Biomedical subjects
J V Leonard
Publications and source records attributed to J V Leonard.
Respiratory-deficient human fibroblasts exhibiting defective mitochondrial DNA replication.
We have characterized cultured skin fibroblasts from two siblings affected with a fatal mitochondrial disease caused by a nuclear genetic defect. Mitochondrial respiratory-chain function was severely decreased in these cells. Southern-blot analysis showed that the fibroblasts had reduced levels of mitochondrial DNA (mtDNA). The mtDNA was unstable and was eliminated from the cultured cells over many generations, generating the rho0 genotype. As the mtDNA level decreased, the cells became more dependent upon pyruvate and uridine for growth. Nuclear-encoded subunits of respiratory-chain complexes were synthesized and imported into the mitochondria of the mtDNA-depleted cells, albeit at reduced levels compared with the controls. Mitochondrial protein synthesis directed by the residual mtDNA indicated that the mtDNA was expressed and that the defect specifically involves the replication or maintenance of mtDNA. This is a unique example of a respiratory-deficient human cell line exhibiting defective mtDNA replication.
Regional variations in medium-chain acyl-CoA dehydrogenase deficiency.
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The management and outcome of propionic and methylmalonic acidaemia.
The management of the severe variants of methylmalonic and propionic acidaemia remains difficult. With conventional therapy of diet, carnitine and antibiotics, mortality is high and long-term complications are common. Liver transplantation appears to be an important alternative.
The hepatic glycogen storage diseases--problems beyond childhood.
The introduction of continuous nocturnal enteral glucose feeds and uncooked cornstarch has improved the prognosis for patients with the hepatic glycogen storage diseases. An increasing number of patients are surviving into adulthood in better health, but still at some medical cost. In this review we examine bone mineralization, renal function, hepatic tumours, and vascular endothelial function in GSD I and cardiac function in GSD III. All females over the age of 5 years with GSD I, III, VI and IX had morphologically polycystic ovaries. Thirteen adult GSD I patients have been studied, and been found to have poor bone mineralization and marked renal glomerular and tubular dysfunction. More than half of these patients also had focal hepatic lesions on sonography and yet vascular endothelial function was preserved in the face of hyperlipidaemia. In 12 GSD III patients, one had a focal hepatic lesion and 6 had pronounced left ventricular hypertrophy, although cardiorespiratory function was normal. These data emphasize the multisystem nature of these disorders and highlight the need for careful longterm follow-up.
Impaired ketogenesis in fructose-1,6-bisphosphatase deficiency: a pitfall in the investigation of hypoglycaemia.
Intermediary metabolite concentrations were measured in blood during fasting in two patients with fructose-1,6-bisphosphatase deficiency. Hypoglycaemia was accompanied by markedly raised levels of plasma free fatty acids, without the expected degree of ketosis. This suggests that there is secondary impairment of ketogenesis in this condition, and could lead to diagnostic confusion.
Ketonuria and medium-chain acyl-CoA dehydrogenase deficiency.
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Catch-up growth in Fanconi-Bickel syndrome with uncooked cornstarch.
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Early signs and course of disease of glutaryl-CoA dehydrogenase deficiency.
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Focal fatty liver change in glycogenosis type 1 A.
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Bone mineralisation in type 1 glycogen storage disease.
UNLABELLED: Radial bone mineral content (BMC) was measured using single photon absorptiometry in 11 prepubertal children, aged 3.4-12.6 years, with glycogen storage disease type 1 (GSD-1), 2 of whom were receiving granulocyte colony stimulating factor (G-CSF) therapy for chronic neutropenia. Patients were short (median height SD score -1.35, range -3.74 to -0.27), and had reduced BMC Z scores (median 1.79, range -6.35 to +0.27) and radial bone width Z scores (median -0.72, range -2.00 to +0.68). Those receiving G-CSF did not differ significantly from the rest of the group. Generally dietary calcium intake was low and urinary calcium excretion increased. Urinary lactate excretion was high but did not correlate with BMC Z scores. Factors regulating bone metabolism (parathyroid hormone and 25-hydroxy vitamin D concentrations) and markers of bone formation (osteocalcin and skeletal alkaline phosphatase) were not increased implying that there was no compensation for increased bone resorption. CONCLUSION: Patients with GSD-1 may be at increased risk of fracture in later life and require close attention to metabolic control and calcium balance.
The prevalence of polycystic ovaries in the hepatic glycogen storage diseases: its association with hyperinsulinism.
OBJECTIVE: There has been much debate concerning the relative contribution of insulin resistance to the development of polycystic ovaries (PCO). We therefore aimed to assess ovarian morphology and insulin/androgen status in females with the hepatic glycogen storage diseases types Ia (GSD-Ia) and III (GSD-III), disorders associated with abnormalities of insulin secretion. DESIGN: A cross-sectional study of ovarian ultrasonography, oral glucose tolerance tests (oGTTs) and single measurements of gonadotrophins and androgens were performed. PATIENTS: Twenty-seven patients were evaluated: 13 with GSD-Ia, median age 11.2 years (range, 3.3-26.7) and 14 with GSD-III, aged 13.2 years (4.2-31.3). None had clinical signs of hyperandrogenism and only two of the 13 adults (15%) had menstrual irregularities. They were compared to 9 normal adult female controls, aged 21-28 years. MEASUREMENTS: Ovarian morphology and volume were measured. Blood glucose and plasma insulin concentrations were measured at the beginning and end of a 2-hour oGTT. Single measures of LH, FSH, testosterone, dehydroepiandrosterone sulphate, androstenedione, IGF-I and SHBG were made on samples taken at the beginning of the oGTT. RESULTS: In both GSD-Ia and III, all those older than 4.8 years of age had a polycystic ovarian appearance. Pre-pubertal GSD-Ia patients had lower basal and 2-hour blood glucose and plasma insulin concentrations than pre-pubertal GSD-III patients. In adults with GSD-Ia and GSD-III, although basal and 2-hour blood glucose concentrations did not differ, both basal and 2-hour plasma insulin concentrations were significantly higher than controls. Serum gonadotrophins, androgens, IGF-I and SHBG were mostly normal. CONCLUSIONS: A polycystic ovarian appearance is a common finding in patients with glycogen storage disease even before puberty. In GSD-III and adults with GSD-Ia, this ovarian appearance was associated with hyperinsulinism, suggesting an aetiological link, but this was not the case in pre-pubertal children with GDS-Ia. Inborn errors of carbohydrate metabolism may act as useful models for examining control mechanisms of ovarian physiology and development.
Hypoglycaemia complicating treatment regimens for glycogen storage disease.
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Brachydactyly and mental retardation: an Albright hereditary osteodystrophy-like syndrome localized to 2q37.
We report five patients with a combination of brachymetaphalangia and mental retardation, similar to that observed in Albright hereditary osteodystrophy (AHO). Four patients had cytogenetically visible de novo deletions of chromosome 2q37. The fifth patient was cytogenetically normal and had normal bioactivity of the alpha subunit of Gs (Gs alpha), the protein that is defective in AHO. In this patient, we have used a combination of highly polymorphic molecular markers and FISH to demonstrate a microdeletion at 2q37. The common region of deletion overlap involves the most telomeric 2q marker, D2S125, and extends proximally for a maximum distance of 17.6 cM. We suggest this represents a consistent phenotype associated with some deletions at 2q37 and that genes important for skeletal and neurodevelopment lie within this region. Screening for deletions at this locus should be considered in individuals with brachymetaphalangia and mental retardation. Furthermore, 2q37 represents a candidate region for type E brachydactyly.
Clouds still gathering over galactosaemia.
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Hyperlipidaemia does not impair vascular endothelial function in glycogen storage disease type 1a.
Patients with glycogen storage disease type 1 (GSD-1) often have marked hyperlipidaemia with abnormal lipoprotein profiles. This metabolic abnormality improves, but is not fully corrected, with dietary therapy and therefore these patients may be at high risk for the development of atherosclerosis. Endothelial dysfunction is an early event in atherogenesis and can be detected in children and young adults at high risk. We studied endothelial function, using a non-invasive ultrasonographic method, in the brachial arteries of 6 adult GSD-1a patients (aged 23-33 years) with mean cholesterol of 7.9 mmol/l (range 4.7 to 14.6) and mean triglycerides of 9.1 mmol/l (range 4.1 to 21.3), and 12 age- and sex-matched normolipidaemic controls. Flow-mediated (endothelium-dependent) dilation was similar in patients and controls (8.2% vs. 10.5%; P = 0.20). Although the patient numbers are small, these results are consistent with the surprising lack of clinically evident atherosclerosis in GSD-1. The reasons these patients appear less susceptible to the damaging arterial effects of hyperlipidaemia are unknown. These results may have implications for others with secondary hyperlipidaemias.
Characterization of a de novo 43-bp deletion of the Gs alpha gene (GNAS1) in Albright hereditary osteodystrophy.
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The allopurinol loading test for identification of carriers for ornithine carbamoyl transferase deficiency: studies in a healthy control population and females at risk.
The increase in orotidine excretion following a 300 mg allopurinol dose has been used for carrier detection in ornithine carbamoyl transferase (OCT) deficiency. This test was evaluated, using three collection periods, in 23 healthy women, 4 obligate heterozygotes and 32 other women at risk of being carriers of OCT deficiency. Four methods for the analysis of orotidine and orotic acid were compared. Using the most reproducible method, the excretion of orotic acid in controls was found to be consistently higher than that of orotidine in all three periods. The distribution of both orotic acid and orotidine excretion of controls was skewed so that standard deviations (S.D.) were calculated after logarithmic transformation. All four obligate heterozygotes showed orotic acid and orotidine excretion in excess of 3 S.D. above the control mean and a further 7 women had one or more excretion values in excess of 3 S.D., while 16 gave a value of less than 2 S.D. for both metabolites. We conclude that the predictive value of the test is good, that both orotic acid and orotidine should be measured to reduce the risk of misclassification and that values greater than 2 S.D. for both in one or more periods should be used as the cut-off point to identify carriers.