Disgenesia troncoencefálica: más allá del síndrome de Moebius / Brainstem dysgenesis: beyond Moebius syndrome

El termino 'disgenesia troncoencefálica' se aplica a los pacientes que presentan afectación congénita de múltiples pares craneales, hipotonía muscular y signos leves de afectación de la vía piramidal. Este término es ventajoso respecto al uso de epónimos 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, así como para mejorar el tratamiento de este grupo de alteraciones del desarrollo que afectan exclusiva o predominantemente al tronco del encéfalo. La revisión de la bibliografía y nuestra experiencia muestran que la mayoría de los casos con afectación selectiva del rombencéfalo se deben a lesiones disruptivas prenatales, mientras que en los casos con afectación del mesencéfalo y el cerebelo, así como en los síndromes polimalformativos con afectación destacada del troncoencéfalo, la topografía de las lesiones es más difusa y menos específica, y la causa hereditaria, más probable. Debido a la amplia heterogeneidad fenotípica asociada a la disgenesia troncoencefálica, es esencial realizar una evaluación individualizada y establecer un plan de tratamiento específico. Los programas de rehabilitación deben comenzar poco después del diagnóstico y centrarse en mejorar las habilidades motoras, dotando al paciente de las herramientas necesarias para afrontar las necesidades diarias en función de la morbilidad asociada. Aunque el pronóstico de la disgenesia troncoencefálica secundaria a lesiones disruptivas depende de la localización y la extensión del territorio vascular afectado, en general, el pronóstico de los pacientes con disgenesia troncoencefálica es mejor de lo que las manifestaciones clínicas iniciales harían suponer

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

Brainstem dysgenesis during the neonatal period: diagnosis and management.

AIMS: To report our neonatal management experience in patients who received a diagnosis of brainstem dysgenesis (BSD). PATIENTS AND METHODS: This study retrospectively reviewed the medical records of 15 neonates with BSD diagnosed between 1984 and 2011. Data on the perinatal period, physical examination, laboratory findings, and management by systems were systematically analyzed. RESULTS: All cases were sporadic. Cocaine abuse and misoprostol use were recorded in two pregnancies. The reason for admission was prematurity (2 of 15), respiratory distress (8 of 15), gastroschisis (1 of 15), and abnormal neurological examination (4 of 15). Clinically, the most commonly affected cranial nerves were the 7th (13 of 15), 9th (11 of 15), 10th (8 of 15), 5th (7 of 15), 12th (7 of 15), 6th (3 of 15), 4th (1 of 15), and 3rd (1 of 15). Five patients required positive pressure ventilation during delivery room resuscitation, three had difficult airways, and two needed tracheostomy during admission. Most patients required nasogastric tube feeding shortly after birth, and four patients had a gastrostomy on discharge. Two patients died of respiratory and cardiac failure. Electromyography and nerve conduction velocity were used to exclude generalized neuromuscular disorders, and in conjunction with other neurophysiological and gastrointestinal tract studies, helped uncover the extent of brainstem involvement in most cases. Cranial magnetic resonance imaging supported the diagnosis in more than half of the patients. CONCLUSIONS: Early diagnosis of BSD is mainly clinical, difficult to establish unless suspected, and crucial to prevent complications. Neonatal care of patients with BSD requires a comprehensive approach that must take into consideration the etiological, anatomical, and pathogenic aspects contributing to the clinical manifestations of this disorder. Care should be provided by multidisciplinary teams, in which neonatologists, pediatric neurologists, nutritionists, physical therapists, and other professionals participate, depending on the associated morbidity in order to improve its management and prognosis.

Leigh Syndrome and the Mitochondrial m.13513G>A Mutation: Expanding the Clinical Spectrum.

The mitochondrial DNA m.13513G>A mutation in the ND5 subunit gene is a frequent cause of Leigh syndrome. Patients harboring this mutation typically present with ptosis and cardiac conduction abnormalities, particularly Wolff-Parkinson-White syndrome, and have a late clinical onset, which contrasts with the typical infantile form. The authors describe a patient presenting with intrauterine growth retardation and visual impairment at 3 months of age, followed by infantile spasms, severe gastrointestinal dysmotility, and neurological regression. The patient had hyperlactacidemia and bilateral basal ganglia and brainstem lesions on MRI. Although he did not present cardiac conduction abnormalities, his mother had been diagnosed with Wolff-Parkinson-White syndrome. The m.13513G>A mutation was found in the patient's muscle and in several tissues of his mother. The present results expand the phenotype of Leigh syndrome associated with the m.13513G>A mutation, which should be suspected in patients with early-onset mitochondrial encephalopathy with infantile spasms or prominent gastrointestinal smooth muscle involvement.

[Reversible encephalopathy caused by valproic acid in an adolescent with idiopathic generalised epilepsy]. / Encefalopatía reversible por ácido valproico en un adolescente con epilepsia generalizada idiopática.

INTRODUCTION: Encephalopathy due to valproic acid (VPA) is a rare complication leading to a disorder that affects the patient's mental status to a greater or lesser extent and which can be accompanied by a paradoxical worsening of the seizures. The diagnosis is obvious when it appears within the context of hyperammonemia or a liver pathology, but can be difficult to diagnose if it appears in isolation in patients who show no other signs of intoxication due to VPA. CASE REPORT: We report the case of an adolescent who suffered idiopathic generalised epilepsy and presented sub-acute cognitive impairment and a worsening of his pattern of seizures some months after starting treatment with VPA. These manifestations were accompanied by a slowing of the baseline electroencephalogram (EEG) tracing; no biochemical signs of overdosage or toxicity that could be attributed to the drug or any other possible aetiology were observed. Withdrawing VPA resulted in a swift improvement in the patient's mental status and in the control of his seizures. Likewise, EEG recordings also returned to normal. CONCLUSIONS: Encephalopathy due to VPA should be considered in patients who present a deterioration of their neurological status, whether associated to an aggravation of their seizures or not, despite the absence of any analytical signs suggestive of VPA toxicity or overdosage. If liver functioning is not affected, withdrawal of the drug will determine the disappearance of the symptoms and will also allow confirmation of the diagnosis.

Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy.

BACKGROUND: Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy. METHODS: We reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females. RESULTS: Symptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found. CONCLUSIONS: Skewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene.

[Clinical variability of polymicrogiria: report of 35 new cases and review of the literature]. / Variabilidad clínica de la polimicrogiria: a propósito de 35 nuevos casos y revisión de la bibliografía.

INTRODUCTION: The study of polymicrogyria with magnetic resonance imaging (MRI) has made possible the report of several series of patients in which the main clinical manifestations differ considerably. The aims of the study were to review the literature and to know the clinical variability of the patients attended in a neuropediatric service. PATIENTS AND METHODS: A retrospective study was conducted between 1989-2011 for the patients attended in our neuro-pediatric service and diagnosed of polymicrogyria by MRI. RESULTS: On the totality of 44 patients having polymicrogyria, 9 did not satisfy de inclusion criteria (Barkovich's radiological criteria). The polymicrogyria was bilateral in 22/35 patients (1 frontal, 22 perisylvian) and unilateral in 13/35 (2 frontal, the rest perisylvian). All patients with bilateral polymicrogyria had intellectual disability, 71% had global development delay, 75% had oromotor disorder and 40% had epilepsy. Patients with unilateral polymicrogyria had the following symptoms: 65% intellectual disability, 55% global development delay, 55% oromotor disorder, 55% epilepsy and 2 patients where free of symptoms (the oldest 2 year old). The initial symptoms were depending upon the age: the oromotor disorder was the most common in the newborn period, global development delay if the symptoms started before 2 years old and after 2 years epilepsy was the initial most common symptom. CONCLUSION: In our study the most common symptom was intellectual disability (independently of the type of poly-microgyria), followed by oromotor disorder and, with fewer proportion, epilepsy (in contrast with other series).

Variabilidad clínica de la polimicrogiria: a propósito de 35 nuevos casos y revisión de la bibliografía / Clinical variability of polymicrogiria: report of 35 new cases and review of the literatureepi

Introducción. El estudio diagnóstico de polimicrogiria mediante resonancia magnética ha facilitado la publicación de varias series de pacientes en las que las manifestaciones clínicas predominantes varían considerablemente. Objetivo. Conocer la variabilidad fenotípica de la polimicrogiria basándose en la serie de pacientes atendidos en nuestro servicio y la revisión de la bibliografía. Pacientes y métodos. Estudio retrospectivo de los pacientes diagnosticados de polimicrogiria mediante resonancia magnética y seguidos en consultas durante los años 1989-2011.Resultados. De un total de 44 pacientes, nueve fueron excluidos por no cumplir los criterios diagnósticos radiológicospropuestos por Barkovich. La polimicrogiria fue bilateral en 22/35 pacientes (una frontal, 21 perisilvianas) y unilateral en13/35 (dos frontales, el resto perisilvianas). Todos los pacientes con polimicrogiria bilateral tenían algún tipo de discapacidadintelectual, un 71% tenía retraso global del desarrollo, un 75% tenía trastorno oromotor y un 40% tenía epilepsia. Los pacientes con polimicrogiria unilateral presentaron discapacidad intelectual (65%), retraso global del desarrollo (55%), trastorno oromotor (55%) y epilepsia (55%), estando asintomáticos dos pacientes (2 años de edad). La presentación clínica de los pacientes dependía de la edad: en el período neonatal, el síntoma guía fue el trastorno oromotor; antes de los 2 años, el retraso global del desarrollo; y partir de los 2 años, la epilepsia. Conclusión. En este estudio, a diferencia de otras series, el síntoma más prevalente fue la discapacidad intelectual (independientemente del tipo de polimicrogiria), seguido del trastorno oromotor y, en menor medida, la epilepsia (AU)

Introduction. The study of polymicrogyria with magnetic resonance imaging (MRI) has made possible the report of severalseries of patients in which the main clinical manifestations differ considerably. The aims of the study were to review the literature and to know the clinical variability of the patients attended in a neuropediatric service. Patients and methods. A retrospective study was conducted between 1989-2011 for the patients attended in our neuropediatric service and diagnosed of polymicrogyria by MRI.Results. On the totality of 44 patients having polymicrogyria, 9 did not satisfy de inclusion criteria (Barkovich’s radiological criteria). The polymicrogyria was bilateral in 22/35 patients (1 frontal, 22 perisylvian) and unilateral in 13/35 (2 frontal, the rest perisylvian). All patients with bilateral polymicrogyria had intellectual disability, 71% had global development delay, 75% had oromotor disorder and 40% had epilepsy. Patients with unilateral polymicrogyria had the following symptoms: 65% intellectual disability, 55% global development delay, 55% oromotor disorder, 55% epilepsy and 2 patients wherefree of symptoms (the oldest 2 year old). The initial symptoms were depending upon the age: the oromotor disorder was the most common in the newborn period, global development delay if the symptoms started before 2 years old and after 2 years epilepsy was the initial most common symptom.Conclusion. In our study the most common symptom was intellectual disability (independently of the type of polymicrogyria), followed by oromotor disorder and, with fewer proportion, epilepsy (in contrast with other series) (AU)

Central hypoventilation and brainstem dysgenesis.

We report on a newborn with congenital hypotonia, unilateral facial palsy, sucking and swallowing difficulties, velopalatine incoordination, and unilateral impairment of the auditory brainstem responses, attributable to brainstem dysgenesis. On follow-up, the child manifested developmental delay and central hypoventilation syndrome during sleep. The ventilation abnormality during sleep with insensitivity to hypercapnia, associated with unilateral facial paralysis, indicates a pontine lesion, including the parafacial respiratory group.

Etanercept-induced myelopathy in a pediatric case of blau syndrome.

Blau syndrome is a rare autoinflammatory disorder within the group of pediatric granulomatous diseases. Mutations in nucleotide-binding oligomerization domain 2 (NOD2/CARD15) are responsible for this condition, which has an autosomal dominant pattern of inheritance and variable expressivity. The clinical picture includes arthritis, uveitis, skin rash, and granulomatous inflammation. Central nervous system involvement is seldom reported, although some isolated cases of seizures, neurosensorial hearing loss, and transient cranial nerve palsy have been described. Treatment consists of nonsteroidal anti-inflammatory drugs, corticosteroids, and immunosuppressive agents, among which anti-tumor-necrosis-factor-alpha (TNF-α) biologic agents, such as etanercept, play an important role. Among the major adverse effects of TNF-α inhibitors, demyelinating disease, multiple sclerosis, and acute transverse myelitis have been reported in adults. We describe a case of pediatric Blau syndrome affected by etanercept-induced myelopathy, manifesting as a clinical syndrome of transverse myelitis. The patient experienced rapid recovery after etanercept was discontinued. To our knowledge, this is the first such case reported in the literature and, possibly, the one with the latest onset, following 8 years of treatment. We discuss the etiopathogenic mechanisms of this reaction and possible explanations for the imaging findings.

Paroxysmal exercise-induced dyskinesia, writer's cramp, migraine with aura and absence epilepsy in twin brothers with a novel SLC2A1 missense mutation.

We report two monochorionic twins that progressively developed, between ages 5 and 10, a combination of episodic neurological disorders including paroxysmal exercise-induced dyskinesia, migraine without or with aura, absence seizures and writer's cramp. CSF/serum glucose ratio was moderately decreased in both patients. Mutational analysis of SLC2A1 gene identified a de novo heterozygous missense mutation in exon 4. This novel mutation has been previously showed to disrupt glucose transport in vitro. Both patients showed immediate and near-complete response to ketogenic diet. This clinical observation suggests that a high index of suspicion for GLUT1 deficiency syndrome is warranted in evaluating patients with multiple neurological paroxysmal events.

Brainstem dysgenesis in an infant prenatally exposed to cocaine.

Many authors described the effects on the fetus of maternal cocaine abuse during pregnancy. Vasoconstriction appears to be the common mechanism of action leading to a wide range of fetal anomalies. We report on an infant with multiple cranial-nerve involvement attributable to brainstem dysgenesis, born to a cocaine-addicted mother.

Muscle genome-wide expression profiling during disease evolution in mdx mice.

Mdx mice show a milder phenotype than Duchenne patients despite bearing an analogous genetic defect. Our aim was to sort out genes, differentially expressed during the evolution of skeletal muscle mdx mouse disease, to elucidate the mechanisms by which these animals overcome the lack of dystrophin. Genome-wide microarray-based gene expression analysis was carried out at 3 wk and 1.5 and 3 mo of life. Candidate genes were selected by comparing: 1) mdx vs. controls at each point in time, and 2) mdx mice and 3) control mice among the three points in time. The first analysis showed a strong upregulation (96%) of inflammation-related genes and in >75% of genes related to cell adhesion, muscle structure/regeneration, and extracellular matrix remodeling during mdx disease evolution. Lgals3, Postn, Ctss, and Sln genes showed the strongest variations. The analysis performed among points in time demonstrated significant changes in Ecm1, Spon1, Thbs1, Csrp3, Myo10, Pde4b, and Adamts-5 exclusively during mdx mice lifespan. RT-PCR analysis of Postn, Sln, Ctss, Thbs1, Ecm1, and Adamts-5 expression from 3 wk to 9 mo, confirmed microarray data and demonstrated variations beyond 3 mo of age. A high-confidence functional network analysis demonstrated a strong relationship between them and showed two main subnetworks, having Dmd-Utrn-Myo10 and Adamts5-Thbs1-Spon1-Postn as principal nodes, which are functionally linked to Abca1, Actn4, Crebbp, Csrp3, Lama1, Lama3, Mical2, Mical3, Myf6, Pxn, and Sparc genes. Candidate genes may participate in the decline of muscle necrosis in mdx mice and could be considered potential therapeutic targets for Duchenne patients.

Laser microdissection-based expression analysis of key genes involved in muscle regeneration in mdx mice.

We have used the mdx mice strain (C57BL/10ScSn-mdx) as an experimental subject for the study of reiterative skeletal muscle necrosis-regeneration with basement membrane preservation. In young mdx muscle, by means of Hematoxylin-Eosin staining, different types of degenerative-regenerative groups (DRG) can be recognized and assigned to a defined muscle regeneration phase. To evaluate the expression of known key-regulatory genes in muscle regeneration, we have applied Laser Capture Microdissection technique to obtain tissue from different DRGs encompassing the complete skeletal muscle regenerative process. The expression of MyoD, Myf-5 and Myogenin showed a rapid increase in the first two days post-necrosis, which were followed by MRF4 expression, when newly regenerating fibers started to appear (3-5days post-necrosis). MHCd mRNA levels, undetectable in mature non-injured fibers, increased progressively from the first day post-necrosis and reached its maximum level of expression in DRGs showing basophilic regenerating fibers. TGFbeta-1 mRNA expression showed a prompt and strong increase following fiber necrosis that persisted during the inflammatory phase, and progressively decreased when new regenerating fibers began to appear. In contrast, IGF-2 mRNA expression decreased during the first days post-necrosis but was followed by a progressive rise in its expression coinciding with the appearance of the newly formed myofibers, reaching the maximum expression levels in DRGs composed of medium caliber basophilic regenerating myofibers (5-7 days post-necrosis). mdx degenerative-regenerative group typing, in conjunction with laser microdissection-based gene expression analysis, opens up a new approach to the molecular study of skeletal muscle regeneration.