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. 2019 Jan 23:9:726.
doi: 10.3389/fgene.2018.00726. eCollection 2018.

Newborn Screening for Methylmalonic Acidemia in a Chinese Population: Molecular Genetic Confirmation and Genotype Phenotype Correlations

Wei Zhou  1 , Huizhong Li  1 , Chuanxia Wang  1 , Xiuli Wang  1 , Maosheng Gu  1
Affiliations

Newborn Screening for Methylmalonic Acidemia in a Chinese Population: Molecular Genetic Confirmation and Genotype Phenotype Correlations

Wei Zhou et al. Front Genet. .

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.

Keywords: MMACHC; MS/MS; MUT; methylmalonic acidemia; newborn screening.

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Figures

FIGURE 1
FIGURE 1
Intracellular vitamin B12 (or cobalamin) metabolism.
FIGURE 2
FIGURE 2
Metabolite measurement of clbC patients. (A) Total homocysteine of plasma. (B) The level of C3. (C) The level of MMA in urine. ∗P < 0.05, ∗∗P < 0.01.
FIGURE 3
FIGURE 3
Metabolite measurement in MMA compared to normal, MMACHC, and MUT patients. (A) The level of C2 on newborn screening. (B) The level of C3 on newborn screening. (C) The C3/C2 ratio on newborn screening.
FIGURE 4
FIGURE 4
The variation of environmental conditions and MMA markers. (A) The changes of air temperature. (B) The changes of humidity. (C) The changes of MMA markers in different seasons. (D) The single index positive rate of MMA.
FIGURE 5
FIGURE 5
Frequency of variant types and mutations in MMACHC gene. (A) Pie chart summarizing the types of MMACHC mutations. (B) Frequency of alleles that identified in cohort.
FIGURE 6
FIGURE 6
The distribution of mutations found in 3 mut-MMA patients. (A) The structure of MUT gene. (B) The family genetic map of three mut-MMA patients. (C) The frequency of MUT alleles. ∗ marked the exons/locations of the mutations identified upon the structure of MUT gene.
See this image and copyright information in PMC

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