J Korean Med Sci.  2023 Nov;38(45):e387. 10.3346/jkms.2023.38.e387.

Combined Malonic and Methylmalonic Aciduria Diagnosed by Recurrent and Severe Infections Mimicking a Primary Immunodeficiency Disease: A Case Report

• Lee JK
• Oh A

• KMID: 2547985
• DOI: http://doi.org/10.3346/jkms.2023.38.e387

Abstract

Combined malonic and methylmalonic aciduria is a rare genetic disorder caused by ACSF3 biallelic variants that results in impaired protein and fat metabolism and the accumulation of malonic and methylmalonic acids. A 52-day-old infant with a fever and a history of possible meningitis during the neonatal period was hospitalized. Multiple lesions of necrotizing lymphadenitis with abscesses in the left inguinal area were treated by incision and drainage along with appropriate antibiotic therapy, which revealed a methicillin-resistant Staphylococcus aureus infection. At 6 months of age, the patient was admitted with anal abscesses. Due to the increased suspicion of primary immunodeficiency disease, genetic testing was conducted, which revealed ACSF3 biallelic variants inherited from both parents. Urine organic acid analysis revealed elevated levels of malonic and methylmalonic acids. At 29 months, the patient showed normal growth and development without any dietary modifications. He had occasional colds, but severe bacterial infections were absent. The prognosis suggests a benign disease course. Here, we present the first reported case of ACSF3 compound heterozygote variants in Korea.

Keyword

Combined Malonic and Methylmalonic Aciduria; Methylmalonic Aciduria; Primary Immunodeficiency Disease

Figure

• 

  Fig. 1 Computed tomography images of multiple intra-abdominal abscesses (arrows) in an infant diagnosed with combined malonic and methylmalonic aciduria. The size of the largest abscess in the left inguinal area was 26.10 mm.

• 

  Fig. 2 Patient’s family pedigree and Sanger sequencing results of the patient’s parents. The patient was found to have inherited a compound heterozygous type of mutation, receiving different mutations from each parent.

Reference

1. Witkowski A, Thweatt J, Smith S. Mammalian ACSF3 protein is a malonyl-CoA synthetase that supplies the chain extender units for mitochondrial fatty acid synthesis. J Biol Chem. 2011; 286(39):33729–33736. PMID: 21846720.

2. Gregg AR, Warman AW, Thorburn DR, O’Brien WE. Combined malonic and methylmalonic aciduria with normal malonyl-coenzyme A decarboxylase activity: a case supporting multiple aetiologies. J Inherit Metab Dis. 1998; 21(4):382–390. PMID: 9700595.

3. Sloan JL, Johnston JJ, Manoli I, Chandler RJ, Krause C, Carrillo-Carrasco N, et al. Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria. Nat Genet. 2011; 43(9):883–886. PMID: 21841779.

4. Alfares A, Nunez LD, Al-Thihli K, Mitchell J, Melançon S, Anastasio N, et al. Combined malonic and methylmalonic aciduria: exome sequencing reveals mutations in the ACSF3 gene in patients with a non-classic phenotype. J Med Genet. 2011; 48(9):602–605. PMID: 21785126.

5. Levtova A, Waters PJ, Buhas D, Lévesque S, Auray-Blais C, Clarke JT, et al. Combined malonic and methylmalonic aciduria due to ACSF3 mutations: Benign clinical course in an unselected cohort. J Inherit Metab Dis. 2019; 42(1):107–116. PMID: 30740739.

6. de Sain-van der Velden MG, van der Ham M, Jans JJ, Visser G, Prinsen HC, Verhoeven-Duif NM, et al. A new approach for fast metabolic diagnostics in CMAMMA. JIMD Rep. 2016; 30:15–22. PMID: 26915364.

7. McLaughlin BA, Nelson D, Silver IA, Erecinska M, Chesselet MF. Methylmalonate toxicity in primary neuronal cultures. Neuroscience. 1998; 86(1):279–290. PMID: 9692761.

8. Wang P, Shu J, Gu C, Yu X, Zheng J, Zhang C, et al. Combined malonic and methylmalonic aciduria due to ACSF3 variants results in benign clinical course in three Chinese patients. Front Pediatr. 2021; 9:751895. PMID: 34900860.

9. Tucci S. Brain metabolism and neurological symptoms in combined malonic and methylmalonic aciduria. Orphanet J Rare Dis. 2020; 15(1):27. PMID: 31969167.

10. Epping M, Wang C, Manoli I, Fraser J, Gomez-Rodriguez J, Elliot G, et al. A knock-out mouse model of CMAMMA (ACSF3 deficiency) displays neurological phenotype and methylmalonic acidemia. In : The 65th Annual Meeting of the American Society of Human Genetics; Oct 6-Oct 10, 2015; Baltimore, MD, USA. Rockville, MD, USA: American Society of Human Genetics;2015.