A rare mutation c.1663G > A (p.A555T) in the MMUT gene associated with mild clinical and biochemical phenotypes of methylmalonic acidemia in 30 Chinese patients

Abstract

Background Methylmalonic acidemia is an inherited organic acid metabolic disease. It involves multiple physiological systems and has variable manifestations. The primary causative gene MMUT carries wide range of mutations, and one of them, c.1663G > A (p.A555T), is considered to be a rare type, which is seen more frequently in Asian than other populations. So far, little is known about the clinical features of patients carrying this mutation. In the present study, we aimed to define the clinical and biochemical features of the patients with this genotype. Methods Among 328 mut type methylmalonic acidemia patients from multiple hospitals in China, we collected 30 compound heterozygous patients sharing the mutation c.1663G > A (p.A555T) in the MMUT gene. Their clinical characteristics and biochemical index were described in detail and compared with methylmalonic acidemia patients without this variant. Results Most of these patients were diagnosed via newborn screening (26/30), treated in a timely manner, and kept healthy (24/30). Disease onset occurred in 7 patients. Developmental delay or intellectual impairment occurred in 4 patients. 100% of these patients (29/29) were responsive to Vitamin B12 administration. The blood propionylcarnitine, blood propionylcarnitine/acetylcarnitine ratio, urinary methylmalonic acid, urinary methylcitric acid before and after treatment in c.1663G > A (p.A555T) carrying patients were much lower than those in non-c.1663G > A (p.A555T) carrying patients. Conclusion Compared to patients with other mutations in the MMUT gene, patients with the c.1663G > A (p.A555T) mutation showed later onset, milder clinical phenotype, lighter biochemical abnormalities, better vitamin B12 responsiveness, lower morbidity, easier metabolic control, and thereby better prognosis. Newborn screening project plays an important role in early diagnosis, treatment, and prognosis of these patients.

Impaired Function of a Rare Mutation in the MMUT Gene Causes Methylmalonic Acidemia in a Chinese Patient

“…Defects in MCM or its coenzyme, cobalamin, lead to the accumulation of methylmalonic acid, which is characteristic of MMA [2][3][4]. MMA, first reported in 1967 [15], is a lethal, severe, and heterogeneous disorder of methylmalonate and cobalamin (cbl; vitamin B12) metabolism.…”

“…Methylmalonic acidemia (MMA) is an autosomal recessive metabolic disorder that is mainly caused by inherited defects in methylmalonyl-CoA mutase (MCM, MUT) or metabolic defects in its cofactor adenosylcobalamin [ 1 , 2 ]. Although the clinical manifestations of children with MMA vary, the most common symptoms and signs include recurrent vomiting, lethargy, seizures, failure to thrive, hypotonia, and mental retardation.…”

Methylmalonic acid, vitamin B12, and mortality risk in patients with preexisting coronary heart disease: a prospective cohort study

“…Notably, a paradox condition of increase in both MMA and B12 might be explained by the decreased sensitivity to B12 treatment [ 10 ]. For instance, one of the most common causes of congenital methylmalonic acidemia is a point mutation leading to inactivation of the mitochondrial enzyme methylmalonyl-CoA mutase (MMUT), which results in no response to treatment with B12 [ 14 , 15 ].…”

Serum differential proteomic profiling of patients with isolated methylmalonic acidemia by iTRAQ

“…Isolated MMA patients with mutations in the MUT gene are usually severely ill with poor prognosis, high early mortality, and high lifelong morbidity ( Jiang et al, 2020 ; Liang et al, 2021 ). The age of death in children with isolated MMA was 2 years, ranging from 5 days to 15 years, and 40% of individuals died and the overall mortality rate was 36%, with all deaths occurring during or after the acute metabolic crisis ( Dionisi-Vici et al, 2006 ).…”