S U M M A R Y1. Evidence of deficiency of, antagonism to, or abnormal dependency upon pyridoxine has been sought in four patients with primary hyperoxaluria. The urinary excretion of kynurenine, 3-hydroxykyurenineY 3-hydroxyanthranilic acid, kynurenic acid and xanthurenic acid, before and after a loading dose of L-tryptophan was used to assess pyridoxine nutrition.2. Three of the four patients studied had abnormal L-tryptophan metabolite excretion patterns, but these were not of the type which is associated with abnormalities of pyridoxine nutrition.3. The changes which were observed are compatible with impaired conversion of kynurenine to 3-hydroxykynurenine by the NADH, dependent kynurenine 3-hydroxylase (EC 1.99.1.5) enzyme system. 4. Large doses of pyridoxine hydrochloride reduced the urinary oxalate excretion by two of the patients to levels which were intermediate between the normal range and the pre-treatment values. This effect was maintained for 6 months, which was the longest period of observation. 5.It is concluded that this action of pyridoxine is mediated by a mechanism which does not involve the correction of an abnormality of pyridoxine metabolism.Primary hyperoxaluria, in which calcium oxalate urolithiasis is accompanied by an elevated urinary oxalate excretion, accounts for only a small proportion of patients with calcium oxalate urinary stones. The urinary oxalate excretion is increased in severe experimentally induced pyridoxine deficiency in man (Faber et al., 1963) as well asin animals (Gershoff et al., 1959a; Andrus, Gershoff k Faragella, 1959), andGershoff, Mayer &Kulczycki (1959b) reported that pyridoxine reduced the urinary oxalate excretion of a group of institutionalized mental defectives who were not taking a pyridoxine deficient diet.Mayer et al. (1968) implicated pyridoxine deficiency as a factor in the causation of calcium

SUMMARY Biochemical and pathological observations on tissues from two patients with Hurler disease (mucopolysaccharidosis IH; a-L-iduronidase deficiency) who had been treated by fibroblast transplants as a means of enzyme replacement treatment are reported.These results and those obtained in three surgical specimens [ligamentum flavum with dura mater from a case of Scheie disease (mucopolysaccharidosis IS; a-L-iduronidase deficiency); a fetus with Hurler disease; and tonsil from a patient with Hunter disease (mucopolysaccharidosis II; a-L-idurono-2-sulphate sulphatase deficiency)] illustrate the inadequacy of routine histological processing to demonstrate the abnormal glycosaminoglycan accumulation in this group of diseases. A combined approach using histochemistry and electron microscopy enables the extent of both extracellular and intracellular involvement to be assessed. The fetus (20 wk gestation) already showed evidence of Hurler disease.The pathological appearances in both of the fibroblast-transplanted patients were those which would have been expected in patients dying with unmodified Hurler disease. There was no detectable a-L-iduronidase activity in the brain, liver, kidney or in fibroblasts cultured from either the transplantation sites or from remote subcutaneous sites in either of the transplanted patients.These results are discussed from the viewpoint of their bearing on the pathophysiology of the mucopolysaccharidoses and proposals for their treatment by enzyme replacement.

We report on a family with a sibship of three children for whom the diagnosis of "an unusual form of metachromatic leukodystrophy (MLD)" had been suggested earlier. The patients had choreiform movements and dystonic posturing accompanied by dysarthria since childhood. The availability of the polymerase chain reaction enabled us to show that the three siblings have a pseudodeficiency genotype (ASAp/ASAp). There was no abnormal sulphatiduria, and we propose that the neurological disease and low arylsulphatase A activity are unrelated to one another in this family. A diagnosis of MLD carries very serious implications, and we recommend that gene amplification by polymerase chain reaction and hybridization with allele-specific oligonucleotide probes should be used to corroborate the diagnosis, especially when there is no abnormal sulphatiduria and when metachromatic material cannot be demonstrated in a sural nerve biopsy.

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1. The enzymic oxidation of glyoxylate to oxalate in the soluble (100 000 g supernatant) fraction of liver and heart tissue from a patient with primary hyperoxaluria and from a non-hyperoxaluric subject have been studied.2. An oxidized nicotinamide-adenine dinucleotide (NAD f)-dependent and a non-NAD+-dependent oxidation of glyoxylate to oxalate were observed in the liver tissue from both sources.3. Evidence is presented that lactate dehydrogenase has a major role in catalysing the reaction in both of the tissues studied. The non-NAD+-dependent oxidations which are catalysed by xanthine oxidase and glycollate oxidase in the liver are relatively unimportant, and they were not detected in the heart.4. An enzyme that catalyses the oxidation of glycollate was also demonstrated in liver tissue. This had a different electrophoretic mobility from the lactate dehydrogenase isoenzymes.5. These findings are discussed with particular reference to human primary hyperoxaluria in which excessive oxalate synthesis occurs.

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This paper reports the clinical and biochemical results in six patients with Hurler disease (Mucopolysaccharidosis IH; McKusick 25280), two patients with Hunter disease (Mucopolysaccharidosis II; McKusick 25285) and one patient with Sanfilippo B disease (Mucopolysaccharidosis IIIB; McKusick 25292) who were treated by fibroblast transplantation. Except for one patient who died for a coincidental reason, the patients have been studied for between 2.5 and 4.5 years. The clinical course of the disease was not materially altered. There was no evidence that the patients had developed immune responses against the transplanted fibroblasts. Transplantation did not produce measurable levels of either alpha-L-iduronidase (EC 3.2.1.76) in the leukocytes from patients with Hurler disease or of N-acetyl-alpha-D-glucosaminidase (EC 3.2.1.50) in the plasma of the patients with Sanfilippo B disease. Under the conditions used for the assay, leukocytes from the patients with Hunter disease had detectable levels of residual alpha-L-idurono-2-sulphate sulphatase activity which were increased after the transplants, although these changes were of inconstant size and their time course was not consistently related to the transplantations. Cytogenetic studies in cases where the donor was of the opposite sex detected only cells of the recipient's sex among the fibroblasts grown from biopsies of the transplantation sites. The technique used would have detected a donor to recipient cell ratio of 1:100. We found no consistent long-term trends in the excretion patterns of glycosaminoglycans and oligosaccharides from either a quantitative or qualitative point of view which could be specifically related to the transplantation. The combined administration of immunosuppressive doses of prednisolone and azathioprine was associated with an increased excretion of the lower molecular weight glycosaminoglycans. We conclude that fibroblast transplantation is not therapeutically useful in the diseases studied.

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