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Review
. 2025 Mar 31;25(1):259.
doi: 10.1186/s12887-025-05613-9.

Methylmalonic acidemia with recurrent hemophagocytic lymphohistiocytosis: a case report and review of the literature

Fumiya Yamashita  1 , Satoshi Akamine  2   3 , Pin Fee Chong  1   4 , Kenichi Maeda  1   5 , Saori Kawakami  1 , Sooyoung Lee  6   7 , Masataka Ishimura  4 , Kei Murayama  8   9 , Yasunari Sakai  4 , Ryutaro Kira  1
Affiliations
Review

Methylmalonic acidemia with recurrent hemophagocytic lymphohistiocytosis: a case report and review of the literature

Fumiya Yamashita et al. BMC Pediatr. .

Abstract

Background: Methylmalonic acidemia is a rare autosomal recessive disorder of propionate catabolism characterized by the accumulation of propionic acid and methylmalonic acid caused by methylmalonyl-CoA mutase deficiency. Clinical presentations range from acute deterioration in the neonatal period to later onset with a heterogeneous clinical course. Metabolite accumulation results in systemic involvement, affecting the nervous, gastrointestinal, and renal system functions and causing cardiomyopathy. Bone marrow dysfunction manifesting as neutropenia and anemia is a common hematological finding. Although rare, three cases of secondary hemophagocytosis were documented.

Case presentation: An 18-year-old male patient diagnosed with methylmalonic acidemia presented with vomiting and altered mental status. He had a medical history of presumably hemophagocytic lymphohistiocytosis (HLH) at the age of 17 months. Physical examination, laboratory tests, and bone marrow aspiration results met the HLH-2004 diagnostic criteria, confirming a recurrent HLH. Although he recovered after intensive treatment, his cognitive function declined. Retrospective analysis revealed higher serum levels of ferritin during acute decompensations compared with nonattack periods. Correlation analysis revealed a strong relationship between serum ferritin and propionylcarnitine, one of the major propionyl-CoA-derived metabolites.

Conclusions: HLH is a rare and underrecognized hematologic emergency in methylmalonic acidemia, and its early diagnosis and treatment are critical. Serum ferritin may be a useful clinical biomarker in the diagnosis of HLH-associated attacks in methylmalonic acidemia.

Keywords: Ferritin; Metabolic attack; Methylmalonic acidemia; Secondary hemophagocytic lymphohistiocytosis.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The studies involving human participants were reviewed and approved by the ethics committee of Fukuoka Children’s Hospital (number 2022–131). Consent for publication: Written informed consent for publication of this study was provided by the participants’ legal guardians. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Summarized pathways involving methylmalonic acidemia metabolism. A scheme showing the metabolic pathways involved in the mitochondrion. Enzymes are shown in blue characters. Boxes indicate the necessary cofactors in the metabolism. Metabolic products are shown in green characters
Fig. 2
Fig. 2
Microscopic evaluation and neuroimaging. a Light microscopic image of bone marrow aspiration shows lipid-laden macrophages and hemophagocytosis of neutrophils (arrows). b Temporal changes in the axial T2-weighted image showing the progression of brain atrophy. Arrows indicate symmetric hyperintensities in the bilateral globus pallidus
Fig. 3
Fig. 3
Clinical course and trend of serum ferritin levels. Green bars indicate the values of serum ferritin obtained during metabolic attacks, and blue bars represent the serum ferritin during nonattacks. The highest value was obtained during acute decompensation complicated by hemophagocytic lymphohistiocytosis (arrow). Line graphs show the value of metabolites concurrently obtained. Abbreviations: 3-OH-PA, 3-hydroxypropionic acid; C3, propionylcarnitine; HLH, hemophagocytic lymphohistiocytosis; MCA, methylcitric acid; MMA, methylmalonic acid; MS, mass spectrometry
Fig. 4
Fig. 4
Interrelationship between ferritin and metabolites of methylmalonic academia. a Serum ferritin levels were higher in samples obtained during metabolic attack. b Pearson correlation analysis shows the strongest correlation between ferritin and C3. Abbreviations: 3-OH-PA, 3-hydroxypropionic acid; C3, propionylcarnitine; Fer, ferritin; MCA, methylcitric acid; MMA, methylmalonic acid
See this image and copyright information in PMC

References

    1. Shibata N, Hasegawa Y, Yamada K, Kobayashi H, Purevsuren J, Yang Y, et al. Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: selective screening vs. expanded newborn screening. Mol Genet Metab Rep. 2018;16:5–10. - PMC - PubMed
    1. Haijes HA, Jans JJM, Tas SY, Verhoeven-Duif NM, van Hasselt PM. Pathophysiology of propionic and methylmalonic acidemias. Part 1: complications. J Inherit Metab Dis. 2019;42:730–44. - PubMed
    1. Gokce M, Unal O, Hismi B, Gumruk F, Coskun T, Balta G, et al. Secondary hemophagocytosis in 3 patients with organic acidemia involving propionate metabolism. Pediatr Hemat Oncol. 2012;29:92–8. - PubMed
    1. Bakshi NA, Al-Anzi T, Mohamed SY, Rahbeeni Z, AlSayed M, Al-Owain M, et al. Spectrum of bone marrow pathology and hematological abnormalities in methylmalonic acidemia. Am J Med Genet A. 2018;176:687–91. - PubMed
    1. Canna SW, Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood. 2020;135:1332–43. - PMC - PubMed

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