Clinical characteristics and genotype analysis of five infants with cblX type of methylmalonic acidemia

Zhejiang Da Xue Xue Bao Yi Xue Ban. 2022 Jun 25;51(3):298-305. doi: 10.3724/zdxbyxb-2022-0194.


Objective: To investigate the clinical and genetic characteristics of infants with cobalamin (cbl) X type of methylmalonic acidemia (MMA).

Methods: The clinical data of 5 infants with cblX type of MMA diagnosed in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine and Shanghai Children's Hospital from the year 2016 to 2020 were collected. The levels of blood acylcarnitines were detected by tandem mass spectrometry, the levels of urinary organic acids were detected by gas-chromatography mass spectrometry, the pathogenic genes were detected by whole exon gene sequencing, and the effect of new pathogenic mutations on three-dimensional protein structure was predicted by bioinformatics analysis.

Results: Five infants with cblX type were diagnosed, including 4 males and 1 female, and the onset age was 0-6 months. The main clinical manifestations of 4 males were intractable epilepsy, mental and motor retardation, metabolic abnormalities presented mild increase of blood homocysteine level. Among them, 3 cases were accompanied by slight increase of urinary methylmalonic acid, and 1 case was accompanied by increase of blood propionylcarnitine (C3) and C3/acetylcarnitine (C2). Gene detection found that 2 cases carried a same hemizygous mutation c.344C>T (p.A115V) of HCFC1 gene, which was the most reported mutation, and the other 2 cases carried novel pathogenic mutations, c.92G>A (p.R31Q) and c.166G>C (p.V56L). These 3 gene mutations located in the Kelch domain of HCFC1 protein. One female infant carried a benign mutation of c.3731G>T (p.R1244L). Her clinical symptoms were mild, and only the urinary methylmalonic acid was slightly increased.

Conclusions: The clinical manifestations of children with cblX type of MMA are intractable epilepsy, mental and motor retardation, and other serious neurological symptoms. Their metabolic abnormalities present the increase of blood homocysteine with methylmalonic acid (urinary methylmalonic acid or/and blood C3, C3/C2). The clinical and biochemical phenotypes are separated, so the diagnosis should be in combination with the results of gene testing.

Keywords: Cobalamin X type; Homocysteine; Host cell factor C1; Methylmalonic acidemia; X-linked.

MeSH terms

  • Acetylcarnitine
  • Amino Acid Metabolism, Inborn Errors
  • China
  • Drug Resistant Epilepsy*
  • Female
  • Genotype
  • Homocysteine
  • Host Cell Factor C1
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Methylmalonic Acid* / urine
  • Vitamin B 12


  • Host Cell Factor C1
  • Homocysteine
  • Acetylcarnitine
  • Methylmalonic Acid
  • Vitamin B 12

Supplementary concepts

  • Methylmalonic acidemia

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