No abstract

X linked adrenoleukodystrophy (X-ALD)is an inherited disorder of peroxisomal metabolism, biochemically characterised by accumulation of saturated very long chain fatty acids. Accumulation of these fatty acids is associated with cerebral demyelination, peripheral nerve abnormalities, and adrenocortical and testicular insuYciency. The lowest estimated birth incidence is one per 100 000. At least six phenotypes can be distinguished, of which the two most frequent are childhood cerebral ALD and adrenomyeloneuropathy. The X-ALD gene has been identified, but thus far no relation between genotype and phenotype has been found. Diagnosis is relatively easy and can be confirmed reliably, and prenatal testing is possible in aVected families. Several therapeutic options, some with promising perspectives, are available. Neurologists and other physicians seem not to be familiar with the many facets of X-ALD. In this review, the clinical presentation, the relative frequencies of the diVerent phenotypes, and the diagnostic and therapeutic options are presented.

Fatty acids are a major source of metabolic fuel in man. Both mitochondria and peroxisomes are capable of fatty acid fl-oxidation (Schulz, 1985). It is generally agreed that the oxidation of medium and long chain fatty acids, which are most abundant in our daily diet, takes place predominantly in mitochondria. In contrast, peroxisomal fl-oxidafion is not so important for energy purposes, but catalyses the chainshortening of a distinct set of substrates which includes very long chain fatty acids, certain mono-and polyunsaturated fatty acids and di-and trihydroxycholestanoic acid (see Wanders et al., 1990 for review). The different physiological functions of mitochondrial and peroxisomal fl-oxidation are reflected in the widely differing clinical consequences of defects in mitochondrial and peroxisomal fl-oxidation, respectively. In recent years an increasing number of inherited diseases in man have been recognized in which there is an impairment in mitochondrial fl-oxidation (Vianey-Liaud et al., 1987). In this paper we report the identification of a new inborn error of mitochondfial fi-oxidation at the level of long chain 3-hydroxyacyl-CoA dehydrogenase in a child who presented at 5 months of age with diarrhoea and vomiting, subsequently followed by increasing lethargy which appeared to be associated with hypoketotic hypoglycaemia. MATERIALS AND METHODS Enzyme activity measurementsThe activity of 3-hydroxyacyl-CoA dehydrogenase was measured in homogenates of cultured skin fibroblasts at 37°C by following the decrease in absorbance at 311

Barth syndrome (BTHS) is a rare X-linked disease characterized by a triad of dilated cardiomyopathy, skeletal myopathy, and neutropenia. The disease is associated with mutations of the TAZ gene, resulting in defective cardiolipin (CL), an important inner mitochondrial membrane component. Untreated boys die in infancy or early childhood from septicemia or cardiac failure. To date, neutrophil function has never been studied. Directed motility and killing activity of neutrophils was investigated in 7 BTHS patients and found normal in those tested. The circulating neutrophils and eosinophils (but not monocytes or lymphocytes) showed annexin-V binding, suggesting phosphatidylserine (PS) exposure due to apoptosis. However, caspase activity was absent in fresh BTHS cells. Unexpectedly, the near absence of CL impacted neither the mitochondrial mass and shape in fresh BTHS neutrophils nor mitochondrial clustering and Bax translocation upon apoptosis. Annexin-V binding to BTHS neutrophils was not caused by phospholipid scrambling. Moreover, freshly purified BTHS neutrophils were not phagocytosed by macrophages. In sum, a massive number of circulating annexin-V-binding neutrophils in the absence of apoptosis can be demonstrated in BTHS. These neutrophils expose an alternative substrate for annexin-V different from PS and not recognized by macrophages, excluding early clearance as an explanation for the neutropenia. (Blood.