Partial acute transverse myelitis is a predictor of multiple sclerosis in children.

BACKGROUND: Acute transverse myelitis (ATM) in children is a rare and often severe disease for which there are few known prognostic factors, particularly the subsequent risk of multiple sclerosis (MS) diagnosis. OBJECTIVES: To determine the clinical course and prognostic factors after a first episode of ATM in children. METHODS: Thirty children below 16 years of age diagnosed with a first neurological episode of ATM were included retrospectively. Clinical evaluation, treatment, laboratory, and MRI data were collected. RESULTS: Median age at onset was 11 years (range 3-15 years). Follow-up data were available for a median of 4 years (range 0.5-16.7 years). Five patients subsequently had a diagnosis of MS (17%), which was associated with acute partial transverse myelitis (odds ratio 5; 95% confidence interval 2.3-11), with a 60% probability of having a relapse at five years (p < 0.01). The 2011 Verhey criteria correctly identified MS in children with the highest specificity (96%) and sensitivity (80%). CONCLUSION: Acute partial transverse myelitis and brain MRI abnormalities at initial presentation are significantly predictive of a subsequent diagnosis of MS in children with ATM. These findings suggest that closer brain MRI monitoring after acute partial transverse myelitis might make the earlier introduction of disease-modifying therapies possible.

Update on transcobalamin deficiency: clinical presentation, treatment and outcome.

Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.

[Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies: Contribution of genetic and clinical databases]. / Variabilité phénotypique et corrélations génotype-phénotype des dystrophinopathies : contribution des banques de données.

The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD database. The collection of 70,000 clinical data for 600 patients with an average longitudinal follow-up of 12years enabled clarification of the natural history of Duchenne and Becker muscular dystrophies and clinical presentations in symptomatic females. We were able to specify the phenotypic heterogeneity of motor, orthopedic and respiratory involvements (severe, standard and intermediary form), of the cardiac disorder (severe, standard or absent cardiomyopathy, absence of correlation between motor and cardiac involvements), and of brain function (mental deficiency in the patients with Becker muscular dystrophy, psychopathological disorders in dystrophinopathies). Phenotypic variability did not correlate with a specific mutational spectrum. We propose a model of phenotypic analysis based on the presence or not of muscular and cardiac involvements (described by age at onset and rate of progression) and brain involvement (described by the type and the severity of the cognitive impairment and of the psychological disorders). The methodology developed for the DMD gene can be generalized and used for other databases dedicated to genetic diseases. Application of this model of phenotypic analysis for each patient and further development of the database should contribute substantially to clinical research providing useful tools for future clinical trials.

Epsilon sarcoglycan mutations and phenotype in French patients with myoclonic syndromes.

BACKGROUND: Myoclonus dystonia syndrome (MDS) is an autosomal dominant movement disorder caused by mutations in the epsilon-sarcoglycan gene (SGCE) on chromosome 7q21. METHODS: We have screened for SGCE mutations in index cases from 76 French patients with myoclonic syndromes, including myoclonus dystonia (M-D), essential myoclonus (E-M), primary myoclonic dystonia, generalised dystonia, dystonia with tremor, and benign hereditary chorea. All coding exons of the SGCE gene were analysed. The DYT1 mutation was also tested. RESULTS: Sixteen index cases had SGCE mutations while one case with primary myoclonic dystonia carried the DYT1 mutation. Thirteen different mutations were found: three nonsense mutations, three missense mutations, three splice site mutations, three deletions, and one insertion. Eleven of the SGCE index cases had M-D and five E-M. No SGCE mutations were detected in patients with other phenotypes. The total number of mutation carriers in the families was 38, six of whom were asymptomatic. Penetrance was complete in paternal transmissions and null in maternal transmissions. MDS patients with SGCE mutation had a significantly earlier onset than the non-carriers. None of the patients had severe psychiatric disorders. CONCLUSION: This large cohort of index patients shows that SGCE mutations are primarily found in patients with M-D and to a lesser extent E-M, but are present in only 30% of these patients combined (M-D and E-M).

[Non epileptic paroxysmal movement disorders in childhood]. / Mouvements anormaux paroxystiques non épileptiques de l'enfant.

Paroxysmal movement disorders are not uncommon in childhood, but are probably under-recognised. Paroxysmal movement disorders are a distinctive group of disorders that represents various clinical situations, characterised by intermittent and episodic disturbances of movement. Diagnosis relies on semiological analysis, mainly based on parental description of the manifestations; video recording (during an EEG-video monitoring or home made video) are often helpful to establish the correct diagnosis. In the large majority of the cases, paroxysmal movement disorders are benign situations. Some of them are transient, as they spontaneously stop over time (benign torticolis of infancy, paroxysmal tonic upgaze). Being familiar with these disorders will lead to accurate diagnosis, so avoiding useless investigations. Most of the time, no treatment will be required, and the families will be informed of the good prognosis.

[Parry-Romberg's syndrome and epilepsy]. / Syndrome de Parry-Romberg et épilepsie.

INTRODUCTION: Parry-Romberg's syndrome or progressive facial hemiatrophy is a rare disorder of unknown etiology which may be accompanied by neurological complications, frequently epilepsy, usually focal refractory epilepsy. The associated brain lesions are located on the same side as the half face atrophy and may progress. OBSERVATION: We report the cases of two patients with Parry-Romberg's syndrome and epilepsy. Neurosurgery was performed in one patient, enabling a histological study. CONCLUSION: The link between Parry-Romberg's syndrome and epilepsy is discussed and the neurodevelopmental theory with vascular dysgenesis is suggested.

[Genetics contribution to the understanding of autism]. / Apport de la génétique à la compréhension de l'autisme.

Autism is a pervasive developmental disorder characterised by an impairment in social interaction and in communication, with unusual behaviour. Genetic factors are predominent in autism pathogenesis, in contrast with the environmental factors that would modulate the phenotype. The genetic polymorphism and the phenotypic heterogeneity make the autism a complex disorder to study. Genetic research on families with multiple affected children and biochemical mechanisms studies represent the sources for identifying the susceptibility genes in autism.

Congenital muscular dystrophy and cerebellar atrophy.

Two siblings and two other unrelated patients had congenital muscular weakness and dystrophic changes but normal immunocytochemical stainings for merosin, dystrophin, and dystrophin-related proteins on muscle biopsy. All had marked ataxia and cerebellar atrophy or hypoplasia. Cerebral white matter and cortical organization appeared normal.

Homogeneous phenotype of the gypsy limb-girdle MD with the gamma-sarcoglycan C283Y mutation.

OBJECTIVE: To characterize the clinical phenotype of LGMD2C in gypsies. BACKGROUND: Limb-girdle muscular dystrophy (LGMD) in gypsies of Western Europe is caused by a homozygous C283Y mutation on the same haplotype, suggesting a founder effect. METHODS: We performed clinical, laboratory, and muscle imaging studies of 40 patients. RESULTS: Mean age at onset was 5.3 years. One half of the patients had loss of ambulation by the age of 12; 13% still could walk after age 16. Calf hypertrophy, scapular winging, macroglossia, and lumbar hyperlordosis were common. Girdle, trunk, and proximal limb flexor muscles had earlier and more severe involvement. Cardiomyopathy was not observed. Five patients in the third decade of life required mechanical ventilation. Scoliosis was common in the nonambulatory stage. CONCLUSIONS: LGMD2C in gypsy patients with C283Y mutation presents a rather homogeneous phenotype, characterized by an initial Duchenne-like progressive course followed by a more prolonged survival rate possibly due to the absence of early respiratory impairment and cardiac failure.

Becker muscular dystrophy: demonstration of the carrier status of a female by immunoblotting and immunostaining.

Becker muscular dystrophy (BMD) often results from in-frame mutations of the dystrophin gene, leading to the production of an altered-sized protein. We examined the expression of dystrophin in a BMD patient and in his asymptomatic mother by Western blot and immunofluorescence. The combination of these techniques allowed us to demonstrate the presence of two different dystrophins, normal-sized or reduced-sized in the muscular fibers of the asymptomatic carrier. This result emphasizes the value of dystrophin analysis for carrier detection and genetic counselling of families with Becker muscular dystrophy.

Merosin positive congenital muscular dystrophy with mental deficiency, epilepsy and MRI changes in the cerebral white matter.

A girl born from consanguineous Turkish parents had marked hypotonia from birth and delayed milestones. She was able to stand unaided by 3 years of age with then progressive worsening of motor abilities. She had a severe non-progressive mental deficiency. Epilepsy occurred by 6 years of age. Ophthalmological investigation was normal. A marked white matter high signal was seen on magnetic resonance imaging without cortical dysplasia. Dystrophic changes were seen on muscle biopsy. Two brothers had had a similar history with early death. Muscular immunocytochemical studies showed a normal staining for dystrophin and all dystrophin related glycoproteins (including 43 and 50 DAG). Merosin staining was normal. This case differs from Fukuyama's congenital dystrophy, from merosin negative congenital muscular dystrophy, or from other congenital muscular dystrophy with CNS dysfunction. It underlines the heterogeneity of congenital muscular dystrophy and the non-specific aspect of white matter changes on neuro-imaging.

A standardized method for the evaluation of respiratory muscle endurance in patients with Duchenne muscular dystrophy.

The aim of the study was to develop a standardized method using controlled breathing to quantify respiratory muscle endurance in children with Duchenne muscular dystrophy (DMD) and to test its reproducibility. In 10 DMD patients, all between 10 and 14 years (mean age, 11.5 +/- 1.5 years), except for two patients of 20 and 22 years, and 10 healthy children (mean age, 12 +/- 1 years), we measured the maximal time (Tlim) that a threshold load fixed at 35% of the individual maximal inspiratory pressure (Pimax) could be tolerated. We asked the children to maintain their rest breathing pattern until exhaustion using visual feedback and an auditory signal. The mean Tlim in the DMD children was 4.45 +/- 1.45 min and values were reproducible. All healthy children were able to obtain Tlim values greater than 30 min. The respiratory muscles of DMD children are more susceptible to fatigue than those of healthy subjects. This method should be satisfactory for estimating the effect of treatment and for the specific training of respiratory muscles in DMD patients without significant learning disability.

Congenital muscular dystrophy and cerebral CT scan anomalies. Results of a collaborative study of the Société de Neurologie Infantile.

We present the results of a collaborative study on the association of congenital muscular dystrophy with central nervous system anomalies revealed by CT scan investigation of 10 patients. In seven children, an abnormal hypodensity of the cerebral white matter is found; in four of these patients, this radiological anomaly is either isolated, or associated with a moderate intellectual impairment; in one case, severe mental retardation and ocular changes had occurred; in the other two cases, the muscular disease was progressing slowly, in association with microcephaly, epilepsy, and moderate mental retardation. Three children were afflicted with a severe early encephalopathy and congenital muscular dystrophy, and presented signs of cortical and subcortical atrophy on CT scan. Two of these patients corresponded to different types of cerebro-ocular dysplasia-muscular dystrophy syndromes, and the third patient of Fukuyama's congenital muscular dystrophy. These observations are discussed and compared with those reported in the literature. The authors emphasize the need to investigate possible cerebral CT scan anomalies in congenital muscular dystrophies, and to look for muscular changes in some prenatal encephalopathies.

McArdle's disease in childhood: report of a new case.

McArdle's disease (glycogenosis type V) is an inherited glycogen storage disease characterized clinically by myalgia, cramps and sometimes myoglobinuria, triggered by exercise. The onset of exercise intolerance is usually in late childhood or adolescence and diagnosis is exceptionally established during infancy. We report the case of a 6-year-old girl who had been complaining of aching muscles for a long time, and who presented after a near-drowning incident, with extensive muscle necrosis, probably secondary to myophosphorylase deficiency-induced cramps. These unusual manifestations led to the diagnosis of this rare disorder. We compare the clinical findings of this case to nine previous reports. This highlights the heterogeneous spectrum of this disease in childhood and supports the distinction of three clinical pictures in childhood: a neonatal form rapidly fatal, a milder form with congenital myopathic symptoms and a benign classical form with myalgia, cramps and pigmenturia.

Cerebrospinal fluid beta-endorphin and cortisol study in Rett syndrome.

An evaluation of cerebrospinal fluid and plasma beta-endorphin and cortisol levels was performed in 15 girls affected with classic Rett syndrome. There were no differences between the patient group and the control group in plasma cortisol and beta-endorphin levels. But in Rett syndrome, a significant increase in beta-endorphin was noted in the cerebrospinal fluid, with an elevation of the cerebrospinal fluid/plasma beta-endorphin ratio and a decrease in cerebrospinal fluid cortisol. A substantial overlap between patients and control group diminishes the diagnostic value of cerebrospinal fluid beta-endorphin assay in girls suspected of having Rett syndrome.

Is hyperprolinemia type I actually a benign trait? Report of a case with severe neurologic involvement and vigabatrin intolerance.

Hyperprolinemia type I is a deficiency of proline oxidase (McKusick 23950), leading to hyperprolinemia and iminoglycinuria, usually with renal involvement. Hyperprolinemia type I is considered a benign trait. We reported a case of hyperprolinemia type I with a severe neurologic disorder and without renal involvement. The patient had marked psychomotor delay and right hemiparesis. Epilepsy was characterized by status epilepticus or a cluster of seizures. Laboratory findings revealed elevated levels of proline in the serum, urine, and cerebrospinal fluid without delta1-pyrroline 5-carboxylate dehydrogenase in the plasma or urine. Fluorescence in situ hybridization excluded a chromosome 22q11 deletion. Vigabatrin inhibits ornithine transaminase. Thus, vigabatrin could lead to a depletion of the normal pool of pyrroline 5-carboxylate dehydrogenase and could aggravate the clinical condition of the child. In this study, vigabatrin was discontinued. In the following months, the patient had marked psychomotor improvement, without modification of the epilepsy. We suggest that vigabatrin should be avoided in hyperprolinemia type I.

Congenital muscular dystrophy with cerebral white matter spongiosis.

Two siblings affected with a slowly progressive congenital myopathy presented mental retardation, epilepsy and craniofacial dysmorphy. The cerebral necropsic study of one of these patients showed severe anomalies of the white matter, with spongiosis, astrogliosis and vascular hyperplasia, whereas a diffuse and marked hypodensity of white matter was observed at cerebral CT scan in the other patient. There were any lesion of cerebellar grey matter, heterotopy, micropolygyria or neuronal destruction. This syndrome seems to be an original variant of congenital neuromyopathy.

Infantile bilateral striatal necrosis following measles.

A previously healthy 4-year-old boy presented with typical measles and demonstrated lesions confined to basal ganglia. The clinical symptoms were an abrupt onset, impaired consciousness and mutism, extrapyramidal signs and severe neurovegetative dysfunction. No modification of the cerebrospinal fluid was observed; laboratory tests were all normal with the exception of a positive serologic test for measles. Cranial magnetic resonance imaging showed abnormal signals in the striatum, affecting the putamen and the caudate nuclei bilaterally. Neurologic improvement occurred within 2 months, with regression of lesions on cranial imaging, suggesting that edema played an important role in the initial stage of the disease.

Benign infantile epilepsy with autosomal dominant inheritance.

Benign cryptogenic infantile epilepsy occurred in 6 infants of 3 families, with similar characteristics suggesting a common physiopathology: onset between 3 and 12 months of age, clusters of brief generalized seizures easily controlled by anti-epileptic drugs, normal psychomotor development, usually normal EEG with, rarely, generalized interictal spike-waves, no recurrence after drug discontinuation, the treatment being no longer than 16 months in most cases. Identical histories were found in parents, uncles and aunts, suggesting an autosomal dominant mode of inheritance. This seems to correspond to an original form of early onset, benign infantile epilepsy.