Polyunsaturated fatty acid status in treated isovaleric acidemia patients.

BACKGROUND/OBJECTIVES: Nutritional deficiencies are frequently observed when treating patients with inborn errors of metabolism due to an unbalanced diet. Thus far, patients with isovaleric acidemia (IVA) who adhere to a restricted protein diet have not been investigated in this respect. We hypothesize that these patients may have a polyunsaturated fatty acid (PUFA) deficiency, leading to potential clinical complications. SUBJECTS/METHODS: We examined the nutritional status by reporting on potential deficiencies in PUFAs in treated IVA patients. A general clinical chemistry work-up as well as gas chromatography flame ionization detector analysis was performed to determine PUFAs in the plasma of 10 IVA patients. RESULTS: The general clinical chemistry tests did not indicate severe hematological abnormalities or nutritional insufficiencies. We identified a significant reduction in plasma PUFA levels, especially in omega-3 (all acids, P<0.001) and omega-6 (in particular 20:3n-6 P<0.0001 and 20:4n-6 P=0.0005) fatty acids. In addition, an elevation in omega-9 fatty acids, with the exception of 20:3n-9 and C22:1n-9, was not suggestive of complete essential fatty acid deficiency but rather indicative of isolated and/or combined omega-3 and omega-6 fatty acid depletion. CONCLUSIONS: This study emphasizes the potential nutritional insufficiencies that may occur because of therapeutic intervention in IVA.

Clinical variability of isovaleric acidemia in a genetically homogeneous population.

Isovaleric acidemia (IVA) is one of the most common organic acidemias found in South Africa. Since 1983, a significant number of IVA cases have been identified in approximately 20,000 Caucasian patients screened for metabolic defects. IVA is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of isovaleryl-CoA and its metabolites. In total, 10 IVA patients and three carriers were available for phenotypic and genotypic investigation in this study. All patients were found to be homozygous for a single c.367 G > A (p.G123R) mutation. The amino acid substitution of a glycine to arginine resulted in a markedly reduced steady-state level of the IVD protein, which explains the nearly complete lack of IVD enzyme activity as assessed in fibroblast homogenates. Despite the genetic homogeneity of this South African IVA group, the clinical presentation varied widely, ranging from severe mental handicap and multiple episodes of metabolic derangement to an asymptomatic state. The variation may be due to poor dietary intervention, delayed diagnosis or even epigenetic and polygenetic factors of unknown origin.

Correlation between the surface hydrophobicities and elution orders of elapid neurotoxins and cardiotoxins on hydrophobic-interaction high-performance liquid chromatography.

Hydrophilic and hydrophobic regions were predicted for Elapid neuro- and cardiotoxins. The contribution of these regions to the retention times of neuro- and cardiotoxins on hydrophobic-interaction HPLC was assessed from the known surface accessibilities of amino acid side-chains within these regions. Differences in retention times between neuro- and cardiotoxins on hydrophobic-interaction HPLC could be attributed to differences in hydrophobicity of regions 6-12 and 22-26 between these two types of toxins. Smaller differences in retention times between cardiotoxins were due to the variable hydrophobicities of regions 1-4 and 26-36.

Adrenoleukodystrophy in a mother and son.

A 6 year old boy died from a degenerative brain disease which was clinically and pathologically typical of adrenoleukodystrophy. Shortly before his disease became manifest his 28 year old mother had presented with similar symptoms, and subsequently died. Her brain showed almost identical features including the presence of pathognomonic ultrastructural inclusions. The accumulation of very long chain fatty acids in cerebral white matter as well as high hexacosanoic to docosanoic acid (C26:22) ratios, substantiated the diagnosis in both cases. This is one of the few documented cases of adrenoleukodystrophy in an adult female, and is almost certainly an example of clinical manifestation of this X-linked inherited disease in a carrier.

The correlation between biochemical and histopathological findings in adrenoleukodystrophy.

Nine areas of the brain from a case of adrenoleukodystrophy were examined histopathologically and by gas chromatography for fatty acid content. The main findings were: (1) the degree of demyelination was related to the pentacosanoic and hexacosanoic to docosanoic acid ratios (C25:0/C22:0 and C26:0/C22:0); gliosis was related to the ratios of several fatty acids to docosanoic acid; (2) there was a shift towards smaller components (C22:0, C23:0, C24:0) of the saturated fatty acid series in the less affected areas, to larger components and various minor components in regions of active demyelination; (3) mainly saturated fatty acids of the middle class components (C24:0, C25:0 and C26:0) were found in severely affected areas where the active process is complete. Because a region of high long chain fatty acid content, lacking histopathological change, was detected, the hypothesis is presented that the primary event in childhood ALD is related to defective lipid metabolism and that this preceeds demyelination.

A multidisciplinary diagnostic/genetic study on the 105 patients with mental retardation of the E.S. Le Grange School.

A comprehensive genetic/diagnostic survey was undertaken at a special school for the mentally retarded involving 105 patients. Cytogenetic, biochemical and clinical investigations were undertaken to establish the contribution of the genetic factors to the problem of mental retardation. Apart from obtaining information about specific children, identifying families at risk, and providing genetic counselling in nearly 50% of cases, data was obtained which could be compared with other similar surveys. According to the aetiological groupings of the patients, 6.7% could be attributed to perinatal damage, 17.1% to chromosomal defects, 4.8% to biochemical disorders, 5.7% to other genetic causes, 12.4% to other prenatal damage, 1.9% to infections, and 51.4% to unknown causes. No individual with the marker X syndrome was found in this group.

The application of a sequential procedure with elimination as a method for the screening for metabolic diseases.

A sequential classification procedure with early elimination, for the screening for metabolic diseases, is presented. Asymptotic properties of the procedure are derived in the Appendix and it is shown that the procedure is asymptotically distribution-free under certain assumptions, and asymptotically at least as efficient as a comparable fixed-sample procedure. With the use of data obtained from 36 mentally retarded patients, the procedure was evaluated by means of a bootstrap simulation. The procedure was then applied to this set of data, with satisfactory results and a considerable economy in observations.

Biochemical evidence for clinically diagnosed adrenoleucodystrophy in two brothers.

Adrenoleucodystrophy (ALD) is a rare, X-linked inherited disease affecting the central nervous system. The clinical findings overlap those of other related progressive neurological diseases and complicate the diagnosis. In this article biochemical analyses of the very-long-chain fatty acid distribution in specimens obtained from 2 related patients clinically diagnosed as having ALD, which unequivocally confirmed the diagnosis, are described. Analyses of the long-chain fatty acids were performed on postmortem brain tissue samples from the one patient. In the other, who is in the terminal phase of the disease, the long-chain fatty acids were analysed in plasma, erythrocytes and fibroblasts from tissue culture. The limitations of the different analyses for biochemical identification of ALD are discussed.

Screening for inborn errors of metabolism among mentally retarded patients. Outcome of a surgery at the Witrand Care and Rehabilitation Centre.

The prevalence of different types of inborn errors of metabolism among the mentally retarded patients at the Witrand Care and Rehabilitation Centre, were determined by means of a biochemical screening survey. These results are compared with those of other surveys in South Africa and abroad. One important result points to substantial differences in the recorded incidences of metabolic defects between surveys. This observation could partially be due to significant differences between the different studies in terms of methodology employed and sampling procedures. The questions raised in this regard are documented and discussed.

Changes in polyribosomes and poly(A)-containing polyribosomal RNA in the uterus of the ovariectomized rat in response to oestradiol-17 beta treatment.

Polyribosome formation and the characteristics of polyribosomal poly(A)-containing RNA from uteri of ovariectomized rats responding to a single dose of oestradiol-17 beta was investigated. The mean proportion of polyribosomes in the atrophic uterus was 65%. In response to 10 micrograms of oestradiol-17 beta/100 g body mass, the amount of polyribosomes increased to 88% 24 h after stimulation. Thereafter the proportion of polyribosomes decreased to a value of 48% at 72h. The pattern of amino acid incorporation in oocytes from Xenopus laevis injected with these polyribosomes was similar to the changes in polyribosome formation and degradation. The polyribosomal poly(A)-containing RNA from the controls consisted of a heterogeneous population of RNA with sedimentation values between 5S and 25S. The hormone stimulation resulted in an increase in both the amount and the size (13S to 35S) of the RNA.