We previously described demyelination in the brain and subacute combined degeneration of the spinal cord in a patient with 5,10-methylenetetrahydrofolate reductase deficiency. To assess the role of methionine, S-adenosylmethionine, folate, and neurotransmitter amine metabolism in the demyelination process, we measured these metabolites in CSF from this patient; the findings are compared with those obtained from three patients in whom neurologic deterioration had been halted by the administration of betaine. Folate concentrations were low, and amine and biopterin metabolism were abnormal in all patients. Methionine and S-adenosylmethionine concentrations were undetectable in the first patient. In those receiving betaine, methionine concentrations were proportional to the dose administered and S-adenosylmethionine concentrations were near normal. The results provide the first evidence for an association between defective S-adenosylmethionine metabolism and demyelination in humans.

SUMMARY A 2-year-old girl with 5,10-methylenetetrahydrofolate reductase deficiency developed subacute combined degeneration of the cord and a leuco-encephalopathy which was confirmed at necropsy. Total folate concentrations in serum, red cells and CSF were markedly reduced whereas vitamin B12 concentrations were normal. In addition the patient had Parkinsonism and reduced concentrations of homovanillic acid, 5-hydroxyindoleacetic acid and total biopterins in cerebrospinal fluid. Folic acid administration was accompanied by fits and acute deterioration in the movement disorder. At necropsy the basal ganglia showed no detectable abnormality. Case report L. C. was born at term weighing 3030 g. She developed normally during the first year of life but thereafter progress slowed. She did not walk until 18 months of age and at 2 /4 years she had only 6 or 7 words and no sentences. At this age she had a febrile illness with drowsiness and over the course of three weeks developmental regression occurred. She became ataxic, stopped walking, crawling, smiling and feeding herself and became incontinent. On examination her weight and length were on the 75th centiles whereas head circumference was on the 3rd centile. Head circumference at the age of 4 months had been on the 50th centile suggesting that impaired brain growth had developed after this age. She was withdrawn, immobile and apathetic, becoming more severely hypokinetic as her disease progressed. Her expression was mostly blank but she appeared frightened when disturbed. There were fine, semi-purposeful movements in the limbs and a Parkinsonian tremor in the arms with cogwheel rigidity and pill-rolling. The movement disorder and the level of social responsiveness fluctuated by the hour. When she could be persuaded to reach out for objects there was also a marked intention tremor. Fasciculation was visible in the muscles of the thigh and tongue and gross wasting was present in the small and large muscles of all limbs. Tone was increased in the legs which were held flexed at the knee and extended at the ankle. Tendon jerks were brisk and plantar responses were extensor; in the terminal stages of the illness ankle jerks were lost. There was a normal response to painful stimuli but it was not possible to assess sensory function more precisely. The optic discs and retinae were normal in all respects and so far as it could be tested vision was 920

Deficiency of 3,B-hydroxy-A5-C27-steroid dehydrogenase, the second enzyme in the sequence that catalyses the synthesis of bile acids from cholesterol, leads to chronic liver disease in childhood as well as to malabsorption of fat and fat soluble vitamins. A 4 year old boy with this condition has been successfully treated by oral administration of a bile acid-chenodeoxycholic acid. He had been jaundiced since birth, grew poorly because of rickets, and had severe pruritus. Plasma transaminase activities were persistently raised. Chenodeoxycholic acid 125 mg twice daily for two months, and then 125 mg daily, cured his jaundice and pruritus, returned his transaminase activities to normal, and eliminated the need for calcitriol for prevention of rickets. On this treatment he has so far remained well for two years. A diagnosis of 3,-

No abstract

The second step in the pathway for synthesis of bile acids from cholesterol is catalysed by the enzyme 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase. Deficiency of this enzyme has been reported to produce cholestatic liver disease with progressive cirrhosis. Treatment with chenodeoxycholic acid led to clinical and biochemical improvement in one patient. We report a further child with this disorder who presented with prolonged neonatal jaundice followed by symptoms of malabsorption of fat-soluble vitamins. Bile acid replacement therapy resulted in clinical and biochemical improvement; it was also possible to demonstrate improvement in the histological appearance of the liver biopsy 4 months after commencing treatment.