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European Journal of Pediatrics

, Volume 155, Issue 5, pp 398–403 | Cite as

Atypical vitamin B12-unresponsive methylmalonic aciduria in a sibship with severe progressive encephalomyelopathy: A new genetic disease?

  • E. Mayatepek
  • G. F. Hoffmann
  • R. Baumgartner
  • A. Schulze
  • C. Jakobs
  • F. K. Trefz
  • H. J. Bremer
Metabolic Diseases
  • 34 Downloads

Abstract

We report on two siblings, a girl of 7 years and a boy of 2 years, who presented in infancy with hypotonia, athetoid movements, myopathy and severe developmental delay. The progressive clinical course was characterized by ophthalmoplegia, pyramidal tract signs, loss of visual contanct and failure to thrive. The older sister died at the age of 7 years. The younger brother followed an almost identical clinical course. MRI of the brain revealed bilateral hypodensities and atrophy of the putamen. Neurophysiological investigations were consistent with peripheral neuropathy. Investigations for neurometabolic disorders in urine, plasma and CSF of both patients revealed a consistent increase of methylmalonic acid in urine, plasma and CSF as well as borderline low free GABA in CSF. Except for an inconstant elevation of lactate in the boy, metabolic acidosis, hypoglycaemia, episodic ketoacidosis, or hyperammonaemia, the usual concomitants of organoacidopathies, were absent in both children. Homocystinuria was excluded. Methylmalonic aciduria did not respond to antibiotic treatment, vitamin B12 therapy nor dietary protein restriction. Incorporation of [14C]propionate into protein in cultured fibroblasts was pathologically but inconsistently decreased. Both patients' cell lines showed only minimal response to hydroxocobalamin and normal methylmalonyl-CoA mutase activity.

Conclusion

Even though the definitive undorlying enzymatic defect in this sibship remains obscure our results suggest a new genetic disorder. This report illustrates that hitherto undescribed metabolic disorders remain to be elucidated even in long investigated areas of intermediary metabolism such as methylmalonic aciduria.

Key words

Methylmalonic aciduria Vitamin B12 GABA Cerebrospinal fluid Encephalomyelopathy 

Abbreviations

Ado-Cbl

adenosylcobalamin

GABA γ

aminobutyric acid

GC-MS

gas chromatography-mass spectrometry

OH-Cbl

hydroxocobalamin

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References

  1. 1.
    Andreula CF, De Blasi R, Carella A (1991) CT and MR studies of methylmalonic acidemia. AJNR 12:410–412Google Scholar
  2. 2.
    Bain MD, Jones M, Borrielo SP, Reed PJ, Tracey BM, Chalmers RA, Stacey TE (1988) Contribution of gut bacteria metabolism to human metabolic disease. Lancet I:1078–1079Google Scholar
  3. 3.
    Baumgartner ER (1983) Activity of the cobalamin dependent MMA-CoA mutase. In: Hall CA (ed) Methods in hematology. Churchill Livingstone, New York, pp 181–195Google Scholar
  4. 4.
    Cooper BA, Rosenblatt DS (1987) Inherited defects of vitamin B12 metabolism. Ann Rev Nutr 7:291–320Google Scholar
  5. 5.
    Fenton WA, Rosenberg LE (1995) Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1423–1449Google Scholar
  6. 6.
    Haas RH, Marsden DL, Capistrano-Estrada S, Hamilton R, Grafe MR, Wong W, Nyhan WL (1995) Acute basal ganglia infarction in propionic acidemia. J Child Neurol 10:18–22Google Scholar
  7. 7.
    Hamilton RL, Haas RH, Nyhan WL, Powell HC, Grafe MR (1995) Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions. J Child Neurol 10:25–30Google Scholar
  8. 8.
    Hoffmann G, Aramaki S, Blum-Hoffmann E, Nyhan WL, Sweetman L (1989) Quantitative analysis for organic acids in biological samples: batch isolation followed by gas chromatographic-mass spectrometric analysis. Clin Chem 35:587–595Google Scholar
  9. 9.
    Hoffmann GF, Meier-Augenstein W, Stöckler S, Surtees R, Rating D, Nyhan WL (1993) Physiology and pathophysiology of organic acids in cerebrospinal fluid. J Inherited Metab Dis 16:648–669Google Scholar
  10. 10.
    Hyland K (1993) Abnormalities of biogenic amine metabolism. J Inherited Metab Dis 16:676–690Google Scholar
  11. 11.
    Jakobs C (1989) Prenatal diagnosis of inherited metabolic disorders by stable isotope dilution GC-MS analysis of metabolites in amniotic fluid: review of four years experience. J Inherited Metab Dis 12:267–270Google Scholar
  12. 12.
    Jakobs C, Jaeken J, Gibson KM (1993) Inherited disorders of GABA metabolism. J Inherited Metab Dis 16:704–715Google Scholar
  13. 13.
    Kok RM, Howells DW, Heuvel CCM van den, Guerand WS, Thompson GN, Jakobs C (1993) Stable isotope dilution analysis of GABA in CSF using simple solvent extraction and electron-capture negative ion mass fragmentography. J Inherited Metab Dis 16:508–512Google Scholar
  14. 14.
    Mahoney MJ, Bick D (1987) Recent advances in inherited methylmalonic acidemias. Acta Paediatr Scand 76: 689–696Google Scholar
  15. 15.
    Matsui SM, Mahoney MJ, Rosenberg LE (1983) The natural course of the inherited methylmalonic acidemias. N Engl J Med 308:857–861Google Scholar
  16. 16.
    Stöckler S, Slavc I, Ebner F, Baumgartner R (1992) Asymptomatic lesions of the basal ganglia in a patient with methylmalonic aciduria. Eur J Pediatr 151:920Google Scholar
  17. 17.
    Sweetman L (1991) Organic acid analysis. In: Hommes FA (ed) Techniques in diagnostic human biochemical laboratories: a laboratory manual. Wiley-Liss Inc, New York, pp 143–176Google Scholar
  18. 18.
    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 34:277–283Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • E. Mayatepek
    • 1
  • G. F. Hoffmann
    • 1
  • R. Baumgartner
    • 2
  • A. Schulze
    • 1
  • C. Jakobs
    • 3
  • F. K. Trefz
    • 1
  • H. J. Bremer
    • 1
  1. 1.Department of General PediatricsUniversity Children's HospitalHeidelbergGermany
  2. 2.University Children's HospitalBaselSwitzerland
  3. 3.Department of PaediatricsFree University HospitalAmsterdamThe Netherlands

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