メチルマロン酸血症

Vitamin B12 (VB12) is essential for treating pediatric methylmalonic acidemia (MMA) by activating methylmalonyl-CoA mutase and reducing toxic metabolite levels. However, its clinical utility is constrained by frequent intramuscular injections (leading to poor compliance) and the low, highly variable bioavailability associated with oral administration. Thus, a long-acting, sustained-release VB12 system is urgently needed. Herein, VB12-loaded multivesicular liposomes (VB12-MVLs) were reported for the first time, prepared via an improved microfluidic-double emulsification method. To overcome the loading limitation imposed by VB12's water solubility, dimethyl-β-cyclodextrin (DM-β-CD) was introduced to construct VB12-β-MVLs. The resulting VB12-MVLs exhibited a characteristic multi-chambered "honeycomb" structure with uniform size (D50 ∼ 14.30 μm) and high encapsulation efficiency (92.43%). DM-β-CD significantly increased the drug concentration from 10.96 to 17.60 mg mL-1. In vivo studies showed that the lipid phase remained at the subcutaneous injection site for >4 days, while the aqueous phase sustained release for up to 7 days. Pharmacokinetic analysis revealed that compared with free VB12 (mean residence time, MRT = 1.50 h), VB12-MVLs extended MRT to 80.69 h, and VB12-β-MVLs further extended it to 121.42 h, with a relative bioavailability of 191.89%. Preliminary safety evaluations indicated no hemolysis, minimal tissue irritation, and no significant changes in hematological or serum biochemical indices. Collectively, the VB12-MVLs platform-particularly VB12-β-MVLs formulation-represents a promising long-acting formulation for MMA, with the potential to reduce dosing frequency and improve the quality of life of pediatric patients while maintaining therapeutic efficacy.

Propionic and methylmalonic acidemias are inborn errors of metabolism in which chronic kidney disease is a well-recognized long-term complication. The early detection of kidney involvement is essential, given that renal tubular dysfunction may develop and persist despite appropriate treatment. However, conventional renal biomarkers usually become altered only after renal impairment has become advanced, limiting their usefulness for identifying early renal damage. In the present study, we evaluated renal function in patients with propionic and methylmalonic acidemias at diagnosis and throughout clinical follow-up. We also evaluated the performance of β2-microglobulin (β2M) as an early biomarker of tubular injury in comparison with conventional markers of kidney function and investigated its correlation with the pro-inflammatory cytokine interleukin-1β (IL-1β). Plasma samples from 31 patients were analyzed and categorized into three groups according to follow-up duration (diagnosis, follow-up until 2 years, and follow-up after 2 years) and compared with healthy age-matched controls. β2M levels were significantly elevated at diagnosis compared with controls and increased progressively during follow-up. Among the conventional markers, creatinine and estimated glomerular filtration rate became significantly altered only during long-term follow-up, while uric acid levels increased progressively throughout the clinical follow-up. β2M was positively correlated with urea, uric acid, and interleukin-1β, suggesting an association between tubular dysfunction, renal impairment and inflammation. These findings demonstrate that β2M becomes altered earlier than conventional renal biomarkers, supporting its potential as a sensitive biomarker of early tubular injury and renal involvement. Moreover, its association with interleukin-1β suggests that β2M may also reflect inflammatory processes involved in the pathophysiology of tubular renal dysfunction in patients with propionic and methylmalonic acidemias.

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.

Since October 2019, screening for methylmalonic acidemia (MMA) has been implemented in the Dutch Newborn Screening (NBS) program. Since implementation, most referrals for MMA have been the result of (maternal) vitamin B12 deficiency. Although vitamin B12 deficiency is an important condition and early detection can confer health benefits, its identification was not the original objective of the screening. We therefore examined whether genetic forms of MMA can be distinguished from acquired forms. Early distinction between these forms is essential for guiding clinical management, informing prognosis, and enabling appropriate genetic counseling. Specifically, we tested whether the use of Collaborative Laboratory Integrated Reports (CLIR) to complement NBS results improved specificity of the test for genetic MMAs. We found that with the use of CLIR, genetic conditions including methylmalonyl-CoA mutase (mut) deficiency and cobalamin (cbl) A, B, C and D deficiency can be partially differentiated from acquired causes. This results in a significant reduction in the number of second-tier tests required. However, this approach may also exclude certain other genetic causes. Based on all findings, we provide considerations and implications for MMA screening that may inform decision-makers in (other) NBS programs.

A previously healthy 19-month-old female presented after her family found her upon awakening to be sleepy, uninterested in eating, and lethargic. On arrival, blood gas showed profound metabolic acidosis with normal lactate that did not improve with normalization of glucose and sodium. Her acidosis continued to worsen, so a broad workup was initiated, considering ingestions, DKA, and inborn errors of metabolism. In collecting further history, the patient's nutrition history included a combination of breastfeeding and a vegan diet followed by her family. Her B12 level returned undetectably low. She improved dramatically over the next several hours after receiving an injection of cyanocobalamin. Ultimately, she was confirmed to have methylmalonic acidemia secondary to severe Vitamin B12 deficiency.