Naohisa Ueda

Correlation between neurological dysfunction with vitamin E deficiency and gastrectomy

OBJECTIVE We previously reported on vitamin E malabsorption after gastrectomy. In this study, we focused on neurological dysfunction due to serum vitamin E decrease during the postgastrectomy period in lager number of patients. METHODS We examined the type of gastrectomy, type of reconstruction, serum vitamin E level, and neurological status for 96 gastrectomy patients. RESULTS Low serum vitamin E levels were observed in 20 patients, and 10 of those patients suffered some neurological symptoms, i.e., peripheral neuropathy, limb or truncal ataxia. Vitamin E levels tended to decrease with time after gastrectomy, and the number of patients with low serum vitamin E levels increased at about 50 months after gastrectomy. This relationship was stronger in total gastrectomy patients than in subtotal gastrectomy patients. Ten patients were given oral vitamin E, and serum vitamin E levels normalized in 9 of the patients and neurological abnormalities improved in 8 patients. An oral intake of 300 mg or more of vitamin E was necessary for normalization of vitamin E levels. CONCLUSIONS Gastrectomy should be considered a risk for vitamin E deficiency and neurological disturbance over the long-term clinical course. An oral vitamin E supply can improve serum vitamin E levels and neurological symptoms.

Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses

Hereditary spastic paraplegia (HSP) is one of the most genetically heterogeneous neurodegenerative disorders characterized by progressive spasticity and pyramidal weakness of lower limbs. Because >30 causative genes have been identified, screening of multiple genes is required for establishing molecular diagnosis of individual patients with HSP. To elucidate molecular epidemiology of HSP in the Japanese population, we have conducted mutational analyses of 16 causative genes of HSP (L1CAM, PLP1, ATL1, SPAST, CYP7B1, NIPA1, SPG7, KIAA0196, KIF5A, HSPD1, BSCL2, SPG11, SPG20, SPG21, REEP1 and ZFYVE27) using resequencing microarrays, array-based comparative genomic hybridization and Sanger sequencing. The mutational analysis of 129 Japanese patients revealed 49 mutations in 46 patients, 32 of which were novel. Molecular diagnosis was accomplished for 67.3% (33/49) of autosomal dominant HSP patients. Even among sporadic HSP patients, mutations were identified in 11.1% (7/63) of them. The present study elucidated the molecular epidemiology of HSP in the Japanese population and further broadened the mutational and clinical spectra of HSP.

P1 and P2 components of human visual evoked potentials are modulated by depth perception of 3-dimensional images

OBJECTIVE To determine the cerebral activity correlated with depth perception of 3-dimensional (3D) images, by recording of human visual evoked potentials (VEPs). METHODS Two figures consisting of smaller and larger squares were presented alternately. VEPs were recorded in two conditions. In condition I, we used two figures which yielded flat 2-dimensional images. In condition II, we used two figures which yielded 3D images, which were concave and convex, respectively. RESULTS P1, P2, and N1/P2 amplitude were significantly greater in condition II than in condition I. The P1/N1 amplitude tended to be greater in condition II than in condition I. P1 and N1 were predominantly distributed over the right temporo-parieto-occipital regions. P2 and N2 were distributed over bilateral parieto-occipital regions. CONCLUSIONS The difference in P1 amplitude between two conditions can be explained by the difference between conditions, one of which yielded depth perception while the other did not, since previous studies showed that P1 and N1 are modulated by perception of images in depth. The role of P2 and the mechanism responsible for the increase in P2 amplitude during condition II remain unknown. SIGNIFICANCE We recorded VEPs and identified electrophysiological correlates of depth perception with 3D images produced by concave/convex figures.

A Novel Mutation in ELOVL4 Leading to Spinocerebellar Ataxia (SCA) With the Hot Cross Bun Sign but Lacking Erythrokeratodermia: A Broadened Spectrum of SCA34

IMPORTANCE Although mutations in 26 causative genes have been identified in the spinocerebellar ataxias (SCAs), the causative genes in a substantial number of families with SCA remain unidentified. OBJECTIVE To identify the causative gene of SCA in 2 Japanese families with distinct neurological symptoms and radiological presentations. DESIGN, SETTING, AND PARTICIPANTS Clinical genetic study at a referral center of 11 members from 2 Japanese families, which started in 1997. MAIN OUTCOMES AND MEASURES Results of neurological examinations and radiological evaluations. The causative mutation was identified using genome-wide linkage analysis and next-generation sequencing. RESULTS Affected members (9 of 11 members [81.8%]) showed slowly progressive cerebellar ataxia (all 9 members [100%]), ocular movement disturbance (all 9 members [100%]), and pyramidal tract signs (8 of 9 members [88.9%]) with an age at onset between the second and sixth decades of life. Besides cerebellar and pontine atrophy, magnetic resonance imaging of the brain revealed the hot cross bun sign (4 of 6 members [66.7%]), pontine midline linear hyperintensity (2 of 6 members [33.3%]), or high intensity in the middle cerebellar peduncle (1 of 6 members [16.7%]), which are all reminiscent of multiple system atrophy in tested patients. Using linkage analysis combined with exome and whole-genome sequencing, we identified a novel heterozygous mutation in the ELOVL fatty acid elongase 4 (ELOVL4) gene (c.736T>G, p.W246G) in both families. Haplotype analysis indicated that it was unlikely that these 2 Japanese families shared a common ancestor. Although a missense mutation in ELOVL4 (c.504G>C, p.L168F) was recently reported to be associated with SCA with erythrokeratodermia variabilis (SCA34) in a French-Canadian family, signs of erythrokeratodermia variabilis were absent in our families. CONCLUSIONS AND RELEVANCE Combined with the results of the family with SCA34 reported previously, this report confirms that mutations in ELOVL4 can cause dominantly inherited neurodegeneration severely affecting the cerebellum and brainstem. We should be aware that the presence of multiple system atrophy-like features on magnetic resonance imaging scans, together with cerebellar and brainstem atrophy, suggests SCA34, even when erythrokeratodermia variabilis is absent. The present study further broadened the spectrum of the clinical presentations of SCA34 associated with mutations in ELOVL4, which is involved in the biosynthesis of very long-chain fatty acids.

Diffuse white matter lesions in a case of herpes simplex encephalitis

Sirs: Herpes simplex encephalitis (HSE) is a viral encephalitis whose symptoms, though treatable, can be severe. One of its early diagnostic hallmarks is bilateral, high signal intensity of the temporal gray matter depicted by magnetic resonance imaging (MRI). This MRI-detected gray matter lesion usually decreases in parallel with improvement in the clinical condition. We report a case in which diffuse white matter lesions developed after successful treatment of HSE. A 59-year-old man suffered a sudden convulsion of the right upper limb and lost consciousness. Upon admission to our hospital, coma and right hemiparesis were confirmed by neurological examination. Cerebrospinal fluid (CSF) study showed pleocytosis (45 cells/3 mm3) with lymphocyte dominance, a protein level of 44 mg/dl, and a glucose level of 91 mg/dl. Herpes simplex virus (HSV) DNA was detected in the CSF by polymerase chain reaction assay. Cranial MRI showed high-intensity lesions in both temporal lobes and the left corona radiata on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (Fig. 1). The patient was diagnosed with HSE and was given acyclovir by intravenous injection for 10 days, but his neurological status did not improve. The patient then received a 7-day course of adenine arabinoside, and gradually regained consciousness. No other convulsive seizures were observed. Although the patient responded to treatment, he remained drowsy and totally aphasic. CSF obtained at 3 months after admission showed a normal cell count (4 cells/3 mm3) and slightly increased protein level (49 mg/dl); thus, treatment of the HSE was thought to be successful. Electroencephalography at 3 months after the onset of the disease showed almost normal wave activity with slightly nonparoxysmal slow waves. Follow-up MRI at this time, however, revealed diffuse white matter lesions (Fig. 2). The white matter lesions as well as the patient’s drowsiness and aphasia were still present at 7 months after diagnosis. There have been some reports of white matter involvement in association with HSE [1, 2, 5]. Takanashi et al. [5] reported HSE in an 11-year-old girl who showed diffuse white matter lesions upon MRI in the subacute stage. The lesions disappeared in the chronic stage, and the authors concluded that the white matter lesions represented edema due to infection. Koenig et al. [2] reported a patient with HSE who showed white matter lesions upon computed tomography after successful treatment with adenine arabinoside. Temporal lobe biopsy revealed cell-mediated demyelination without reactivation of the HSV infection. The white matter involvement in our case also appeared in the chronic phase of the disease without evidence of HSV reactivation. These findings suggest that the white matter involvement associated with HSE is a demyelination that occurs as an autoimmune response following viral infection. Some recent reports have shown a limited but marked cytotoxic T-lymphocyte response to HSV infection [4, 6]. There may be some relation between this cytotoxic T-lymphocyte response and the autoimmune reaction. More immunological investigations of LETTER TO THE EDITORS

A Japanese case of cerebellar ataxia, spastic paraparesis and deep sensory impairment associated with a novel homozygous TTC19 mutation

Mitochondrial complex III (CIII) deficiency comprises a group of complex and heterogeneous genetic disorders. TTC19 mutations constitute a rare cause of CIII deficiency and are associated with neurological disorders in childhood and adulthood. Herein, we describe a 27-year-old Japanese man with cerebellar ataxia, spastic paraparesis, loss of deep sensation, mild frontal lobe dysfunction and transient psychiatric symptoms. Brain magnetic resonance imaging showed cerebellar atrophy and bilateral high-intensity signals in the inferior olives and regions adjacent to periaqueductal gray matter, on T2-weighted images. On whole-exome sequencing, we detected a novel homozygous frameshift mutation c.157_158dup [p.Pro54Alafs*48] in TTC19. Mitochondrial enzyme assays confirmed mild impairment of CIII enzymatic activity in lymphoblasts, which was consistent with TTC19-related CIII deficiency. His symptoms and radiological findings demonstrated an early stage or mild form of this disease, and further clarify the characteristics of patients with rare TTC19 mutations.

Multiple cerebral infarction and cardiomyopathy with pheochromocytoma.

A 44-year-old woman was admitted to our hospital with altered mental status and weakness in the left upper and lower limbs. A brain magnetic resonance imaging indicated multiple cerebral infarctions in the bilateral frontal and parietal lobes and in the left occipital lobe. Magnetic resonance angiography indicated overall arterial wall irregularity and stenosis. An electrocardiogram showed negative T waves, troponin I was elevated at 0.60 ng/mL, and an echocardiogram showed severe hypokinesis, leading to a diagnosis of ischemic heart disease; however, no stenosis was found at cardiac catheterization. No other etiology for the angiopathy could be found. Whole-body computed tomography demonstrated an adrenal tumor and urinary catecholamine levels were elevated. Following excision of the adrenal tumor, a diagnosis of pheochromocytoma was made. Postoperatively, the patients arterial stenosis and cardiac abnormalities improved. It was hypothesized that the patients cardiomyopathy and vasospasm were secondary to excessive catecholamine secretion from the pheochromocytoma.