三谷 忠宏

OBJECTIVE: This study aimed to evaluate the dynamics of the neutrophil-to-lymphocyte ratio (NLR) during the initial hospitalization of patients with eating disorders (EDs) and to assess its potential as a biomarker for monitoring disease severity and treatment response. METHODS: A retrospective chart review was conducted with 55 patients aged ≤ 16 years diagnosed with anorexia nervosa or avoidant/restrictive food intake disorder and admitted to Jichi Medical University Hospital between 2015 and 2021. Sociodemographic and clinical characteristics including sex, age, rate of weight gain, percentage of ideal body weight (%IBW), tube feeding treatment, and NLR were obtained. Statistical analyses used a mixed model for repeated measures to assess NLR changes regarding %IBW and other clinical factors. RESULTS: The NLR at admission was lower in the malnourished state but increased with weight recovery. MMRM revealed that tube feeding treatment (β = 0.538) and restoration of %IBW (β = 0.029) significantly predicted an increase in the NLR. The interaction between tube feeding and the quadratic term of %IBW was also significant, indicating distinct patterns of NLR changes: without tube feeding, NLR increased linearly with weight recovery, whereas with tube feeding, NLR exhibited a non-linear, upward-convex parabolic trend. DISCUSSION: These findings suggest that NLR may offer an objective recovery marker less influenced by patient self-report. Monitoring NLR before and after tube feeding may help distinguish true physiological recovery from transient stress responses, providing complementary information to conventional assessments. Further research is warranted to establish its clinical relevance.

The 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) is a mitochondria-localized protein involved in the biosynthesis of coenzyme Q10 in the electron transfer system, and its variants have been reported to cause progressive neurodegenerative diseases such as neonatal leukoencephalopathy and hereditary spastic paraplegia. In this case report, we present a case of a nine-year-old girl with exotropia with a novel HPDL variant who underwent strabismus surgery. She was referred to the ophthalmology department with exotropia and a history of progressive spastic paraplegia with gait disturbance. Brain MRI showed no remarkable findings. Whole-exome sequencing revealed a homozygous variant c.1040delC (p.Thr347Metfs*66) in the HPDL gene. Ophthalmic examination revealed a best-corrected visual acuity of 20/12 in both eyes. Fundoscopy showed retinal discoloration at the level of the retinal pigment epithelium in the right eye. As the patient had intermittent exotropia with good convergence, she was followed up conservatively. One year after the initial examination, the patient could not keep her eyes in a central position by convergence. The alternate prism cover test revealed exotropia of 80 prism diopters. We diagnosed that intermittent exotropia had deteriorated into constant exotropia. The patient's family requested a strabismus surgery, which was conducted under general anesthesia. Standard left lateral rectus recession, left medial rectus resection, and right lateral rectus recession were also performed. Postoperatively, her exotropia was reduced, and she achieved good convergence. The patient and her family were satisfied with the surgical outcome, and no recurrence was noted one year postoperatively. Our results provide important information for the associations of variant in HPDL with progressive spastic paraplegia, strabismus and retinal changes and broaden the genetic spectrum of HPDL-related disease. This is the first report to present a novel HPDL variant and document the performance of strabismus surgery for constant exotropia.

SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays from 21 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants show reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicate that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 reveals that most disease-associated missense variants are located within the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants show reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

BACKGROUND: MECP2 Duplication Syndrome, also known as X-linked intellectual developmental disorder Lubs type (MRXSL; MIM: 300260), is a neurodevelopmental disorder caused by copy number gains spanning MECP2. Despite varying genomic rearrangement structures, including duplications and triplications, and a wide range of duplication sizes, no clear correlation exists between DNA rearrangement and clinical features. We had previously demonstrated that up to 38% of MRXSL families are characterized by complex genomic rearrangements (CGRs) of intermediate complexity (2 ≤ copy number variant breakpoints < 5), yet the impact of these genomic structures on regulation of gene expression and phenotypic manifestations have not been investigated. METHODS: To study the role of the genomic rearrangement structures on an individual's clinical phenotypic variability, we employed a comprehensive genomics, transcriptomics, and deep phenotyping analysis approach on 137 individuals affected by MRXSL. Genomic structural information was correlated with transcriptomic and quantitative phenotypic analysis using Human Phenotype Ontology (HPO) semantic similarity scores. RESULTS: Duplication sizes in the cohort ranging from 64.6 kb to 16.5 Mb were classified into four categories comprising of tandem duplications (48%), terminal duplications (22%), inverted triplications (20%), and other CGRs (10%). Most of the terminal duplication structures consist of translocations (65%) followed by recombinant chromosomes (23%). Notably, 65% of de novo events occurred in the Terminal duplication group in contrast with 17% observed in Tandem duplications. RNA-seq data from lymphoblastoid cell lines indicated that the MECP2 transcript quantity in MECP2 triplications is statistically different from all duplications, but not between other classes of genomic structures. We also observed a significant (p < 0.05) correlation (Pearson R = 0.6, Spearman p = 0.63) between the log-transformed MECP2 RNA levels and MECP2 protein levels, demonstrating that genomic aberrations spanning MECP2 lead to altered MECP2 RNA and MECP2 protein levels. Genotype-phenotype analyses indicated a gradual worsening of phenotypic features, including overall survival, developmental levels, microcephaly, epilepsy, and genitourinary/eye abnormalities in the following order: Tandem duplications, Other complex duplications, Terminal duplications/Translocations, and Triplications encompassing MECP2. CONCLUSION: In aggregate, this combined analysis uncovers an interplay between MECP2 dosage, genomic rearrangement structure and phenotypic traits. Whereas the level of MECP2 is a key determinant of the phenotype, the DNA rearrangement structure can contribute to clinical severity and disease expression variability. Employing this type of analytical approach will advance our understanding of the impact of genomic rearrangements on genomic disorders and may help guide more targeted therapeutic approaches.

Seizures in patients with developmental and epileptic encephalopathies (DEEs) are often highly resistant to various antiseizure medications. Perampanel (PER) is a novel antiseizure medication that non-competitively inhibits the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and is expected to reduce seizure frequency not only for focal seizures and generalized tonic-clonic seizures (GTCS) but also for other seizure types. This study aimed to clarify the long-term therapeutic efficacy and tolerability of PER in patients with DEEs. We analyzed data regarding patients' background characteristics, medication retention, trends in seizure frequency, and adverse events obtained from 24 patients with DEEs who had been on PER treatment for 60 months. The retention rates were 62.5% and 46.9% at 12 and 60 months, respectively. At 60 months after PER initiation, the rate of patients with > 50% seizure reduction was 33.3%, 33.3%, 38.5%, 54.5%, 54.5%, and 36.4% among patients with atypical absence seizures, tonic seizures, focal seizures, GTCS, myoclonic seizures, and atonic seizures, respectively. The frequency of adverse events was 70.8%. PER showed long-term efficacy in various seizure types. PER is a promising treatment option for patients with DEEs.