Hydrocephalus in cblC type methylmalonic acidemia

  • Kaihui Zhang
  • Min Gao
  • Guangyu Wang
  • Yingying Shi
  • Xiaoying Li
  • Yvqiang Lv
  • Guangye Zhang
  • Zhongtao GaiEmail author
  • Yi LiuEmail author
Original Article


Methylmalonic acidemia (MMA) is a typical type of organic acidemia caused by defects in methylmalonyl-CoA mutase or adenosyl-cobalamin synthesis. Hydrocephalus (HC), results from an imbalance between production and absorption of cerebrospinal fluid (CSF), causeing enlarged cerebral ventricles and increased intracranial pressure, is a condition that requires urgent clinical decision-making. MMA without treatment could result in brain damage. However, HC in MMA was rarely reported. In this study, 147 MMA were identified from 9117 high risk children by gas chromatography mass spectrometry (GC/MS) for organic acidurias screening in urine samples and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for amino acids detection in blood samples. Totally 10 cases with MMA and HC were determined by brain MRI/CT, as well as gene mutation testing either by high throughput sequencing or Sanger sequencing. Besides, homocysteine was also analyzed for the 10 MMA with HC. Out of them, 9 cases carry out compound heterozygous mutations or homozygous mutation in MMACHC gene, and 1 case has MUTmutation. The mutation c.609G > A in MMACHC was the most common in the cbl type patients. Although MMA has a high incidence in Shandong province of China, especially cblC type. All of the 10 patients were not correctly diagnosed before developing HC. As a result, when a child develops progressive and refractory HC, the screening for inherited metabolic diseases should be immediately conducted.


Methylmalonic academia Hydrocephalus MUT MMACHC cblC type 



This work was financially supported by the Science and technology development project of Shandong Health Department (2013WS0009) and Natural Science Training Foundation of Shandong Province (ZR2014HP051). The authors are grateful to the patients and their parents for their contribution to the study. We would like to thank SinoPath (Beijing) Medical Laboratory for technical support.

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest.


  1. Baethmann M, Wendel U, Hoffmann GF, Göhlich-Ratmann G, Kleinlein B, Seiffert P, Blom H, Voit T (2000) Hydrocephalus internus in two patients with 5,10-methylenetetrahydrofolate reductase deficiency. Neuropediatrics 31(6):314–317CrossRefGoogle Scholar
  2. Carrillo-Carrasco N, Chandler RJ, Venditti CP (2012) Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management. J Inherit Metab Dis 35(1):91–102CrossRefGoogle Scholar
  3. Devi AR, Naushad SM (2017) Targeted exome sequencing for the identification of complementation groups in methylmalonic aciduria: a south Indian experience. Clin Biochem 50(1–2):68–72CrossRefGoogle Scholar
  4. Fischer S, Huemer M, Baumgartner M, Deodato F, Ballhausen D, Boneh A, Burlina AB, Cerone R, Garcia P, Gökçay G, Grünewald S, Häberle J, Jaeken J, Ketteridge D, Lindner M, Mandel H, Martinelli D, Martins EG, Schwab KO, Gruenert SC, Schwahn BC, Sztriha L, Tomaske M, Trefz F, Vilarinho L, Rosenblatt DS, Fowler B, Dionisi-Vici C (2014) Clinical presentation and outcome in a series of 88 patients with the cblC defect. J Inherit Metab Dis 37(5):831–840CrossRefGoogle Scholar
  5. Fraser JL, Venditti CP (2016) Methylmalonic and propionic acidemias: clinical management update. Curr Opin Pediatr 28(6):682–693CrossRefGoogle Scholar
  6. Gmeiner M, Wagner H, van Ouwerkerk WJR, Senker W, Holl K, Gruber A (2018) Abdominal pseudocysts and peritoneal catheter revisions: surgical long-term results in pediatric hydrocephalus. World Neurosurg 111:e912–e920CrossRefGoogle Scholar
  7. Han B, Cao Z, Tian L, Zou H, Yang L, Zhu W, Liu Y (2016) Clinical presentation, gene analysis and outcomes in young patients with early-treated combined methylmalonic acidemia and homocysteinemia (cblC type) in Shandong province, China. Brain and Development 38(5):491–497CrossRefGoogle Scholar
  8. Han LS, Huang Z, Han F, Wang Y, Gong ZW, Gu XF (2017) Eight novel MUT loss-of-function missense mutations in Chinese patients with isolated methylmalonic academia. World J Pediatr 13(4):381–386CrossRefGoogle Scholar
  9. Huemer M, Mulder-Bleile R, Burda P, Froese DS, Suormala T, Zeev BB, Chinnery PF, Dionisi-Vici C, Dobbelaere D, Gökcay G, Demirkol M, Häberle J, Lossos A, Mengel E, Morris AA, Niezen-Koning KE, Plecko B, Parini R, Rokicki D, Schiff M, Schimmel M, Sewell AC, Sperl W, Spiekerkoetter U, Steinmann B, Taddeucci G, Trejo-Gabriel-Galán JM, Trefz F, Tsuji M, Vilaseca MA, von Kleist-Retzow JC, Walker V, Zeman J, Baumgartner MR, Fowler B (2016) Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency. J Inherit Metab Dis 39(1):115–124CrossRefGoogle Scholar
  10. Keyfi F, Talebi S, Varasteh AR (2016) Methylmalonic Acidemia diagnosis by laboratory methods. Rep Biochem Mol Biol 5(1):1–14PubMedPubMedCentralGoogle Scholar
  11. Kraemer MR, Sandoval-Garcia C, Bragg T, Iskandar BJ (2017) Shunt-dependent hydrocephalus: management style among members of the American Society of Pediatric Neurosurgeons. J Neurosurg Pediatr 20(3):216–224CrossRefGoogle Scholar
  12. Lerner-Ellis JP, Tirone JC, Pawelek PD, Dore C, Atkinson JL, Watkins D, Morel CF, Fujiwara TM, Moras E, Hosack AR, Dunbar GV, Antonicka H, Forgetta V, Dobson CM, Leclerc D, Gravel RA, Shoubridge EA, Coulton JW, Lepage P, Rommens JM, Morgan K, Rosenblatt DS (2006) Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 38(1):93–100CrossRefGoogle Scholar
  13. Lerner-Ellis JP, Anastasio N, Liu J, Coelho D, Suormala T, Stucki M, Loewy AD, Gurd S, Grundberg E, Morel CF, Watkins D, Baumgartner MR, Pastinen T, Rosenblatt DS, Fowler B (2009) Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Hum Mutat 30(7):1072–1081CrossRefGoogle Scholar
  14. Liu MY, Yang YL, Chang YC, Chiang SH, Lin SP, Han LS, Qi Y, Hsiao KJ, Liu TT (2010) Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria. J Hum Genet 55(9):621–626CrossRefGoogle Scholar
  15. Ma M, Wu M, Li Y, Wu D, Zhang B (2018) Shunt surgery for early-onset severe hydrocephalus in methylmalonic acidemia: report on two cases and review of the literature. Childs Nerv Syst 34(7):1417–1421CrossRefGoogle Scholar
  16. Pupavac M, Tian X, Chu J, Wang G, Feng Y, Chen S, Fenter R, Zhang VW, Wang J, Watkins D, Wong LJ, Rosenblatt DS (2016) Added value of next generation gene panel analysis for patients with elevated methylmalonic acid and no clinical diagnosis following functional studies of vitamin B12 metabolism. Mol Genet Metab 117(3):363–368CrossRefGoogle Scholar
  17. Radmanesh A, Zaman T, Ghanaati H, Molaei S, Robertson RL, Zamani AA (2008) Methylmalonic acidemia: brain imaging findings in 52 children and a review of the literature. Pediatr Radiol 38(10):1054–1061CrossRefGoogle Scholar
  18. Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR (1997) Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inherit Metab Dis 20(4):528–538CrossRefGoogle Scholar
  19. Rossi A, Cerone R, Biancheri R, Gatti R, Schiaffino MC, Fonda C, Zammarchi E, Tortori-Donati P (2001a) Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings. AJNR Am J Neuroradiol 22(3):554–563PubMedGoogle Scholar
  20. Rossi A, Biancheri R, Tortori-Donati P (2001b) The pathogenesis of hydrocephalus in inborn errors of the single carbon transfer pathway. Neuropediatrics 32(6):335–336CrossRefGoogle Scholar
  21. Sosvorová L, Bešťák J, Bičíková M, Mohapl M, Hill M, Kubátová J, Hampl R (2014) Determination of homocysteine in cerebrospinal fluid as an indicator for surgery treatment in patients with hydrocefalus. Physiol Res 63(4):521–527PubMedGoogle Scholar
  22. Villoria JG, Pajares S, Lopez RM, Marin JL, Ribes A (2016) Neonatal screening for inherited metabolic diseases in 2016. Semin Pediatr Neurol 23(4):257–272CrossRefGoogle Scholar
  23. Worgan LC, Niles K, Tirone JC, Hofmann A, Verner A, Sammak A, Kucic T, Lepage P, Rosenblatt DS (2006) Spectrum of mutations in Mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat 27(1):31–43CrossRefGoogle Scholar
  24. Wu LY, An H, Liu J, Li JY, Han Y, Zhou AH, Wang F, Jia JP (2017) Manic-depressive psychosis as the initial symptom in adult siblings with late-onset combined Methylmalonic aciduria and Homocystinemia, cobalamin C type. Chin Med J 130(4):492–494CrossRefGoogle Scholar
  25. Yaeger SK, Marin JR (2017) An infant diagnosed with hydrocephalus by point-of-care ultrasound. Pediatr Emerg Care 33(4):287–289CrossRefGoogle Scholar
  26. Ye B, Smerin D, Gao Q, Kang C, Xiong X (2018) High-throughput sequencing of the immune repertoire in oncology: applications for clinical diagnosis, monitoring, and immunotherapies. Cancer Lett 416:42–56CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Kaihui Zhang
    • 1
  • Min Gao
    • 1
  • Guangyu Wang
    • 2
  • Yingying Shi
    • 3
  • Xiaoying Li
    • 4
  • Yvqiang Lv
    • 1
  • Guangye Zhang
    • 1
  • Zhongtao Gai
    • 1
    Email author
  • Yi Liu
    • 1
    Email author
  1. 1.Pediatric Research InstituteQilu Children’s Hospital of Shandong UniversityJinanChina
  2. 2.Department of NeurosurgeryQilu Children’s Hospital of Shandong UniversityJinanChina
  3. 3.Department of ImagingQilu Children’s Hospital of Shandong UniversityJinanChina
  4. 4.Department of NeonatologyQilu Children’s Hospital of Shandong UniversityJinanChina

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