Methylmalonic acidaemia (MMA) is a genetic metabolic disorder caused by congenital defects that may result in multisystem damage. However, MMA complicated with acute myeloid leukemia (AML) is very rare. Here, we report a case of MMA with AML in a boy aged 7 years and 6 months. The boy was screened for MMA after birth and received long-term treatment with dietary control, vitamin B12, and L-carnitine. He was readmitted at the age of 7 years and 6 months with systemic bleeding spots and was diagnosed with AML by bone marrow cytology. When the diagnosis was clear, the patient received chemotherapy in addition to maintenance treatment for MMA. His blood routine, liver and kidney function, blood biochemistry, blood glucose, blood lipids, lactic acid and blood ammonia were monitored continuously. Bone marrow cytology one month after starting chemotherapy showed complete remission. Sorafenib was also added during chemotherapy and was discontinued 1 year after completion of chemotherapy. At the end of chemotherapy, he chose venetoclax for consolidation, and to date, the patient's condition is stable, with sustained CR and no relapse. MMA combined with AML is rare. The prevention of infection, comprehensive assessment of nutritional status, continuous monitoring of related indicators and overall situation should be prioritized and comprehensive and individualized treatment approaches are paramount.

Cobalamin C (Cbl-C) defect causes methylmalonic acidemia, homocystinuria, intellectual disability and visual impairment, despite treatment adherence. While international guidelines recommend parenteral hydroxocobalamin (OH-Cbl) as effective treatment, dose adjustments remain unclear. We assessed OH-Cbl therapy impact on biochemical, neurocognitive and visual outcomes in early-onset Cbl-C patients treated with different OH-Cbl doses over 3 years. Group A (n = 5), diagnosed via newborn screening (NBS), received high-dose OH-Cbl (median 0.55 mg/kg/day); Group B1 (n = 3), NBS-diagnosed, received low-dose OH-Cbl (median 0.09 mg/kg/day); Group B2 (n = 12), diagnosed on clinical bases, received low-dose OH-Cbl (median 0.06 mg/kg/day). Biochemical analyses revealed better values of homocysteine, methionine and methylmalonic acid in Group A compared to Group B1 (p < 0.01, p < 0.05 and p < 0.01, respectively) and B2 (p < 0.001, p < 0.01 and p < 0.001, respectively). Neurodevelopmental assessment showed better outcome in Group A compared to low-dose treated Groups B1 and B2, especially in Developmental Quotient, Hearing and Speech and Performance subscales without significant differences between Group B2 and Group B1. Maculopathy was detected in 100%, 66% and 83% of patients in the three groups, respectively. This study showed that "high-dose" OH-Cbl treatment in NBS-diagnosed children with severe early-onset Cbl-C defect led to a significant improvement in the metabolic profile and in neurocognitive outcome, compared to age-matched patients treated with a "low-dose" regimen. Effects on maculopathy seem unaffected by OH-Cbl dosage. Our findings, although observed in a limited number of patients, may contribute to improve the long-term outcome of Cbl-C patients.

Cerebellar microhemorrhages have not been previously documented in methylmalonic acidemia with homocystinuria (MMA-HC), a rare inherited metabolic disorder. Herein, we reported an 18-year-old female presented with acute gait instability and dysarthria post-febrile illness. Biochemical testing revealed severe hyperhomocysteinemia. Brain MRI demonstrated bilateral cerebellar DWI/FLAIR hyperintensities. Whole-exome sequencing confirmed compound heterozygous MMACHC mutations, establishing cblC-type MMA-HC diagnosis. Symptoms resolved after one month of vitamin-based therapy. Follow-up 3.0 T MRI and 7.0 T MRI susceptibility-weighted imaging (SWI) uncovered multiple punctate cerebellar vermian microhemorrhages-a previously unreported finding. This case highlights an unusual adult-onset presentation of MMA-HC and represents the first report of SWI-detectable cerebellar vermis microhemorrhages with this condition, visualized. This finding suggests that cerebellar microhemorrhages may be an under-recognized feature in MMA-HC, particularly detectable using high-field SWI during acute exacerbations, and contributes to a more comprehensive understanding of the neurological complications in this metabolic disorder.

Methylmalonic acidemia combined with homocystinuria (cblC) can lead to infantile maculopathy. Although significant visual deterioration is commonly reported in early-onset cblC, we found poor awareness regarding formal assessments of ocular complications, especially in newborns, and of how these complications relate to the timing of therapy initiation. In this work, we present our experience and perform a literature review. We performed sequential fundus examinations, optical coherence tomography (OCT) and full-field electroretinography (ERG) under sedation following detection of signs of retinal degeneration. We also assessed visual fields using kinetic attraction perimetry. We report a newborn who was referred on the eighth day of life, following a diagnosis of cblC through newborn screening (NBS), and who began treatment that same day. Close monitoring of retinal changes through fundus examinations allowed the detection of signs of retinal degeneration at 3 months, which progressed when checked at 5 months. At 7 months, OCT showed retinal thinning with the appearance of bull's eye maculopathy in the corresponding region on fundoscopy; ERG revealed a reduction in the amplitude of both scotopic and photopic components, whereas kinetic attraction perimetry showed no abnormalities. Genetic investigation confirmed the disease, compound heterozygous for a nonsense variant in MMACHC and a splicing one in PRDX1. In cblC, retinal degeneration occurs in the first months of life despite timely treatment and adequate biochemical control, and it may manifest before any signs of visual deprivation appear. However, there is an early, narrow window during which therapy may slow down retinal degeneration enough to prevent sensory nystagmus. We recommend initiating therapy immediately after biochemical diagnosis, along with close ophthalmological monitoring, before the appearance of any signs.

Combined methylmalonic acidemia and homocystinuria cblC type (cblC) is a multisystemic disease with diverse clinical presentations and known genotype-phenotype correlations. This study aims to define and explain the phenotypes and outcomes associated with the MMACHC variant c.1A>G (p.M1V), previously reported in several cases. A retrospective review of 54 Chinese patients with cblC carrying the MMACHC c.1A>G variant was conducted. Clinical features, including onset age, initial symptoms, biochemical index and prognosis were analyzed and compared with 100 cblC patients without this variant. The variant's pathogenicity was investigated by in vitro experiments. Twenty-nine (54 %) of 54 individuals with the c.1A>G variant were diagnosed via newborn screening (NBS) and 23 (79 %) remained asymptomatic. Among 19 symptomatic patients, 12 (63 %) developed symptoms after 1 year of age, with cognitive decline being the most common initial symptom (55 %). Before treatment, all analyzed biochemical indexes except homocysteine showed reduced levels in the c.1A>G group compared to the Control group. Post-treatment, the poor prognosis rate and some metabolite levels in the c.1A>G group were significantly decreased compared to those in the Control group. Western blotting indicated that c.1A>G significantly reduced MMACHC protein expression, and co-immunoprecipitation provided evidence for impaired interaction between the variant MMACHC and methionine synthase (MTR). The c.1A>G variant in MMACHC is associated with later-onset disease, milder phenotypes and improved clinical outcomes in cblC patients. Functional studies suggest that this variant reduces MMACHC translation efficiency and disrupts its interaction with MTR. Our findings underscore the utility of NBS for early diagnosis and better management in c.1A>G-associated cblC.