Patients with a sodium channel alpha 1 gene mutation show wide phenotypic variation.

We investigated the roles of mutations in voltage-gated sodium channel alpha 1 subunit gene (SCN1A) in epilepsies and psychiatric disorders. The SCN1A gene was screened for mutations in three unrelated Japanese families with generalized epilepsy with febrile seizure plus (GEFS+), febrile seizure with myoclonic seizures, or intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC). In the family with GEFS+, one individual was affected with panic disorder and seizures, and another individual was diagnosed with Asperger syndrome and seizures. The novel mutation V1366I was found in all probands and patients with psychiatric disorders of the three families. These results suggest that SCN1A mutations may confer susceptibility to psychiatric disorders in addition to variable epileptic seizures. Unidentified modifiers may play critical roles in determining the ultimate phenotype of patients with sodium channel mutations.

Brain MRI findings of older patients with Pallister-Killian syndrome.

Pallister-Killian syndrome (PKS) is a disorder caused by a mosaic tetrasomy of chromosome 12p, which manifests with dysmorphism, intellectual disabilities, auditory disturbance, and epilepsy. Here, we describe the findings of brain magnetic resonance (MR) imaging in two patients with PKS. One patient, a 43-year-old man, showed multiple lesions with high signal intensity on T2-weighted image (WI) in the basal ganglia, and widespread T2 elongation in the periventricular white matter. The same signal change was also present in the pontine base. The other patient, a 37-year-old woman, showed T2-high lesions in the bilateral putamina and the parietal periventricular white matter. There was prominent atrophy of the cerebellum and brainstem in this latter case. Both cases showed cortical atrophy with frontal predominance, with accompanying dilatation of the lateral ventricles. Hypoplastic corpus callosum was also present in both cases. Cerebral atrophy with ventricular dilatation has been often described in PKS cases, but many of the MR findings in the present patients have never been reported. Such findings may appear with advancing age in PKS. Since 12p mosaicism is rarely detected in peripheral blood lymphocytes, examination of buccal mucosal cells with fluorescent in situ hybridization method is preferable for the diagnosis of PKS. Recognition of the characteristic features on cranial MR imaging, in addition to the characteristic facial appearance in adulthood, should prompt the correct diagnosis of adult PKS patients.

Molecular identification of adrenal inner zone antigen as a heme-binding protein.

The adrenal inner zone antigen (IZA), which reacts specifically with a monoclonal antibody raised against the fasciculata and reticularis zones of the rat adrenal, was previously found to be identical with a protein variously named 25-Dx and membrane-associated progesterone receptor. IZA was purified as a glutathione S-transferase-fused or His(6)-fused protein, and its molecular properties were studied. The UV-visible absorption and EPR spectra of the purified protein showed that IZA bound a heme chromophore in high-spin type. Analysis of the heme indicated that it is of the b type. Site-directed mutagenesis studies were performed to identify the amino-acid residues that bind the heme to the protein. The results suggest that two Tyr residues, Tyr107 and Tyr113, and a peptide stretch, D99-K102, were important for anchoring the heme into a hydrophobic pocket. The effect of IZA on the steroid 21-hydroxylation reaction was investigated in COS-7 cell expression systems. The results suggest that the coexistence of IZA with CYP21 enhances 21-hydroxylase activity.

Laryngeal dystonia in xeroderma pigmentosum.

We report on three patients with xeroderma pigmentosum group A (XPA) who showed laryngeal stridor in their 20s. The stridor appeared on feeding and emotional excitation, was exaggerated during respiratory infection and was life-threatening on some occasions. Adduction of the vocal cords during inspiration, observed by laryngoscopy, confirmed laryngeal dystonia in all cases. This type of focal dystonia may be characteristic in XPA and requires special attention during the management of these patients to avoid serious complications.

[Disturbed respiratory cycle accompanying hypoxic-ischemic encephalopathy].

We report the case of a 2-year-old boy who experienced total asphyxia at 4 months of age, and suffered abnormalities at specific phases of the respiratory cycle. The patient was bedridden due to severe tetraplegia and showed little response to external stimuli. He has been tube-fed since the initial asphyxia and a tracheotomy was performed after recurrent hypoxic episodes as a result of the respiratory dysfunction. Upon examination, his respiratory pattern was characterized by arrest during the inspiratory phase with a possible over-riding secondary inspiration. The respiratory pause at the inspiratory phase was markedly prolonged during an episode of pulmonary infection, resulting in recurrent cyanosis that necessitated artificial ventilation. The "second" inspiration typically occurred during the mid- or late-inspiratory phases, with this pattern often shown to be variable after epileptic seizures. The characteristic breathing of this patient suggested that difficulty in forming a normal respiratory cycle, other than during periods of hypoventilation or apnoea, could be a significant respiratory dysfunction following asphyxiation. Strategies for the management of such patients should be carefully designed after close observation of breathing patterns within the respiratory cycle, and with consideration for the influence of epileptic seizures and other inputs from somatic afferents.

[A case of long-term survival of a patient with infantile Alexander disease diagnosed by DNA analysis].

Alexander disease is a hereditary disorder of myelin degeneration. The pathological feature of the brain is the characteristic inclusion bodies in astrocytes called Rosenthal fibers. The major components of the Rosental fibers are known to be alpha B-crystallin and glial fibrillary acidic protein (GFAP). In recent years, reports have indicated mutations of the GFAP gene in patients with Alexander disease. The R239 mutation (R239C, R239H) tends to cause comparatively more severe conditions among the GFAP mutations. In this study. we examined a long-term survival case of a patient (age 25 years, 7 months) with infantile Alexander disease with an R239C mutation confirmed by DNA analysis. There are no past reports of subjects with the R239C mutation who had as prolonged a long-term survival as our case. Our subject's condition was not as severe as those with the R239H mutation. The clinical progress in those other reports also varied by case. The R239C mutation does not show as much correlation with the clinical presentation as the R239H mutation. We believe that factors such as the environment also play a part in the prognosis of the disease.

Infantile spongiform leukoencephalopathy: clinical and neuropathologic findings.

A 10-month-old male with spongy leukoencephalopathy is presented. Neurologic manifestations included feeding difficulties, horizontal nystagmus, and spasticity at 5 months of age. His head circumference was within the normal range. Radiologic examination demonstrated a diffuse white matter disorder. There was no detectable biochemical abnormality. He followed a neurologically progressive course. Neuropathologic findings revealed characteristic vacuolar changes in the white matter located immediately under the cortex with spongy alterations of the entire subcortical white matter, including intense astrocytic gliosis and marked vascular hyperplasia. Tissue of the matrix was destroyed in the deep white matter to form cystic areas of degeneration. White matter myelin development was severely disturbed compared with that of a normal infant of the same age. Cortical neuronal cells were preserved and did not reveal any specific abnormalities. Electron microscopic examination revealed that each vacuole in the white matter was covered by several layers of myelin structures, and intralamellar splits of white matter myelin were observed. These neuropathologic findings are also observed in some known inherent metabolic disorders. The present patient, however, did not demonstrate any metabolic abnormalities. These findings suggested a new genetic disorder of myelin metabolism.

Mild phenotype in Pelizaeus-Merzbacher disease caused by a PLP1-specific mutation.

We present the case of a 26 year-old man who developed normally until he began having difficulty walking at age 12. He subsequently became unable to stand at 15 years old and exhibited mental regression and generalized tonic convulsions by age 20. Magnetic resonance imaging revealed incomplete myelination of cerebral white matter, which resembled that of Pelizaeus-Merzbacher disease. By sequencing the proteolipid protein 1 (PLP1) gene, we found a novel mutation (c.352_353delAG (p.Gly130fs)) in the latter half of exon 3 (exon 3B) that is spliced out in the DM20 isoform. Exon 3B mutations are known to cause a mild phenotype since they do not disturb DM20 production. Mutations that truncate PLP1 correlate with a mild phenotype by activating the nonsense-mediated decay mechanism that specifically detects and degrades mRNAs containing a premature termination codon. This attenuates the production of toxic mutant PLP1. The very mild presentation in the present case seems to be derived from the unique nature of the mutation, which preserves DM20 production and decreases mutant PLP1.

Autopsy case of acute encephalopathy linked to familial hemiplegic migraine with cerebellar atrophy and mental retardation.

A 19-year-old female patient, who had exhibited esotropia, mild cerebellar ataxia, mild mental retardation, and cerebellar atrophy on magnetic resonance images at the age of 15, developed signs of acute encephalopathy, and thereafter died of disseminated intravascular coagulation on the day of her admission. Both her mother and sister suffered from attacks of hemiplegic migraine, mild mental retardation, and cerebellar ataxia. Neuropathological examinations revealed acute changes in the widespread cerebral cortex, chronic degenerative changes in the anterior lobe of the cerebellar vermis, axonal spheroids in the Goll's nucleus, pseudo-calcinosis in the globus pallidus, and glial bundles in the cranial nerves. The most fascinating features were changes of Purkinje cells, such as cactuses (asteroid bodies, dendritic expansions), somatic sprouts, and torpedoes. These changes may be characteristic of familial hemiplegic migraine with cerebellar atrophy, as well as the other metabolic diseases, such as Menkes' kinky hair disease, infantile (Tay-Sachs type) amaurotic idiocy, organic mercury intoxication, and mitochondrial encephalopathy, of which cases often exhibit such pathological changes of Purkinje cells. Therefore, familial hemiplegic migraine may share some metabolic abnormalities with the diseases mentioned above.