石原 尚子

BACKGROUND: This study aimed to clarify the clinical profiles of patients with tuberous sclerosis complex (TSC) in the general population by a regionally based survey of medical facilities in a region with 7.5 million residents, and investigate differences in clinical profiles according to medical facility size and type. METHODS: A survey was sent to 146 hospitals and clinics regarding clinical profiles of patients with TSC who lived in Aichi Prefecture, Japan, between 2013 and 2018. Medical facilities were classified as large hospitals (≥750 beds or a children's hospital), small hospitals (<750 beds), institutions for handicapped children, and private clinics. RESULTS: Information was obtained of 232 patients (median age, 25 years; range, 1-81 years). Estimated prevalence of TSC was 3.1 per 100,000. Cortical tubers were present in 88 %, epilepsy in 81 %, autism spectrum disorder in 44 %, and subependymal giant cell astrocytoma in 17 %. Hypomelanotic macules, facial angiofibroma, renal angiomyolipoma, and cardiac rhabdomyoma were present in >50 % of patients. Rates of epilepsy with frequent seizures and autism spectrum disorder were both higher in patients in institutions for handicapped children. In more than half of patients in institutions for handicapped children information on cranial MRI findings was not obtained. CONCLUSIONS: Our regionally based study confirmed the clinical profiles previously reported in specialized hospitals for TSC and found that clinical characteristics differed among the types and sizes of medical facilities. Multicenter information sharing and collaboration between general hospitals and institutions for handicapped children are important for the comprehensive care of patients with TSC.

UBA1 is an E1 ubiquitin-activating enzyme that initiates the ubiquitylation of target proteins and is thus a key component of the ubiquitin signaling pathway. Three disorders are associated with pathogenic variants of the UBA1 gene: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, lung cancer in never smokers (LCINS), and X-linked spinal muscular atrophy (XL-SMA, SMAX2). We here report a case of infantile respiratory distress syndrome followed by continuing neuromuscular symptoms. We identified a de novo hemizygous mutation, c.1660 C > T (p.Pro554Ser), in exon 15 of the UBA1 gene in this baby. This missense mutation was located with the AAD (active adenylation domain) of the protein, a known hotspot of SMAX2 mutations. This case lends support to the genotype-phenotype correlation regarding the UBA1 mutation and its related diseases.

7歳男児。体育の授業中に足を滑らせて顔面から転倒し、2時間後に眩暈・頭痛・嘔吐が出現した。近医を受診し、頭部MRIで左小脳半球に脳梗塞が認められた。発症3ヵ月後に施行されたフォロー目的のMRIで右頭頂葉と右小脳半球に小梗塞を認められ、精査目的で当院に紹介された。脳血管造影で、頸部の右捻転により左椎骨動脈が狭窄する所見と内膜の解離所見を認め、Bow hunter症候群による椎骨動脈解離および多発性脳梗塞と診断した。解離部とその近位の左椎骨動脈のコイル塞栓術を行い、術後4ヵ月の現在まで脳梗塞の再発は認めていない。

GATA4 is known to be a causative gene for congenital heart disease, but has also now been associated with disorders of sexual development (DSD). We here report a pathogenic variant of GATA4 in a 46,XY DSD patient with an atrial septal defect, identified by whole-exome sequencing to be c.487C>T (p.Pro163Ser). This mutation resulted in reduced transcriptional activity of the downstream gene. When we compared this transcriptional activity level with other GATA4 variants, those that had been identified in patients with cardiac defects and DSD showed less activity than those in patients with cardiac defect only. This suggests that the normal development of the heart requires more strict regulation of GATA4 transcription than testicular development. Further, when the different variants were co-expressed with wild-type, the transcriptional activities were consistently lower than would be expected from an additive effect, suggesting a dominant-negative impact of the variant via dimer formation of the GATA4 protein. Since these pathogenic GATA4 variants are occasionally identified in healthy parents, a threshold model of quantitative traits may explain the cardiac defect or DSD phenotypes that they cause.