Atsuo Nezu

Proteolipid protein gene duplications causing Pelizaeus-Merzbacher disease: Molecular mechanism and phenotypic manifestations

Pelizaeus‐Merzbacher disease (PMD) is an X‐linked disorder characterized by dysmyelination of the central nervous system (CNS) caused by mutations involving the proteolipid protein gene (PLP). In addition to point and frameshift mutations in the coding region, duplications involving the entire PLP have been recognized recently as a major genetic abnormality causing PMD. We devised an interphase fluorescence in situ hybridization (FISH) assay to establish an efficient screening test for PLP duplication. Thirteen patients from 11 Japanese PMD families were determined to have PLP duplications. This molecular diagnostic FISH test also readily detected female carriers. Molecular analysis revealed that the size of the duplication and location of the breakpoints showed striking variation. Fiber FISH demonstrated that the duplication is tandem in nature. Haplotype analysis indicated an intrachromosomal origin for the duplication. These results suggest that an unequal sister chromatid exchange in male meiosis is likely to be the major mechanism leading to the formation of the duplication. Patients with the duplication commonly present with a mild PMD phenotype. Two patients with an exceptionally severe clinical phenotype carried large duplications, suggesting that either the larger duplicated segment incorporates additional dosage‐sensitive genes or that the location of the duplication junction may affect the phenotype. Ann Neurol 1999;45:624–632

Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia therapy

Abstract Background : To establish a treatment strategy for acute encephalopathy and encephalitis associated with influenza virus infection, the pathophysiology of the disease was investigated through manifestations and laboratory findings of patients.

Functional recovery in hemiplegic cerebral palsy: ipsilateral electromyographic responses to focal transcranial magnetic stimulation.

The patterns of functional recovery after unilateral cerebral damage occurring in the prenatal to infantile periods were studied in nine patients with hemiplegic cerebral palsy. Motor evoked potentials (MEPs) recorded from the small hand muscles were investigated using focal transcranial magnetic stimulation (TMS). The MEPs findings could be separated into three subtypes based on the features of ipsilateral MEPs elicited by TMS over the unaffected motor cortex. Bilateral MEPs of similar latency were obtained in three patients. These patients each having a congenital lesion invariably exhibited mirror movements and severe hemiparesis. Meanwhile, ipsilateral MEPs with markedly prolonged latency were demonstrated in two other patients, who exhibited synergistic associated movements and severe hemiparesis caused by an acquired lesion. In the remaining four patients, who showed mild hemiparesis without such abnormal interlimb coordinations, there were no ipsilateral MEPs. Thus, we suggest that TMS is useful for confirming the electrophysiological findings relevant to functional recovery in hemiplegic cerebral palsy underlying such abnormal interlimb coordinations. Specifically, bilateral MEPs of similar latency were considered consistent with compensatory mirror movements originating from bilateral motor representation in the unaffected motor cortex.

Chronic subdural hematoma, as an initial manifestation of glutaric aciduria type-1

A 10-month-old male with glutaric aciduria type-1 (GA-1) is reported. This patient showed frequent partial motor seizures, irritability, and involuntary movements, including oral dyskinesia at the age of 3 months. On admission, magnetic resonance (MR) scanning revealed a chronic subdural hematoma and widening of the bilateral insular cisterns. Urine organic acid analysis showed marked excretion of glutaric acid, 3-hydroxy glutaric acid and glutaconic acid, suggesting GA-1. Removal of the subdural hematoma was effective for the irritability but not for the extrapyramidal signs. This is the first report of a subdural hematoma as an initial symptom in a patient with GA-1. However, the complication of subdural fluid collection in GA-1 is not rare. To our knowledge, of 29 patients with GA-1 who underwent computed tomographic or MR scans, 5 had subdural fluid collection. Disproportional hypoplasia of the temporal lobes may be a suggestive etiology of subdural fluid collection/chronic subdural hematoma.

Serial magnetic resonance imaging in children with postinfectious encephalitis

We analyzed follow-up magnetic resonance images (MRI) in eight children with clinical postinfectious encephalitis (PIE), and discussed their pathogeneses. Three categories of MRI findings were apparent: (1) multifocal lesions in the white matter with/without basal ganglia involvement consistent with acute disseminated encephalomyelitis (ADEM) (three patients); (2) single or multifocal lesions localized only in the gray matter (two patients); and (3) localized lesions in the brain stem, basal ganglia or cerebellum. Some lesions in the patients in Categories 1 and 2 migrated or were resolved quickly, sometimes within 10 days. Gadolinium caused linear or spotty enhancement in the patients in Category 2. These findings suggest that Categories 1 and 2 are a self-limiting allergic angiopathy without demyelination. In contrast, the lesions in the patients in Category 3 were fixed, and not resolved within 6 months (three patients). The pathogenesis of Category 3 is not known. All except one patient had no prednisolone (PSL) therapy, however; all lesions were resolved completely or markedly reduced in size, which indicates PSL therapy is not always necessary in patients with PIE.

Clinical and radiological variability of influenza-related encephalopathy or encephalitis

Abstract Background: Influenza‐related encephalopathy or encephalitis is not rare in children. However, it is not well understood why the brain lesion develops from influenza infection. The purpose of this study was to clarify its pathogenesis by analyzing the clinical and neuroradiological findings in patients having influenza‐related brain lesions.

An MRI and MRS study of Pelizaeus-Merzbacher disease

Earlier reports on T2-weighted magnetic resonance imaging (MRI) in the classical form of Pelizaeus-Merzbacher disease seemed to divide the patterns of the high-intensity lesions in the white matter into three subtypes: type I, diffusely hemispheric and corticospinal; type II, diffusely hemispheric without brainstem lesions; and type III, patchy in the hemispheres. The four boys presented in our study, between 10 and 17 years of age, with classical Pelizaeus-Merzbacher disease, who all had a duplicated proteolipid protein gene, invariably manifested type I despite their various clinical severities. Follow-up MRI after an interval of 5 years and proton magnetic resonance spectroscopy was performed in three of the patients. The white matter on the last MRI was unchanged in volume and the distribution of high-intense areas. Proton magnetic resonance spectroscopy revealed no abnormal peaks. These results were consistent with the lack of definite neurologic regression in the last 5 years and with the pathologic characteristics of well-preserved axons and the absence of sclerosis. Further study is required to precisely determine whether the patterns of MRI findings can be divided into subtypes corresponding to those of proteolipid protein gene abnormalities.

Acute confusional migraine and migrainous infarction in childhood

We report two children with acute confusional migraine (ACM) and another with migrainous infarction (MI), aged 7-12 years. There was a family history of migraine in all patients. The patients, who were all right-handed, all manifested sudden onset of consciousness disturbance and other neurological deficits as the first aura in their life. The symptoms in all cases almost completely resolved spontaneously within 24 h, but transient occipital slowing on EEG with laterality corresponding to the side of migrainous origin lasted more than 24 h. In the cases of ACM in the critical phase, although MRI and MR angiography showed no abnormal findings, IMP-SPECT performed within 48 h of migraine attacks revealed a regional change in cerebral blood flow, which is one particular case demonstrated hypoperfusion in the left posterior cerebral artery (PCA) territory. Therefore, although ACM was diagnosed clinically by exclusion, SPECT was thought helpful for the diagnosis of ACM. We speculated that transient hypoperfusion affecting the dominant-sided PCA territory involving the medial temporal structures was responsible for the confusion with amnesia in ACM, in contrast to the lack of confusion or amnesia in the case of MI showing cystic encephalomalacia in the right thalamic and hippocampal regions.

Transcranial magnetic stimulation in benign childhood epilepsy with centro-temporal spikes

Motor cortical excitability was studied using transcranial magnetic stimulation (TMS) in 10 age-matched controls, and 13 children with benign childhood epilepsy with centro-temporal spikes (BECT), with a mean age of 11.2 +/- 2.0 years (five untreated, and eight treated with sodium valproate (VPA) and well controlled). Motor evoked potentials (MEPs) elicited by TMS through a circular coil were recorded from the first dorsal interosseous muscle (FDI) while relaxed. There was no significant difference in latency or duration of MEPs, or central motor conduction time among controls, untreated and treated patients. The threshold intensity for TMS in the untreated patients (63.0 +/- 14.8%, mean +/- SD) was similar to that in controls (63.0 +/- 12.5%), while the threshold intensity in the treated patients (79.4 +/- 11.8%) was significantly higher than that in the other groups. A significant increase in threshold intensity (15 +/- 4.1%) was also observed in the untreated patients retested after starting VPA treatment. No adverse effects occurred during TMS in any subjects. Thus, motor cortical hyperexcitability in BECT was not recognized in the present TMS study, while VPA was confirmed to have an effect on the threshold intensity for TMS.

Disrupted SOX10 Regulation of GJC2 Transcription Causes Pelizaeus-Merzbacher-Like Disease

Mutations in the gap junction protein gamma‐2 gene, GJC2, cause a central hypomyelinating disorder; Pelizaeus‐Merzbacher‐like disease (PMLD; MIM311601). Using a homozygosity mapping and positional candidate gene approach, we identified a homozygous mutation (c.‐167A>G) within the GJC2 promoter at a potent SOX10 binding site in a patient with mild PMLD. Functionally, this mutation completely abolished the SOX10 binding and attenuated GJC2 promoter activity. These findings suggest not only that the SOX10‐to‐GJC2 transcriptional dysregulation is a cause of PMLD, but also that GJC2 may be in part responsible for the central hypomyelination caused by SOX10 mutations. ANN NEUROL 2010;68:250–254