ホモシスチン尿症

UNLABELLED: Hyperhomocysteinemia in adolescence typically prompts investigation for classical inborn errors of sulfur amino acid metabolism, including cystathionine β-synthase deficiency and cobalamin-dependent remethylation disorders. However, persistent elevations may also arise from interactions between common genetic polymorphisms and acquired nutritional conditions that alter one-carbon metabolism. CASE PRESENTATION: We report an 18-year-old male with type 1 diabetes mellitus, celiac disease on a strict gluten-free diet, congenital unilateral sensorineural hearing loss, and persistent isolated hyperhomocysteinemia. At age 16, he presented with an acute visual field disturbance and right occipital cortical MRI changes suggestive of ischemia. Plasma homocysteine was persistently between 50 and 65 μmol/L.Extensive metabolic and genetic investigations, including targeted gene panels, whole-exome and research whole-genome sequencing, mitochondrial DNA sequencing, mitochondrial complex activities in fibroblasts, and fibroblast complementation, excluded classical homocystinuria and remethylation defects. Sequential trials of pyridoxine, hydroxocobalamin, and high-dose betaine produced modest or transient improvement. Re-analysis of exome data showed homozygosity for the common MTHFR c.665C>T (p.Ala222Val) variant. Family testing revealed that his father (TT) and mother (CT) had normal homocysteine (10.9 and 10.4 μmol/L), indicating that MTHFR TT alone is insufficient to cause a biochemical phenotype and functions as a susceptibility factor. Combined oral methylfolate (1,000 µg daily) and vitamin B12 (cyanocobalamin 1,000 µg daily) reduced homocysteine from 66 to 24.6 μmol/L in 8 weeks. CONCLUSION: This case illustrates multifactorial hyperhomocysteinemia arising from interactions between celiac disease-related micronutrient vulnerability and reduced MTHFR activity. Recognition of gene-nutrient interactions is important when classical metabolic disorders are excluded and may guide targeted therapy.

Homocystinuria (HCU) is an inborn error of metabolism and a conformational disorder chiefly caused by missense mutations in the cystathionine beta-synthase (CBS) gene. These mutations often cause CBS destabilization, misfolding and dysfunction resulting in CBS deficiency and pathological accumulation of homocysteine. Morphological changes in mitochondria were described in HCU patients and mouse models; however, their functional significance has remained unknown. Here, we characterized the impact of CBS deficiency due to expression of the most common HCU-causing variant CBS I278T on mitochondrial function using three cellular models of HCU: mouse hepatocytes, human fibroblasts and newly developed CRISPR/Cas9-modified HEK293 cells. We found that the expression of the CBS I278T variant resulted in the unfolded protein response, oxidative stress and impaired cellular energy metabolism in all three cellular models of HCU. Mitochondrial respiration and ATP production were substantially impaired. Bioenergetic deficit correlated morphologically with mitochondrial swelling and loss of cristae and functionally with decreased membrane potential and cytosolic mitochondrial DNA release. Impaired clearance of damaged, non-functional mitochondria was caused by compromised mitophagy activation and dysfunctional lysosomes. Methionine restriction substantially reduced plasma total homocysteine and rescued mitochondrial function of hepatocytes isolated from treated Tg-I278T HCU mice. Importantly, CBS-knockout HEK293 cells showed normal proteostasis and mitochondrial function indicating that CBS I278T misfolding is the main cause and trigger of the described pathological phenotype. These findings provide the first mechanistic insight into the impaired cellular bioenergetics in HCU.

UNLABELLED: Elevated serum vitamin B12 concentrations are commonly attributed to vitamin supplementation and are often considered a benign laboratory finding. However, persistent hypercobalaminemia may reflect underlying disease processes, including inherited metabolic disorders (IMDs). Data regarding the clinical significance of elevated vitamin B12 levels in patients with IMDs remain limited. To describe the clinical and diagnostic characteristics of children with elevated serum vitamin B12 concentrations evaluated at a tertiary pediatric metabolic center, with particular attention to confirmed inherited metabolic disorders and documented prescribed vitamin B12 treatment. This retrospective study included 185 patients with serum vitamin B12 concentrations ≥ 910 pg/mL who were evaluated at a tertiary pediatric metabolic referral center between September 2022 and January 2026. Diagnoses were categorized as confirmed inherited metabolic disorder (IMD), probable/provisional IMD, non-metabolic genetic disorder, or unresolved. Patients were then grouped according to confirmed IMD status and documented prescribed vitamin B12 treatment. Demographic characteristics, laboratory findings, organ involvement, and available longitudinal vitamin B12 measurements were analyzed. Among 185 patients with elevated serum vitamin B12 concentrations, 52 (28.1%) met the criteria for a confirmed IMD. The four analysis groups comprised confirmed IMD without documented prescribed vitamin B12 treatment (n = 23), no confirmed IMD without documented prescribed vitamin B12 treatment (n = 106), confirmed IMD with documented prescribed vitamin B12 treatment (n = 29), and no confirmed IMD with documented prescribed vitamin B12 treatment (n = 27). In Group 1, the median initial concentration was 2000 pg/mL (IQR 1881-2000). Prespecified pairwise comparisons showed higher initial vitamin B12 concentrations in Group 1 than in Group 2 (Holm-adjusted p = 0.032), whereas comparisons with Groups 3 and 4 were not significant. The confirmed IMD spectrum included organic acidemias, amino acid metabolism disorders, mitochondrial disorders, lysosomal and peroxisomal disorders, glycogen storage disease, Wilson disease, and other defined metabolic conditions. Longitudinal observations were heterogeneous and were available for only a subset of patients; they are therefore presented as illustrative cases rather than evidence of a general pattern. CONCLUSIONS: This study provides a descriptive characterization of a selected tertiary-center cohort with elevated serum vitamin B12 concentrations. Confirmed IMDs were present in 28.1% of the cohort, including 23 children without documented prescribed vitamin B12 treatment. In the absence of a contemporaneous normal-vitamin-B12 control group or an unselected IMD cohort, these findings do not establish prevalence, discrimination, diagnostic accuracy, or an epidemiological association. WHAT IS KNOWN: • Elevated serum vitamin B12 concentrations in children are commonly attributed to supplementation, althoughpersistent unexplained hypercobalaminemia may be associated with underlying disease.. • Evidence regarding the clinical signifi cance of hypercobalaminemia and its relationship with inherited metabolicdisorders in children remains limited.. WHAT IS NEW: • In this selected tertiary pediatric metabolic center cohort, 52 of 185 children (28.1%) met the prespecifi ed criteriafor a confi rmed inherited metabolic disorder; among patients without documented prescribed vitamin B12 treatment,organic acidemias and mitochondrial disorders were the most frequently represented diagnostic categories. • Persistent unexplained hypercobalaminemia is a nonspecifi c biochemical fi nding that may prompt consideration ofan inherited metabolic disorder only in children with compatible clinical features.

Cobalamin-related remethylation disorders (cbl-RD) are rare, heterogenous conditions with a wide phenotypic spectrum, including prenatal and early infantile manifestations. Data on pregnancy outcomes in affected women and the efficacy and safety of prenatal treatment of affected fetuses remain limited. Here we report (1) five women with cbl-RDs (3 cblC/epi-cblC, 1 cblD, 1 cblE) who had in total nine pregnancies and (2) eight fetuses with cbl-RD (7 cblC, 1 cblF) diagnosed and treated prenatally. All affected mothers were treated with hydroxocobalamin (OHCbl) during pregnancy and two also received betaine and carnitine. Complications included three preterm deliveries and nephrotic-range proteinuria in one previously undiagnosed mother with cblE. All offspring had favourable outcomes. In pregnancies with affected fetuses, OHCbl was administered to the mother between gestational weeks 5 and 32 at varying doses. Prenatally treated cblC cases exhibited attenuated phenotypes without microcephaly, epilepsy, or severe multisystemic disease. Notably, three of five infants harbouring severe MMACHC variants, who received high-dose pre- and postnatal OHCbl, exhibited normal neurodevelopment and no maculopathy up to age 2-3 years, though variability in genotype, treatment regimens, and duration of follow-up limit generalizability. A literature review identified nine additional pregnancies in women with cbl-RD and seven prenatally treated fetuses, with follow-up available for three. Collectively, our main findings support the safety of maternal and fetal OHCbl treatment during pregnancy. We recommend that when combined with preconception counselling, early standardized diagnosis, optimal monitoring and postnatal care, prenatal OHCbl therapy can improve pregnancy outcomes and mitigate neurodevelopmental and ophthalmic complications in cbl-RD.

Reference bias is an issue that affects most genomic studies analysing short reads mapped to a reference genome1,2. It can be mitigated by mapping to multiple haplotypes represented in a pangenome3-5. Here we introduce two new methods to address reference bias: Emblask for pangenome construction and Weaver for mapping to pangenomes at scale. Emblask is a hybrid long- and short-read haplotype-resolved dual assembly pipeline for parent-offspring trio data. Using Emblask, we assembled 698 Icelandic haplotypes and added them to the Human Pangenome Reference Consortium (HPRC) pangenome4 to construct an Icelandic pangenome reference (HPRC-ICE) including 51.41 million small variants. We mapped the short reads of 57,630 Icelanders to HPRC-ICE with Weaver and called 98.96 million variants, representing a 6.17% increase over mapping to a linear reference. We uncovered new variants in low-mappability regions, including a pathogenic single nucleotide polymorphism (SNP) in GBA1 that associates with early onset Parkinson's disease and a missense SNP in CBS that is pathogenic for homocystinuria. We replicated the GBA1 association in the UK Biobank6 with a targeted remapping of 429,193 British and Irish participants.