86 Case report

REFERENCE

Van Gennip AH, Van Bree-Blom EJ, Wademan SK et al (1981) Liquid chromatography of urinary pyrimidines for the evaluation of primary and secondary abnormalities of pyrmidine metabolism. In Hawk GL, Champlin PB, Hutton RF, Mol C, eds. Biological~Biomedical Applications of Liquid Chromatography III. New York: Marcel Dekker, 285 - 296.

J. Inher. Metab. Dis. 18 (1995) 86-87 © SSIEM and Kluwer Academic Publishers. Printed in the Netherlands

CASE REPORT

Molybdenum eofaetor deficiency associated with D a n d y - W a l k e r mal format ion

G. Pintos-Morell j*, M. A. Naranjo 1, M. Artigas ~, M. Roge j, M. Rodes 2, M. J. ColF, J. L. Johnson 3 and K. V. Rajagopalan 3

~Department of Pediatrics, University Hospital 'Germans Trias i Pujol', Badalona; 2Institute of Clinical Biochemistry, Cerdanyola, Spain; ~Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, USA *Correspondence: Department of Pediatrics, University Hospital 'Germans Trias i Pujol', 08916 Badalona, Spain

Molybdenum cofactor deficiency (McKusick 252150) is an autosomal recessive disorder usually presenting in the neonatal period with intractable seizures. At present it has been well documented in more than 40 patients. The molybdenum cofactor is essential for the function of three enzymes: sulphite oxidase, xanthine dehydrogenase and aldehyde oxidase; its deficiency leads to the typical features of neonatal seizures, profound neurological abnormalit ies, abnormal facial features, ectopia lentis, urolithiasis and characteristic biochemical defects. It is still not clear whether the brain damage occurs as a result of accumulation of a toxic metabolite or perhaps because of insufficient sulphate production (Duran et al 1978; Johnson and Wadman 1989).

The case we present, a boy, was the fourth child of a Moroccan couple with first- grade consanguinity. Their first child was a healthy boy and two females died in the neonatal period; we had no further information about them. Pregnancy and delivery were uneventful and birth weight, height and head circumference were normal for gestational age. Nine days after birth the child was admitted to our hospital because the parents observed subtle myoclonies and feeding difficulties, features similar to those displayed by his two deceased sisters. The physical examination showed hypertonia, hyperreflexia, erratic eye movements and myoclonies, mainly under stimulation. Facies was coarse and somewhat hirsute. Routine laboratory investigations of blood, urine and cerebrospinal fluid, as well as lactate, pyruvate, ammonia, urine and plasma amino acids, urine organic acids, TORCH serology and cytogenetic study, showed no abnormalities. The EEG demonstrated a disorganized pattern. Brainstem auditory evoked potentials showed bilateral neurogenic hypoacusia. Non-obstructive asymmetric septal hypertrophy and permeable foramen ovale were observed in echocardiography. Cranial CT scan showed a Dandy-Walker complex (posterior fossa

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Case report 87

cystic malformation and cerebellar dysgenesis) with altered myelinization of the nuclei of the base and cystic subcortical areas, predominantly frontal. At 2.5 months he needed CSF diversion for increasing hydrocephalus and surgical intervention for bilateral inguinal herniation.

At 14 months he was admitted again, presenting acute pneumococcal pneumonia. At this time extreme hypouricaemia was observed, suggesting, together with the neurological deficit, the diagnosis of a combined deficiency of sulphite oxidase and xanthine oxidase. Two colorimetric tests for sulphite in fresh urine were positive; urine chromatographic analysis showed increased amount of taurine, thiosulphate, sulphocysteine, xanthine and hypoxanthine; urothione was not detected, while compound Z was abundant in urine, allowing the assignment of this patient to the complementation group B of molybdenum cofactor deficiency (Johnson et al 1989).

Renal ultrasonography demonstrated multiple renal calculi that were not radio- opaque, and ophthalmological examination revealed lens subtuxation. A vertebral malformation at L2 - inferior beak, - was observed in a plain radiograph, and a non- specific alteration of the normal pattern of glycosaminoglycan excretion (increased excretion of dermatan sulphate) was detected in urine. However, lysosomal enzyme studies in cultured skin fibroblasts and serum hydrolases were strictly normal. The pattern of oligosaccharide excretion in urine was normal. A diet oriented to avoid sulphur amino acid precursors was initiated, but the patient died from cardiorespiratory arrest 2 months after admission. Parents did not allow necropsy for cultural and religious considerations.

This is the first case of molybdenum cofactor deficiency described with a severe Dandy-Walker complex. The possibility of a toxic accumulated metabolite leading to a precocious CNS injury that mimics a structural malformation is very intriguing. In addition, we noted the presence of a vertebral malformation, together with asymmetric septal hypertrophy and bilateral inguinal herniation with an altered urine glycosaminoglycan excretion. Either the accumulation of sulphites or the lack of sulphate could be implicated in an abnormal mucopolysaccharide anabolism.

REFERENCES

Duran M, Beemer FA, Heiden CVD, Korteland J, De Bree PK, Brink Met al (1978) Combined deficiency of xanthine oxidase and sulphite oxidase: a defect of molybdenum metabolism or transport? J lnher Metab Dis 1: 175- 178.

Johnson JL, Wadman SK (1989) Molybdenum cofactor deficiency. In Scriver CR, Beaudet AL, Sly WS, Valle DL, eds. The Metabolic Basis o f Inherited Disease, 6th edn. New York: McGraw-Hill, 1463 - 1475.

Johnson JL, Wuebbens MM, Mandell R, Shih VE (1989) Molybdenum cofactor biosynthesis in humans. Identification of two complementation groups of cofactor deficient patients and preliminary characterization of a diffusible molybdopterin precursor. J Clin Invest 83: 897-903.

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