Clinical and genetic analysis of methylmalonic aciduria in 60 patients from Southern China: a single center retrospective study

Abstract

Background: Methylmalonic aciduria (MMA) is a group of rare genetic metabolic disorders resulting from defects in methylmalonyl coenzyme A mutase (MCM) or intracellular cobalamin (cbl) metabolism. MMA patients show diverse clinical and genetic features across different subtypes and populations.

Methods: We retrospectively recruited 60 MMA patients from a single center and diagnosed them based on their clinical manifestations and biochemical assays. We then performed genetic analysis to confirm the diagnosis and identify the causal variants.

Results: We confirmed the common clinical manifestations of MMA reported previously. We also described four rare MMA cases with unusual symptoms or genetic variants, such as pulmonary hypertension or limb weakness in late-onset patients. We identified 15 MMACHC and 26 MMUT variants in 57 patients, including 6 novel MMUT variants. Two patients had only one MMAA variant each, and one patient had mild MMA due to mitochondrial DNA depletion syndrome caused by a SUCLA2 variant. Among 12 critically ill patients, isolated MMA was associated with higher C3, blood ammonia, and acidosis, while combined MMA was linked to hydrocephalus on skull MRI. MMACHC c.658-660delAAG and MMUT c.1280G > A variants were correlated with more severe phenotypes.

Conclusions: Our study demonstrates the clinical and genotypic heterogeneity of MMA patients and indicates that metabolic screening and genetic analysis are useful tools to identify rare cases.

Keywords: MMACHC gene; MMUT gene; Methylmalonic aciduria; Pulmonary hypertension; SUCLA2 gene.

Fig. 1

Case 1: Ultrasound suggests moderate to severe pulmonary hypertension, mild tricuspid regurgitation, minimal pericardial effusion (a). The image below presents the patient’s echocardiogram taken four months later, indicating a transition to mild levels of both pulmonary arterial hypertension and tricuspid regurgitation (b); Case 2: Bone marrow images show moderate anemia and increased bone marrow cells (c-f). Case 3: The images depict the enhancement of the anterior and posterior roots of the horizontal spinal nerves at levels T12-L2. The ‘g’ image represents the transverse weighted imaging (TWI) scan, while the ‘h’ image illustrates the enhanced TWI. Case 4: Symmetrical signal abnormalities and atrophy in the bilateral basal ganglia, with dilation of the supratentorial ventricles. Slight enhancement of the meninges in the left frontal region (i, j)

Fig. 2

This figure provides a schematic representation of the variant distribution on the MMUT gene identified in our study. It specifically illustrates the locations of the 26 distinct variants we discovered. Variants that are novel to this study are emphasized in red, while the known pathogenic variants are depicted in black