Derek A. Applegarth

The high incidence of valproate hepatotoxicity in infants may relate to familial metabolic defects.

The incidence of fatal hepatic failure associated with valproic acid (VPA) therapy is highest in children under the age of three years, particularly in those with developmental delay. The pathogenesis of VPA hepatotoxicity is unclear but may relate to the accumulation of a toxic metabolite of VPA which impairs fatty-acid oxidation. We describe two unrelated infants with developmental delay who developed hepatic failure while receiving VPA. Siblings of both children subsequently developed hepatic steatosis and intractable seizures without being exposed to VPA. This suggests that the two children who developed liver failure when receiving VPA may have had a familial metabolic disorder. Familial metabolic disorders may account partly for the higher incidence of fatal hepatotoxicity described in infants receiving VPA.

Biochemical investigation of a child with molybdenum cofactor deficiency

A girl aged eight months, who presented with developmental delay and dislocated optic lenses, was diagnosed as having combined sulfite oxidase and xanthine dehydrogenase deficiencies consistent with molybdenum cofactor deficiency. The diagnosis was confirmed by demonstrating the absence in urine of urothione, a molybdenum cofactor metabolite. Prenatal diagnosis excluded the disease in the mothers second pregnancy. A summary of an in vitro study of molybdenum cofactor synthesis in the patient is given.

Pseudoarylsulfatase-A deficiency in the neurologically impaired patient.

The demonstration of low arylsulfatase-A (ASA) activity in leucocytes or fibroblasts is used often to establish the diagnosis of metachromatic leucodystrophy (MLD). However, low ASA activity is observed also in pseudo-ASA deficiency which may be as common as MLD. We report two patients with pseudo ASA deficiency who had abnormal neurological findings consistent with atypical MLD. Because the measurement of ASA activity is neither a sensitive nor specific method with which to establish a diagnosis of MLD, this diagnosis should be confirmed by nerve biopsy, measurement of urinary sulfatide or a cerebroside sulfate loading test, using cultured fibroblasts.

Isolation of pure, active α2 macroglobulin from small-scale plasma samples

Abstract Physiologically “active” α2 macroglobulin (α2M) of at least 98% purity can be isolated in high yield from small-scale plasma samples regardless of plasma haptoglobin type. The technique described herein, involving cibacron blue sepharose chromatography and immunoadsorption is suitable for purification of α2M from plasma samples of 5 ml.

Free and total serum valproate concentrations: their relationship to seizure control, liver enzymes and plasma ammonia in children.

The relationships between total and free serum valproate (VPA) concentrations and seizure control, serum liver enzyme activity and plasma ammonia concentration were studied in 61 epileptic children. Enzyme-immunoassay (EMIT)R methods gave higher values of total VPA concentration than gas-liquid chromatography (GLC) methods. In over 80% of children with complete seizure control the ranges of total VPA concentration were 140-420 mumol/L with GLC methods and 210-560 mumol/L with EMIT methods. The range of free VPA concentrations in 78% of children with complete seizure control was 8.8-26.4 mumol/L. Increased liver enzyme activity was observed in 6 of the 61 children and raised plasma ammonia concentration in 11 of 50 children. Plasma ammonia concentration was related to total serum VPA but was not related to free serum VPA. Increased serum liver enzyme activity was related to VPA dose per kg but not to free or total serum VPA concentration. Thus free VPA concentrations do not appear to be more useful than total VPA concentrations in predicting seizure control and do not correlate with liver enzyme activity or plasma ammonia concentration.

Protease binding by α2 macroglobulin in cystic fibrosis

Abstract The interaction of α 2 macroglobulin (α 2 M) with exogenous proteases has been reported by others to be abnormal in cystic fibrosis (CF). We have re-examined these claims. Four parameters were considered: (1) the molar protease binding of α 2 M; (2) the interaction of bovine cationic trypsin (BCT), complexed to α 2 M, with low molecular mass substrate, benzoyl arginine ethyl ester (BAEE); (3) the stability of formed α 2 M-BCT complexes; and (4) the subunit structure of α 2 M. We have found CF α 2 M to be similar to control α 2 M in every respect studied.

The influence of anticonvulsants on fasting plasma ammonia and amino acid levels

We examined fasting levels of plasma ammonia, glutamine, glycine, and ornithine in patients taking three anticonvulsants - phenobarbital, carbamazepine and valproic acid. Contrary to previous reports no striking abnormalities were seen.

Assessment of protease-binding by α2 macroglobulin in multiple sclerosis

Abstract Following reports that α 2 -macroglobulin ( α 2 M) is abnormal in multiple sclerosis (MS), we assessed the interaction of α 2 M with a model protease bovine cationic trypsin. Two parameters were investigated: (1) the binding of α 2 M to trypsin, and (2) the ability of the trypsin- α 2 M complexes to hydrolyze benzoyl arginine ethyl ester. In both respects, MS α 2 M was found to be similar to control α 2 M.