Combined Malonic and Methylmalonic Aciduria Due to ACSF3 Variants Results in Benign Clinical Course in Three Chinese Patients

Ping Wang; Jianbo Shu; Chunyu Gu; Xiaoli Yu; Jie Zheng; Chunhua Zhang; Chunquan Cai

doi:10.3389/fped.2021.751895

Combined Malonic and Methylmalonic Aciduria Due to ACSF3 Variants Results in Benign Clinical Course in Three Chinese Patients

Front Pediatr. 2021 Nov 25:9:751895. doi: 10.3389/fped.2021.751895. eCollection 2021.

Authors

Ping Wang^{1

2}, Jianbo Shu^{1

2}, Chunyu Gu^{1

2

3}, Xiaoli Yu⁴, Jie Zheng^{1

2}, Chunhua Zhang⁵, Chunquan Cai^{1

2

6}

Affiliations

¹ Tianjin Pediatric Research Institute, Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China.
² Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China.
³ Graduate College of Tianjin Medical University, Tianjin, China.
⁴ Department of Neurology, Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China.
⁵ Matsumoto Institute of Life Science (MILS) International, Yokohama, Japan.
⁶ Department of Neurosurgery, Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China.

Abstract

Introduction: Combined malonic and methylmalonic aciduria (CMAMMA) is a rare metabolic disease caused by biallelic variants in ACSF3 gene. The clinical phenotype is highly heterogeneous in this disorder, ranging from asymptomatic to severe symptoms. No cases with CMAMMA were reported in China. Materials and Methods: In this study, three Chinese pediatric patients were diagnosed with CMAMMA unexpectedly while being treated for other ailments. To better characterize CMAMMA in a Chinese population, we made a multidimensional analysis with detailed clinical phenotype, semi-quantitative detection of urine organic acid, and analysis of ACSF3 gene variants. Results: The clinical presentation of these patients is quite different; their main complaints were anemia, jaundice, or abnormal urine test, respectively. They showed no symptoms of the classic methylmalonic academia, but urine organic acid analysis showed elevated malonic acid and methylmalonic acid in all the patients repeatedly. Variants were found at four sites in ACSF3 gene. Patient 1 carried the compound heterogeneous variant c.689G> A (p.Trp230^*)/c.1456G> A (p.Ala486Thr). A compound heterozygous variant c.473C> T (p.Pro158Leu)/c.1456G> A (p.Ala486Thr) was identified in patient 2. Patient 3 harbored a novel homozygous variant c.1447A> G (p.Lys483Glu). Conclusions: Three Chinese patients were diagnosed with CMAMMA caused by ACSF3 variants. Their clinical course revealed that CMAMMA can be a benign condition that does not affect individual growth and development, but severe clinical phenotype may appear when other triggers exist. This study systematically elaborates CMAMMA in a Chinese population for the first time, broadens the spectrum of gene variant, and provides a strong basis for the etiological study of this disorder.

Keywords: ACSF3 gene; Chinese population; benign condition; combined malonic and methylmalonic aciduria; novel variant.