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

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.

Rapid screening of MMACHC gene mutations by high‐resolution melting curve analysis

“…A kind of disorder in intracellular cobalamin (cbl) metabolism and belonging to organic academia, cblC is a rare genetic metabolic disease with autosomal recessive inheritance (Deodato, Boenzi, Santorelli, & Dionisi‐Vici, 2006). It is the most common type of methylmalonic acidemia (MMA) combined with homocysteinemia (HC); its incidence is between 1:46,000 and 1:200,000 in European and American countries (Cusmano‐Ozog et al, 2007; Weisfeld‐Adams et al, 2010), and varies greatly from 1:3,220 to 1:21,488 in China (Guo et al, 2018; Han et al, 2016; Zhou, Li, Wang, Wang, & Gu, 2019). The clinical phenotypes of cblC are diverse and atypical, have varying degrees of severity and usually involve multiple systems.…”

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

“…A recent global large size systematic literature review exposed that estimates of MMA (all types) detection rates were 1/126,582, 1/81967, 1/81967, and 1/16556 newborns in Asia-Paci c, Europe, North America and the Middle East and North Africa (MENA) regions, respectively [3]. The incidence of MMA in China varies signi cantly from region to region and was reported to be 1/38,667 in Shanghai [4], 1/46,531 in Zhejiang province [5], 1/6,032 in Henan province [6], 1/40166 in Jiangsu Suzhou district [7], 1/16,883 in Jiangsu Xuzhou district [8] and 1/5589 in Shandong Jining district [9]. The expanded screening program for newborns by tandem mass spectrometry (MS/MS) is currently performed in an increasing number of regions of China.…”

“…Indians have many kinds of mutations and c.1863A>T (p.K621N), c.1943G>A (p.G648D), and c.1889G > A(p.G630E) are relatively frequent [12]; c.322C>T (p.R108C) was identi ed to be frequent in Hispanic patients, while c.2150G>T (p.G717V) was identi ed as frequent in black patients [13]. In China, the most common mutations include c.729_730insTT(p.D244Lfs*39), c.1106G>A (p.R369H), c.323G>A (p.R108H), and c.1107dupT (p.T370Yfs*22) [8,14]. The c.1663G>A (p.A555T) mutation in the MMUT gene is relatively rare, which is so far reported only in a few cases [7,[15][16][17][18].…”

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

“…The incidence of MMA ranges from 1:48,000 to 1:250,000 worldwide [3,4]. The incidence of MMA in China varies significantly from region to region and was reported to be 1:38,667 in Shanghai [5], 1:46,531 in Zhejiang province [6], 1:6,032 in Henan province [7], 1:40166 in Jiangsu Suzhou district [8], 1:16,883 in Jiangsu Xuzhou district [9] and 1:5589 in Shandong Jining district [10]. The expanded screening program for newborns by tandem mass spectrometry (MS/MS) is currently performed in an increasing number of regions of China.…”

“…Indians have many kinds of mutations and c.1863A > T (p.K621N), c.1943G > A (p.G648D), and c.1889G > A(p.G630E) are relatively frequent [14]; c.322C > T (p.R108C) was identified to be frequent in Hispanic patients, while c.2150G > T (p.G717V) was identified as frequent in black patients [15]. In China, the most common mutations include c.729_730insTT(p.D244Lfs*39), c.1106G > A (p.R369H), c.323G > A (p.R108H), and c.1107dupT (p.T370Yfs*22) [9,16]. The c.1663G > A (p.A555T) mutation in the MMUT gene is rare, which is so far reported only twice in two patients [17,18].…”