Intragenic rearrangements in LARGE and POMGNT1 genes in severe dystroglycanopathies.

Dystroglycanopathies are a heterogeneous group of muscular dystrophies with autosomal recessive inheritance characterized by abnormal glycosylation of alpha-dystroglycan. The most severe phenotypes are Walker-Warburg Syndrome (WWS) and muscle-eye-brain disease (MEB) presenting with lissencephaly type II (LIS II) and in which muscular dystrophy is associated with mental retardation and eye abnormalities. To date, six distinct genes, POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE and recently in one case DPM3, have been shown to be involved in dystroglycanopathies. Genomic sequencing alone is still frequently used for diagnosis purpose, not allowing detection of intragenic rearrangements at the heterozygous state contrarily to RNA analysis, quantitative PCR and CGH array analysis. These latter methods enabled us to identify four new intragenic rearrangements in the LARGE gene in three fetuses with WWS, born to two unrelated families: deletion of exons 9-10 and duplication of introns 1-4 for the first family and deletion of exons 4 and 7 for the second one; and a deletion of the last six exons of the POMGNT1 gene in two unrelated MEB patients. Genomic dosage studies using emerging tools such as CGH array should be included in routine molecular analysis of dystroglycanopathies, not only for the screening of the LARGE gene in which this kind of mutation seems to be more frequent than point mutations, but also for the other involved genes, especially in severe clinical cases.

A common pattern of brain MRI imaging in mitochondrial diseases with complex I deficiency.

OBJECTIVE: To identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including Leigh syndrome. Human complex I comprises seven core subunits encoded by mitochondrial DNA (mtDNA) and 38 core subunits encoded by nuclear DNA (nDNA). Moreover, its assembly requires six known and many unknown assembly factors. To date, no correlation between genotypes and brain MRI phenotypes has been found in complex I deficiencies. DESIGN AND SUBJECTS: The brain MRIs of 30 patients carrying known mutation(s) in genes involved in complex I were retrospectively collected and compared with the brain MRIs of 11 patients carrying known mutations in genes involved in the pyruvate dehydrogenase (PDH) complex as well as 10 patients with MT-TL1 mutations. RESULTS: All complex I deficient patients showed bilateral brainstem lesions (30/30) and 77% (23/30) showed anomalies of the putamen. Supratentorial stroke-like lesions were only observed in complex I deficient patients carrying mtDNA mutations (8/19) and necrotising leucoencephalopathy in patients with nDNA mutations (4/5). Conversely, the isolated stroke-like images observed in patients with MT-TL1 mutations, or the corpus callosum malformations observed in PDH deficient patients, were never observed in complex I deficient patients. CONCLUSION: A common pattern of brain MRI imaging was identified with abnormal signal intensities in brainstem and subtentorial nuclei with lactate peak as a clue of complex I deficiency. Combining clinico-biochemical data with brain imaging may therefore help orient genetic studies in complex I deficiency.

Severe neonatal episodic laryngospasm due to de novo SCN4A mutations: a new treatable disorder.

BACKGROUND: Myotonia is unusual in infants, and not well-known. METHODS: We describe neonatal life-threatening features of myotonia caused by de novo mutations in the muscle sodium channel gene SCN4A. RESULTS: Three male neonates initially displayed episodic laryngospasms, with face and limb myotonia appearing later. We found SCN4A de novo mutations in these neonates: p.Gly1306Glu in 2 unrelated cases and a novel mutation p.Ala799Ser in the third. Two patients survived their respiratory attacks and were efficiently treated by sodium channel blockers (mexiletine, carbamazepine) following diagnosis of myotonia. CONCLUSION: Severe neonatal episodic laryngospasm is a new phenotype caused by a sodium channelopathy, which can be alleviated by channel blockers.

Febrile brain stroke and tuberculous meningitis: persisting threat in non-endemic countries.

Tuberculous meningitis is uncommon in western countries and its outcome is poor when it is not diagnosed and treated in good time. Here, we present a case of febrile brain stroke revealing a tuberculous arachnoiditis in a 13-month-old infant living in a non-endemic country. Thanks to prompt specific antibiotherapy, the clinical outcome was globally favourable in spite of the occurrence of an asymptomatic brain tuberculoma, which disappeared spontaneously. Although tuberculous meningitis is rare in non-endemic countries, it must be evoked in strokes occurring in a febrile context.

Insidious peripheral neuropathy occurring under treatment in infantile MTHFR deficiency.

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency was diagnosed in a 1-month-old baby with signs of cerebral distress. Under a classic treatment using methionine supplementation, methyl donor (betaine) folinic acid, vitamin B(6) and vitamin B(12), the neuromotor development was satisfactory. At 15 years of age, however, despite no clear modification of the biochemical markers in body fluids, she developed a clinically overt peripheral axonal neuropathy. Only partial clinical improvement was obtained after reinforcement of betaine doses. Surveillance of the peripheral nerve is indicated in MTHFR deficiency, including in the infantile form with a good therapeutic compliance.

[Arterial ischemic stroke in the healthy child. Practical approach (neonate and foetus excluded)]. / Accident artériel ischémique cérébral d'apparence primitive chez l'enfant. Démarche pratique (nouveau-né et foetus exclus).

Primary stroke can be due to embolism or an obstructive process of the vascular wall. Embolism may come from a parietal lesion of a large artery in the neck (traumatic dissections), from a cryptic cardiopathy, from a venous thrombosis associated with a right-left shunt. Among pathologies of endocranial arteries, the most frequent is the acute, postviral arteriopathy of the sus-clinoïd carotid, which evolves toward stabilisation or regression. Insidious obstructive arteriopathies of the Willis circle, including development of a transparenchymal suppletive circulation (Moya-Moya disease), cumulate chronic circulatory insufficiency and repetitive strokes. Inflammatory multifocal cerebral arteriopathies mainly involve mean and small arteries. Most of them are secondary to a multisystemic disease, but some are primary. The basic investigation is anatomical and begins with MRI. Emergency conventional cerebral angiography is discussed when heparinotherapy is difficult to decide (evolutive thrombosis), or when an endovascular intervention appears possible (anoeuvrism). Secondarily, conventional angiography is indicated in any chronic situation where a precise anatomical follow-up is necessary. Investigations of the cardiovascular system, of the thrombophilic risk, of a dysimmune process are discussed according to the clinico-anatomical diagnosis.

[Spectacular neurologic manifestations after mild head trauma: retrospective study on 51 children]. / Manifestations neurologiques spectaculaires après traumatisme crânien bénin: étude rétrospective de 51 enfants.

UNLABELLED: Mild head traumas, as a rule, remain a- or paucisymptomatic. In a few cases however, spectacular manifestations develop despite absence of intracerebral lesion. POPULATION, METHODS: We have studied retrospectively 51 such children and contacted their family in order to clarify the follow-up. RESULTS: The dominant symptoms allowed to categorize the following situations: syncope-like loss of consciousness (11 cases), seizures (6), severe headaches with neurologic signs (15), confusion (8), visual disorders (6), amnesic ictus (5). Recurrences were possible but benign: in 8/11 children in the group "syncopes", in 1/6 in the group "seizures", in 5/21 in the 4 other groups. In the latter 4 groups, 11/21 children developed common migraine. Except for the only case who developed epilepsy later on, scholarship was normal in the 25 cases with sufficient follow-up. DISCUSSION: Beside syncopes and seizures, the long-lasting episodes suggested a migrainous pathogeny, perhaps at a maturative stage where the trigger of migrainous mechanism is at a low level in the brain. CONCLUSION: The mildness of the knock, the normality of CT scan including when the symptoms are present and the normality of both consciousness and examination once the symptoms have disappeared allow to avoid further investigations.

The association between developmental handicaps and traumatic brain injury during pregnancy: an issue that deserves more systematic evaluation.

AIMS: Trauma during pregnancy is commonly viewed as benign for the foetus when the delivery occurs normally. This study revisits that point of view. METHOD: We included eighteen patients having a neurological handicap with an anamnesis of an accident during pregnancy and a follow-up sufficient to determine a definite outcome. RESULTS: Pregnancy outcome and observed management. Foetal abnormalities were detected in six cases between the first and the thirteenth day after the trauma. Emergency delivery or rapid birth after signs of foetal distress occurred in five cases. One baby died soon after birth. One-third of cases were not submitted to any investigation. VARIOUS NEUROLOGICAL HANDICAPS WERE RECORDED: Congenital microcephaly (three patients), congenital hydrocephalus (three), Infantile cerebral hemiplegy (six), quadriplegy with severe encephalopathy (four), diplegy (one), clumsiness with cerebellar atrophy (one), Moebius syndrome (one), mental retardation with autistic features (two), learning disability (one) auditory agnosia (one). Cerebral imaging showed macroscopic abnormalities in fourteen patients, evoking various pathogenetic hypotheses. CONCLUSION: The association between maternal trauma and foetal brain lesions lacks sufficient investigation in many cases. Prospective studies are needed to clarify both medical and legal issues. Guidelines are proposed for obstetrical and paediatric management after significant maternal trauma.

Allelic heterogeneity of SMARD1 at the IGHMBP2 locus.

Spinal Muscular Atrophy with Respiratory Distress (SMARD) is an autosomal recessive disorder characterized by neurogenic muscular atrophy due to progressive anterior horn cell degeneration and early life-threatening respiratory failure ascribed to diaphragmatic dysfunction. SMARD is clinically and genetically heterogeneous. SMARD type 1 is characterized by onset of respiratory failure within the first weeks of life and has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We report here the identification of nine novel IGHMBP2 mutations in five SMARD1 patients, including seven missense [ c.587A>G (p.Gln196Arg), c.647C>T (p.Pro216Leu), c.752T>C (p.Leu251Pro), c.1693G>A (p.Asp565Asn), c.1730T>C (p.Leu577Pro), c.1807C>T (p.Arg603Cys), c.1909C>T (p.Arg637Cys)] and two nonsense mutations [ c.1488C>A (p.Cys496X), c.2368C>T (p.Arg790X)]. Interestingly, 7 of 9 mutations occurred at highly conserved residues of the putative DNA helicase domain. The identification of novel IGHMBP2 variants will hopefully help diagnosing SMARD1 and contribute to a better functional characterization of IGHMBP2 gene product.

[Neonatal thrombosis of the jugular veins: long-term repercussions on cerebral development (two cases)]. / Thrombose néonatale des veines jugulaires: retentissement à long terme sur le développement cérébral (à propos de deux cas).

Bilateral obstruction of the internal jugular veins is rare in the neonatal period and no long-term follow-up has been reported yet. We report two cases. The first developped an extensive thrombosis of superior veina cava related to a central veinous line, the second an unilateral thrombosis of the transverse-sigmoid sinus associated to a constitutional hypoplasia of the contralateral jugular vein. In the latter case, no cause or risk factor was noticeable, except for a forceps delivery. In both cases the clinical course was dominated by the development of a prominent collateral network of cervico-facial veins and by a progressive macrocrania. According to MRImaging, the latter was not related to a dilation of CSF spaces, but to a macro-encephaly, either by inflation of the vascular veinous compartment inside the parenchyma or by genuine brain's overgrowth. Long-term follow-up showed a grossly normal course, both from the neurological and the scholar point of view. However, slight neuropsychological anomalies were noticed, bringing some shade on the prognosis.

Phoneme perception in a neonate with a left sylvian infarct.

We report the case of a neonate tested three weeks after a neonatal left sylvian infarct. We studied her perception of speech and non-speech stimuli with high-density event-related potentials. The results show that she was able to discriminate not only a change of timbre in tones but also a vowel change, and even a place of articulation contrast in stop consonants. Moreover, a discrimination response to stop consonants was observed even when syllables were produced by different speakers. Her intact right hemisphere was thus able to extract relevant phonetic information in spite of irrelevant acoustic variation. These results suggest that both hemispheres contribute to phoneme perception during the first months of life and confirm our previous findings concerning bilateral responses in normal infants.

[At the crossroads between developmental and degenerative diseases: the cerebellar disorders of early infancy. Classification and practical approach]. / Au carrefour de la pathologie développementale et de la pathologie dégénérative: les maladies cérébelleuses de la première enfance. Démembrement et approche pratique.

The developmental characteristics of the cerebellum, including its histogenesis which persists well beyond birth, explain, at least in part,why the mechanisms of cerebral disorders of infancy remain equivocal. The nosology of certain congenital ataxias, especially those with cerebellar hypoplasia, remains ambiguous, at the crossroads between early degenerative disease and congenital non-progressive anomalies. We have revisited the clinical approach to the most frequent situations: (1) the careful dysmorphology work-up must search for any element of various recognizable syndromes, especially those transmitted by autosomal recessive inheritance. An update of list of such syndromes is provided. (2) Cerebellum imaging must be obtained as early as possible and re-documented with a long-term follow-up. Emerging 3D techniques should help improve morphological evaluation. (3) One the contrary, a complex biochemical work-up, looking for metabolic diseases, is required only when the clinical and radiological evaluations provide unusual data. (4) Mental status is always the most relevant element of prognosis. t is frequently compromised, including in congenital non-progressive ataxia with normal imaging. Beyond the classical strategies, the genetic approach must take into consideration possible phenotypic homologies with natural or experimental animal models. This approach is illustrated by the recent discovery of mutations with the human homolog of the Reeler gene in a subset of cerebellar agenesis associated with other dysgenetic elements.

[Encephalopathy associated with severe bacterial infections: "presuppurative encephalitis" or "toxi-infectious disorder"?]. / Encéphalopathie associée aux infections bactériennes sévères de l'enfant: "encéphalite présuppurative" ou "syndrome toxi-infectieux"?

Three children are reported, exhibiting encephalopathic symptoms in the course of a severe bacterial infection, though they had no sign of intracranial purulent collection nor metabolic disturbances: the first was associated with a appendicular peritonitis, the second with a purulent knee arthritis, the third with a pneumoccus septicemia. The elements are reviewed that favor either a true septic encephalitis, i.e. microscopic presuppurative foci, versus a toxiinfectious process, either by direct action of toxins or through intracerebral activation of pre-inflammatory cytokines. Whatever the mechanism involved in individual cases, the treatment is mainly based on prompt administration of the convenient antibiotics.

[SPECT-identified hypoperfusion of the left temporomesial structures in a Kleine-Levin syndrome]. / Hypoperfusion temporomésiale gauche en TEMP dans un syndrome de Kleine-Levin.

A 13-year-old boy developed typical features of Kleine-Levin syndrome. Routine investigations and MRI were normal. SPECT, performed both during an attack and during a symptom-fee period, demonstrated clear hypoperfusion of the left mesiotemporal structures. The possible implications of this finding are discussed.

Critical illness neuromuscular disease: clinical, electrophysiological, and prognostic aspects.

BACKGROUND: Critical illness neuromuscular disease, which has been recognised as a distinct clinical entity in adults, remains poorly described in children. AIMS: To assess retrospectively the clinical, electrophysiological, and prognostic features of the disease. METHODS: Retrospective study in a children's university hospital. RESULTS: Five critically ill patients presented with generalised paralysis, associated with long lasting failure to breathe in three. The cause of the generalised paralysis was critical illness neuropathy in two, acute myopathy in two, and mixed neuromyopathy in one. CONCLUSIONS: Neuromuscular disease should be suspected in critically ill children with muscle weakness. Because corticosteroids and muscle relaxants appear to trigger some types of intensive care unit neuromuscular disease in children, their use should be restricted or administered at the lowest doses possible.

Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor.

Central core disease (CCD) is an autosomal dominant congenital myopathy. Diagnosis is based on the presence of cores in skeletal muscles. CCD has been linked to the gene encoding the ryanodine receptor (RYR1) and is considered to be an allelic disease of malignant hyperthermia susceptibility. However, the report of a recessive form of transmission together with a variable clinical presentation has raised the question of the genetic heterogeneity of the disease. Analyzing a panel of 34 families exclusively recruited on the basis of both clinically and morphologically expressed CCD, 12 different mutations of the C-terminal domain of RYR1 have been identified in 16 unrelated families. Morphological analysis of the patients' muscles showed different aspects of cores, all of them associated with mutations in the C-terminal region of RYR1. Furthermore, we characterized the presence of neomutations in the RyR1 gene in four families. This indicates that neomutations into the RyR1 gene are not a rare event and must be taken into account for genetic studies of families that present with congenital myopathies type 'central core disease'. Three mutations led to the deletion in frame of amino acids. This is the first report of amino acid deletions in RYR1 associated with CCD. According to a four-transmembrane domain model, the mutations concentrated mostly in the myoplasmic and luminal loops linking, respectively, transmembrane domains T1 and T2 or T3 and T4 of RYR1.

Respiratory chain deficiency in Alpers syndrome.

Alpers syndrome is a progressive encephalopathy of early onset, characterized by rapid and severe developmental delay, intractable seizures and liver involvement in a previously healthy child. Here, we report on respiratory chain enzyme deficiency in the liver of four unrelated children presenting with epileptic encephalopathy and liver involvement diagnosed as Alpers syndrome. Interestingly, oxidative phosphorylation in skeletal muscle was normal in 4/4 and blood and CSF lactate in 3/4 patients. Liver involvement had a late clinical onset in patients with previously isolated epileptic encephalopathy. Based on these observations, we suggest 1. to give consideration to respiratory chain deficiency in the diagnosis of severe epileptic encephalopathy in childhood, even when no clinical or biological evidence of liver involvement or lactic acidosis is noted, and 2. to investigate the respiratory chain in a needle biopsy of the liver in children with epileptic encephalopathy prior to valproate administration if biochemical indications for respiratory chain disease or hepatic disturbance are noted, as this drug is believed to occasionally trigger hepatic failure and fatal outcome.