D. M. Danks

Cytomegalovirus in Human Milk

KNOWLEDGE of the usual modes of transmission of cytomegalovirus (CMV) infection is incomplete.1 The possibility of viral transmission from infected cervical secretions to infants at the time of del...

Early treatment of Menkes disease with parenteral Cooper-Histidine: Long-term follow-up of four treated patients

We report on the long-term clinical course of 4 boys with Menkes disease, treated from early infancy with parenteral copper-histidine, with follow-up over 10-20 years. Three of the 4 had male relatives with a severe clinical course compatible with classical Menkes disease. As a consequence of early treatment, our patients have normal or near-normal intellectual development, but have developed many of the more severe somatic abnormalities of the related disorder, occipital horn syndrome, including severe orthostatic hypotension in 2. In addition, 1 boy developed a previously unreported anomaly, namely, massive splenomegaly and hypersplenism as a consequence of a splenic artery aneurysm. Previously reported molecular studies in 2 of these patients had shown gene defects which would have predicted a truncated and probably nonfunctional gene product. Despite the favorable effects on the neurological symptoms, parenteral copper treatment for Menkes disease should still be regarded as experimental. The development of more effective treatments must await a more precise delineation of the role which the Menkes protein plays in intracellular copper trafficking.

“Cerebral” lactic acidosis: defects in pyruvate metabolism with profound brain damage and minimal systemic acidosis

Six patients are described with a combination of early onset of neurological symptoms, gross cerebral changes and elevated concentrations of pyruvate and lactate in cerebrospinal fluid. Although at least five of the six patients appear to have a generalised defect in pyruvate metabolism, reflected in deficient pyruvate dehydrogenase activity in cultured fibroblasts, systemic acidosis was not a problem clinically and blood pyruvate and lactate concentrations were only slightly raised. The localisation of significant clinical and biochemical problems to the central nervous system, coupled with the difficulties in making the diagnosis if analysis of cerebrospinal fluid (CSF) is not performed, lead us to term this condition “cerebral” lactic acidosis.

Malonyl coenzyme a decarboxylase deficiency

A patient is described with a deficiency of the mitochondrial enzyme, malonyl CoA decarboxylase — an inborn error of metabolism not recognized previously. The enzyme defect was first suspected because of persistent excretion of malonic and methylmalonic acids in urine in a child with repeated episodes of vomiting, some requiring hospitalization. Disturbances of lipid metabolism were demonstrated.

Cerebro-hepato-renal (Zellweger) syndrome, adrenoleukodystrophy, and Refsum's disease: plasma changes and skin fibroblast phytanic acid oxidase

SummaryCerebro-hepato-renal (Zellweger) syndrome, adrenoleukodystrophy, and Refsums disease patients can be divided into at least five distinct groups, according to the nature of their plasma changes and their fibroblast phytanic acid oxidase activities. The biochemical changes in the plasma vary from an increase in a single metabolite or group of structurally related metabolites, such as in X-linked adrenoleukodystrophy (ALD) and classical Refsums disease, to an increase in a number of structurally distinct metabolites, as in neonatal ALD/Zellweger syndrome, and infantile Refsums disease. All patients, with the exception of those with the X-linked form of adrenoleukodystrophy are deficient in phytanic acid oxidase activity. The great similarity observed in neonatal adrenoleukodystrophy/Zellweger syndrome and infantile Refsums disease suggests that the basic biochemical lesion in each may be similar or at least closely related.

Copper and liver disease.

There has been some limited progress in the understanding of the basic defect in Wilson disease and the gene concerned has been located to the chromosome region 13q14. Treatment with zinc has emerged as a definite alternative to penicillamine administration and some shortcomings and/or hazards of both forms of therapy have emerged as their modes of action have been studied more carefully. Tetrathimolybdate may have a place in treatment, espacially when rapid complexing of copper is important. Hepatic copper accumulation occurs in a number of cholestatic diseases and they play an important part in pathogenesis and can occasionally lead to neurological toxic effects. Copper overload in the new-born period when biliary excretion of copper is inefficient may establish a vicious cyle of copper accumulation and liver damage in Indian childhood cirrhosis and less frequently in babies in other countries.

Trimethylaminuria, fish odour syndrome: a new method of detection and response to treatment with metronidazole

SummaryTrimethylaminuria is an autosomal recessive disorder involving deficientN-oxidation of the dietary-derived amine trimethylamine (TMA). TMA, a volatile tertiary amine, accumulates and is excreted in urine of patients with deficient TMA oxidase activity. Treatment strategies for this condition are limited. We report a new stable-isotope dilution method for rapid sequential analysis of TMA concentrations and the clinical and biochemical response to treatment with metronidazole.

X-linked pyruvate dehydrogenase E1α subunit deficiency in heterozygous females : variable manifestation of the same mutation

SummaryThree female patients are described with pyruvate dehydrogenase (PDH) deficiency as a result of mutation in the X-linked gene for the E1α subunit of the complex. Two of these patients illustrate typical presentations of PDH E1α deficiency, with severe neurological dysfunction, degenerative changes and developmental anomalies in the brain, together with variable lactic acidosis. The third patient extends the known spectrum of the condition to include mild to moderate mental retardation and seizures in an adult. All three patients have the same mutation in the PDH E1α gene. This mutation, a C-to-T substitution in a CpG dinucleotide in amino acid codon 302 (designated R302C), results in the replacement of arginine by cysteine at this position. The mildly affected adult was the mother of one of the other patients, making this the first described instance of mother-to-daughter transmission of a mutation causing PDH E1α deficiency. The genetic basis of the variable expression of X-linked PDH E1α deficiency in heterozygous females is discussed.

Familial occurrence of meconium ileus

A recurrence rate for meconium ileus of 39% was found among C.F. affected siblings in a study of 488 families with at least one C.F. child born over a 24 year period. The recurrence rate was highly significant and indicated a familial trend for the occurrence of meconium ileus. The findings of the study support the existence of genetic heterogeneity in cystic fibrosis.

Dihydrofolate Reductase Deficiency Causing Megaloblastic Anemia in Two Families

To determine the cause of severe megaloblastosis detected at birth and at four weeks in two unrelated infants their bone marrow and liver cells were studied. Both patients had abnormal deoxyuridine suppression tests, corrected to normal by 5-formyl tetrahydrofolic acid. Liver-cell homogenate from one patient had a previously undetectable level of dihydrofolate reductase restored to normal by high cation concentration in the assay. Activity of the liver-cell homogenate from the other patient, which was one quarter of the normal level, was restored to only half normal activity by high cation concentration. Dihydrofolic acid reductase deficiency prevents this conversion of folic acid to tetrahydrofolic acid; the enzyme activity appears to differ in each patient. A satisfactory clinical response in both patients followed parenteral therapy with 5-formyl tetrahydrofolic acid. One sibling in each family died of a similar illness. Autosomal recessive inheritance is probable.