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).

[Human herpes virus type 6, etiology of an acute encephalitis in childhood: case report]. / L'HHV-6, une cause de leucoencéphalite aiguë disséminée du nourrisson: à propos de 1 observation.

Primary infection with human herpesvirus-6 (HHV-6) causes the classical roseola infantum. Otherwise the infection is clinically silent but it may sometimes be responsible for central nervous system involvement. In order to illustrate such a type of lesions, we report on a 16-month-old girl with acute leucoencephalitis. The disease started with pyrexia 40 degrees C, followed by an episode of seizure, erythematous rash on the trunk and then coma. Brain MRI showed wide lesions on white matter. HHV-6 DNA was detected by PCR in the CSF and serum at the acute stage, and tests for HHV-6 antibody showed a significant increase of IgG antibody titre between acute and convalescent sera. One month later complete clinical recovery was observed while the MRI showed a partial disappearance of the lesions. The sero-conversion associated with the detection of the viral DNA in the serum identified a primary HHV-6 infection and the detection of viral nucleic acid in CSF gives arguments for the responsibility of the virus in the pathogenesis. When facing an acute leuco-encephalitis in infants, it is important to perform exhaustive virology investigations to rule out the implication of HHV-6 as well as other commonly incriminated pathogens (EBV, CMV, mycoplasma, enterovirus) to avoid accusing wrongly the vaccines.

Diffuse cortical dysplasia, or the 'double cortex' syndrome: the clinical and epileptic spectrum in 10 patients.

Diffuse neuronal migration disorders associated with epilepsy can now be recognized by modern neuroimaging techniques, particularly high-resolution MRI. We report 10 patients with a recently described MRI picture of continuous or generalized band heterotopia underlying the cortical mantle, giving the appearance of a "double cortex." They have epilepsy, and almost all have mental retardation. The epileptic disorder varies in nature and degree of severity. Patients may present with infantile spasms, a Lennox-Gastaut syndrome, or other forms of secondary generalized or multifocal epilepsy. Response to medical treatment is variable. Callosotomy may lead to considerable reduction of drop attacks, present in 60%. Mental retardation is usually mild or moderate, and only rarely severe. It correlates with the type of epileptic syndrome, and is greater in patients with more disorganized cortex overlying the heterotopia. Recognition of this entity by MRI is important for appropriate diagnosis of the epileptic disorder, planning of therapeutic strategy, and prognosis.

Verbal and visual memory impairment in children with epilepsy.

Verbal and visual memory performances were evaluated in 60 epileptic children and 60 normal control subjects with Signoret's Memory Battery scale. Eighteen patients had idiopathic generalized epilepsy and 42 had partial epilepsy, mostly of the temporal (n = 28) and frontal (n = 10) lobes. Memory scores were statistically lower in epileptics than in controls and significant differences were found within each group: (1) children with idiopathic generalized epilepsy had a slight depression of visual memory; (2) memory disorder was more severe in partial epilepsy; and (3) children with left and right temporal lobe epilepsy had marked memory deficits related to hemispheric specialization.

Is Rett syndrome a chromosome breakage syndrome?

Lymphocytes from venous blood from 15 girls with Rett syndrome (RTS), 7 girls with RTS "forme fruste," and 46 unrelated control females were examined. All subjects had a normal karyotype using RHG and RTBG technique. The frequency of gaps and breaks was determined for each group. A significantly higher (P < 0.01) frequency of chromosome breakage was observed in RTS subjects compared to controls. This work suggests that an increased tendency to chromosome breakage may be part of a genetically determined disorder in RTS patients.

Segregation of three reciprocal translocations in the same family: t(3;4), t(5;10), and t(15;21).

A male infant with static antenatal encephalopathy and epilepsy was found to have a duplication of 5p12----5pter and deficiency of 10p13----10pter. Each of his parents was a carrier of a balanced reciprocal translocation. A third translocation was found in the maternal grandfather. The pedigree of each translocation and the segregation of parental reciprocal translocations are discussed.

Gene for nonspecific X-linked mental retardation (MRX 47) is located in Xq22.3-q24.

We describe a large family with nonspecific X-linked mental retardation (MRX 47). An X-linked recessive transmission is suggested by the inheritance from the mothers in two generations of a moderate to severe form of mental retardation in six males, without any specific clinical findings. Two point linkage analysis demonstrated significant linkage between the disorder and two markers in Xq23 (Zmax = 3.75, theta = 0). Multipoint linkage analyses confirmed the significant linkage with a maximum lod score (Z = 3.96, theta = 0) at DXS1059. Recombination events observed with the flanking markers DXS1105 and DXS8067 delineate a 17 cM interval. This interval overlaps with several loci of XLMR disorders previously localized in Xq23-q24, which are reviewed herein.

Effects of undernutrition on glial maturation.

Rats of Wistar strain were conceived and breast-fed until the 25th day by mothers maintained on a low protein (5%) and low caloric (21 calories/day) diet, producing a severe deficiency in weight body growth (more than 50% at the 10th day) and of the weight of the central nervous system (40% on the 15th day) both in the cerebral hemispheres and the spinal cord. Histological and biochemical analysis of the central nervous system shows: (1) Glial proliferation is insufficient and delayed, the number of glial cells is reduced by 50% on the 10th day in the cuneatus and gracilis tracts and the density of the glial cells is reduced by 50% in the corpus callosum at the 19th day. (2) Maturation of the glial cells is greatly retarded, especially in the corpus callosum a structure which matures late. On the 19th day, the majority of the cells in this structure still have a glioblastic appearence, whereas in the normal rat, at this age the majority of the glial cells are oligodendrocytes. (3) These abnormalities of glial maturation agree well with the delay of the increase of DNA, RNA and protein measured in the spinal cord and cerebral hemispheres. (4) There is a defect in myelination assessed by estimation of the density of the myelin fibres, and a definitive reduction in the caliber of the spinal tracts.

Intrathecal synthesis of interferon-alpha in infants with progressive familial encephalopathy.

IFN-alpha was detected in cerebrospinal fluid and/or sera from 7 of 8 patients with a progressive familial encephalopathy associated with calcifications of the basal ganglia and white matter alterations. The secretion of IFN-alpha was prolonged, as shown by its presence at different times between birth and 5 years, and was not associated with IFN-gamma. Virological investigations excluded various congenital infections. In only 2 patients, high levels of Epstein-Barr virus antibodies were observed, indicating the possibility of an abnormal response to viral infection rather than a congenital infection. Further investigations are required for characterization of the recessive autosomal trait of this syndrome and its relation to the IFN system.

Deletions of mitochondrial DNA in Kearns-Sayre syndrome and ocular myopathies: genetic, biochemical and morphological studies.

Genetic, biochemical and morphological investigations were conducted on skeletal muscle mitochondria from 6 cases of ocular myopathy: 4 cases with Kearns-Sayre syndrome (KSS) and 2 with chronic progressive external ophthalmoplegia. All of these 6 cases showed mitochondrial DNA (mtDNA) deletions in addition to normal sized DNA in the quadriceps muscle. The deletions ranging from 3 to 8 kbp were also mapped between nucleotides 5500 and 16000 by Southern blot. The deleted genes encoded for some subunits of complexes I, IV, V and 5-10 tRNAS. The boundaries of the deletions have been sequenced in three patients. Five patients had mitochondrial respiratory chain deficiency in complex I as shown by the low oxygen consumption in isolated mitochondria using three NAD(+)-linked substrates. Mitochondria with an abnormal ultrastructure were also observed in 2 cases. A good relationship between the cytochrome c oxidase deficiency and the amount of deleted mtDNA was shown in our present investigations.

A case of mitochondrial encephalomyopathy associated with a muscle coenzyme Q10 deficiency.

We report severe coenzyme Q10 deficiency of muscle in a 4-year-old boy presenting with progressive muscle weakness, seizures, cerebellar syndrome, and a raised cerebro-spinal fluid lactate concentration. State-3 respiratory rates of muscle mitochondria with glutamate, pyruvate, palmitoylcarnitine, and succinate as respiratory substrates were markedly reduced, whereas ascorbate/N,N,N',N'-tetramethyl-p-phenylenediamine were oxidized normally. The activities of complexes I, II, III and IV of the electron transport chain were normal, but the activities of complexes I+III and II+III, both systems requiring coenzyme Q10 as an electron carrier, were dramatically decreased. These results suggested a defect in the mitochondrial coenzyme Q10 content. This was confirmed by the direct assessment of coenzyme Q10 level by high-performance liquid chromatography in patient's muscle homogenate and isolated mitochondria, revealing levels of 16% and 6% of the control values, respectively. We did not find any impairment of the respiratory chain either in a lymphoblastoid cell line or in skin cultured fibroblasts from the patient, suggesting that the coenzyme Q10 depletion was tissue-specific. This is a new case of a muscle deficiency of mitochondrial coenzyme Q in a patient suffering from an encephalomyopathy.

Childhood dermatomyositis: clinical course of 36 patients treated with low doses of corticosteroids.

Thirty-six patients with juvenile dermatomyositis, seen consecutively between 1983 and 1996 and treated initially with low doses of corticosteroids (prednisolone 1 mg/kg/day), were studied retrospectively to evaluate their long-term evolution and to identify factors predictive of the functional outcome. After a mean follow-up of 4.9 years, 28 (78%) of the patients were well without functional impairment; five patients had inactive disease but with persisting disabilities; and three patients had active disease despite several years of treatment. Fifteen children (42%) developed dystrophic calcifications which, in five of these patients, interfered with functions. These patients treated for juvenile dermatomyositis with a low dose corticosteroid regimen had an evolution identical to that of the published series of patients treated with higher doses and probably had a better quality of life. The best predictors of good functional recovery and minimal calcinosis were early treatment after the onset of symptoms and low creatine kinase serum level at the time of diagnosis.

Reversible hearing loss in a patient with cryptococcosis.

A 16-year-old girl had hearing loss, paroxysmal tremor, gait disorders, and psychiatric disturbances as the initial manifestations of a cryptococcal meningoencephalitis. Imaging demonstrated an obstructive hydrocephalus, and neuro-otological explorations showed a retrocochlear deafness and diffuse brainstem involvement. Emphasis is on the deafness, which rarely occurs as a presenting symptom in this condition, and on its dramatic improvement following antimycotic therapy.

Bilateral porencephalic defect in a newborn after injection of benzol during pregnancy.

Porencephaly is usually considered to be a prenatal brain lesion due to a circulatory failure. We report a case of bilateral porencephaly with heterotopia and absence of the septum pellucidum in a newborn. The mother had received several injections of benzol during pregnancy with an intent of inducing abortion. The possibility of a causal relationship between the administration of benzol and the occurrence of the defect is supported by the existence of previously reported cases of cerebral malformations following maternal exposure to organic solvents.

[Myoclonic epilepsy with non-progressive encephalopathy]. / Epilepsies myocloniques des encéphalopathies non progressives avec états de mal myocloniques.

We report 6 cases of particular type of myoclonic epilepsy with non-progressive encephalopathy. It consists of a syndrome characterized by an onset of seizures in the first year of life, frequent myoclonic status, generalized spikes and waves on EEG and an unfavourable outcome with encephalopathy. At the beginning, the diagnosis is difficult, the symptomatology later suggests a progressive encephalopathy. In the present study, a detailed analysis of the early electroencephalographic aspects and of the arguments in favour of a non-progressive encephalopathy is proposed. Hypothesis of perinatal vascular lesions mainly involving the central areas is forwarded.

Menkes disease: a Golgi and electron microscopic study of the cerebellar cortex.

A neuropathological study of a case of Menkes disease is reported, illustrating the involvement of different types of neuronal cells. The cerebellum showed the most striking abnormalities: severe lack of internal granule cells. Purkinje cells with weeping willow pattern, numerous segmental enlargements of dendritic trunks and secondary branches, and presence of numerous eosinphilic spherical bodies in the molecular layer were the most conspicuous features. Using electron microscopy, the dendritic enlargements were observed to be made of both proliferated and enlarged mitochondria, and of saccules of smooth endoplasmic reticulum. The spheroid bodies in the molecular layer were mainly made of concentric lamellar structures which seemed to be proliferated smooth endoplasmic reticulum. The relationship between these morphological abnormalities and the metabolic disorder of Menkes disease is discussed.

Clinical and EEG video-polygraphic features of epileptic spasms in a child with dihydropteridine reductase deficiency. Efficiency of hydrocortisone.

West syndrome is an epileptic encephalopathy which includes psychomotor deterioration. In rare cases, it is due to an inherited, progressive metabolic disease. We report a 2 year-old child with dihydropteridine reductase deficiency who developed hypsarrhythmia and infantile spasms which were documented on video-polygraphic EEG. Despite dietary restriction of phenylalanine, and oral administration of amine precursors, the initial course was unfavorable. A beneficial effect from hydrocortisone was then observed, with control of spasms and improvement of psychomotor delay.

Cerebral lymphoma and HIV encephalitis in a case of paediatric AIDS, with pre-existing multicystic encephalomalacia.

A case of intracerebral malignant B cell lymphoma associated with encephalitis typical of Human Immunodeficiency Virus (HIV) infection is described in a 4 year old child, with post-transfusion Acquired Immune Deficiency Syndrome (AIDS) and severe pre-existing cystic encephalomalacia. This report further documents B cell lymphoma as the commonest cause of an intracerebral mass, and an important cause of death in paediatric AIDS. That more than one pathological process may be responsible for neurological symptoms in paediatric AIDS is also emphasised.

[Subcortical laminal heterotopia and lissencephaly: cerebral malformations of X-linked inheritance]. / Hétérotopies laminaires sous-corticales et lissencéphalie: malformations cérébrales d'origine familiale commune, liée à l'X.

Subcortical laminar heterotopia (band heterotopia) is a brain malformation now recognized by MRI. We report 3 families (2 previously described) in which several members had subcortical laminar heterotopia or a more severe malformation (agyria/pachygyria). In these families, subcortical laminar heterotopia were observed in women and were associated with epilepsy or slight mental retardation depending on the extend of heterotopia. Males had lissencephaly with refractory epilepsy and severe mental retardation. The pedigrees of these families demonstrate that these 2 malformations originate from a single genetic origin. A single X-linked dominant gene is postulated. Diagnosis of subcortical laminar heterotopia in a female or lissencephaly in a male (except in the case of Miller-Dieker syndrome) requires appropriate genetic counselling in the family: brain imaging should be performed in relatives.

[Congenital hereditary motor and sensory neuropathy]. / Neuropathies héréditaires sensitivomotrices à début congénital.

The authors report 6 cases of hereditary sensorimotor neuropathy (HSMN) presenting with the following clinical features: (1) severe outcome (3 out of 6 patients died before the age of 4 years), and (2) intellectual impairment (3 out of 6 cases). Histopathological study of nerve biopsies gave heterogeneous results: there was one case of axonal neuropathy (HSMN II of Dyck and Lambert), one case of demyelinating neuropathy with Schwann's cell proliferation (HSMN III of Dyck and Lambert), and one case of giant axonal neuropathy. The last three cases displayed an original pattern hitherto unknown in classical delayed HSMN, with complete disappearance of myelinated sheaths and Schwann's cell proliferation. This particular pattern did not seem to be due to the biopsy being performed at an early stage, since in one case a second biopsy showed the same histological features.