pneumoniae. En el caso 1 se ha observado la persistencia de signos de disfunción cerebelosa, mientras que el caso 2 está asintomático. Ambos pacientes muestran una llamativa atrofia cerebelosa en las RM cerebrales practicadas a lo largo de su control clínico. Conclusiones. Debe considerarse la infección por M. pneumoniae en pacientes con cerebelitis aguda que presenten resolución incompleta de la disfunción cerebelosa o que evolucionen de forma precoz hacia la atrofia cerebelosa. Las manifestaciones neurorradiológicas iniciales no permiten predecir el pronóstico neurológico final (AU)

Introduction. Acute cerebellitis is an uncommon complication following Mycoplasma pneumoniae infection. A benign and self-limited course has been described in the few reports found of this association. Case reports. We report twopatients with an apparently M. pneumoniae-induced acute cerebellitis that resulted in cerebellar atrophy. Patients presented with a cerebellar syndrome including ataxia, hypotonia, dysarthric speech and dysmetria, which were preceded by signs of respiratory infection. Initial brain magnetic resonance imaging (MRI) in case 1 was normal but in case 2 it displayed striking cerebellar swelling, small fourth ventricle and supratentorial ventriculomegaly which was self-limited and did not requiren euro surgical intervention. Serological studies confirmed a recent M. pneumoniae infection. Case 1 has followed an unfavourable clinical course, with incomplete resolution of cerebellar dysfunction, while case 2 has remained asymptomatic. Follow-up brain MRI have demonstrated prominent cerebellar atrophy in both patients. Conclusions. M. pneumoniae infection should be considered in those patients with acute cerebellitis showing an incomplete resolution of cerebellar dysfunction or those who develop early cerebellar atrophy. The presenting MRI findings do not seem to predict final neurological outcome (AU)

[Subacute sclerosing panencephalitis: combined treatment with interferon alpha and intraventricular ribavirin]. / Panencefalitis esclerosante subaguda: tratamiento combinado con interferón alfa y ribavirina intraventricular.

INTRODUCTION: Subacute sclerosing panencephalitis (SSPE) is a chronic neurodegenerative disease secondary to an infection of the central nervous system by the measles virus, with no effective treatment. The introduction of therapy with intraventricular interferon alpha (IFN-alpha) and its later association with ribavirin aroused new expectations. In experimental studies the two drugs were seen to exert a synergic effect in reducing viral replication. Therapeutic studies carried out in patients with SSPE with the two pharmaceuticals have offered contradictory findings. CASE REPORTS: We present the cases of two patients with an early-onset, fast progressing form of SSPE, who were treated with a combined regime of oral isoprenosin, intraventricular IFN-alpha and ribavirin, which was administered intravenously in one case and intraventricularly in the other. At the beginning of treatment the patients' deterioration stabilised briefly and temporarily, but then renewed its progress. CONCLUSIONS: Combined therapy with intraventricular IFN-alpha and ribavirin was not effective in our patients. The late onset and rapidly progressing symptoms of the disease may have had an effect on the poor results obtained.

Panencefalitis esclerosante subaguda: tratamiento combinado con interferon alfa y ribavirina intraventricular / Subacute sclerosing panencephalitis: combined treatment with interferon alpha and intraventricular ribavirin

Introducción. La panencefalitis esclerosante subaguda (PEES) es una enfermedad neurodegenerativa crónica secundaria a una infección del sistema nervioso central por el virus del sarampión, sin un tratamiento efectivo. La introducción del tratamiento con interferón alfa (IFN-a) intraventricular y la asociación posterior de ribavirina despertó nuevas expectativas. En estudios experimentales se comprobó un efecto sinérgico de ambos fármacos en la disminución de la replicación vírica. Los estudios terapéuticos realizados en pacientes afectos de PEES con ambos fármacos han dado resultados discordantes. Casos clínicos. Presentamos dos pacientes afectos de PEES con una forma de inicio precoz y rápidamente progresiva, que se trataron con una pauta combinada de isoprenosina oral, IFN-a intraventricular y ribavirina endovenosa en un caso, e intraventricular, en el otro. Al inicio del tratamiento. los pacientes presentaron una estabilización temporal breve de su deterioro, para después progresar de nuevo. Conclusión. El tratamiento combinado con IFN-a intraventricular y ribavirina no ha sido efectivo en nuestros pacientes. Es posible que su inicio tardío y la forma de presentación rápidamente progresiva de la enfermedad hayan influido en los malos resultados (AU)

Introduction. Subacute sclerosing panencephalitis (SSPE) is a chronic neurodegenerative disease secondary to an infection of the central nervous system by the measles virus, with no effective treatment. The introduction of therapy with intraventricular interferon alpha (IFN-α) and its later association with ribavirin aroused new expectations. In experimental studies the two drugs were seen to exert a synergic effect in reducing viral replication. Therapeutic studies carried out in patients with SSPE with the two pharmaceuticals have offered contradictory findings. Case reports. We present the cases of two patients with an early-onset, fast progressing form of SSPE, who were treated with a combined regime of oral isoprenosin, intraventricular IFN-α and ribavirin, which was administered intravenously in one case and intraventricularly in the other. At the beginning of treatment the patients’ deterioration stabilised briefly and temporarily, but then renewed its progress. Conclusions. Combined therapy with intraventricular IFN-α and ribavirin was not effective in our patients. The late onset and rapidly progressing symptoms of the disease may have had an effect on the poor results obtained (AU)

Epilepsia y alteración del pelo en un lactante / Epilepsy and hair alterations in a neonate

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[Congenital insensitivity to pain with anhidrosis associated with congenital myasthenic syndrome]. / Insensibilidad congénita al dolor con anhidrosis asociada a síndrome miasténico congénito.

INTRODUCTION: Congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a rare autosomal recessive disorder featuring recurrent fever episodes, inability to sweat, absent response to noxious stimuli, self mutilating behavior and mental retardation. It has been associated with mutations in the NTRK1 gene, located in 1q21-22 and encoding a high-affinity NGF receptor. CASE REPORT: An 8-year-old boy, the first son of consanguineous parents, presented with hypotonia, episodic hyperpyrexia and global developmental delay since the neonatal period. In addition to these signs, typical of CIPA, he displayed some other not previously described in this disease, such as facial dysmorphism, a severe swallowing disorder and a myogenic EMG pattern, that led to the initial suspicion of a muscle disorder. Molecular genetics studies uncovered a mutation c.C2011T in exon 15 of the NTRK1 gene. Genetic counselling was possible in the following pregnancy of the couple, where the female fetus was found to harbour the mutation in heterozygosity. The subsequent diagnosis of a congenital myasthenic syndrome in this sister led to neurophysiological re-evaluation of the probandus, in whom a myasthenic pattern of muscle activation was also found. CONCLUSIONS: A patient with CIPA and congenital myasthenic syndrome is described. CIPA must be the first diagnostic hypothesis when assessing a patient with insensitivity to pain, anhidrosis and self-mutilation. Given the rather homogeneous presentation of CIPA, the occurrence of atypical myopathic manifestations should raise the suspicion of a concurrent disorder. The present consanguineous kindred illustrates a rare instance of transmission of two mutated alleles giving rise to two unrelated, infrequent neurological syndromes.

Insensibilidad congénita al dolor con anhidrosis asociada a síndrome miasténico congénito / Congenital insensitivity to pain with anhidrosis associated with congenital myasthenic syndrome

Introducción. La insensibilidad congénita al dolor con anhidrosis (CIPA) o neuropatía hereditaria sensitivoautonómica de tipo IV (HSAN IV) es un raro trastorno autosómico recesivo caracterizado por episodios recurrentes de fiebre, anhidrosis, ausencia de sensibilidad al dolor y retraso mental de gravedad variable. Se asocia a mutaciones en el gen NTRK1, localizado en el cromosoma 1q21-22, que codifica uno de los receptores del factor de crecimiento nervioso. Caso clínico. Describimos el caso de un niño de 8 años de edad, primer hijo de padres consanguíneos, que presenta hipotonía, episodios de hiperpirexia y retraso global desde el período neonatal, manifestaciones típicas de la CIPA, además de signos previamente no descritos en esta enfermedad como son anomalías fenotípicas, un grave trastorno de deglución durante los primeros meses de vida y un patrón miógeno en el estudio neurofisiológico, que condujeron a la sospecha inicial de proceso miopático. El estudio genético molecular detectó una mutación c.C2011T en el exón 15 del gen NTRK1. El hallazgo de dicha mutación en heterocigosidad en la hermana menor del paciente permitió efectuar consejo genético. Sin embargo, el diagnóstico de un síndrome miasténico congénito en esta hermana y la posterior observación de hallazgos neurofisiológicos miasteniformes también en nuestro paciente permiten explicar la existencia de estas manifestaciones atípicas de la CIPA. Conclusiones. Presentamos un paciente afecto de CIPA y síndrome miasténico congénito. Debe considerarse la posibilidad de CIPA como primera hipótesis diagnóstica en la valoración de un paciente con insensibilidad al dolor, anhidrosis y automutilación. Dada la considerable homogeneidad clínica de la CIPA, la aparición de signos atípicos miopáticos debe despertar la sospecha de algún otro trastorno asociado. La familia consanguínea que presentamos ilustra la situación muy poco frecuente de transmisión de dos alelos mutados, causantes de dos enfermedades neurológicas supuestamente monogénicas, a un mismo individuo (AU)

Introduction. Congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a rare autosomal recessive disorder featuring recurrent fever episodes, inability to sweat, absent response to noxious stimuli, self mutilating behavior and mental retardation. It has been associated with mutations in the NTRK1 gene, located in 1q21-22 and encoding a high-affinity NGF receptor. Case report. An 8-year-old boy, the first son of consanguineous parents, presented with hypotonia, episodic hyperpyrexia and global developmental delay since the neonatal period. In addition to these signs, typical of CIPA, he displayed some other not previously described in this disease, such as facial dysmorphism, a severe swallowing disorder and a myogenic EMG pattern, that led to the initial suspicion of a muscle disorder. Molecular genetics studies uncovered a mutation c.C2011T in exon 15 of the NTRK1 gene. Genetic counselling was possible in the following pregnancy of the couple, where the female fetus was found to harbour the mutation in heterozygosity. The subsequent diagnosis of a congenital myasthenic syndrome in this sister led to neurophysiological re-evaluation of the probandus, in whom a myasthenic pattern of muscle activation was also found. Conclusions. A patient with CIPA and congenital myasthenic syndrome is described. CIPA must be the first diagnostic hypothesis when assessing a patient with insensitivity to pain, anhidrosis and selfmutilation. Given the rather homogeneous presentation of CIPA, the occurrence of atypical myopathic manifestations should raise the suspicion of a concurrent disorder. The present consanguineous kindred illustrates a rare instance of transmission of two mutated alleles giving rise to two unrelated, infrequent neurological syndromes (AU)

[Brainstem dysgenesis: Möbius, Cogan and Pierre Robin syndromes revisited]. / Disgenesia troncoencefálica: los síndromes de Möbius, Cogan y Pierre Robin en revisión.

We propose the term brainstem dysgenesis to designate patients with congenital dysfunction of the cranial nerves and muscle tone due to prenatal lesions or anomalies of the brainstem. In some patients, the dysgenesis is genetically determined and can be isolated or form part of a more extensive polymalformation syndrome (mutations of organizing or regulatory genes). In most patients with brainstem dysgenesis, however, the disorder is caused by prenatal destructive or disruptive lesions of vascular origin. Depending on the vessels involved and the magnitude of the lesion, clinical manifestations can range from intrauterine death to mild involvement of several cranial nerves. Clinical findings in some of these patients may coincide with those described in Möbius, Pierre Robin or Cogan syndromes and, if that is the case, the eponym will indicate the location of the brainstem lesion. Clinical manifestations in most patients with brainstem dysgenesis, however, do not fit into any of the aforementioned syndromes. In these circumstances the term brainstem dysgenesis should be used followed by a detailed description of each patient's clinical findings and/or the brainstem segment presumably involved. The prognosis of patients with brainstem dysgenesis due to prenatal destructive lesions depends on the magnitude of the vascular territory involved and, in most cases, is better than the initial clinical manifestations would indicate.

Disgenesia troncoencefálica: los síndromes de Möbius, Cogan y Pierre Robin en revisión / Brainstem dysgenesis: Möbius, Cogan and Pierre Robin syndromes revisited

Proponemos el término disgenesia troncoencefálica para denominar a los enfermos con disfunción congénita de pares craneales, tono muscular y otras estructuras troncoencefálicas, debidas a lesiones o anomalías prenatales localizadas en el tronco del encéfalo. En algunos pacientes, la disgenesia tiene un origen genéticamente determinado y puede presentarse de forma aislada o formar parte de un síndrome polimalformativo más extenso (genes organizadores/reguladores). En la mayoría de los enfermos con disgenesia troncoencefálica la causa del trastorno se debe a lesiones destructivas o disruptivas prenatales de naturaleza vascular. En función de la extensión de la lesión y del territorio vascular involucrado, las consecuencias oscilandes de la muerte intraútero hasta la afectación discreta de algunos pares craneales. El tipo de manifestaciones clínicas de alguno de estos pacientes puede coincidir con las descritas por Möbius, Pierre Robin o Cogan y, en este caso, el epónimo sirve para identificar la localización de la lesión en el tronco del encéfalo. Sin embargo, en la mayoría de pacientes la sintomatología no coincide o excede a la descrita inicialmente por los autores anteriormente mencionados. Estos casos deberían clasificarse como subtipos de disgenesia troncoencefálica y para su correcta denominación debería incluirse la enumeración detallada de los pares craneales y/o los segmentos del romboencéfalo involucrados. El pronóstico de los pacientes con disgenesia troncoencefálica debida a lesiones destructivas prenatales depende de las estructuras afectadas y, en muchos de los casos, es mejor de lo que las manifestaciones clínicas iniciales puedan hacer suponer (AU)

We propose the term brainstem dysgenesis to designate patients with congenital dysfunction of the cranial nerves and muscle tone due to prenatal lesions or anomalies of the brainstem. In some patients, the dysgenesis is genetically determined and can be isolated or form part of a more extensive polymalformation syndrome (mutations of organizing or regulatory genes). In most patients with brainstem dysgenesis, however, the disorder is caused by prenatal destructive or disruptive lesions of vascular origin. Depending on the vessels involved and the magnitude of the lesion, clinical manifestations can range from intrauterine death to mild involvement of several cranial nerves. Clinical findings in some of these patients may coincide with those described in Möbius, Pierre Robin or Cogan syndromes and, if that is the case, the eponym will indicate the location of the brainstem lesion. Clinical manifestations in most patients with brainstem dysgenesis, however, do not fit into any of the aforementioned syndromes. In these circumstances the term brainstem dysgenesis should be used followed by a detailed description of each patient’s clinical findings and/or the brainstem segment presumably involved. The prognosis of patients with brainstem dysgenesis due to prenatal destructive lesions depends on the magnitude of the vascular territory involved and, in most cases, is better than the initial clinical manifestations would indicate (AU)

[A patient with bilateral lesion in the striatum and slowly progressive dystonia secondary to T14487C mutation in the ND6 gene of complex I of the mitochondrial respiratory chain]. / Paciente con lesión bilateral del estriado y distonía lentamente progresiva secundarias a la mutación T14487C en el gen ND6 del complejo I de la cadena respiratoria mitocondrial.

INTRODUCTION: A large number of diseases present as bilateral striatal lesion syndrome (BSLS). Clinical manifestations, course and prognosis of these diseases are extremely variable. On the basis of their evolutive course, they can be separated into two major groups: acute, which include toxic, infectious or parainfectious causes, and subacute or chronic, in which inborn errors of metabolism, especially mitochondrial disorders, are the main causes. CASE REPORT: We report a detailed clinical follow-up of a 18 years old Caucasian male who, at the age of four, presented with BSLS. A respiratory chain defect was suspected on the basis of slowly progressive dystonia and cognitive impairment, changes in serial MRI studies, and the finding of 'trabecular fibers' as well as a 50% decrease of the complex I activity in striated-skeletal muscle specimen. Blood, urine and CSF markers classically associated with respiratory chain diseases were normal. Molecular studies identified a new pathogenetic mutation (T14487C) in the mitochondrial ND6 gene of the respiratory chain complex I. CONCLUSION: Mitochondrial metabolism disorders should be ruled out in patients presenting with a subacute or chronic form of BSLS even in the absence of other common mitochondrial disease markers.

Paciente con lesión bilateral del estriado y distonía lentamente progresiva secundarias a la mutación T14487C en el gen ND6 del complejo I de la cadena respiratoria mitocondrial / A patient with bilateral lesión in the striatum and slowly progressive dystonia secondary to T14487C mutation in the ND6 gene of complex I

Introducción. El síndrome de lesión bilateral del estriado (SLBE) constituye la forma de presentación de un elevado número de enfermedades. Las manifestaciones clínicas, la evolución y el pronóstico de las mismas es muy variable. En función de su curso evolutivo, éstas pueden dividirse en dos grandes grupos: unas, de presentación aguda, que suelen responder a causas tóxicas, infecciosas o parainfecciosas, y otras, subagudas o crónicas, cuya causa fundamental son los errores congénitos del metabolismo. Caso clí- nico. Varón de 18 años que, a los 4 años de edad, debutó con un SLBE. Se sospechó un defecto de la cadena respiratoria mitocondrial sobre la base de la distonía y la alteración de las funciones cognitivas lentamente progresiva, la evolución de las imágenes en la resonancia magnética cerebral y el hallazgo de fibras trabeculadas, así como una disminución del 50% en la actividad del complejo I en el músculo estriado. Sin embargo, las determinaciones bioquímicas en la sangre, la orina y el líquido cefalorraquídeo, encaminadas a detectar trastornos en la función mitocondrial, fueron repetidamente normales. Los estudios moleculares identificaron una nueva mutación patogenética (T14487C) del gen mitocondrial ND6 del complejo I de la cadena respiratoria mitocondrial. Conclusiones. Deben descartarse trastornos del metabolismo mitocondrial cuando se valoren pacientes afectados de un SLBE de curso clínico cronicorrecurrente, incluso en ausencia de otros marcadores que así lo sugieran (AU)

Introduction. A large number of diseases present as bilateral striatal lesion syndrome (BSLS). Clinical manifestations, course and prognosis of these diseases are extremely variable. On the basis of their evolutive course, they can be separated into two major groups: acute, which include toxic, infectious or parainfectious causes, and subacute or chronic, in which inborn errors of metabolism, especially mitochondrial disorders, are the main causes. Case report. We report a detailed clinical follow-up of a 18 years old Caucasian male who, at the age of four, presented with BSLS. A respiratory chain defect was suspected on the basis of slowly progressive dystonia and cognitive impairment, changes in serial MRI studies, and the finding of ‘trabecular fibers’ as well as a 50% decrease of the complex I activity in striatedskeletal muscle specimen. Blood, urine and CSF markers classically associated with respiratory chain diseases were normal. Molecular studies identified a new pathogenetic mutation (T14487C) in the mitochondrial ND6 gene of the respiratory chain complex I. Conclusion. Mitochondrial metabolism disorders should be ruled out in patients presenting with a subacute or chronic form of BSLS even in the absence of other-common mitochondrial disease markers (AU)