Clinical features of spinal muscular atrophy (SMA) type 2.

Infantile spinal muscular atrophy (SMA) type 2 is sometimes called intermediate SMA to indicate the disease severity. Generally, psychomotor development is normal until the age of 6 to 8 months, with the acquisition of a stable sitting position. The early signs are muscle weakness, mostly affecting the lower limbs, generalized hypotonia and areflexia. The consequences of motor neuron degeneration are functional and orthopaedic, respiratory, nutritional, socio-professional, and psychological. The implementation of standardized care (i.e., standard of care recommendations) has improved the quality of life and survival outcome of patients. The emergence of innovative therapies, some of which are now available, should further improve the clinical evolution of this disease. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

[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.

Lower extremity surgery in muscular dystrophy.

INTRODUCTION: The natural progression of neuromuscular diseases results in inevitable musculotendinous contractures, most often in spite of early treatment. Surgery corrects this. The aim of this study was to evaluate the results of tendon surgery in these cases. MATERIALS AND METHODS: Twenty children with muscular dystrophy underwent hip surgery (tensor fascia lata tenectomy, rectus femoris and sartorius tenotomy), knee surgery (gracilis, semitendinosus and semimembranosus tenotomies) and/or ankle surgery (lengthening or tenotomy of the Achilles tendon with or without posterior tibial tendon transfer). Articular range of motion was evaluated preoperatively, 6 months after surgery, at 1 year and at the final follow-up (7.4 years). RESULTS: Three children underwent surgery before they had lost their walking capacity, eight soon afterwards, and nine long afterwards. Surgery was bilateral in all cases: 38 hips, 12 knees and 36 ankles with 22 posterior tibial tendon transfers. Hip extension, which was limited by a 30° flexion contracture improved to 10° and stabilized at 14° at the final follow-up. Adduction which was -19° before surgery increased to 35° and had stabilized at 32° at the final follow-up. Knee flessum (38°) was only slightly improved (24°) and had regressed at the final follow-up. Equinus deformity (42°) was corrected to 9° of dorsal flexion with a slight loss (2°) at the final follow-up. Varus was improved from 11° to 6°, but this had regressed at 1 year (10°) and at the final follow-up (11°). Achilles tendon tenotomies resulted in 28° of dorsal flexion at 6 months compared to 20° with lengthening. Correction of varus was better with posterior tibial tendon transfer at 6 months, 1 year and at the final follow-up (11° versus 5°). In the three patients who underwent surgery before losing their walking ability, one continued walking for 1 year and two for 6 months. None of the eight patients who underwent surgery soon after losing ambulation were able to regain walking. All patients were able to continue device assisted upright positioning for a mean 3 years. DISCUSSION: Hip and ankle surgery can release contractures. In the knees, surgery should be restricted to cases with knee flessum greater than 30°. The best results are obtained with extensive m. tensor fascia lata tenectomy and posterior tibial tendon transfer. Achilles tendon tenotomy results in better recovery of dorsal flexion. Surgery is indicated when contractures are severe and the patient is no longer able to walk. The aim should not be to continue walking but to release contractures, so that the patient can continue assisted upright positioning as long as possible. Especially in cases of asymmetric contractures, surgery can help slow the progression of scoliosis.

The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein.

BACKGROUND: Succinate-CoA ligase deficiency is responsible for encephalomyopathy with mitochondrial DNA depletion and mild methylmalonic aciduria. Mutations in SUCLA2, the gene encoding a ß subunit of succinate-CoA ligase, have been reported in 17 patients until now. Mutations in SUCLG1, encoding the α subunit of the enzyme, have been described in two pedigrees only. METHODS AND FINDINGS: In this study, two unrelated patients harbouring three novel pathogenic mutations in SUCLG1 were reported. The first patient had a severe disease at birth. He was compound heterozygous for a missense mutation (p.Pro170Arg) and a c.97+3G>C mutation, which leads to the complete skipping of exon 1 in a minigene expression system. The involvement of SUCLG1 was confirmed by western blot analysis, which showed absence of SUCLG1 protein in fibroblasts. The second patient has a milder phenotype, similar to that of patients with SUCLA2 mutations, and is still alive at 12 years of age. Western blot analysis showed some residual SUCLG1 protein in patient's fibroblasts. CONCLUSIONS: Our results suggest that SUCLG1 mutations that lead to complete absence of SUCLG1 protein are responsible for a very severe disorder with antenatal manifestations, whereas a SUCLA2-like phenotype is found in patients with residual SUCLG1 protein. Furthermore, it is shown that in the absence of SUCLG1 protein, no SUCLA2 protein is found in fibroblasts by western blot analysis. This result is consistent with a degradation of SUCLA2 when its heterodimer partner, SUCLG1, is absent.

[A case of acquired encephalopathy in a child. A cause that we thought had disappeared]. / Un cas d'encéphalopathie acquise de l'enfant. A propos d'une cause que l'on croyait disparue.

Subacute central nervous system infection must be considered in any infant presenting with progressive encephalopathy. We present the case of an 18-month-old child with normal neuromotor development until the age of 14 months admitted for spastic hypertonia of the legs and arms associated with axial hypotonia. The mother reported that she recently had been found to be HIV-seropositive. HIV antibodies were negative during the first trimester of pregnancy. On the child's blood sample, the HIV test was positive associated with a major decrease in CD4 cell count. Viral load (ARN-PCR) was 720 copies par millilitre. On brain MRI, hypersignals were found in the white matter. HIV related encephalopathy caused by maternal fetal transmission was diagnosed. After 2 months of antiretroviral treatment (azidothymidine, lamivudine, and boosted lopinavir), the child's neurological condition improved. HIV infection must be suspected in all infants with progressive encephalopathy. The HIV test in pregnant women must be proposed at the beginning of pregnancy and repeated during the last trimester.

[ATR-X syndrome: a new mutation in the XNP/ATRX gene near the helicase domain]. / Syndrome ATR-X: une nouvelle mutation du gène XNP/ATRX à proximité du domaine hélicase.

The alpha-thalassemia/mental retardation syndrome, X linked, also named ATR-X syndrome is a X-linked mental retardation syndrome. Mutations have been found in the ATRX gene in about one half of the patients. We report a typical clinical case. The clinical evidence leads us to continue the analysis of the gene despite a negative first screening. Indeed a new mutation was found, just behind the helicase domain, bringing up the interest of an effective collaboration between physicians and biologists.

Prenatal diagnosis of a craniopharyngioma: a new case with radical surgery and review.

CASE REPORT: A case of the antenatal diagnosis of a craniopharyngioma with radical surgery in the neonatal period is reported. REVIEW OF THE LITERATURE: We have reviewed the literature of such cases in an attempt to isolate specific features in this age group and to determine the appropriate management. Only six cases of the truly antenatal diagnosis of craniopharyngiomas have been reported. Diagnosis has resulted from routine ultrasound during pregnancy or from polyhydramnios. Clinically, there is often macrocephaly due to hydrocephalus or a significant-sized tumor. CONCLUSIONS: Management of these rare cases is controversial with high postoperative mortality and significant morbidity, including panhypopituitarism, visual disturbance, and neuropsychological disorders. From the available literature, no conclusions concerning the management can be drawn at present, due to the rarity of early surgical intervention. Our case, despite the lack of important follow-up, seems to confirm the possibility of attempting radical surgery in the neonatal period as a result of advances both in surgical techniques and in neonatal intensive care.

K(ATP) channel openers, adenosine agonists and epileptic preconditioning are stress signals inducing hippocampal neuroprotection.

Many models of induced ischemic and epileptic tolerance have now been described in the brain. Although detailed mechanisms underlying such protections still remain largely unknown, induction of heat shock proteins is amongst the endogenous responses believed to play an important role in cellular defense mechanisms. This study reveals that the development of epileptic tolerance also coincides with the induction of the 70,000 mol. wt heat shock protein expression within the time window of protection. Adenosine agonists or ATP-sensitive potassium channel openers have also been shown to exert strong neuroprotective effects when injected shortly prior to a severe ischemic or epileptic insult. The present work shows that adenosine receptor activation and ATP-sensitive potassium channel opening induce 70,000 mol. wt heat shock protein expression in the rat hippocampus and are able to mimic neuroprotection driven by preconditioning. R-phenylisopropyladenosine, a purine agonist, or (-)cromakalim, an ATP-sensitive potassium channel opener, was administered three days prior to a lethal ischemic or epileptic episode to mimic preconditioning. Neurodegeneration was assessed using Cresyl Violet staining and cellular DNA fragmentation visualized by the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling method. 70, 000 mol. wt heat shock protein expression was analysed by western blotting and immunohistochemistry. The results show a long-lasting neuroprotection induced by activation of adenosine receptors or ATP-sensitive K(+) channels as early as three days prior to induction of a severe ischemic or epileptic challenge. This protective effect is associated with enhanced 70,000 mol. wt heat shock protein expression also occurring three days following administration of R-phenylisopropyladenosine or (-)cromakalim. These findings support the idea that preconditioning doses of R-phenylisopropyladenosine and (-)cromakalim act as mild cellular stresses inducing neuroprotection in a manner similar to a mild kainate treatment prior to a lethal ischemic or severe epileptic insult three days later. They also suggest that a delayed 70,000 mol. wt heat shock protein expression induced by excitatory neuronal stresses such as short ischemia, mild kainic acid treatment or activation of adenosine receptors and ATP-sensitive potassium channels is predictive of neuronal survival against a subsequent lethal injury.

Importance of searching for associated mitochondrial DNA alterations in patients with multiple deletions.

Multiple mitochondrial DNA (mtDNA) deletions have been reported in patients with autosomal dominant and recessive disorders. We studied several affected and one non-affected individuals belonging to a pedigree in which the inheritance of the pathological trait was compatible with an autosomique dominant transmission. Affected members had late-onset multisystem disorders with multiple mtDNA deletions in skeletal muscle. But this family presented a striking difference from previously described cases, because none of the patients had progressive external ophthalmoplegia (PEO). We also studied one young boy with a no contributary family history. He had a cerebellar ataxia with PEO and multiple mtDNA deletions in muscle. Molecular analysis revealed that in the first family, repeated sequences were present at the breakpoint junctions, whereas such motifs were not found in the young patient's case. In the first family, we evidenced mtDNA point mutations in clones containing breakpoint junctions and a 9-bp motif triplication in the intergenic COII/tRNA(Lys) region, whereas this sequence is repeated twice in the wild type mtDNA. Our results suggest that multiple deletions observed in the two pedigrees result from different molecular mechanisms and point out the role of repeated sequences in the first pedigree. No mtDNA repair system has been described in mammals so far, but the molecular abnormalities found in the first family suggest that a defect in an mtDNA repair system, homologous to the E. coli MutHLS pathway, could be responsible for such a phenotype.

Genetics of laminin alpha 2 chain (or merosin) deficient congenital muscular dystrophy: from identification of mutations to prenatal diagnosis.

Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of muscle disorders, with autosomal recessive inheritance. Absence of the laminin alpha 2 chain in the skeletal muscle of patients with classical CMD has permitted the identification of a subgroup, referred to as 'merosin-deficient CMD or laminin alpha 2 chain deficient CMD'. We first identified a nonsense and a splice site mutation in laminin alpha 2 gene (LAMA2) (Glu1241 stop, 4573-2A-->T). We report here new mutations: nonsense mutations (Glu210stop, Trp2316stop) and 1- and 2-bp deletions (2418 delta C, 6968 delta TA), which result in truncation of the protein either in the short arm domains or in the C terminal globular domain and complete merosin deficiency. Another subgroup, referred to as 'partially-deficient in laminin alpha 2 chain' has been identified recently, and a LAMA2 missense mutation (Cys996Arg) has been shown to cause this partial deficiency. The laminin alpha 2 chain, together with the beta 1 or beta 2 and gamma 1 chains forms either laminin-2 (alpha 2-beta 1-gamma 1) or laminin-4 (alpha 2-beta 2-gamma 1). The LAMA2 mutations induce the formation of abnormal laminins which probably dramatically disturb the assembly and stability of the laminin network, one of the major components of the extracellular matrix in skeletal muscle. We report also the first prenatal diagnosis performed by direct mutation analysis.

The human brain age 7-11 years: a volumetric analysis based on magnetic resonance images.

Volumetric magnetic resonance image (MRI)-based morphometry was performed on the brains of 30 normal children (15 males and 15 males) with a mean age of 9 years (range 7-11 years). This age range lies in a late but critical phase of brain growth where not volumetric increment will be small but when the details of brain circuity are being fine-tuned to support the operations of the adult brain. The brain at this age is 95% the volume of the adult brain. The brain of the female child is 93% the volume of the male child. For more than 95% of brain structures, the volumetric differences in male and female child brain are uniformly scaled to the volume difference of the total brain in the two sexes. Exceptions to this pattern of uniform scaling are the caudate, hippocampus and pallidum, which are disproportionately larger in female than male child brain, and the amygdala, which is disproportionately smaller in the female child brain. The patterns of uniform scaling are generally sustained during the final volumetric increment in overall brain size between age 7-11 and adulthood. There are exceptions to this uniform scaling of child to adult brain, and certain of these exceptions are sexually dimorphic. Thus, with respect to major brain regions, the cerebellum in the female but not the male child is already at adult volume while the brainstem in both sexes must enlarge more than the brain as a whole. The collective subcortical gray matter structures of the forebrain of the female child are already at their adult volumes. The volumes of these same structures in the male child, by contrast, are greater than their adult volumes and, by implication, must regress in volume before adulthood. The volume of the central white matter, on the other hand, is disproportionately smaller in female than male child brain with respect to the adult volumes of cerebral central white matter. By implication, relative volumetric increase of cerebral central white matter by adulthood must be greater in the female than male brain. The juxtaposed progressive and regressive patterns of growth of brain structures implied by these observations in the human brain have a soundly established precedent in the developing rhesus brain. There is emerging evidence that sexually dimorphic abnormal regulation of these terminal patterns of brain development are associated with gravely disabling human disorders of obscure etiology.

[Post-traumatic hypopituitarism after skull injury: apropos of 3 cases]. / Hypopituitarisme post-traumatisme crânien: à propos de trois cas.

BACKGROUND: Hypopituitarism is a rare but well-known complication of cranial trauma. In the absence of overt diabetes insipidus, its recognition is difficult as the onset of clinical symptoms can be very progressive, up to several years. CASE REPORTS: Three children, aged 8, 9 and 2 years, respectively, were admitted after a cranial trauma. Manifestations of diabetes insipidus occurred a few days later in two patients; one of them developed secondary growth hormone deficiency, hypothyroidism and hypogonadism, only evidenced at the age of 14 years. The third patient also developed manifestations of hypothalamic and/or pituitary hormone deficiencies without diabetes insipidus at the age of 12 years-6 months. MRI showed complete severance of the pituitary stalk in two patients and absence of posterior pituitary signal in one of the two patients with diabetes insipidus. CONCLUSION: Growth disorders and/or hypogonadism may occur many years after a trauma that may have been forgetten. Search for such an etiology and dynamic MRI are necessary in identifying heterogenous hypophyseal lesions.

Abnormal alpha-aminoadipic acid excretion in a newborn with a defect in platelet aggregation and antenatal cerebral haemorrhage.

alpha-Aminoadipic acid (alpha AA) is an intermediate in lysine metabolism. We report a new case with alpha AA excess in urine and plasma, without alpha-ketoadipic acid, in a full-term male child born to unrelated parents; he presented at 24h of life with seizures that failed to respond to phenobarbital, clonazepam, and Vigabatrin and death occurred on the 38th day of life. Brain imaging suggested antenatal haemorrhage. Small quantities of alpha AA were also detected in the blood and urine of both parents and a healthy brother, all three of whom exhibited the same defect in platelet aggregation as the deceased child. Both parents had decreased levels of plasma neopterin, a finding that might be related to the immunodeficiency described in other cases.

The young adult human brain: an MRI-based morphometric analysis.

Morphometric analysis was performed on three-dimensional MRI scans of 10 male and 10 female young adults with four principal objectives: (1) to characterize in vivo volumes of whole brain and substructures, (2) to explore volumetric symmetry in bilateral structures, (3) to consider the extent to which volumetric measures are dimorphic in the male and female brain, and (4) to provide a normal volumetric database for the young adult brain. Total brain volumes ranged between 1173 and 1626 cm3. All bilateral structures were symmetric or nearly symmetric in volume, with the exception of a slightly larger right neocortex and amygdala, and larger left lateral ventricle. Male brains were larger in volume than female brains, a difference that reached significance for cerebellar but not for cerebral hemisphere volume. In females, there was less cerebral white matter while caudate volume was larger than in the male brains. The proportions of caudate and hippocampus relative to total cerebral volumes were larger in females than in males. These four measures accurately predicted gender in 85% of the subjects by discriminant analysis. No gender differences were noted in the structural symmetry analysis. These results represent the first step in establishing a comprehensive database of morphometric parameters, with unexpected findings relative to brain symmetry and sexual dimorphism.

Long latency event-related potentials (P300) in gifted children.

In children, P3 latency decreases with increasing age. This decrease could be linked with the maturation of cognitive processes. According to this hypothesis, event-related potentials P3 were recording in gifted children to research an electrophysiological correlation with the mental precocity. Auditory long latency event-related potentials were recorded in 10 gifted children (IQs over 140) and 23 control subjects. The part of variance related to age was extracted by comparing deviations from regression line as a function of age. Stimulus-evoked N1 component latency was not statistically different in the two populations. Event-related P3 component latency was significantly shorter in the gifted children at Cz (P < 0.05). Inter-peak interval N1-P3 was significantly shorter at all three recording sites (P < 0.01 at Fz and CZ, P < 0.02 at Pz). These results suggest a relationship between the P3 component and cognitive ability in children.

The germinative zone produces the most cortical astrocytes after neuronal migration in the developing mammalian brain.

The origin of astrocytes of the mouse neocortex during the fetal and early postnatal periods as determined by immunocytological, autoradiographic, electron microscopic and antimitotic methods is described. Most astrocytes destined for the white matter and the infragranular cortical layers are derived from the transformation of radial glial cells between P0 and P10 with an inside-out pattern. This cell metamorphosis is not directly preceded by mitosis and involves the activation of the radial glial lysosomal apparatus. In opposition to recent hypotheses, our findings suggest that most astrocytes destined for the supragranular cortical layers are produced in the germinative zone after the migration of the infragranular neurons and themselves migrate afterwards to the upper cortex between E16 and the first postnatal days. These astrocytes do not display an intermediate stage of the radial glial cell and do not participate in the pattern of appearance of the deeper astrocytes. This second step of astrocytogenesis is a condition for normal cytoarchitectonic development and the maintenance of the supragranular layers, since the deprivation of the astrocytic equipment of the supragranular layers by an antimitotic drug drastically reduces the number of supragranular neurons.

[A case of deep sleep myoclonus in newborn infants]. / A propos d'un cas de myoclonies du sommeil profond du nouveau-né.

The authors report on the case of a newborn infant without pathological history suffering from severe and lasting myoclonus occurring during deep sleep and associated with normal electroencephalogram. Deep sleep myoclonus is a benign syndrome which disappears spontaneously within a few months. The long-term prognosis is excellent, but the etiology remains unknown.

[A therapeutic trial of mazindol versus placebo in Duchenne muscular dystrophy. A one-year follow-up study of 14 children]. / Essai thérapeutique du mazindol contre placebo dans la dystrophie musculaire de Duchenne. Suivi de l'évolution pendant 1 an chez 14 enfants.

A simple-blind therapeutic trial of mazindol (2 mg/d) versus placebo in 14 boys with Duchenne muscular dystrophy, 5 to 13 years old, for 12 months was conducted in order to analyse the efficacy of this drug on the natural history of the disease. Evaluation of muscle strength by manual testing, motor ability by functional testing and timed tests, weight, height, serum CK and pulmonary function were performed every two months. The differences in evolution between groups were significant only for weight and height. However comparison of muscle strength and of vital capacity expressed as percent of predicted at the beginning and at the end of the study suggested a beneficial trend in the mazindol-treated group.