Methylmalonic acidemia (MMA) is a metabolite such as methylmalonic acid and propionic acid caused by metabolic disorders of methylmalonyl-CoA mutase (MCM) or its coenzyme cobalamin (vitamin B12). Accumulation in the body affects the catabolism of isoleucine, valine, methionine, threonine, thymine and odd-carbon fatty acids, thereby causing damage to organs, especially the nervous system[1]. May manifest as lethargy, vomiting, metabolic acidosis, hyperammonemia, and encephalopathy. Long-term complications include developmental and intellectual disability, hypotonia, cardiomyopathy, pancreatic insufficiency, osteopenia, and renal insufficiency[2–3]. For MMA, early detection, early diagnosis, and early treatment can help improve the prognosis. Simple MMA, which is usually more common in the neonatal period and can also develop in infancy, can manifest as metabolic acidosis, hyperammonemia, encephalopathy, or progressively worsening brain dysfunction[2, 4], requiring hospitalization Treatment, severe acute metabolic disorders lead to death[5–7]. In this study, the incidence was more common in infancy, followed by infancy, and the combined nervous system involvement was more common, which was consistent with the literature reports. Therefore, after the child is born, if in the process of growth and development, the children gradually appear intelligence, movement, language backward and other manifestations, or unexplained anemia, liver and kidney function damage, abnormal cardiac function or cardiac malformation etc[4,8−11], all need to be alert to the occurrence of MMA. Unexplained seizures or status epilepticus can occur in children with simple MMA. If not detected and treated early and in time, death may occur quickly. Current studies have pointed out that the mortality rate of children with simplex is about 26–40%[12–14]. In this study, children under 1 year old have a higher mortality risk than those over 1 year old. Younger age and emergency admission have a higher mortality rate. Simplex The mortality rate of children was 45.5% higher than that of combined type (16.1%). The mortality rate of children with simple type was slightly deviated from those reported in the literature and did not match, which may be related to the small number of children collected.
Elevated levels of methylmalonic acid (MMA) in the blood accompanied by elevated homocysteine are called combined MMA[15–16]. Studies have found that MMA can involve multiple organs, including the central nervous system, retina, liver, kidney, blood, cardiovascular, skin, etc. Other studies have pointed out that it can lead to macular defects, thrombotic microangiopathy, etc[17], and sometimes lead to the occurrence of pulmonary hypertension[18–19]. Nervous system involvement is common, and lethargy, hypotonia, microcephaly, and seizures are the most common neurological manifestations. Imaging may show white matter lesions, basal ganglia, globus pallidus lesions, hydrocephalus, and brain atrophy. The neurological involvement of the children in this study is consistent with that reported in the literature. There were also 2 cases of Dandy-Walker malformation. The basal ganglia (especially the globus pallidus) is the most frequently affected area in MMA patients. The mechanism may be related to the blocked mitochondrial oxidative function. Cytochrome C oxidase and reduced succinate dehydrogenase activity are associated with accumulation of toxic organic acid metabolites in vivo, resulting in damage to the basal ganglia, especially the globus pallidus[20–22]. Ventricular dilatation, brain atrophy, and white matter changes are abnormal MRI changes in MMA patients, and these manifestations are closely related to developmental delay. The MRI findings of the children in this study were consistent with those reported in the literature[23]. In this study, there was a boy in early childhood who was unconscious and accompanied by convulsions when he was admitted to the hospital. Hematuria tandem mass spectrometry showed no abnormality. It was considered to be encephalitis, and he received anticonvulsant, hormone anti-inflammatory, and gamma globulin immunotherapy. The symptoms did not relieve, and it gradually transformed into status epilepticus, and eventually died clinically. The parents' complete genetic testing indicated that the patient was combined with methylmalonic acidemia. In this study, no retroretinal macular defect was found in the children. One patient had nystagmus, and another patient had skin marbling, hypertension, pulmonary hypertension, and cardiac insufficiency[24]. associated with homocysteinemia.In patients with this type of MMA, there is a disorder of methionine synthase, which catalyzes the methylation of homocysteine, and its production disorder results in a blockage of methylation, a cofactor of B vitamins required for homocysteine metabolism ( Nutrient deficiencies including folic acid, vitamin B6, and/or B12 (methylcobalamin) can induce hyperhomocysteine[25]. Homocysteine accumulation can affect renal endothelial and mesangial cell function, increase the intraglomerular pressure, and at the same time the accumulation of some toxic metabolites in the body leads to nephrotoxicity, participates in the inflammatory response of the renal cortex, and leads to renal damage, mainly tubulointerstitial damage, mainly renal tubular dysfunction, renal tubular acidosis or renal hypertension. A small number of patients also have glomerular lesions mainly, manifested as proteinuria and hematuria [26]. The children in this study had abnormal renal function. Abnormal renal function, manifested as urine occult blood, urine protein positive, and renal hypertension in some children, consistent with the reports in the literature.
Hyperhomocysteinemia(HHcy) is an independent risk factor for cardiovascular disease. In childhood, structural cardiac abnormalities, especially left-to-right shunt congenital heart disease, are the main cause of PH[27]. Defective synthesis of the coenzymes adenosylcobalamin and methylcobalamin has been reported to be a major mediator of pH due to mitochondrial dysfunction[28]. It is also possible that studies indicate that MMA may lead to endothelial cell damage, leading to thrombosis of pulmonary capillaries, thereby inducing PH[29]. In this study, there were 3 cases of children, including 1 child with congenital heart disease-atrial septal defect-ventricular septal defect, which is consistent with the literature reports, and two children with MMA involving severe lung lesions and poor cardiac function, resulting in occurrence of PH.
Hematologic abnormalities are common in MMA. Some of our children showed pancytopenia, some showed simple thrombocytopenia, and some showed anemia, which was considered to be the inhibition of bone marrow hematopoiesis after the accumulation of toxic metabolites[30]. Patients with MMA may be at risk for osteoporosis[31], possibly due to chronic acidosis (leading to osteoclast activation and osteoblast inhibition), impaired renal function, and insufficient dietary intake of calcium, phosphate, and vitamin D Optimizing calcium and phosphate intake and vitamin D supplementation may be beneficial for bone health [32].
For the treatment of MMA, based on drug therapy, intramuscular injection of vitamin B12 can reduce the concentration of methylmalonic acid[33–34]. L-carnitine can promote the excretion of propionyl and prevent carnitine deficiency[1], while limiting protein intake. Combined MMA requires oral betaine, which is used to lower homocysteine. In our patient, after a clear diagnosis, standard treatment and dietary management, the level of methylmalonic acid in urine tandem mass spectrometry showed a gradual downward trend[35]. For simple MMA, if there are repeated metabolic disorders and repeated hospitalizations, which seriously affect the quality of life, liver transplantation can be considered. It has been reported that after liver and/or kidney transplantation, the number of metabolic decompensation is reduced[36–37], and biochemical markers (C3, C3/C2 ratio, urinary methylmalonic acid, urinary methylcitrate) are improved[38–39].
Although the clinical manifestations of methylmalonic acidemia are different and can involve multiple systems, the simple type and the combined type have different prognosis. The simple type has a higher mortality rate, an early age of onset, severe organ damage, and a poor prognosis. The prognosis of children with simple MMA is better than that of children with simple MMA. Although the children have multiple organ damage, after standardized treatment, the clinical symptoms and laboratory indicators of the children have improved, and the quality of life of the children has improved.