Antenatal diagnosis of inborn errors of metabolism.
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Amniocentesis↗
Biomedical subjects
J E Wraith
Publications and source records attributed to J E Wraith.
No sensory neuropathy during pyridoxine treatment in homocystinuria.
Seventeen patients with cystathionine synthase deficiency homocystinuria were examined clinically and neurophysiologically for evidence of sensory neuropathy. All had received high dose pyridoxine (vitamin B-6) for many years. Absence of neurological disturbance in all cases suggests long term treatment with pyridoxine in the dosages used in homocystinuric patients is not harmful.
Adolescent↗
Geleophysic dysplasia.
We describe 2 children with geleophasic dysplasia. Prominent cardiac disease in one of the patients caused death at an early age. The history of consanguinity in one of the families supports autosomal recessive mode of inheritance. Histological and ultrastructural changes suggest that a disturbance in the relations between cell membrane and extracellular matrix may be involved in the pathogenesis.
Abnormalities, Multiple↗
Carpal tunnel syndrome in the mucopolysaccharidoses and related disorders.
Eighteen patients with various mucopolysaccharidoses or mucolipidosis III were studied electrophysiologically to determine the presence or absence of carpal tunnel syndrome. In 17 patients this was clearly demonstrated, the only exception being a boy with mucopolysaccharidosis II, age 6 months at testing. All patients had a remarkable lack of symptoms. Carpal tunnel syndrome is a very common complication of the mucopolysaccharidoses and mucolipidosis III and should be actively looked for in affected patients. Early diagnosis and treatment offer the best chance of a good response to surgery.
Adolescent↗
A clinician's view of the mass screening of the newborn for inherited diseases: current practice and future considerations.
The case for or against mass screening for inherited diseases is discussed. There is universal acceptance for mass screening for phenylketonuria and congenital hypothyroidism. The case for mass screening for galactosaemia and for maple syrup urine disease is not very strong; they could be considered under the heading of 'urgent screening of the sick newborn'. It is difficult to find good arguments for mass screening for congenital adrenal hyperplasia. For screening for glucose-6-phosphate dehydrogenase deficiency and sickle cell disease, the established criteria for mass screening do not apply. A simple tool for early detection is now available and the population afflicted with a mutant gene which causes major health problems should receive special attention from its government. It is too early to offer any comment about cystic fibrosis screening; further developments must be awaited.
Cystic Fibrosis↗
Diagnosis and management of inborn errors of metabolism.
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Humans↗
Sulfite oxidase deficiency: clinical, neuroradiologic, and biochemical features in two new patients.
Sulfite oxidase deficiency is characterized by severe neurologic dysfunction, dislocation of the lenses, and the accumulation and excretion of inorganic sulfite, thiosulfate, and S-sulfocysteine. We present the clinical, radiologic, and biochemical findings in two patients with this condition. In both, neurologic problems started soon after birth and progressed rapidly to profound mental retardation, microcephaly, blindness, and spastic quadriparesis. Seizures were a persistent problem throughout the course of their illness. The neurologic abnormalities were associated with progressive destruction of brain tissue. We established the diagnosis of sulfite oxidase deficiency by demonstrating the characteristic abnormal metabolites in urine. However, commonly used screening procedures do not detect these compounds, and dislocation of the lenses is usually a late feature of the disease. As a result, the diagnosis may be easily overlooked, especially during infancy. Specific investigations for sulfite oxidase deficiency are indicated for any baby with severe, progressive neurologic disease.
Atrophy↗
Maternal phenylketonuria: successful outcome in four pregnancies treated prior to conception.
The management of four pregnancies in two phenylketonuric women is described. A successful outcome in these pregnancies is ascribed to the initiation of treatment prior to conception and the maintenance of tight control with serum phenylalanine between 100 and 400 mumol/l throughout the gestation period. A trial of diet is desirable before a decision is made about pregnancy and before contraception is ceased. Close contact must be maintained with female phenylketonurics throughout their reproductive life to ensure that this process is followed.
Child↗
"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.
Acidosis, Lactic↗
A patient with severe type of epimerase deficiency galactosaemia.
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Carbohydrate Epimerases↗
Rhizomelic chondrodysplasia punctata: clinical, pathologic, and biochemical findings in two patients.
The clinical, pathologic, and biochemical features of rhizomelic chondrodysplasia punctata are described in two patients. Although both patients had clinical and radiologic similarities, one patient survived for only 13 days and the other is still alive at 8 years. The most prominent pathologic feature was the marked degenerative change in the chondrocytes from resting cartilage. Fibroblast alkyldihydroxyacetone phosphate synthase activity was markedly reduced in both patients (approximately 10% of control mean); in contrast, dihydroxyacetone phosphate acyltransferase activity was only moderately reduced (50% of control mean). Alkyl and alk-l-enyl ether (plasmalogens) levels were very low in brain and liver. The accumulation of phytanic acid observed in plasma or liver was paralleled by a reduced ability of the patients' fibroblasts to oxidize phytanic acid. Our data indicate that the genetic defect in rhizomelic chondrodysplasia punctata results in abnormalities in two apparently unrelated pathways (i.e., phytanic acid oxidation and ether lipid biosynthesis.
Brain↗
Mild Sanfilippo syndrome: a further cause of hyperactivity and behavioural disturbance.
Sanfilippo syndrome (mucopolysaccharidosis type III) usually presents with severe behavioural disturbance and it has characteristic features. The patient's condition follows a neurodegenerative course; death generally occurs in the second decade. Five patients, from three families, who presented with a mild variety of the syndrome are reported here. Four of the five patients did not show the usual somatic features, and none showed regression. It is important that clinicians be aware of this mild variant so that appropriate tests can be undertaken in retarded children and adults.
Adult↗
Endocardial fibroelastosis in mucopolysaccharidosis type VI.
This case report describes two siblings less than 1 year of age who presented severely ill with a dilated cardiomyopathy. Full blood examination in both cases revealed marked granularity of neutrophils suggestive of mucopolysaccharidosis type VI. There were no physical features of a mucopolysaccharidosis but biochemical evaluation confirmed mucopolysaccharidosis type VI in both children. Autopsy in one patient confirmed endocardial fibroelastosis and electron microscopy of fibroblasts in the myocardium showed distention with membrane-bound vacuoles, consistent with a mucopolysaccharidosis. These siblings developed endocardial fibroelastosis before other clinical manifestations of the mucopolysaccharidosis. Assessment for metabolic causes of a cardiomyopathy is important, as cardiac disease may be the initial manifestation of a metabolic disease.
Endocardial Fibroelastosis↗
Episodes of severe metabolic acidosis in a patient with 3-methylglutaconic aciduria.
Persistent excretion of 3-methylglutaconic acid was found in a 6-month-old infant with multiple minor physical malformations and delayed development. During two episodes of intercurrent viral illness, the patient developed severe metabolic acidosis and excreted large amounts of lactate, 3-hydroxybutyrate and acetoacetate. The excretion of 3-methylglutaconic acid did not change during these episodes, nor did it increase following leucine loading. In vitro studies suggest that in this patient, as in the majority of other patients with 3-methylglutaconic aciduria, a primary defect in leucine metabolism is not responsible for the biochemical abnormality.
Abnormalities, Multiple↗
The mucopolysaccharidoses.
The experience of the Royal Children's Hospital in managing patients with mucopolysaccharidosis is discussed. All share the common feature of abnormal storage, within lysosomes, of partially degraded glycosaminoglycans, but different diseases within the group as a whole present different problems. The presentation, diagnosis and clinical outcome of 69 affected children are described.
Child↗
Galactosaemia.
This paper reviews galactosaemia and describes the experience of the Willink Biochemical Genetics Unit in the management of classical galactosaemia. Galactokinase and UDPgalactose-4-epimerase deficiency are dealt with briefly. The former disorder is readily treated with a galactose free diet and if this is started early in life, the only complication, cataracts, is avoided. Epimerase deficiency is a relatively 'new' disorder and little is known about the eventual outcome of affected patients. Early observations suggest that the prognosis is likely to be poor even in those patients diagnosed and treated soon after birth. Classical galactosaemia leads to a number of long term complications. The prognosis for normal mental development in affected patients is poor. Unfortunately this does not appear to be reversible by early diagnosis and treatment and whilst every effort should be made to establish an early diagnosis our experience suggests that there is no difference in the ultimate mental development between those who are detected within the first two weeks of life and those before the age of six weeks. In addition female homozygotes are at a very high risk of developing ovarian failure at an early age.
Female↗
Velo-cardio-facial syndrome presenting as holoprosencephaly.
A baby with holoprosencephaly and the tetralogy of Fallot is described. The mother had operative correction of the same cardiac lesion and shows features typical of the velo-cardio-facial syndrome, an autosomal dominant disorder. The association between holoprosencephaly and this condition has not been previously reported. When holoprosencephaly is found associated with congenital heart disease, velo-cardio-facial syndrome should be sought in other family members.
Abnormalities, Multiple↗
Limitations of enzyme replacement therapy: current and future.
Orphan drug legislation passed in the USA in 1983 and in Europe in 1999 has encouraged biotechnology companies to develop treatments for diseases that the industry previously ignored because they affect only small numbers of people and promised only limited profitability. Incentives, exclusivity and the freedom to charge sufficient to cover development costs has led to a niche market, and patients with lysosomal storage disorders have been one of the main beneficiaries of these developments. The recombinant production of highly purified enzymes that are modified to improve tissue targeting has been a direct result of this legislation. The spectacular clinical and financial success of Cerezyme (and previously Ceredase, Genzyme) for the treatment of Gaucher disease has led to the development of enzyme replacement treatment(s) for Fabry disease and mucopolysaccharidoses types I and VI. A number of other enzyme replacement therapies are at an earlier stage in development and the next 12 months could see the launch of therapies for mucopolysaccharidosis type II and Pompe disease. Like all medical treatments, this approach has some limitations. Not all patients are suitable for treatment, some organs and tissues are corrected more readily than others, and there are problems with gauging efficacy in these highly variable disorders. Finally, the therapies are expensive, limiting access to patients from those countries that are able to afford expensive health care.
Animals↗