GFAP mutations, age at onset, and clinical subtypes in Alexander disease.

OBJECTIVE: To characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations. METHODS: We present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and χ(2) tests to assess the effects of common GFAP mutations. Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes. RESULTS: LCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course. CONCLUSIONS: AAO and the GFAP mutation site are important clinical predictors in AxD, with clear correlations to defined patterns of phenotypic expression. We propose revised AxD subtypes, type I and type II, based on analysis of statistically defined patient groups.

De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies.

BACKGROUND: Mutations of voltage-gated sodium channel alpha(II) gene, SCN2A, have been described in a wide spectrum of epilepsies. While inherited SCN2A mutations have been identified in multiple mild epilepsy cases, a de novo SCN2A-R102X mutation, which we previously reported in a patient with sporadic intractable childhood localization-related epilepsy, remains unique. To validate the involvement of de novo SCN2A mutations in the etiology of intractable epilepsies, we sought to identify additional instances. METHODS: We performed mutational analyses on SCN2A in 116 patients with severe myoclonic epilepsy in infancy, infantile spasms, and other types of intractable childhood partial and generalized epilepsies and did whole-cell patch-clamp recordings on Na(v)1.2 channels containing identified mutations. RESULTS: We discovered 2 additional de novo SCN2A mutations. One mutation, SCN2A-E1211K, was identified in a patient with sporadic infantile spasms. SCN2A-E1211K produced channels with altered electrophysiologic properties compatible with both augmented (an approximately 18-mV hyperpolarizing shift in the voltage dependence of activation) and reduced (an approximately 22-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation and a slowed recovery from inactivation) channel activities. The other de novo mutation, SCN2A-I1473M, was identified in a patient with sporadic neonatal epileptic encephalopathy. SCN2A-I1473M caused an approximately 14-mV hyperpolarizing shift in the voltage dependence of activation. CONCLUSIONS: The identified de novo mutations SCN2A-E1211K, -I1473M, and -R102X indicate that SCN2A is an etiologic candidate underlying a variety of intractable childhood epilepsies. The phenotypic variations among patients might be due to the different electrophysiologic properties of mutant channels.

[A case of carbamazepine intoxication with alpha coma and status epilepticus].

We report a 14-year-old girl with carbamazepine intoxication who developed alpha coma and status epilepticus. She fell into deep coma and developed frequent generalized convulsions. The EEG during coma showed diffuse alpha activity predominantly in the frontal area. Serum carbamazepine concentration was 42.8 micrograms/ml. The convulsions were suppressed by diazepam only transiently, and by midazolam completely. Although half a day had passed since carbamazepine ingestion, we could wash out much of drug remnants by gastric lavage. Thereafter, the serum concentration of carbamazepine decreased efficiently and the patient recovered dramatically without complication. Early diagnosis and appropriate treatments should improve the prognosis of carbamazepine intoxication.

Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome.

Proximal symphalangism is an autosomal-dominant disorder with ankylosis of the proximal interphalangeal joints, carpal and tarsal bone fusion, and conductive deafness. These symptoms are shared by another disorder of joint morphogenesis, multiple synostoses syndrome. Recently, it was reported that both disorders were caused by heterozygous mutations of the human noggin gene (NOG). To date, seven mutations of NOG have been identified from unrelated families affected with joint morphogenesis. To characterize the molecular lesions of proximal symphalangism, we performed analyses of NOG in three Japanese individuals with proximal symphalangism. We found three novel mutations: g.551G>A (C184Y) in a sporadic case of symphalangism, g.386T>A (L129X) in a familial case of symphalangism, and a g.58delC (frameshift) in a family with multiple synostosis syndrome. Characteristic genotype-phenotype correlations have not been recognized from the mutations in the NOG gene.

Progressive facial hemiatrophy after epileptic seizures.

Intractable complex partial seizures developed in a 3-year-old female with normal intracranial findings on computed tomography. Frontal paramedian band-like depression of the skin gradually developed thereafter, and progressive facial hemiatrophy (Parry-Romberg syndrome) was diagnosed. Computed tomography scanning at 5 years of age revealed multiple parenchymal calcifications and low-density areas in the white matter of the frontoparietal lobes. Epileptic seizures, one of the major neurologic complications of progressive facial hemiatrophy, could precede the succeeding neurocutaneous changes.

Immunoliposome-mediated gene transfer into cultured myotubes.

We encapsulated marker genes, pRSV-lacZ or pRSV-luc, in immunoliposomes conjugated with antibody targeting laminin B2 in the basal lamina of myotubes. The immunoliposomes were incubated with matured non-proliferating myotubes differentiated from C2C12 myoblasts. We then evaluated the efficiency of gene transfection by measuring luciferase activity and beta-galactosidase staining. The immunoliposomes conjugated with the antibody specific for myotubes were three times as efficient as control immunoliposomes conjugeted with an antibody not specific for myotubes. However, the efficiency was no more than that by the cationic liposomes without the antibody. These results suggest that laminin B2 is not effective in enhancing the efficiency of gene transfection for non-proliferating myotubes. A specific antibody for surface antigen other than laminin B2 should be chosen in further studies.

A case of moyamoya-like vessels combined with brain anomaly.

We report here a rare case of moyamoya-like vessels combined with brain anomaly. MR imaging revealed a small corpus callosum and stenosis of the internal carotid arteries. T2-weighted images revealed multiple hyperintense lesions in the cerebral deep white matter, suggesting ischemic or abnormal myelinated tissues. Cerebral angiography showed aplastic carotid siphons and anomalous aneurysmal dilatation of the petrous portion of the internal carotid arteries. The terminal portion of the internal carotid arteries and horizontal portion of the middle cerebral artery were stenotic with moyamoya-like vessels.

Migratory basal ganglia lesions in subacute sclerosing panencephalitis (SSPE): clinical implications of axonal spread.

We report a boy with subacute sclerosing panencephalitis (SSPE) who exhibited parkinsonian symptoms four months after onset. The symptoms improved after administration of levodopa. One year after onset, bilateral symmetric lesions appeared in the substantia nigra and the putamen, as observed using magnetic resonance imaging. After a one-year interval, the lesions migrated to the bilateral caudate and the cerebellar dentate nuclei. The series of migratory legions, each of which was connected by axonal pathways originating from the substantia nigra, suggests axonal spread of the SSPE virus.

Positron emission tomography in juvenile Alexander disease.

A 13-year-old boy with cervical kyphosis was diagnosed as having juvenile Alexander disease because of the typical MRI findings, abnormally elevated alphaB-crystallin and heat shock protein 27 in the cerebrospinal fluid. Positron emission tomography with 18F-fluorodeoxyglucose demonstrated hypometabolism in the frontal white matter corresponding to the areas with leukodystrophy. However, the overlying gray matter preserved normal glucose metabolism.

3-Methylglutaconic aciduria type I: clinical heterogeneity as a neurometabolic disease.

3-Methylglutaconic (3-MGC) aciduria with 3-methylglutaconyl-CoA hydratase deficiency (3-MGC aciduria type I) is a rare inherited metabolic disease of L-leucine catabolism. We describe a 9-month-old Japanese boy with this disorder who showed progressive neurological impairments presented as quadriplegia, athetoid movements and severe psychomotor retardation from 4 months of age. This finding indicates the existence of clinical heterogeneity in 3-MGC aciduria type I, suggesting it may present as a neurometabolic disease.

SSPE following neonatal measles infection.

The authors report a case of subacute sclerosing panencephalitis in a child who had measles during the neonatal period. At 3 years, 6 months of age, over a period of a few weeks, the patient lost the ability to sit unaided as a result of progressive truncal ataxia, without apparent cognitive changes, simulating acute cerebellar ataxia. His symptoms improved in 1 month, and he was able to walk again with support, but mental alteration and periodic mild head nodding on awakening followed. His illness was diagnosed as subacute sclerosing panencephalitis on the basis of the elevated titers of measles antibodies in the cerebrospinal fluid. Measles infection before 1 year of age is a risk factor of subacute sclerosing panencephalitis, but reports about patients with neonatal measles infection are rare. Immaturity of the brain at the time of measles infection may not only be a risk factor but may also influence the clinical course of the disease.

Acute cerebellitis caused by Coxiella burnetii.

We report a childhood case of severe acute cerebellitis caused by Coxiella burnetii. After 10 days of fever and headache, the patient fell into a drowsy state. Examination of the cerebrospinal fluid (CSF) revealed pleocytosis, an increased level of protein, and negative results in bacterial and viral studies. Magnetic resonance imaging demonstrated a herniated tonsil compressed by the swollen vermis. Administration of minocycline relieved the patient's clinical symptoms. C. burnetii was isolated from the CSF obtained during convalescence.

Enzyme therapy in Gaucher disease type 2: an autopsy case.

A Japanese patient with Gaucher disease type 2 was treated with enzyme therapy, alglucerase, from 7 to 22 months of age. Whereas hematologic parameters were normalized and hepatosplenomegaly was alleviated, no improvement in neurologic symptoms occurred, and the patient died of respiratory failure at age 22 months. Postmortem examination revealed massive intra-alveolar infiltration of Gaucher cells in lungs and in the central nervous system, i.e., the presence of Gaucher cells in the perivascular Virchow-Robins spaces in the cortex and deep white matter and extensive lamilar necrosis with reactive proliferation of blood vessels and macrophage infiltration of the cerebral cortex. It is suggested that enzyme therapy, with thus far recommended dose, does not prevent long-term respiratory and central nervous system involvement in severe varients of Gaucher disease.

Childhood multiple sclerosis treated with plasmapheresis.

We report a case of multiple sclerosis in a 7-year-old boy. He experienced three episodes in 8 months and was repeatedly treated with a high dose of methylprednisolone. During the third episode, to avoid the side effects associated with frequent high doses of steroid, we substituted plasmapheresis for methylprednisolone, initially performing it for 3 days and continuing it every 2 to 3 weeks according to the fluctuating values of antinuclear antibody. The patient improved markedly after initiation of plasmapheresis and has been relapse-free for more than 18 months. The effectiveness of plasmapheresis for treatment of multiple sclerosis in adults is variable and has seldom been reported in children. Our case suggests that plasmapheresis as an alternative therapy is useful for steroid-dependent or severe types of multiple sclerosis even in childhood, especially when its chronic course is assessed by antinuclear antibody titers.

Cranial computed tomography scans of premature babies predict their eventual learning disabilities.

It remains difficult to predict, early enough to intervene effectively, the risk of the development of learning disabilities among extremely low birth weight (ELBW) infants (birth weights less than 1,000 g). We prospectively studied the relationship between dilatations of lateral ventricles of the cranial computed tomography (CT) scan taken at the postconceptional age of 40 weeks and learning disabilities in their school age. Using a computer digitizer, we measured the areas of ventricles on cranial CT scans. The mean area of lateral ventricles of the learning disabilities-suspected group was significantly larger than that of the control group (392.9 and 277.4 mm2, respectively; P < .01). There were no significant differences between the two groups in gestation, birth weight, physical measurements, and developmental quotients at early school age. The dilatation of the lateral ventricles assessed by cranial CT at the corrected term may be one of the first predictors of learning disabilities recognizable at early school age.