Bilateral periventricular nodular heterotopia in France: frequency of mutations in FLNA, phenotypic heterogeneity and spectrum of mutations.

Bilateral periventricular nodular heterotopia (BPNH) is the most common form of periventricular heterotopia. Mutations in FLNA, encoding filamin A, are responsible for the X linked dominant form of BPNH (FLNA-BPNH). Recently, atypical phenotypes including BPNH with Ehlers-Danlos syndrome (BPNH-EDS) have been recognised. A total of 44 FLNA mutations have so far been reported in this phenotype. Most of these mutations lead to a truncated protein, but few missense mutations have also been described. Here, the results of a mutation screening conducted in a series of 32 BPNH patients with the identification of 12 novel point mutations in 15 patients are reported. Nine mutations were truncating, while three were missense. Three additional patients with BPNH-EDS and a mutation in FLNA are described. No phenotype-genotype correlations could be established, but these clinical data sustain the importance of cardiovascular monitoring in FLNA-BPNH patients.

A gene for an autosomal recessive lower motor neuron disease with childhood onset maps to 1p36.

OBJECTIVE: To describe the clinical features of a novel variant of autosomal recessive lower motor neuron disease (LMND) with childhood onset and to map the disease-causing gene. METHODS: The authors performed a clinical study in a large consanguineous African family. After linkage exclusion to SMN1 and SOD1 loci, they performed a genome-wide linkage analysis to map the underlying genetic defect. RESULTS: This novel variant of LMND with childhood onset and autosomal recessive mode of inheritance is characterized by a progressive symmetric and generalized involvement of the musculature. Four of the five affected patients had muscle weakness since age 3, strongly worsening during childhood and leading to generalized tetraplegia in adulthood. Genetic analyses using homozygosity mapping strategy assigned this progressive generalized LMND locus to an interval of 3.9 cM (or 1.5 megabases) on chromosome 1p36, between loci D1S508 and D1S2633 (Z(max) = 3.79 at theta = 0.00 at locus D1S253). This region encloses 27 candidate genes. CONCLUSION: Genetic mapping of a novel rare phenotype of lower motor neuron disease opens the way toward the identification of a new gene involved in motor neuron degeneration, located in the 1p36 chromosomal region.

[Maxillary and sphenoid sinusitis complicated by acute inflammatory optic neuritis in a 12-year-old patient]. / Sinusite maxillaire et sphénoïdale compliquée de neuropathie optique inflammatoire aiguë chez un patient de 12 ans.

Acute inflammatory optic neuritis (retrobulbar optic neuritis) is an uncommon but described complication of acute sinusitis. It is due to a close anatomic relationship between the sinus and the optic nerve. Inflammatory mechanism is dominant with a possible bilateral neuritis, especially among children. In the reported case, as usual in childhood, visual acuity loss has been particularly severe, and recovery slow (it takes usually 6 weeks) but almost complete. Primary treatment is medical, with antibiotics and corticosteroids that must be prescribed for a prolonged time.

[The presentation of childhood systemic lupus erythematosus with neurological symptoms: three-case reports]. / Modes de révélation neurologiques du lupus érythémateux disséminé de l'enfant: trois observations.

INTRODUCTION: neurological symptoms occurring during childhood, especially if unusual or recurrent, should attract attention. METHODS: We report three cases of childhood lupus revealed by neurological symptoms. RESULTS: Misdiagnosis was frequent and time from symptom onset to diagnosis of lupus reached up to six months. CONCLUSION: After careful history taking and physical examination, complementary tests should include erythrocyte sedimentation rate, blood count, platelets, and in some cases an immunological study with antinuclear antibodies.

[Loss of consciousness in a child due to loperamide]. / Perte de connaissance chez une jeune enfant secondaire à la prise de lopéramide.

Loperamide is an antidiarrheal peripheral opiate agonist, with rare neurological secondary effects. We report the case of a 26-month-old child who had impaired consciousness under treatment by loperamide, and was treated successfully with naloxone. Limitations of the use of loperamide in young children are underlined. Naloxone may be used in case of impaired consciousness, for a diagnostic as well as therapeutic purpose.

Demyelinating peripheral neuropathy associated with hemophagocytic lymphohistiocytosis. An immuno-electron microscopic study.

We report the case of an 11-year-old male who developed subacute diffuse polyradiculoneuropathy, associated with digestive symptoms and Epstein-Barr virus infection. Parental consanguinity was present. The laboratory findings including bone marrow smear were consistent with hemophagocytic lymphohistiocytosis (HLH). Electrophysiological study of peripheral nerves revealed an intense and diffuse demyelinating process. The histological nerve lesions were severe and purely demyelinating. Most axons were intact. There was a diffuse infiltration of the nerve parenchyma by mononuclear cells. Immuno-electron microscopic study evidenced entry of macrophages into Schwann cell cytoplasm with dissociation of myelin sheaths. This boy died several months after the onset of the neuropathic symptoms. HLH is a rare genetic or acquired disorder in childhood characterized by abnormal immune activation, which induces an uncontrolled inflammatory response with sustained hyperactivation of T lymphocytes and macrophages. Only very rare cases of peripheral nerve involvement have been described in HLH. This is the first case showing that peripheral nerves, as other viscera, may be destroyed by the macrophagic infiltration, which characterizes HLH.

[Unusual good prognosis for X-linked myotubular myopathy]. / Forme inhabituelle de bon pronostic de la myopathie myotubulaire liée à l'X.

Recessive X-linked myotubular myopathy has recently been shown to be linked to the mutation of a gene located in the Xq28 region. Evolution is used to be considered as fatal but mild forms or forms with a better prognosis have been recorded since. We report a case in a patient, whose parents were warned of fatal outcome once the diagnosis was made during the neonatal period. The reaction of the parents was to avoid any relationship with medical care. Ten years later the patient was seen in relatively good health thus proving that the evolution was more favourable than anticipated.

X-linked Charcot-Marie-Tooth disease with connexin 32 mutations: clinical and electrophysiologic study.

OBJECTIVE: To relate X-linked Charcot-Marie-Tooth disease (CMTX) phenotypes to gender and type of neuropathy by the study of a large series of CMTX patients with proven Cx32 point mutations. BACKGROUND: CMTX is an X-linked form of Charcot-Marie-Tooth disease, caused by mutations in the connexin 32 gene. Males are usually more severely affected and have slower nerve conduction velocities than females. METHODS: Forty-eight patients from 10 families with Cx32 mutations were examined clinically and electrophysiologically. Mutations were characterized in index cases by automatic sequencing and detected in at-risk individuals by polymerase chain reaction (PCR)-restriction or single strand conformation polymorphism (SSCP) analysis. Two patients from different families had light and electron microscopy examination of a sural nerve biopsy. RESULTS: Males (n = 21) were more severely affected than females (n = 27), although six of the females were severely disabled. In the majority of males, the median motor nerve conduction velocity (MNCV) was between 30 and 40 m/s, whereas in females it ranged from 30 to normal values. Two children with mutation, a 6-year-old boy and a 7-year-old girl, were normal clinically and electrophysiologically. In most patients, the amplitude of motor nerve compound muscle action potentials (CMAP) was reduced in all nerves tested. MNCV was reduced as a function of the degree of axonal loss. A significant correlation was found between the decrease in CMAP amplitude and MNCV in the median, ulnar, and peroneal nerves. Sural nerve biopsies in one patient with a missense and one with a nonsense mutation both showed axonal neuropathy. CONCLUSION: Electrophysiologic and histologic findings support primary axonal neuropathy in CMTX with Cx32 mutations. Clinical and electrophysiologic data in males with different missense mutations in the of Cx32 gene differed significantly. Furthermore, males with a nonsense mutation (Arg22Stop) had earlier onset and a more severe phenotype than males with missense mutations.

Congenital insensitivity to pain with anhydrosis. Report of two unrelated cases.

Two unrelated female cases of congenital insensitivity to pain with anhydrosis are presented. The first case was born from consanguineous parents. In both cases, onset of manifestation was observed in infancy with automutilation and recurrent fever. Both were mentally retarded. They underwent a peripheral nerve biopsy respectively at 3 and 33 years. A dramatic loss of unmyelinated fibers was observed in both cases. Myelinated fibers were also moderately reduced in number, especially those of smallest diameter; this loss was more marked in the second patient who was adult when the peripheral nerve was studied. Clusters of regenerating myelinated fibers were seen in both cases. Such histological observations might suggest a slowly progressive disorder. The cases are discussed together with previous reports dealing with congenital insensitivity to pain.

[Biopercular polymicrogyria associated with congenital ophthalmoplegia caused by nuclear lesion of the common oculomotor nerve]. / Polymicrogyrie bioperculaire associée à une ophtalmoplégie congénitale par atteinte du noyau du nerf moteur oculaire commun.

Developmental pseudobulbar palsies seem to be different from the adult form described by Foix, Chavany and Marie. They usually include a major speech delay and severe epileptic seizures. In one clinicopathological case, neuroradiological imaging showed a macrogyric aspect of both rolandic operculi and unilateral destruction of pes pedunculari. Microscopic examination showed a four-layered polymicrogyria involving the first temporal gyrus and in the brainstem a selective destruction of the left oculomotor nucleus. Thus, the macrogyric aspect could be related to post migratory disorder occurring late in the cortical development. The brain stem lesion, destroying unilaterally the third cranial nerve nucleus gives a good example of the complex somatotopia of this oculomotor nucleus.

[Herpes encephalitis in newborn infants. Retrospective study of 12 cases]. / Encéphalite herpétique du nouveau-né. Etude rétrospective de douze observations.

BACKGROUND: Herpes simplex virus (HSV) may cause severe disease in neonates with high mortality and devastating sequelae. Adenine arabinoside (ara-A) and acyclovir can be effective in treating the neonatal disseminated disease, but optimal doses of the drugs are still debated. PATIENTS: The files of 12 neonates treated for HSV infection between May 1983 and April 1989 in 9 departments of pediatrics were studied. The following data were analysed: age at initial signs, clinical manifestations, CSF abnormalities, viral and immunological studies, imaging techniques used to detect brain damage, doses and duration of treatment. RESULTS: The mean age at the first infectious signs was 12.3 +/- 9.3 days and neurological manifestations were first seen at 18.3 +/- 7.7 days. Acyclovir was given intravenously for 2 to 4 weeks at doses of 30 mg/kg/24 hr (5 patients) or 60 mg/kg/24 hr (7 patients) at an average of 7.7 days after the first clinical manifestations. The initial dose of 30 mg/kg/24 hr was increased to 50 or 60 mg/kg/24 hr in 3 patients. Five patients died during treatment, and 5 had severe sequelae; follow-up for the 2 remaining patients was not possible. There was no correlation between prognosis and the dose of acyclovir, which was well tolerated in all patients. CONCLUSIONS: The best results are obtained when treatment is started early. This retrospective study failed to show any dose-dependent difference in the efficacy of acyclovir. A prospective study with different doses would be useful.

[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.

[Giant axonal neuropathy: intermediate filament disease with involvement of the peripheral and central nervous system]. / Neuropathie à axones géants: maladie des filaments intermédiaires avec atteinte du système nerveux périphérique et central.

We report a case of giant axonal neuropathy in a 14 year-old turkish boy with progressive chronic neuropathy and central involvement with mental retardation. CT showed a low density and MRI imaging multiple cavities and hypersignals of the white matter. Nerve and skin biopsies revealed an accumulation of neurofilaments in axonal swellings and an accumulation of intermediate filaments in fibroblasts, Schwann cells, endothelial cells. These findings are in accordance with the reported cases. Giant axonal neuropathy results from a generalized disorder of the intermediate filaments, but the precise biochemical defect is unknown. We would agree with Maia (1988) to name this affection "Giant Axonal Disease".

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.

Peripheral neuropathy associated with erythrophagocytic lymphohistiocytosis.

A 12 year old patient who developed clinical, biochemical and histological features of erythrophagocytic lymphohistiocytosis is described. In contrast to previously reported cases, the prominent neurological feature was a subacute sensorimotor polyneuropathy. Sural nerve biopsy showed a marked reduction of myelinated fibres and severe axonal lesions, absence of histiocyte infiltration and deposits of IgM along the epineurium. In addition to the hypertriglyceridaemia previously described in this condition, an elevation of plasma very long-chain fatty acids and phytanic acid was found which suggests a transient impairment of peroxisomal functions.

[Neonatal cardiac tumour: diagnostic and therapeutic problems. One case (author's transl)]. / Tumeur du coeur chez le nouveau-né. Une observation.

We report a case of cardiac tumour, presenting as cardiac failure during the first hours of life and refractory hypoxia. The diagnosis was made with difficulty by angiography which revealed a filling defect in the right atrium, whilst echocardiography had shown only a localised pericarditis. The tumour (which extended into the pericardium) was found to fill the right atrium and appeared to extend towards the venae cavae and the left atrium, contraindicating any attempt at excision. The newborn infant died on D7 of a strictly intra-atrial well-limited fibromyoma.