Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy

Orphanet Journal of Rare Diseases

Daniela Karall⁷  Matthias R Baumgartner¹  Brian Fowler⁶  Klaus Seppi²  Ronny Beer²  Ilse Kern⁴  Karine Hadaya³  Sabine Scholl-Bürgi⁷  Martina Huemer⁵ 

[1] Radiz ¿ Rare Disease Initiative Zürich, University Zürich, Zürich, Switzerland;Department of Neurology, Innsbruck Medical University, Innsbruck, Austria;Divisions of Nephrology and Transplantation, Geneva University Hospitals, Geneva, Switzerland;Pediatric Nephrology & Metabolism, Children¿s Hospital, University of Geneva, Geneva, Switzerland;Department of Pediatrics, LKH Bregenz, Bregenz, Austria;Division of Metabolic Diseases and Children¿s Research Center, University Children¿s Hospital Zürich, Zürich, Switzerland;Clinic for Pediatrics I; Inherited Metabolic Disorders, Innsbruck Medical University, Innsbruck, Austria

关键词: Pulmonary artery hypertension;    Thrombosis;    Haemolytic uraemic syndrome;    Funicular myelosis;    Myelopathy;    Psychiatric disorder;    Cobalamin;    Vitamin B12;   

Others  :  1149381
DOI  :  10.1186/s13023-014-0161-1

 received in 2014-07-02, accepted in 2014-10-09,  发布年份 2014

【 摘 要 】

Background

The cblC defect is a rare inborn error of intracellular cobalamin metabolism. Biochemical hallmarks are elevated homocysteine and low methionine in plasma accompanied by methylmalonic aciduria. Due to the heterogeneous clinical picture, patients with the late-onset form of the disease (onset >12 months) come to the attention of diverse medical specialists, e.g. paediatricians, neurologists, nephrologists, psychiatrists or haematologists. The report reviews the published clinical data and adds three new cases to raise awareness for this severe but often treatable disease.

Methods

The Pubmed and the Cochrane databases were searched for clinical reports on cblC patients and three unreported cases are presented to illustrate the clinical spectrum.

Results

Reports on 58 cases (30 females, 22 males, 6?=?no information) and the three new cases underlined the clinical heterogeneity of the disease. Time between first symptoms and diagnosis ranged from three months to more than 20 years. Haemolytic uraemic syndrome and pulmonary hypertension were main presenting symptoms in preschool children. In older children/adolescents, psychiatric symptoms, cognitive impairment, ataxia and myelopathy were frequently observed while thromboembolic events and glomerulopathies were almost exclusively seen in adults. Brain atrophy, white matter lesions and myelopathy were frequently encountered. The majority of patients showed marked biochemical and clinical response to treatment with parenteral hydroxocobalamin combined with oral betaine, folate, carnitine and rarely methionine. The course was less favourable in late treated or untreated patients.

Conclusions

The late-onset cblC defect is a rare disease and unfortunately, diagnosis is often delayed. Raising awareness for this disorder can significantly improve patients¿ outcome and perspective by timely initiation of targeted treatment. Newborn screening (NBS) for the cblC defect might be of benefit especially for late-onset patients since treatment seems efficient when initiated before irreversible organ damage. In general, inborn errors of metabolisms should be considered in unexplained medical cases at any age, especially in patients with multisystemic disease. More specifically, total homocysteine in plasma and methylmalonic acid in urine/plasma should be measured in unexplained neurologic, psychiatric, renal, haematologic and thromboembolic disease.

【 授权许可】

   
2014 Huemer et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Lerner-Ellis JP, Gradinger AB, Watkins D, Tirone JC, Villeneuve A, Dobson CM, Montpetit A, Lepage P, Gravel RA, Rosenblatt DS: Mutation and biochemical analysis of patients belonging to the cblB complementation class of vitamin B12-dependent methylmalonic aciduria. Mol Genet Metab 2006, 87(3):219-225.
• [2]Fowler B: Genetic defects of folate and cobalamin metabolism. Eur J Pediatr 1998, 157:S60-S66.
• [3]Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR: Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inherit Metab Dis 1997, 20(4):528-538.
• [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: Clinical presentation and outcome in a series of 88 patients with the cblC defect. J Inherit Metab Dis 2014, 37(5):831-840.
• [5]Morel CF1, Lerner-Ellis JP, Rosenblatt DS: Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. Mol Genet Metab 2006, 88(4):315-321.
• [6]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: Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Hum Mutat 2009, 30:1072-1081.
• [7]Wang F, Han L, Yang Y, Gu X, Ye J, Qiu W, Zhang H, Zhang Y, Gao X, Wang Y: Clinical, biochemical, and molecular analysis of combined methylmalonic academia and hyperhomocysteinemina (cblC type) in China. J Inherit Metab Dis 2010, 33(Suppl 3):S435-S442.
• [8]Weisfeld-Adams JD, Bender HA, Miley-Åkerstedt A, Frempong T, Schrager NL, Patel K, Naidich TP, Stein V, Spat J, Towns S, Wasserstein MP, Peter I, Frank Y, Diaz GA: Neurologic and neurodevelopmental phenotypes in young children with early-treated combined methylmalonic acidemia and homocystinuria, cobalamin C type. Mol Genet Metab 2013, 110(3):241-247.
• [9]Gold R, Bogdahn U, Kappos L, Toyka KV, Baumgartner ER, Fowler B, Wendel U: Hereditary defect of cobalamin metabolism (homocystinuria and methylmalonic aciduria) of juvenile onset. J Neurol Neurosurg Psychiatry 1996, 60:107-108.
• [10]Goodman SI, Moe PE, Hammond KB, Mudd HS, Uhlendorf W: Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem Med 1970, 4:500-515.
• [11]Lin HJ, Neidich JA, Salazar D, Thomas-Johnson E, Ferreira BF, Kwong AM, Lin AM, Jonas AJ, Levine S, Lorey F, Rosenblatt DS: Asymptomatic maternal combined homocystinuria and methylmalonic aciduria (cblC ) detected through low carnitine levels on newborn screening. J Pediatr 2009, 155:924-927.
• [12]Gündüz M, Ekici F, Oezaydin E, Ceylaner S, Perez B: Reversible pulmonary arterial hypertension in cobalamin-dependent cobalamin C disease due to a novel mutation in the MMACHC gene.Eur J Pediatr 2014, [Epub ahead of print]
• [13]Kömhoff M, Roofthooft MT, Westra D, Teerstra TK, Losito A, van de Kar NCAJ, Berger RMF: Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency. Pediatr 2013, 132:e540-e544.
• [14]Bouts AH, Roofthooft MTR, Salomons GS, Davin JC: CD-46 associated atypical hemolytic uremic syndrome with uncommom course caused by cblC deficiency. Pediatr Nephrol 2010, 25:2547-2548.
• [15]Van Hove JLK, Van Damme-Lombaerts R, Grünewald S, Peters H, Van Damme B, Fryns JP, Arnout J, Wevers R, Baumgartner ER, Fowler B: Cobalamin disorder Cbl-C presenting with late-onset thrombotic microangiopathy. Am J Med Gen 2002, 111:195-201.
• [16]Kilic M, Köksal Özgül R, Dursun A, Tokatli A, Kalkanoglu-Sivri HS, Anlar B, Fowler B, Coskun T: Cobalamin C defect: a patient of late-onset type with homozygous p.R132 mutation. Turkish J Pediatr 2013, 55:633-636.
• [17]Guigonis V, Fremeaux-Bacchi V, Giraudier S, Favier R, Borderie D, Massy Z, Mougenot B, Rosenblatt DS, Deschenes G: Late-onset thrombotic microangiopathy caused by CblC disease: association with a factor H mutation. Am J Kidney Dis 2005, 45:588-595.
• [18]Wang X, Sun W, Yang Y, Jia J, Li C: A clinical and gene analysis of late-onset combined methylmalonic aciduria and homocystinuria, cblC type, in China. J Neurol Sc 2012, 318:155-159.
• [19]Ben-Omran TI, Wong H, Blaser S, Feigenbaum A: Late-onset cobalamin-C disorder: a challenging diagnosis. Am J Med Genet Part A 2007, 143A:979-984.
• [20]Augoustides-Savvopoulou P, Mylonas I, Sewell AC, Rosenblatt DS: Reversible dementia in an adolescent with cblC disease: Clinical heterogeneity within the same family. J Inher Metab Dis 1999, 22:756-758.
• [21]Shinnar S, Singer HS: Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence. A treatable cause of dementia and myelopathy. NEJM 1984, 311:451-454.
• [22]Roze E, Gervais D, Demeret S, Ogier De Baulny H, Zittoun J, Benoist JF, Said G, Pierrot-Deseilligny C, Bolgert F: Neuropsychiatric disturbances in presumed late onset cobalamin C disease. Arch Neurol 2003, 60:1457-1462.
• [23]Brunelli SM, Meyers KEC, Guttenberg M, Kaplan P, Kaplan BS: Cobalamin C deficiency complicated by an atypical glomerulopathy. Pediatr Nephrol 2002, 17:800-803.
• [24]Thauvin-Robinet C, Roze E, Couvreur G, Horellou MH, Sedel F, Grabli D, Bruneteau G, Tonneti C, Masurel-Paulet A, Perennou D, Moreau T, Giroud M, Ogier De Baulny H, Giraudier S, Faivre L: The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. J Neurol Neurosurg Psychiatry 2008, 79:725-728.
• [25]Cornec-Le Gall E, Delmas Y, De Parscau L, Doucet L, Ogier H, Benoist JF, Fremeaux-Bacchi V, Le Meur Y: Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency. Am J Kidney Dis 2013, 63:119-123.
• [26]Bodamer OA, Rosenblatt DS, Appel SH, Beaudet AL: Adult-onset combined methylmalonic aciduria and homocystinuria (cblC). Neurology 2001, 56:1113.
• [27]Backe PH, Ytre-Arne M, Røhr AK, Brodtkorb E, Fowler B, Rootwelt H, Bjørås M, Mørkrid L: Novel deletion mutation identified in a patient with late-onset combined methylmalonic acidemia and homocystinuria, cblC Type. JIMD Rep 2013, 11:79-85.
• [28]Powers JM, Rosenblatt DS, Schmidt RE, Cross A, Black JT, Moser AB, Moser HW, Morgan DJ: Neurological and neuropathologic heterogeneitiy in two brothers with cobalamin C deficiency. Ann Neurol 2001, 49:396-400.
• [29]Tsai ACH, Morel CF, Scharer G, Yang M, Lerner-Ellis JP, Rosenblatt DS, Thomas JA: Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance. Am J Med Genet Part A 2007, 143A:2430-2434.
• [30]Boxer AL, Kramer JH, Jphnston K, Goldman J, Finley R, Miller BL: Executive dysfunction in hyperhomocysteinemia responds to homocysteine-lowering treatment. Neurol 2005, 64:1431-1434.
• [31]Fowler B, Whitehouse C, Wenzel F, Wraith JE: Methionine and serine formation in control and mutant human cultured fibroblasts: evidence for methyl trapping and characterization of remethylation defects. Pediatr Res 1997, 41(1):145-151.
• [32]Richard E, Jorge-Finnigan A, Garcia-Villoria J, Merinero B, Desviat LR, Gort L, Briones P, Leal F, Pérez-Cerdá C, Ribes A, Ugarte M, Pérez B: Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Hum Mutat 2009, 30(11):1558-1566.
• [33]Nogueira C, Aiello C, Cerone R, Martins E, Caruso U, Moroni I, Rizzo C, Diogo L, Leão E, Kok F, Deodato F, Schiaffino MC, Boenzi S, Danhaive O, Barbot C, Sequeira S, Locatelli M, Santorelli FM, Uziel G, Vilarinho L, Dionisi-Vici C: Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. Mol Genet Metab 2008, 93(4):475-480.
• [34]Surtees R: Demyelination and inborn errors of the single carbon transfer pathway. Eur J Pediatr 1998, 157(2):S118-S121.
• [35]Bodamer OA, Sahoo T, Beaudet AL, O¿Brien WE, Bottiglieri T, Stöckler-Ipsiroglu S, Wagner C, Scaglia F: Creatine metabolism in combined methylmalonic aciduria and homocystinuria. Ann Neurol 2005, 57(4):557-560.
• [36]Martinelli D, Deodato F, Dionisi-Vici C: Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis 2011, 34:127-135.
• [37]Kölker S, Sauer SW, Hoffmann GF, Müller I, Morath MA, Okun JG: Pathogenesis of CNS involvement in disorders of amino acid and organic acid metabolism. J Inherit Metab Dis 2008, 31(2):194-204.
• [38]Zsengellér ZK, Aljinovic N, Teot LA, Korson M, Rodig N, Sloan JL, Venditti CP, Berry GT, Rosen S: Methylmalonic acidemia: a megamitochondrial disorder affecting the kidney.Pediatr Nephrol 2014, [Epub ahead of print]
• [39]Sedel F, Baumann N, Turpin JC, Lyon-Caen O, Saudubray JM, Cohen D: Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inher Metab Dis 2007, 30:631-641.
• [40]Herrmann W, Schorr H, Bodis M, Knapp JP, Müller A, Stein G, Geisel J: Role of homocysteine, cystathionine and methylmalonic acid measurement for diagnosis of vitamin deficiency in high-aged subjects. Eur J Clin Invest 2000, 30(12):1083-1089.
• [41]Iqbal N, Azar D, Yun YM, Ghausi O, Ix J, Fitzgerald RL: Serum methylmalonic acid and holotranscobalamin-II as markers for vitamin B12 deficiency in end-stage renal disease patients. Ann Clin Lab Sci 2013, 43(3):243-249.
• [42]Debreceni B, Debreceni L: The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease. Cardiovasc Ther 2014, 32(3):130-138.
• [43]Malouf R, Grimley Evans J: No evidence that folic acid with or without vitamin B12 improves cognitive function of unselected elderly people with or without dementia. Long-term supplementation may benefit cognitive function of healthy older people with high homocysteine levels.Cochrane Database 2009, Published Online.
• [44]Zhang C, Chi FL, Xie TH, Zhou YH: Effect of B-vitamin supplementation on stroke: a meta-analysis of randomized controlled trials. PLoS One 2013, 25(8(11)):e81577.
• [45]Taylor CM, Machin S, Wigmore S: Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 2010, 148:37-47.