Faculty Profiles - TAKASHIMA Hiroshi

Matsuura E., Nozuma S., Dozono M., Kodama D., Tanaka M., Kubota R., Takashima H. . Iliopsoas Muscle Weakness as a Key Diagnostic Marker in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) . Pathogens12 ( 4 ) 2023.4

Language：Japanese Publisher：Pathogens

Human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a slowly progressive neurological disease that arises from HTLV-1 infection. Pathologically, the condition is characterized by diffuse myelitis, which is most evident in the thoracic spinal cord. Clinical manifestations of the infectious disease, HAM/TSP, are empirically known to include weakness of the proximal muscles of the lower extremities and atrophy of the paraspinal muscles, which is characteristic of the distribution of disturbed muscles usually seen in muscular diseases, except that the upper extremities are almost normal. This unique clinical presentation is useful information for physicians and physical therapists involved in diagnosing and rehabilitating patients with HAM/TSP, as well as critical information for understanding the pathogenesis of HAM/TSP. However, the precise pattern of muscle involvement in this condition has yet to be reported. The purpose of this study was to identify the muscles affected by HAM/TSP in order to understand the pathogenesis of HAM/TSP as well as to aid in the diagnosis and rehabilitation of HAM/TSP. A retrospective review of medical records was conducted on 101 consecutively admitted patients with HAM/TSP at Kagoshima University Hospital. Among 101 patients with HAM/TSP, all but three had muscle weakness in the lower extremities. Specifically, the hamstrings and iliopsoas muscle were the most frequently affected in over 90% of the patients. Manual muscle testing (MMT) revealed that the iliopsoas was the weakest of the muscles assessed, a consistent feature from the early to advanced stages of the disease. Our findings demonstrate a unique distribution of muscle weakness in HAM/TSP, with the proximal muscles of the lower extremities, particularly the iliopsoas muscle, being the most frequently and severely affected.

DOI： 10.3390/pathogens12040592

Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Mika Dozono, Takahiro Hobara, Fumikazu Kojima, Yutaka Noguchi, Mika Takeuchi, Jun Takei, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Yusuke Sakiyama, Akihiro Hashiguchi, Eiji Matsuura, Yuji Okamoto, Jun Sone, Hiroshi Takashima . Clinical phenotypic diversity of NOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan. . Journal of neurology, neurosurgery, and psychiatry94 ( 8 ) 622 - 630 2023.3International journal

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: NOTCH2NLC GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few NOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of NOTCH2NLC-related IPNs. METHOD: Among 2692 Japanese patients clinically diagnosed with IPN/Charcot-Marie-Tooth disease (CMT), we analysed NOTCH2NLC repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of NOTCH2NLC repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR. RESULTS: NOTCH2NLC repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8-59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7-61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear. CONCLUSIONS: These findings of this study help us understand the clinical heterogeneity of NOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.

DOI： 10.1136/jnnp-2022-330769

Higuchi Yujiro, Takashima Hiroshi . 【神経・精神疾患の遺伝学】Charcot-Marie-Tooth病の臨床遺伝学(【Genetics of neurological and psychiatric disorders】Clinical genetics of Charcot-Marie-Tooth disease) . Journal of Human Genetics68 ( 3 ) 199 - 214 2023.3

Hamada Yuki, Shigehisa Ayano, Kanda Yoshiki, Ikeda Mei, Takaguchi Go, Matsuoka Hideki, Takashima Hiroshi . Enhancement of the Ivy Sign during an Ischemic Event in Moyamoya Disease(タイトル和訳中) . Internal Medicine62 ( 4 ) 617 - 621 2023.2

Language：English Publisher：(一社)日本内科学会

症例は67歳女性。突然に左片麻痺、左同名半盲、左半側空間無視が出現した。頭部MRI検査で右頭頂葉に脳梗塞を認めた。Fluid-attenuated inversion recovery(FLAIR)画像ではクモ膜下腔にivy signを認め、それらは梗塞領域の拡大とともに増加・拡大した。脳血管造影所見からもやもや病と診断し、抗血栓療法は回避して、ドパミン点滴静注による血圧コントロールと濃グリセリン・果糖点滴静注による脳浮腫の拡大予防を継続したところ、神経症状と脳梗塞の進行は抑止され、ivy signも消失した。ivy signは脳梗塞の拡大とともに増強し、虚血の解除とともに消失したことから、血行力学的変化が起こったことが示唆された。

Hamada Yuki, Matsuoka Hideki, Takashima Hiroshi . Development of Ivy Sign and Infarction in the Lateral Part of the Hemisphere or the Middle Cerebral Artery Territory in Association with Steno-occlusive Involvement of the Posterior Cerebral Artery in Moyamoya Disease . Internal Medicineadvpub ( 0 ) 1703 - 1704 2023

Nagata R, Matsuura E, Nozuma S, Dozono M, Noguchi Y, Ando M, Hiramatsu Y, Kodama D, Tanaka M, Kubota R, Yamakuchi M, Higuchi Y, Sakiyama Y, Arata H, Higashi K, Hashiguchi T, Nakane S, Takashima H . Anti-ganglionic acetylcholine receptor antibodies in functional neurological symptom disorder/conversion disorder. . Frontiers in neurology14 1137958 2023

Language：English Publisher：Frontiers in Neurology

Objective: Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by autonomic failure associated with the presence of anti-ganglionic acetylcholine receptor (gAChR) antibodies; however, several studies have reported that individuals with anti-gAChR antibodies present with central nervous system (CNS) symptoms such as impaired consciousness and seizures. In the present study, we investigated whether the presence of serum anti-gAChR antibodies correlated with autonomic symptoms in patients with functional neurological symptom disorder/conversion disorder (FNSD/CD). Methods: Clinical data were collected for 59 patients presenting with neurologically unexplained motor and sensory symptoms at the Department of Neurology and Geriatrics between January 2013 and October 2017 and who were ultimately diagnosed with FNSD/CD according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Correlations between serum anti-gAChR antibodies and clinical symptoms and laboratory data were analyzed. Data analysis was conducted in 2021. Results: Of the 59 patients with FNSD/CD, 52 (88.1%) exhibited autonomic disturbances and 16 (27.1%) were positive for serum anti-gAChR antibodies. Cardiovascular autonomic dysfunction, including orthostatic hypotension, was significantly more prevalent (75.0 vs. 34.9%, P = 0.008), whereas involuntary movements were significantly less prevalent (31.3 vs. 69.8%, P = 0.007), among anti-gAChR antibody-positive compared with -negative patients. Anti-gAChR antibody serostatus did not correlate significantly with the frequency of other autonomic, sensory, or motor symptoms analyzed. Conclusions: An autoimmune mechanism mediated by anti-gAChR antibodies may be involved in disease etiology in a subgroup of FNSD/CD patients.

DOI： 10.3389/fneur.2023.1137958

Yuan JH, Higuchi Y, Hashiguchi A, Ando M, Yoshimura A, Nakamura T, Hiramatsu Y, Sakiyama Y, Takashima H . Gene panel analysis of 119 index patients with suspected periodic paralysis in Japan. . Frontiers in neurology14 1078195 2023

Language：English Publisher：Frontiers in Neurology

Introduction: Genetic factors are recognized as the major reason for patients with periodic paralysis. The goal of this study was to determine the genetic causes of periodic paralysis in Japan. Methods: We obtained a Japanese nationwide case series of 119 index patients (108 men and 11 women) clinically suspected of periodic paralysis, and a gene panel analysis, targeting CACNA1S, SCN4A, and KCNJ2 genes, was conducted. Results: From 34 cases, 25 pathogenic/likely pathogenic/unknown significance variants were detected in CACNA1S (nine cases), SCN4A (19 cases), or KCNJ2 (six cases), generating a molecular diagnostic rate of 28.6%. In total, seven variants have yet been found linked to periodic paralysis previously. The diagnostic yield of patients with hypokalemic and hyperkalemic periodic paralyzes was 26.2 (17/65) and 32.7% (17/52), respectively. A considerably higher yield was procured from patients with than without positive family history (18/25 vs. 16/94), onset age ≤20 years (24/57 vs. 9/59), or recurrent paralytic attacks (31/94 vs. 3/25). Discussion: The low molecular diagnostic rate and specific genetic proportion of the present study highlight the etiological complexity of patients with periodic paralysis in Japan.

DOI： 10.3389/fneur.2023.1078195

Mitsui J., Matsukawa T., Uemura Y., Kawahara T., Chikada A., Porto K.J.L., Naruse H., Tanaka M., Ishiura H., Toda T., Kuzuyama H., Hirano M., Wada I., Ga T., Moritoyo T., Takahashi Y., Mizusawa H., Ishikawa K., Yokota T., Kuwabara S., Sawamoto N., Takahashi R., Abe K., Ishihara T., Onodera O., Matsuse D., Yamasaki R., Kira J.I., Katsuno M., Hanajima R., Ogata K., Takashima H., Matsushima M., Yabe I., Sasaki H., Tsuji S. . High-dose ubiquinol supplementation in multiple-system atrophy: a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial . eClinicalMedicine59 101920 2023

Language：Japanese Publisher：eClinicalMedicine

Background: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients. Methods: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol. Findings: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (−1.7 [95% CI, −3.2 to −0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]). Interpretation: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo. Funding: Japan Agency for Medical Research and Development.

DOI： 10.1016/j.eclinm.2023.101920

Hiramatsu Yu, Sakiyama Yusuke, Takashima Hiroshi . Neuroinfection and preventive medicine . Neurological Therapeutics40 ( 2 ) 99 - 103 2023

Language：Japanese Publisher：Japanese Society of Neurological Therapeutics

The discovery and approval of novel treatments and vaccines are altering the trajectory of neuroinfectious illnesses.As for bacterial meningitis, the pneumococcal vaccine and Haemophilus influenzae type b vaccine have reduced the incidence of bacterial meningitis in children. The pneumococcal vaccine is now routinely administered to adults as well to prevent pneumonia, but problems of serotype substitution have arisen, including for children. Additionally, recently approved medications for the treatment of systemic myasthenia gravis and neuromyelitis optica spectrum diseases, such as eculizumab and labulizumab, increase the risk of meningococcal infection in adults and may result in meningitis. As a result, it is critical to immunize patients against meningococcal meningitis before administration and to describe the risks to the patient and family.For tetanus, additional immunization with absorbed tetanus toxoid or concomitant use of human tetanus immune globulin should be taken into account, depending on the condition of the wound. According to an evaluation of contamination, wound depth, and consequences from neuropathy or ischemia, aggressive debridement should be taken into consideration for non–open wounds.Vaccines for shingles have been approved for patients over 50 years of age, both live attenuated vaccines and genetically engineered vaccines. Given that both are successful in avoiding the disease's start, it is important to recognize the benefits and drawbacks of each and employ them appropriately.The Japanese encephalitis virus, a flavivirus, is subject to routine vaccination in childhood, but it is known that the antibody retention rate declines in adults, and additional vaccination should be considered for those who work in rural areas in endemic areas. Although Japan has not licensed a vaccine for the tick–borne encephalitis virus, the administration should be taken into account if the individual will be living in an area where it is common or will be visiting a forest.There is also disagreement over the effectiveness of long–term SARS–CoV–2 vaccines, and further understanding of the etiology is preferred.

DOI： 10.15082/jsnt.40.2_99

Nozuma S., Matsuura E., Tanaka M., Kodama D., Matsuzaki T., Yoshimura A., Sakiyama Y., Nakahata S., Morishita K., Enose-Akahata Y., Jacoboson S., Kubota R., Takashima H. . Identification and tracking of HTLV-1-infected T cell clones in virus-associated neurologic disease . JCI Insight8 ( 7 ) 2023

Language：Japanese Publisher：JCI Insight

Human T lymphotropic virus type 1-assoicated (HTLV-1-associated) myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory disease caused by the persistent proliferation of HTLV-1-infected T cells. Here, we performed a T cell receptor (TCR) repertoire analysis focused on HTLV-1-infected cells to identify and track the infected T cell clones that are preserved in patients with HAM/TSP and migrate to the CNS. TCRβ repertoire analysis revealed higher clonal expansion in HTLV-1-infected cells compared with noninfected cells from patients with HAM/TSP and asymptomatic carriers (ACs). TCR clonality in HTLV-1-infected cells was similar in patients with HAM/TSP and ACs. Longitudinal analysis showed that the TCR repertoire signature in HTLV-1-infected cells remained stable, and highly expanded infected clones were preserved within each patient with HAM/TSP over years. Expanded HTLV-1-infected clones revealed different distributions between cerebrospinal fluid (CSF) and peripheral blood and were enriched in the CSF of patients with HAM/TSP. Cluster analysis showed similarity in TCRβ sequences in HTLV-1-infected cells, suggesting that they proliferate after common antigen stimulation. Our results indicate that exploring TCR repertoires of HTLV-1-infected cells can elucidate individual clonal dynamics and identify potential pathogenic clones expanded in the CNS.

DOI： 10.1172/jci.insight.167422

Nozaki Ichiro, Hashiguchi Akihiro, Takashima Hiroshi, Yamashita Yoko, Higashide Tomomi, Iwasa Kazuo, Ono Kenjiro . Charcot-Marie-Tooth Disease with A Novel Variant in Gap Junction Protein Beta 1 Presenting with Visual Field Defects . Internal Medicineadvpub ( 0 ) 3033 - 3036 2023

Language：English Publisher：The Japanese Society of Internal Medicine

Pathogenic variants in Gap Junction Protein Beta 1 (GJB1) cause X-linked Charcot-Marie-Tooth (CMT) disease type 1 (CMTX1), which is a common hereditary motor and sensory neuropathy. A 45-year-old man presented with progressive muscle weakness, atrophy, sensory disturbance of all limbs from childhood, and visual field defects in both eyes at 40 years old. A segregation analysis revealed a novel variant, c.173 C>A (p. P58H), in the GJB1 gene. Patients with variants at codon 58 in GJB1 showed clinically varied phenotypes, ranging from demyelinating neuropathy to cerebellar ataxia. This patient may represent one of the various clinical phenotypes of GJB1 variants.

DOI： 10.2169/internalmedicine.1403-22

M.D. Imoto Makiko, M.D. Nakamura Kota, M.D. Inoue Kimiko, M.D. Ph.D. Ando Masahiro, M.D. Ph.D. Higuchi Yujiro, M.D. Ph.D. Takashima Hiroshi, M.D. Ph.D. Okuda Shiho . Involvement of autonomic nervous system since middle age in elderly patient with giant axonal neuropathy caused by novel genetic mutation . Rinsho Shinkeigaku63 ( 9 ) 566 - 571 2023

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Societas Neurologica Japonica

A 69-year-old man began to experience difficulty with walking at the age of 5 years and started use of a cane at around 13 years, then finally started using a wheelchair at 17 years old. A diagnosis of Charcot-Marie-Tooth disease was previously determined at another hospital, though neither peripheral nerve biopsy nor gene analysis was conducted. He visited our institution at the age of 54 years and irregular outpatient examinations were started, which indicated slowly progressive muscle weakness and sensory disturbance of the limbs, leading to a decline in activities of daily living. Gene analysis at 60 years old identified a novel homozygous missense mutation in the gigaxonin gene, c.1478A>C, p.E493A. Intellectual capacity was preserved and kinky hair was not present, though complications such as vocal cord paralysis, paralytic ileus, and dysarthria were noted starting at age 61. Based on these findings, the patient was diagnosed with a mild form of giant axonal neuropathy.

DOI： 10.5692/clinicalneurol.cn-001822

Other Link： https://search.jamas.or.jp/link/ui/2024004707

Yoshimoto Yukiyo, Yoshimoto Shoko, Kakiuchi Kensuke, Miyagawa Rumina, Ota Shin, Hosokawa Takafumi, Ishida Shimon, Higuchi Yujiro, Hashiguchi Akihiro, Takashima Hiroshi, Arawaka Shigeki . Spatial Fluctuation of Central Nervous System Lesions in X-linked Charcot-Marie-Tooth Disease with a Novel GJB1 Mutation . Internal Medicineadvpub ( 0 ) 571 - 576 2023

Language：English Publisher：The Japanese Society of Internal Medicine

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1), the most common form of CMTX, is caused by gap-junction beta 1 (GJB1) mutations. We herein report a 25-year-old Japanese man with disorientation, right hemiparesis, and dysarthria. Brain magnetic resonance imaging (MRI) showed high signal intensities in the bilateral cerebral white matter on diffusion-weighted imaging. He had experienced 2 episodes of transient central nervous system symptoms (at 7 and 13 years old). A genetic analysis identified a novel GJB1 mutation, c.169 C>T, p.Gln57*. MRI abnormalities shifted from the cerebral white matter to the corpus callosum and had disappeared at the five-month follow-up. Transient changes between these lesions may indicate CMTX1.

DOI： 10.2169/internalmedicine.1713-23

Takei J., Higuchi Y., Ando M., Yoshimura A., Yuan J.H., Fujisaki N., Tokashiki T., Kanzato N., Jonosono M., Sueyoshi T., Kanda N., Matsuoka H., Okubo R., Suehara M., Matsuura E., Takashima H. . Microbleed clustering in thalamus sign in CADASIL patients with NOTCH3 R75P mutation . Frontiers in Neurology14 1241678 2023

Language：Japanese Publisher：Frontiers in Neurology

Background and objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan. Methods: We conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images. Results: Among the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign). Conclusion: We propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.

DOI： 10.3389/fneur.2023.1241678

Jun-Hui Yuan, Xiaoyang Cheng, Eiji Matsuura, Yujiro Higuchi, Masahiro Ando, Akihiro Hashiguchi, Akiko Yoshimura, Ryo Nakachi, Jun Mine, Takeshi Taketani, Kenichi Maeda, Saori Kawakami, Ryutaro Kira, Shoko Tanaka, Kazuaki Kanai, Fadia Dib-Hajj, Sulayman D Dib-Hajj, Stephen G Waxman, Hiroshi Takashima . Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders. . Journal of the peripheral nervous system : JPNS28 ( 4 ) 597 - 607 2023International journal

Language：Japanese Publishing type：Research paper (scientific journal)

BACKGROUND AND AIMS: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. METHODS: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. RESULTS: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed. INTERPRETATION: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations.

DOI： 10.1111/jns.12590

Masuda Aiko, Hamada Yuki, Matsuoka Hideki, Takashima Hiroshi . Eagle Syndrome Induced by the Head Retroflexion . Internal Medicineadvpub ( 0 ) 1669 - 1670 2023

Higuchi Y., Ando M., Kojima F., Yuan J., Hashiguchi A., Yoshimura A., Hiramatsu Y., Nozuma S., Fukumura S., Yahikozawa H., Abe E., Toyoshima I., Sugawara M., Okamoto Y., Matsuura E., Takashima H. . Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum . Journal of Neurology271 ( 1 ) 419 - 430 2023

Language：Japanese Publisher：Journal of Neurology

Background and objective: Biallelic mutations in the COA7 gene have been associated with spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), and a notable clinical diversity has been observed. We aim to identify the genetic and phenotypic spectrum of COA7-related disorders. Methods: We conducted comprehensive genetic analyses on the COA7 gene within a large group of Japanese patients clinically diagnosed with inherited peripheral neuropathy or cerebellar ataxia. Results: In addition to our original report, which involved four patients until 2018, we identified biallelic variants of the COA7 gene in another three unrelated patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and c.449G > A (p.C150Y; novel). Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia. Despite experiencing an initial transient positive response to levodopa and deep brain stimulation, he became bedridden by the age of 19. Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration. Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients. Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties. A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G), uncovered a common haplotype block. Conclusion: COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display a dystonia-predominant phenotype. We propose that COA7 should be considered as a new causative gene for infancy-onset generalized dystonia, and COA7 gene screening is recommended for patients with unexplained dysfunctions of the central and peripheral nervous systems.

DOI： 10.1007/s00415-023-11998-3

髙嶋博 . Discovery 新・感染症学−真の脳炎・脳症の原因を求めて− . 神経感染症28 ( 1 ) 1 2023

Ishikawa R., Nakamori M., Takenaka M., Aoki S., Yamazaki Y., Hashiguchi A., Takashima H., Maruyama H. . Case report: Mitochondrial trifunctional protein deficiency caused by HADHB gene mutation (c.1175C>T) characterized by higher brain dysfunction followed by neuropathy, presented gadolinium enhancement on brain imaging in an adult patient . Frontiers in Neurology14 1187822 2023

Language：Japanese Publisher：Frontiers in Neurology

Mitochondrial trifunctional protein (MTP) deficiency is an autosomal recessive disorder caused by impaired metabolism of long-chain fatty acids (LCFAs). Childhood and late-onset MTP deficiency is characterized by myopathy/rhabdomyolysis and peripheral neuropathy; however, the features are unclear. A 44-year-old woman was clinically diagnosed with Charcot-Marie-Tooth disease at 3 years of age due to gait disturbance. Her activity and voluntary speech gradually decreased in her 40s. Cognitive function was evaluated and brain imaging tests were performed. The Mini-Mental State Examination and frontal assessment battery scores were 25/30 and 10/18, respectively, suggesting higher brain dysfunction. Peripheral nerve conduction studies revealed axonal impairments. Brain computed tomography showed significant calcification. Magnetic resonance imaging revealed an increased gadolinium contrast-enhanced signal in the white matter, suggesting demyelination of the central nervous system (CNS) due to LCFAs. The diagnosis of MTP deficiency was confirmed through genetic examination. Administration of L-carnitine and a medium-chain fatty triglyceride diet was initiated, and the progression of higher brain dysfunction was retarded within 1 year. This patient's presentation was suggestive of CNS demyelination. The presence of brain calcification, higher brain dysfunction, or gadolinium enhancement in the white matter in patients with peripheral neuropathy may be suggestive of MTP deficiency.

DOI： 10.3389/fneur.2023.1187822