Abstract
This study describes a cblE type of homocystinuria associated with haemolytic-uremic syndrome (HUS) features. We report on a male infant aged 43 days presenting with failure to thrive, hypotonia, pancytopaenia, HUS symptoms (microangiopathic haemolytic anaemia and thrombocytopaenia with signs of renal involvement) and fatal evolution. An underlying cobalamin disorder was diagnosed after a bone marrow examination revealed megaloblastic changes associated with hyperhomocysteinaemia. An urinary organic acid analysis revealed normal methylmalonic acid excretion. The cblE diagnosis was confirmed with a complementation analysis using skin fibroblasts and genetic studies of the MTRR gene. The patient treatment included parenteral hydroxocobalamin, carnitine, betaine and folinic acid, but there was no response. After the autopsy, the histopathological examination of the kidneys showed marked myointimal proliferation and narrowing of the vascular lumen. The central nervous system showed signs of haemorrhage that affected the putamen and the thalamus; diffuse white matter lesions with spongiosis, necrosis and severe astrogliosis were also observed. Microangiopathy was observed with an increase in vessel wall thickness, a reduction of the arterial inner diameter and capillary oedema. The signs of necrosis and haemorrhage were detected in the cerebellum, the cerebellar peduncles, the tegmentum and the bulbar olives.
In conclusion, cblE should be considered when diagnosing patients presenting with HUS signs and symptoms during the newborn period. Despite early diagnosis, however, the specific treatment measures were not effective in this patient.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Chenel C, Wood C, Gourrier E, Zittoun J, Casadevall I, Ogier H (1993) Neonatal hemolytic-uremic syndrome, methylmalonic aciduria and homocystinuria caused by intracellular vitamin B 12 deficiency. Value of etiological diagnosis. Arch Fr Pediatr 50:749–754
Fowler B, Whitehouse C, Wenzel F, Wraith JE (1997) Methionine and serine formation in control and mutant human cultured fibroblasts: evidence for methyl trapping and characterization of remethylation defects. Pediatr Res 41:145–151
Geraghty MT, Perlman EJ, Martin LS et al (1992) Cobalamin C defect associated with hemolytic-uremic syndrome. J Pediatr 120:934–937
Giménez A, Camacho JA, Vila J et al (2008) Síndrome hemolítico-urémico. Revisión de 58 casos. An Pediatr 69:297–303
Hajjar KA (1993) Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 91:2873–2879
Kind T, Levy J, Lee M, Kaicker S, Nicholson JF, Kane SA (2002) Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period. J Pediatr Hematol Oncol 24:327–329
Labrune P, Zittoun J, Duvaltier I et al (1999) Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency. Eur J Pediatr 158:734–739
Müller P, Horneff G, Hennermann JB (2007) A rare error of intracellular processing of cobalamine presenting with microcephalus and medaloblastic anemia: a report of 3 children. Klin Pediatr 219:361–367
Noris M, Bucchioni S, Galbusera M et al (2005) Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement. J Am Soc Nephrol 16:1177–1183
Rodgers GM, Kane WH (1986) Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 77:1909–1916
Rosenblatt DS, Whitehead M (1999) Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin Hematol 36:19–34
Rosenblatt DS, Aspler AL, Shevell MI et al (1997) Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inherit Metab Dis 20:528–538
Russo P, Doyon J, Sonsino E, Ogier H, Saudubray JM (1992) A congenital anomaly of vitamin B12 metabolism: a study of three cases. Hum Pathol 23:504–512
Sharma AP, Greenberg CR, Prasad AN, Prasad C (2007) Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder. Pediatr Nephrol 22:2097–2103
Skovby F (2003) Disorders of sulfur amino acids. In: Blau N, Duran M, Blaskovics ME, Gibson KB (eds) Physician’s guide to the laboratory diagnosis of metabolic diseases. Springer-Verlag, Berlin, pp 243–260
Stamler JS, Osborne JA, Jaraki O et al (1993) Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 91:308–318
Tuchman M, Kelly P, Watkins D, Rosenblatt DS (1988) Vitamin B 12-responsive megaloblastic anemia homocystinuria and transient methylmalonic aciduria in Cbl E disease. J Pediatr 113:1052–1056
Vilaseca MA, Vilarinho L, Zavadakova P et al (2003) CblE type of homocystinuria: mild clinical phenotype in two patients homozygous for a novel mutation in the MTRR gene. J InheritMetab Dis 26:361–369
Willard HF, Ambani LM, Hart AC, Mahoney MJ, Rosenberg LE (1976) Rapid prenatal and postnatal detection of inborn errors of propionate, methylmalonate, and cobalamin metabolism: a sensitive assay using cultured cells. Hum Genet 34:277–283
Wilson A, Leclerc D, Rosenblatt DS, Gravel RA (1999) Molecular basis for methionine synthase reductase deficiency in patients belonging to the CBLE complementation group of disorders in folate/cobalamin metabolism. Hum Mol Genet 8:2009–2016
Zavadakova P, Fowler B, Zeman J, Suormala T, Pristoupilova K, Kozich V (2002) CblE type of homocystinuria due to methionine synthase reductase deficiency: clinical and molecular studies and prenatal diagnosis in two families. J Inherit Metab Dis 25:461–76
Zavadakova P, Fowler B, Suormla T et al (2005) CblE type of homocystinuria due to methionine synthase reductase deficiency: functional correction by minigene expression. Hum Mutat 25:239–247
Zimmerhackl LB, Besbas N, Jungraithmayr T et al (2006) Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin Thromb Hemost 32:113–120
Acknowledgements
The groups are funded by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) of the Instituto de Salud Carlos III, an initiative of the MICINN, Spain.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Matthias Baumgartner
Appendices
Synopsis
The vascular involvement in the kidneys and the central nervous system was demonstrated by the contribution of the cblE defect to patient mortality, despite early diagnosis and treatment.
Contribution Details
D. Palanca and J. Ortiz assisted with the clinical data collection and drafting of the manuscript. A. Garcia-Cazorla contributed to the neurological evaluation and the critical revision of the manuscript. C Jou, V. Cusí and M. Suñol interpreted the histopathological studies and assisted with the critical revision of the manuscript. T. Toll provided the differential diagnosis and assisted with the haematological data collection and the manuscript revision. B. Perez contributed to the molecular genetic analysis and interpreted the results. A. Ormazabal and R. Artuch provided the biochemical diagnosis and interpretation and assisted with the study design and drafting of the manuscript. B. Fowler assisted with the complementation studies and the interpretation of results.
Guarantor
Rafael Artuch
Conflict of Interest Statement
The authors declare no conflicts of interest.
Funding Details
The authors confirm that the study content has not been influenced by the study sponsors. Financial support was provided by CIBERER (an initiative of the Instituto de Salud Carlos III) and from the “Agència de Gestió d’Ajuts Universitaris i de Recerca-Agaur” (2009SGR00971). RA and AGC are supported by the “Intensificación de la actividad Investigadora” programme of ISCIII. BF was supported by Swiss National Foundation, grant number 320000_122568/1. All grants are competitive and public.
Ethics Approval
The parents of the infant in the index case signed an informed consent agreement in accord with the Helsinki Declaration of 1964 revised in Edinburgh in 2000. Our hospital ethics committee approved the study.
Rights and permissions
Copyright information
© 2012 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Palanca, D. et al. (2012). cblE-Type Homocystinuria Presenting with Features of Haemolytic-Uremic Syndrome in the Newborn Period. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Case and Research Reports, 2012/5. JIMD Reports, vol 8. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2012_161
Download citation
DOI: https://doi.org/10.1007/8904_2012_161
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-33432-0
Online ISBN: 978-3-642-33433-7
eBook Packages: MedicineMedicine (R0)