Abstract
Background: Methylmalonic acidemia (MMA) incidence was evaluated based on newborn screening in Xuzhou from November 2015 to December 2017, and the clinical, biochemical and molecular characteristics of patients with MMA harboring MMACHC and MUT mutations were summarized.Methods: During the study, 236,368 newborns were screened for MMA by tandem mass spectrometry (MS/MS) in the Maternity and Child Health Care Hospital of Xuzhou. C3, C3/C2 and methionine, and tHcy if necessary, were measured during the first screening. Blood samples from the infants and/or their family members were used for DNA analysis. The entire coding regions of the MMACHC and MUT genes associated with MMA were sequenced by DNA MassARRAY and next-generation sequencing (NGS).Results: Eleven patients with MMACHC mutations and three with MUT mutations were identified among the 236,368 screened newborns; the estimated total incidence of MMA was 1:16,883. Among the MMA patients, two died of infection-triggered metabolic crisis approximately 3 months after birth. All the patients identified had two mutant alleles except for one individual with early-onset disease. The most common MMACHC mutation was c.609G > A. The laboratory levels of C3 and C3/C2 were elevated in MMA individuals compared to other infants. Importantly, we demonstrate that accelerated C2 degradation is related to air temperature and humidity.Conclusion: Our study reports the clinical characteristics of MMA and diagnosis through MS/MS and NGS. There was a higher incidence of MMA with homocysteinemia than of isolated MMA in Xuzhou. Insight from this study may help explain the high false-positive rate of MMA in summer.
Highlights
Methylmalonic acidemia (MMA) comprises a series of autosomal recessive inherited disorders of organic acid metabolism
The patients with clbC disease exhibited increased methylmalonic acid levels (>5 mg/gCr) in the urine and elevated total plasma homocysteine (>13.56 μmol/L) (Table 1). 11 of the 14 individuals were diagnosed with combined MMA and hyperhomocysteinemia, and the diagnoses were confirmed by MMACHC gene sequencing
Newborn screening by MS/MS revealed a small increase in the blood C3 concentration and an increased C3/C2 ratio
Summary
Methylmalonic acidemia (MMA) comprises a series of autosomal recessive inherited disorders of organic acid metabolism. MMA causes various clinical symptoms including recurrent vomiting, metabolic acidosis, and even developmental delay. MMA can be classified into two common types: isolated MMA and combined MMA and homocysteinemia, which are caused by deficiency in the MUT or MMACHC gene, respectively. The most common biochemical hallmark of these defects is the accumulation of methylmalonic acid and homocysteine in the blood and urine due to the dysfunction in MeCbl and AdoCbl (Carrillo-Carrasco et al, 2012; Huemer et al, 2014). Methylmalonic acidemia (MMA) incidence was evaluated based on newborn screening in Xuzhou from November 2015 to December 2017, and the clinical, biochemical and molecular characteristics of patients with MMA harboring MMACHC and MUT mutations were summarized
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