Atsuo Kikuchi

Edema requires management tailored to its underlying etiology; however, in some cases the cause remains elusive. We describe a 79‐year‐old woman with lifelong unexplained peripheral edema. Comprehensive evaluation excluded common etiologies such as heart failure, renal dysfunction, and venous thrombosis. Whole‐genome sequencing identified a novel homozygous splice‐site variant (NM_018676.4:c.58+2T>G) in the thrombospondin‐1 domain–containing protein 1 ( THSD1 ) gene, which has previously been associated with non‐immune hydrops fetalis (NIHF). This report describes, to our knowledge, the first elderly patient with chronic peripheral edema harboring a likely pathogenic THSD1 variant, suggesting that THSD1‐related disease may, in rare instances, persist beyond the perinatal period and present into late adulthood. Although causality cannot be established definitively from a single case, the findings highlight the potential utility of genetic testing in adults with chronic unexplained edema.

Glycosylphosphatidylinositol (GPI) serves as an anchor protein for human cells, and genetic defects in this protein can lead to inherited GPI deficiency (IGD). Intellectual disability, distinctive facial features, epilepsy, hyperphosphatasia, and multiple organ anomalies characterize IGD, with severity varying based on the affected genes. A 53‐day‐old male, born to nonconsanguineous parents, presented with poor feeding and fever. The patient exhibited unique facial characteristics, hyperphosphatasia, and reduced complement levels. During his 2.5‐month admission, he exhibited recurrent fever and infection. Whole‐genome sequencing revealed compound heterozygous variants in the PIGW gene, c.[173T>C];[617_620del], p.[Leu58Pro];[Val206Glyfs*3]. Flow cytometry indicated a marked decrease in CD16 expression on granulocytes, leading to the diagnosis of IGD in the patient. This patient exhibited persistent low complement levels (CH50, C3, and C4) alongside elevated immune complexes, which may reflect complement activation secondary to infections. Transient complement abnormalities of this kind may occasionally accompany recurrent infections in patients with GPI biosynthesis defect 11. This case broadens the phenotypic spectrum of PIGW ‐related IGD and highlights the importance of further research to clarify the relationship between infection, complement activation, and GPI biosynthesis.

The molecular classification of T-cell acute lymphoblastic leukemia (T-ALL) remains incomplete, limiting risk stratification and the development of targeted therapies. Enhancer hijacking is a critical oncogenic mechanism that deregulates proto-oncogenes by repositioning cis-regulatory regions via structural variants. Here, we performed an integrated analysis of pediatric and adult T-ALL and mixed phenotype acute leukemias (MPALs), using whole-genome and whole-transcriptome sequencing. This analysis identified a group of 14 patients with predominantly T-lineage neoplasms driven by a t(14;16)(q32;q24) translocation, harboring universal GATA3 mutations and CDKN2A/B deletions. Mechanistically, this translocation repositions the ThymoD locus downstream of BCL11B, causing monoallelic, ectopic overexpression of FENDRR and mesenchymal transcription factor genes FOXF1 and FOXC2, activating epithelial-mesenchymal transition (EMT) transcription signatures. Immunophenotypic and single-cell RNA-seq analyses revealed marked lineage ambiguity with myeloid and B-cell differentiation potentials specific to this subtype. Furthermore, functional analyses in CD34-positive cord blood cells demonstrated that FOXF1 overexpression promotes myeloid differentiation while suppressing T-cell differentiation, serving as a key factor for lineage specification. Clinically, this subtype was detected in 0.15-4.0% of T-ALL/MPAL cases depending on the cohort, showing a median age of 15 years and enrichment in adolescents and young adults (AYA). Importantly, patients with t(14;16)(q32;q24) have an extremely poor prognosis, showing a trend toward worse outcomes than high-risk groups such as KMT2A-rearranged early T-cell progenitor (ETP)-like, SPI1-rearranged, and LMO2 γδ-like T-ALLs. The unique molecular landscape and poor prognosis of patients with the t(14;16)(q32;q24) translocation underscore the need for the development of novel subtype-specific therapeutic approaches.

Introduction: ADCY5-related dyskinesia is an autosomal dominant movement disorder with limited treatment options because many standard medications are ineffective. Caffeine has shown efficacy in ADCY5-related dyskinesia as an adenosine A2A receptor antagonist, but optimal dosing remains uncertain. Case Presentation: We report a 24-year-old woman with paroxysmal dyskinesia since early childhood, consisting of chorea, dystonia, and myoclonus upon waking. More than 15 medications failed. Whole-exome sequencing identified a mosaic ADCY5 variant (p.R418Q, 7% variant allele frequency). Caffeine escalation from 100 to 600 mg worsened symptoms. Four months later, she found that unsweetened canned coffee containing approximately 100 mg of caffeine per can, taken 1–3 times daily, reduced her symptoms and helped her maintain daily employment. In a self-controlled analysis of 39 coffee-intake events, dyskinesia episodes during the 6 h after coffee intake were significantly fewer than during the preceding 6 h (p = 0.002). Conclusion: This case demonstrates successful symptom control in ADCY5-related dyskinesia using patient-directed, low-dose caffeine therapy. The striking response suggests a narrow therapeutic window for caffeine in this condition and that patient self-titration may be valuable in optimizing treatment response.

Galactose, a monosaccharide, plays diverse biological roles in energy production, especially in the glycolysis and glycosylation of proteins and lipids. Galactose metabolism is mediated by the Leloir pathway, which comprises four key enzymes. Following lactose hydrolysis, galactose mutarotase (GALM) catalyzes the anomerization of β-D-galactose to α-D-galactose, providing a substrate for the downstream pathway. In 2019, GALM deficiency was defined as the fourth type of galactosemia. Affected individuals may develop cataracts similar to those observed in individuals with galactokinase deficiency, disrupting the subsequent steps in the Leloir pathway. However, cataracts generally occur less frequently and tend to be milder in patients with GALM deficiency, likely because of the partial compensation provided by spontaneous galactose mutarotation in aqueous solutions. Because lactose, the primary dietary source of galactose, is the predominant carbohydrate consumed until weaning, the timely initiation of lactose restriction can prevent or even reverse cataract formation. To date, other complications or adverse events, including those in heterozygous carriers of GALM variants, have not been clearly demonstrated. This review aims to synthesize current knowledge and findings of GALM deficiency on molecular mechanisms, clinical presentation, diagnostic approaches, carrier risk, and dietary management, with particular emphasis on cataract prevention and reversibility through early lactose restriction. By consolidating available evidence, we propose future research directions, with broader implications for newborn screening programs, clinical decision-making, and a deeper understanding of galactose metabolism.

BACKGROUND: Medulloblastoma can cause extraneural metastasis, particularly to the bones. However, only a few reports have shown that hypercalcemia occurs with medulloblastoma, and there are no reports on hypercalcemia causing consciousness disturbance. OBSERVATIONS: A 17-year-old male patient was treated for medulloblastoma with spinal and intracranial metastasis. He underwent subtotal resection, followed by radiotherapy to the craniospinal axis, posterior fossa, and primary site, as well as high-dose chemotherapy with autologous hematopoietic stem cell transplantation. He achieved complete remission after the initial treatment. However, 30 months after tumor resection, he developed headache, nausea, fatigue, and pain in the limbs and back, followed by consciousness disturbance. He had severe hypercalcemia (17.7 mg/dL) and multiple bone metastases. His symptoms improved with hypercalcemia treatment, and salvage chemotherapy resulted in complete remission of the recurrent disease. LESSONS: Previous studies have not reported consciousness disturbance caused by hypercalcemia due to medulloblastoma bone metastasis. Hypercalcemia causes various symptoms, affecting the neurological, cardiac, and gastrointestinal systems. Some of its symptoms, such as fatigue, nausea, vomiting, and bradycardia, are similar to those of increased intracranial pressure. Therefore, hypercalcemia attributed to bone metastases should be considered in the differential diagnosis of consciousness disturbance during the course of medulloblastoma. https://thejns.org/doi/10.3171/CASE25318

Introduction: Variants affecting a microsatellite on the non-coding region of chromosome 15q26.1 are associated with familial non-autoimmune thyroid abnormalities characterized by mild congenital hypothyroidism (CH) with elevated thyroglobulin (Tg) levels. Some individuals who carry these variants may develop multinodular goiter (MNG) if left untreated. Although these variants have been recognized as genetic etiologies of CH, nongoitrous, 3 (CHNG3), the associated severity of CH remains unclear. Methods: A cohort of 63 participants diagnosed with CH at Tohoku University underwent screening for genetic variants on 15q26.1. We then analyzed the clinical phenotypes of the variant-carrying participants. Results: We identified five 15q26.1 variant carriers from four families among the cohort. Family histories of thyroid abnormalities were documented in three of these five cases. The variant carriers had mild CH phenotypes, with two discontinuing levothyroxine treatment and the others requiring relatively low doses (1.33–1.89 µg/kg/day) at their final visit. During levothyroxine treatment, serum thyroglobulin and thyroid-stimulating hormone (TSH) levels were within the reference ranges at the majority of the evaluation points. Three of the five participants continued treatment into adulthood, whereas the other two discontinued it and maintained serum TSH levels within the reference range. All five participants exhibited normal intellectual development and stature. Conclusion: These findings provide further evidence supporting the role of 15q26.1 variants as a common genetic etiology of CH, with clinical phenotypes including transient CH. Early genetic evaluation may facilitate the identification of 15q26.1 variant carriers among patients who are diagnosed with CH.

Carnitine plays an essential role in maintaining energy homeostasis and metabolic flexibility. Various medications, such as pivalate-conjugated antibiotics, valproic acid, and anticancer agents, can induce carnitine deficiency, inhibit the utilization of fatty acid, and contribute to the development of hypoglycemia. No studies have linked oral semaglutide to carnitine deficiency. Herein, we report the case of a 34-year-old male patient with multiple acyl-CoA dehydrogenase deficiency who developed carnitine deficiency attributable to salcaprozic acid sodium (SNAC) in oral semaglutide. The patient was diagnosed with type 2 diabetes mellitus at 32 years of age and was treated with semaglutide injections. Hypoglycemic symptoms appeared after switching to oral semaglutide, and the mean levels of blood-free carnitine significantly decreased. Liquid chromatography–tandem mass spectrometry analysis revealed a peak corresponding to the SNAC–carnitine complex (m/z 423.24) in the urine exclusively during the oral administration of semaglutide. The MS/MS spectra at m/z 423.24 contained peaks consistent with those of the SNAC and carnitine product ions. Our results suggest that through complexation with carnitine, SNAC may induce carnitine deficiency. Healthcare providers should monitor for carnitine deficiency when administering SNAC-containing medications to at-risk individuals. Furthermore, this case can raise more significant concerns about the potential impact of pharmaceutical excipients like SNAC on metabolic pathways.