Yuichi Higashiyama

The Neural Basis of Typewriting: A Functional MRI Study

To investigate the neural substrate of typewriting Japanese words and to detect the difference between the neural substrate of typewriting and handwriting, we conducted a functional magnetic resonance imaging (fMRI) study in 16 healthy volunteers. All subjects were skillful touch typists and performed five tasks: a typing task, a writing task, a reading task, and two control tasks. Three brain regions were activated during both the typing and the writing tasks: the left superior parietal lobule, the left supramarginal gyrus, and the left premotor cortex close to Exner’s area. Although typing and writing involved common brain regions, direct comparison between the typing and the writing task revealed greater left posteromedial intraparietal cortex activation in the typing task. In addition, activity in the left premotor cortex was more rostral in the typing task than in the writing task. These findings suggest that, although the brain circuits involved in Japanese typewriting are almost the same as those involved in handwriting, there are brain regions that are specific for typewriting.

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.

A novel SCARB2 mutation causing late‐onset progressive myoclonus epilepsy

Progressive myoclonus epilepsy (PME) is a clinically heterogeneous disorder characterized by myoclonus, epilepsy, and progressive neurological deteriorations, typically with cerebellar signs and dementia. Recently, the scavenger receptor class, member 2 gene (SCARB2) was found to be mutated in PME with or without renal failure, in patients showing preserved intellect, disease onset at approximately 20 years of age, and death usually by 35. Here, we encountered two Japanese siblings (Fig. 1A) with late-onset PME without renal failure having a novel homozygous SCARB2 mutation. Patient 1 (III-9) developed normally. At age 43, myoclonic jerks were noted in her upper limbs when writing. After a few months, gait instability started, leading to falling without loss of consciousness. Action myoclonus and gait instability gradually worsened, and her speech was slurred. She became wheelchair bound at age 51, and bedridden at 54. Now, at 58, cognitive ability, ocular movements, and eyegrounds were preserved (i.e., no cherry-red spots). Generalized hyperhidrosis and dyspnea with marked myoclonus occurred in the stressed condition and/or during anxiety. Tonic clonic seizures also appeared. Biochemical examination indicated healthy renal function. Preserved alpha background activity with no epileptic discharge was found by EEG. Somatosensory-evoked potentials were normal. Brain MRI was normal with no apparent atrophy (Fig. 1B). Brain perfusion single-photon emission computed tomography (SPECT) showed decreased regional cerebral blood flow in the bilateral dorsolateral frontal lobes (Fig. 1C), which might be related to psychiatric symptoms. The elder brother of patient 1 (patient 2, III-3) developed normally. At age 52, gait instability was noted. At 57, voice and upper-limb tremor triggered by movements was recognized. At 62, he started using a wheelchair and dysphagia occurred. At 63, a convulsive seizure occurred once. At the same age, an acute ischemic stroke on his right corona radiata developed. At 68, regardless of his bedridden state and limb contracture with severe myoclonus triggered by movements, his mental function was preserved. Biochemical examination indicated normal renal function. To identify the causative mutation, whole exome sequencing was performed using genomic DNA from patient 1. As a result, three homozygous contiguous mutations were detected in exon 11 of SCARB2. Sanger sequencing confirmed a homozygous c.1385_1390delinsATGCATGCACC (p.Gly462Aspfs*34) in patient 1, instead of three contiguous mutations (Fig. 1D). The mutation was undetected in 200 Japanese control alleles as well as the public exome database of the National Heart, Lung, and Blood Institute exome sequencing project (5,378 exomes). The mutation cosegregated with those affected (Fig. 1D). To examine whether the frameshift mutation leads to nonsense-mediated messenger RNA (mRNA) decay (NMD), reverse-transcriptase polymerase chain reaction was performed. We confirmed that the amount of mutant SCARB2 mRNA is comparable to that of wild-type mRNA (Fig. 1E), indicating that mutant mRNA is not subjected to NMD and the abnormal gene product may be postulated. Loss-of-function mutations in SCARB2 are known to cause PME with or without renal failure. Residual SCARB2 function can be related to the exceptionally late-onset PME in these patients.

White matter hyperintensities on MRI in dementia with Lewy bodies, Parkinson's disease with dementia, and Alzheimer's disease

BACKGROUND In dementia with Lewy bodies (DLB) and Parkinsons disease with dementia (PDD), it is still debated whether white matter hyperintensities (WMH) on MRI reflect atherosclerotic cerebrovascular changes or Alzheimers disease (AD)-related pathology such as cerebral amyloid angiopathy. To examine AD-related pathology in DLB and PDD, we compared the severity of WMH and medial temporal lobe atrophy among patients with DLB, PDD, non-demented PD (PDND), and AD. METHODS We retrospectively studied sex- and age-matched outpatients with AD, DLB, PDD, and PDND, as well as subjects without central nervous system disorders as normal controls (n=50 each). All subjects underwent 1.5-T MRI examinations, and WMH detected by T2-weighted images or fluid-attenuated inversion recovery images were semiquantified according to the Fazekas method. Medial temporal lobe atrophy (MTA) was visually assessed by the MTA score. RESULTS WMH were more prominent in AD, DLB, and PDD patients than in PDND patients and normal controls (NCs). DLB as well as AD showed more severe WMH than PDD. Visual assessment of medial temporal lobe atrophy showed that AD patients had the most severe atrophy, followed by DLB, PDD, and PDND patients, and NC subjects in that order. MTA scores showed significant correlations with WMH severity. CONCLUSION Our results indicated that DLB was more similar to AD than to PDD in terms of MRI findings, suggesting that WMH in DLB may reflect mainly AD-related pathology rather than atherosclerotic cerebrovascular changes.

Two cases of anaphylactic shock by methylprednisolone in neuromyelitis optica

Steroid pulse therapy with methylprednisolone (mPSL) succinate ester is the most common treatment for neuromyelitis optica (NMO); no cases of anaphylaxis have been reported to date. Here, we report two cases of anaphylactic shock induced by mPSL pulse therapy in patients with NMO and concurrent systemic lupus erythematosus. Both patients had received several courses of mPSL pulse therapy without any problems previously. Repeated mPSL pulse therapy and comorbid humoral autoimmune disease might increase the risk of anaphylaxis. Corticosteroids without succinate esters should be considered as an alternative therapy to prevent anaphylaxis.

A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10−9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10−18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

Severe rebound relapse of multiple sclerosis after switching from fingolimod to dimethyl fumarate

Dimethyl fumarate (DMF) was the second oral disease‐modifying drug to be approved for multiple sclerosis (MS) in Japan, after fingolimod. Switching from fingolimod to DMF treatment is becoming increasingly common, because DMF has shown a better risk–benefit profile and an equivalent efficacy to fingolimod.

Correction: The Neural Basis of Typewriting: A Functional MRI Study

Fig 1 is an incorrect, previous version. Please view the corrected Fig 1 here. Fig 1 A diagram of the assumptions underlying the present analysis.