Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy.

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.

The prevalence and identification of risk factors for NIDDM in urban Africans in Cape Town, South Africa.

OBJECTIVE: To determine the prevalence of NIDDM and associated risk factors in urban Africans in Cape Town, South Africa. RESEARCH DESIGN AND METHODS: With a three-stage, proportional, stratified, random cluster method, we sampled 1000 Africans, > 30 yr of age, living in African residential areas in Cape Town. We assessed glucose tolerance with a 75-g oral glucose tolerance test, according to World Health Organization criteria, and obtained anthropometric and demographic data. RESULTS: The response rate was 79%. The prevalence of NIDDM was 8.0% (confidence interval 5.8-10.3%), age-adjusted to world population figures and that of impaired glucose tolerance, 7.0% (confidence interval 4.9-9.1%). Multivariate analysis indicated that increased age (odds ratio 4.18), upper-segment fat distribution (odds ratio 2.94), proportion of life spent in an urban area (odds ratio 2.32), and obesity (odds ratio 2.31) were significant independent risk factors for NIDDM. In contrast, sex, family history, alcohol intake, and physical activity were not independent risk factors. Only increased age (odds ratio 4.06) was a significant risk factor for impaired glucose tolerance. CONCLUSIONS: The prevalence of NIDDM in urban Africans in Cape Town, South Africa, is moderately high, and considerably higher than previous reports from Africa. The association of NIDDM with urbanization has important implications in view of the large-scale urbanization occurring in southern Africa.

Continuous flow plasma exchange in the treatment of homozygous familial hypercholesterolemia.

We report the clinical and laboratory effects of continuous-flow plasma exchange in two patients suffering from homozygous familial hypercholesterolemia. In one (Case 1) plasmapheresis was performed at fortnightly intervals over a period of 18 months; in the other (Case 2) the necessity for surgical relief of an associated supravalvular aortic stenosis resulted in premature termination of the trial. The plasma cholesterol levels in both patients fell by 35 per cent from the mean before study in the course of treatment. In Case 1 this was associated with marked regression of the patient's xanthomas, disappearance of the S-T segment depression seen on effort electrocardiograms obtained prior to the introduction of plasmapheresis, possible widening of the stenosis present at the origin of the left anterior descending coronary artery, and a marked increase in exercise tolerance and diminished frequency of anginal attacks. Cessation of cholestyramine and clofibrate administration during this study did not in any way reverse the reduction of plasma cholesterol achieved by means of plasmapheresis combined with drug therapy. We conclude that plasmapheresis has a role to play in the management of patients with homozygous familial hypercholesterolemia.

Nephrocalcinosis in children.

Nephrocalcinosis is an uncommon condition is childhood. The commonest cause is renal tubular acidosis, although this may not manifest itself radiographically until adolescence. Recognizing the calcification as either cortical, medullary or mixed is not always possible, but may sometimes be an aid to differentiate metabolic from vascular causes.

Fatal liver failure due to ketoconazole treatment of a girl with Cushing's syndrome.

A patient is reported who developed fatal liver failure on ketoconazole treatment for Cushing's syndrome. It is recommended that metyrapone be used when hypercortisolism has to be controlled as a temporary measure in childhood and adolescence.

Diencephalic syndrome with long-term survival.

Infants and young children with the diencephalic syndrome exhibit a normal activity level despite profound marasmus. Investigation reveals an intracranial tumour and evidence of endocrine dysfunction. The condition is easily missed in Third World countries with a high prevalence of nutritional marasmus. The advent of computer tomography and magnetic resonance imaging has simplified diagnosis. The syndrome was diagnosed in 1981 in a boy of 20 months who had a large hypothalamic tumour. Initial endocrine studies revealed very high growth hormone levels. After radiotherapy, these levels reverted to normal for a time but have subsequently declined in keeping with a state of hypopituitarism. The boy's long-term survival has afforded an opportunity for study over eight years. During this time, growth has been slow but sustained. There has been some fall off in intellectual capacity. Characteristic features of the diencephalic syndrome are normal activity and a state of euphoria in a profoundly marasmic child. Investigation reveals the presence of an intracranial tumour and evidence of endocrine dysfunction. Though there are earlier references, the condition first came to medical attention at the annual meeting of the British Paediatric Association in 1951 when Russell described the typical features. In Third World countries where childhood marasmus is common, the syndrome is easily overlooked. The present report concerns a boy who has been closely followed for more than eight years.

[The value of potassium phosphate supplements in the treatment of diabetic ketoacidosis. Effects upon 2.3-diphosphoglycerate and tissue oxygenation (author's transl)]. / Traitement de la céto-acidose diabétique: intérêt d'un supplément de phosphate de potassium. Effet sur le 2,3-diphosphoglycérate et l'oxygénation tissulaire.

Amongst 8 diabetics with severe ketoacidosis and treated identically, 4 received intravenous supplements of potassium phosphate (25 mmol PO4/I) for 24 hours. This resulted in blood 2.3-diphosphoglycerate and in vivo P50 levels which were invariably higher than in the control subjects and a fall in lactate/pyruvate ratio. These results reflect improved tissue oxygenation.

Functional hypoparathyroidism in infantile hypocalcaemic stage I vitamin D deficiency rickets.

Nine infants with stage I rickets were found to have an inappropriate functional hypoparathyroidism with severe hypocalcaemia. Possible mechanisms, therapy and prevention are discussed.

Making the change to U-100 insulins. A patient education guide.

This article is designed as educational material for insulin-dependent diabetics and is intended to help them and their doctors make the change to U-100 insulins without difficuulty. The aim of the transfer is to reduce potentially dangerous confusion and dosage errors which have resuited from the current availability of multiple strengths of insulins and types of syringes.

Pure oestrogen-secreting feminizing adrenocortical adenoma.

A 6-year-old boy presented with gynaecomastia. There was no clinical or biochemical evidence of excessive androgenic or glucorticoid activity, but urinary oestrogen levels were raised. An adrenocortical adenoma, demonstrated by x-ray, was surgically removed. Oestrogen levels fell immediately. 3 years later the boy shows complete regression of the gynaecomastia and no signs of recurrence.

Familial hyperchylomicronaemia in four families. Problems in diagnosis, management, and aetiology reviewed.

We report on the clinical and biochemical findings of 8 patients with familial hyperchylomicronaemia (type I hyperlipoproteinaemia) from 4 separate kindreds. The diagnosis is generally easily established by the presence, in standing plasma, of a creamy chylomicron layer over a clear infranatant and by the large predominance of triglycerides over cholesterol in the plasma. Additional aids are the presence of chylomicrons on lipoprotein electrophoresis and the markedly reduced liberation of lipolytic activity into the plasma of these patients, after the administration of heparin. Difficulties in diagnosis may arise in patients on reduced fat diets, resulting in an increase of very low density lipoproteins and a type IV or V phenotype. The precise nature of the primary genetic defect remains to be established but the disorder appears to be aetiologically distinct from type IV or V hyperlipoproteinaemia. Reduction of chylomicron, and hence of triglyceride values in the plasma, is wholly dietary.

Hyperglycaemic emergencies are a common problem.

OBJECTIVE: To determine the number, type, precipitating factors and mortality associated with diabetic emergencies admitted to Groote Schuur Hospital. DESIGN: Administered questionnaire survey. SETTING: Groote Schuur Hospital, Cape Town. METHODS: All patients admitted from September 1991 to January 1992 with elevated blood glucose concentrations who required intravenous insulin and fluids were evaluated by an administered questionnaire prior to discharge from hospital. Patients were divided into four groups according to presence of ketosis, standard bicarbonate level and serum osmolality: (i) mild diabetic keto-acidosis (DKA); (ii) severe DKA; (iii) hyperosmolar state; and (iv) hyperglycaemia. RESULTS: There were 131 admissions in 122 patients. Sixty-five occurred in non-insulin-dependent diabetics, 45 in insulin-dependent diabetics and 12 in pancreatic diabetics. There were similar numbers of admissions in the four groups of hyperglycaemic emergencies. The mortality rate was 3% in the mild DKA and hyperglycaemic groups, significantly lower (P < 0.05) than in the hyperosmolar group (19%). The mortality rate was 11% in the severe DKA group (P > 0.05 v. other groups). Sixty-two per cent of participants had achieved Standard 4 to Standard 8 education. Only 39% were employed at the time of interview. Diabetic knowledge and general compliance were assessed as poor. Infections and poor compliance with hypoglycaemic therapy were the dominant precipitating factors. CONCLUSION: Hyperglycaemic emergencies precipitated largely by infections and poor compliance and associated with considerable morbidity and mortality commonly require admission to hospital. Improvement in diabetic education is required to reverse the current situation.

The effect of an intensive education programme on the glycaemic control of type I diabetic patients.

The effect of patient education on glycaemic control in insulin-dependent diabetes mellitus was assessed in 20 patients selected from the Diabetes Clinic, Groote Schuur Hospital. Education in all aspects of self-care was given to small groups of between 5 and 7 patients. Biochemical tests including measurement of fasting blood glucose (FBG) and glycosylated haemoglobin (HbA1c), were performed during a 6-week 'control' period before the educational course, and again during a 6-week 'test' period after it. The mean HbA1c fell from 10.05 +/- 0.43% at the end of the control period to 8.47 +/- 0.25% at the end of the test period (P less than 0.001). FBG levels dropped from 13.53 +/- 0.84 mmol/l at the commencement of the study to 10.83 +/- 1.29 mmol/l before the educational course, and to 9.41 +/- 0.72 mmol/l at the completion of the study. We therefore conclude that intensive education of this nature is of benefit in improving glycaemic control, at least in the short term.

A bolus/basal multiple injection regimen in type I diabetes. A multicentre trial using a new 'fountain-pen' device for short-acting human insulin as well as long-acting human insulin.

A trial was undertaken to ascertain the effect and acceptability of a multiple insulin injection regimen (MII) in patients with insulin-dependent diabetes mellitus using short-acting monocomponent human soluble insulin (Actrapid HM; Novo) for pre-meal bolus injections with the NovoPen injection device (Novo) and long-acting human insulin (Ultratard HM; Novo) at bedtime. Fifty-four patients, all previously on twice-daily short/intermediate-acting human insulin (Monotard HM; Novo) and Actrapid HM, were randomly selected. There was a significant overall improvement in diabetic control over the 12 weeks of the trial, the glycosylated haemoglobin (Hb A1) dropping from a mean of 9.8 +/- 2.2% to 8.6 +/- 1.7% (P less than 0.05). MII, using the NovoPen, was found to be more convenient than conventional insulin administration by 92% of the subjects. It is concluded that the NovoPen is a useful and convenient means of administering pre-meal boluses in an MII regimen, with a very high rate of acceptance by patients of all ages.

Apolipoprotein B detected in the plasma of a patient with homozygous hypobetalipoproteinaemia: implications for aetiology.

A hypobetalipoproteinaemic kindred is described in which the proband manifested the clinical and biochemical features of the homozygous state. Unlike the apparent complete absence of apolipoprotein B in the plasma of the five cases of homozygous hypobetalipoproteinaemia reported so far, we were able to demonstrate minute quantities of this protein (approximately 0.025% of normal) in the plasma of the proband. This finding suggests that the disorder may not result from a structural gene defect but may rather reflect a failure of secretion.

Two siblings with episodic ketoacidosis and decreased activity of succinyl-CoA:3-ketoacid CoA-transferase in cultured fibroblasts.

Succinyl-CoA:3-ketoacid CoA-transferase deficiency leads to a severe ketoacidosis presenting in infancy. We describe two siblings of African ancestry who presented with repeated episodes of ketoacidosis. Both had a positive test for salicylate in the absence of salicylate ingestion. Analysis of urine for organic acids revealed the presence of acetoacetate and 3-hydroxybutyrate. Succinyl-CoA:3-ketoacid CoA-transferase activities in cultured fibroblasts were 11% and 18% of control values.