The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.
The dysmorphic form of multiple acyl-CoA dehydrogenation deficiency (glutaric aciduria type II, GAII, McKusick 23168) has only been described in four families to date (Sweetman et al., 1980;Lehnert et al., 1982;Goodman et al., 1983;Boue et al., 1984). Here we report the presentation and diagnosis of a new case of this severe disorder.Infant I. was a female born at 38 weeks gestation after an uneventful pregnancy to Pakistani immigrant parents whose grandparents were first cousins. Labour was precipitated by spontaneous rupture of membranes and was accompanied ~ by a small antepartum haemorrhage. Of five previous pregnancies, one had resulted in intrauterine death at 34 weeks, postmortem examination showing an absent left kidney, and one had resulted at term in a fresh stillbirth showing no congenital anomaly. Of the three live-born infants, two are well and one died aged 18 months in Pakistan.The infant was not asphyxiated at birth, weighed 2.54 kg and developed hypothermia (34.6°C) by the age of one hour. Examination revealed an unresponsive, hypotonic infant with decreased muscle bulk. Apart from talipes equinovarus, there were no joint contractures but there was loss of skin elasticity. There were abnormal facies with small eyes, a larg~ anterior fontanelle and low set ears. There were bilateral renal swellings in the absence of a palpable bladder. Investigations included a blood urea level of 12.7 mmol L-1, a plasma bicarbonate level of 13.1mmolL -1 and a glucose level of 1.7mmolL -1. Routine medical care was given and the infant died aged 21 hours.At the postmortem examination both kidneys were massively enlarged weighing 99 and 95 g respectively. Their cut surfaces showed numerous minute cysts up to 0.2 cm in diameter in the cortex. There was some blurring of the normal cortico--medullary junction and the medulla appeared oedematous and slightly mucoid. The only other abnormality was patchy pallor in the liver.Histology of the kidneys showed numerous cysts in the cortex, lined by cuboidal epithelium. Between the cysts there were fairly numerous rather immature glomeruli but only a few normal tubules. The medullae were composed" of loose mature mesenchymal tissue and blood vessels with only a few cystically dilated tubules lined by cuboidal or flattened epithelium. Scattered throughout the kidneys were small loci of haemopoietic tissue. The liver showed extensive fatty change with nearly all the liver cells containing small or medium-sized fat droplets. In 1Department of Chemical Pathology,
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