Cobalamin (Cbl) C/D Deficiency: Clinical, Neurophysiological and Neuroradiologic Findings in 14 Cases

The early onset type of cobalamin (Cbl) C/D deficiency is characterised by feeding difficulties, failure to thrive, hypotonia, seizures, microcephaly and developmental delay. It has an unfavourable outcome, often with early death and significant neurological impairment in survivors. While clinical and biochemical features of Cbl C/D deficiency are well known, only a few isolated case reports are available concerning neurophysiological and neuroimaging findings. We carried out clinical, biochemical, neurophysiological and neuroradiologic investigations in 14 cases with early-onset of the Cbl C/D defect. Mental retardation was identified in most of the cases. A variable degree of supratentorial white matter atrophy was detected in 11 cases by MR imaging and tetraventricular hydrocephalus was present in the remaining 3 patients. Waking EEG showed a clear prevalence of epileptiform abnormalities, possibly related to the high incidence of seizures in these cases. Increased latency of evoked responses and/or prolongation of central conduction time were the most significant neurophysiological abnormalities. The selective white matter involvement, shown both by neuroradiologic and neurophysiological studies, seems to be the most consistent finding of Cbl C/D deficiency and may be related to a reduced supply of methyl groups, possibly caused by the dysfunction in the methyl-transfer pathway.

Key words

Methylmalonic aciduria - Homocystinuria - Magnetic resonance imaging - Magnetic resonance angiography - Neurophysiological investigations

References

• 1 Baumgartner E R, Wick H, Maurer R, Egli N, Steinmann B. Congenital defect in intracellular cobalamin metabolism resulting in homocystinuria and methylmalonic aciduria.  Helv Paediat Acta. 1979;  34 465-482
• 2 Bellini C, Cerone R, Bonacci W, Caruso U, Magliano C P, Serra G. et al . Biochemical diagnosis and outcome of 2 years treatment in a patient with combined methylmalonic aciduria and homocystinuria.  Eur J Pediatr. 1992;  151 818-820
• 3 Brandstetter Y, Weinhouse E, Splaingard M L, Tang T T. Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (Cbl-C type).  Am J Med Genet. 1990;  36 167-171
• 4 Caruso U, Lupino S, Schiaffino M C, Romano C. Capillary GC-MS stable isotope dilution of methylmalonic acid in plasma: a candidate reference method for the diagnosis and the follow-up of methylmalonic acidaemias.  Chromatographia. 1993;  36 212-214
• 5 Cerone R, Schiaffino M C, Caruso U, Lupino S, Gatti R. Minor facial anomalies in combined methylmalonic aciduria and homocystinuria due to defect in cobalamin metabolism.  J Inher Metab Dis. 1999;  22 247-250
• 6 Engelbrecht V, Rassek M, Huismann J, Wendel U. MR and proton MR spectroscopy of the brain in hyperhomocysteinemia caused by methylenetetrahydrofolate reductase deficiency.  AJNR. 1997;  18 536-539
• 7 Enns G M, Barkovich A J, Rosenblatt D S, Frederick D R, Weisiger K, Ohnstad C. et al . Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin.  J Inher Metab Dis. 1999;  22 599-607
• 8 Fowler B, Whitehouse C, Wenzel F, Wraith J E. Methionine and serine formation in control and mutant human cultured fibroblasts: Evidence for methyl group trapping and characterisation of remethylation defects.  Pediat Res. 1997;  41 145-151
• 9 Fowler B, Jakobs C. Post- and prenatal diagnostic methods for the homocystinurias.  Eur J Pediatr. 1998;  157 (Suppl 2) S88-S93
• 10 Fowler B. Genetic defects of folate and cobalamin metabolism.  Eur J Pediatr. 1998;  157 (Suppl 2) S60-S66
• 11 Geraghty M T, Perlman E J, Martin L S, Hayflick S J, Casella J F, Rosenblatt D S. et al . Cobalamin C defect associated with hemolytic-uremic syndrome.  J Pediatr. 1992;  120 934-937
• 12 Greitz D, Greitz T. The pathogenesis and hemodynamics of hydrocephalus.  Int J Neuroradiol. 1997;  3 367-375
• 13 Mamlok R J, Isenberg J N, Rassin D K. A cobalamin metabolic defect with homocystinuria, methylmalonic aciduria and macrocytic anemia.  Neuropediatrics. 1986;  17 94-99
• 14 Mitchell G A, Watkins D, Melançon S B, Rosenblatt D S, Geoffroy G, Orquin J. et al . Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria.  J Pediatr. 1986;  108 410-415
• 15 Ogier de Baulny H, Gérard M, Saudubray J M, Zittoun J. Remethylation defects: guidelines for clinical diagnosis and treatment.  Eur J Pediatr. 1998;  157 (Suppl 2) S77-S83
• 16 Raybaud C, Girard N. Anatomic MRI study of commissural agenesis and dysplasia of the telencephalon (Agenesis of the corpus callosum and related anomalies). Clinical correlations and morphogenetic interpretation.  Neurochirurgie. 1998;  44 (Suppl 1) 38-60
• 17 Ribes A, Briones P, Vilaseca M A, Lluch M, Rodes M, Maya A. et al . Methylmalonic aciduria and homocystinuria: biochemical studies, treatment, and clinical course of a Cbl-C patient.  Eur J Pediatr. 1990;  149 412-415
• 18 Rosenblatt D S, Aspler A L, Shevell M I, Pletcher B A, Fenton W A, Seashore M R. Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC).  J Inher Metab Dis. 1997;  20 528-538
• 19 Scriver C R, Beaudet A L, Sly W S, Valle D. The metabolic and molecular bases of inherited disease, 7th ed. New York; McGraw-Hill 1995
• 20 Shinnar S, Singer H S. Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence. A treatable cause of dementia and myelopathy.  New Engl J Med. 1984;  311 451-454
• 21 Surtees R, Leonard J, Austin S. Association of demyelination with deficiency of cerebrospinal-fluid S-adenosylmethionine in inborn errors of methyl-transfer pathway.  Lancet. 1991;  338 1550-1554
• 22 Surtees R. Biochemical pathogenesis of subacute combined degeneration of the spinal cord and brain.  J Inher Metab Dis. 1993;  16 762-770
• 23 Surtees R. Demyelination and inborn errors of the single carbon transfer pathway.  Eur J Pediatr. 1998;  157 (Suppl 2) S18-S21
• 24 Traboulsi E I, Silva J C, Geraghty M T, Maumenee I H, Valle D, Green W R. Ocular histopathologic characteristics of cobalamin C type vitamin B₁₂ defect with methylmalonic aciduria and homocystinuria.  Am J Ophthalmol. 1992;  113 269-280
• 25 van der Knaap M S, Valk J. Magnetic resonance of myelin, myelination, and myelin disorders. 2nd Edition. Berlin, Heidelberg; Springer 1995