Showing papers in "Journal of Inherited Metabolic Disease in 1986"

Dietary Problems of Phenylketonuria: Effect on CNS Transmitters and their Possible Role in Behaviour and Neuropsychological Function

Abstract: Thirty years ago it was observed that the synthesis of serotonin, dopamine and norepinephrine was impaired in untreated phenylketonuria (PKU) as judged either by a decreased concentration in the blood or decreased excretion in the urine of these neurotransmitters, or of their metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). Fifteen years later, when early treatment of PKU with a phenylalanine restricted diet was routinely introduced, an inverse relationship was found between phenylalanine levels and the urinary excretion of dopamine and serotonin. An inverse relationship between blood phenylalanine levels and cerebrospinal fluid (CSF) concentrations of HVA and 5-HIAA has repeatedly been reported during the past 10 years. Recently, the effect of the discontinuation of diet in PKU on the synthesis of dopamine, norepinephrine and serotonin has been examined, and the possible relationship between low levels of these neurotransmitters and impaired performance on neuropsychological tests has been evaluated. In some PKU patients the performance on neuropsychological tests of higher integrative function is impaired after discontinuation of diet, especially when blood phenylalanine values exceed 1200 mumol/L, and the patients often complain of lack of concentration and emotional instability. When these patients return to a 'relaxed' phenylalanine restricted, tyrosine enriched diet, the impaired neuropsychological and behavioural functions appear to be reversible. One mechanism may involve an impaired synthesis of dopamine and serotonin, as the improvement is accompanied by an increase in dopamine and serotonin excretion and a significant increase in CSF concentrations of HVA and 5-HIAA.(ABSTRACT TRUNCATED AT 250 WORDS)

Infantile Refsum's disease: biochemical findings suggesting multiple peroxisomal dysfunction.

Abstract: Infantile Refsum's disease was diagnosed in three male patients, presenting with facial dysmorphia, retinitis pigmentosa, neurosensory hearing loss, hepatomegaly, osteopenia and delayed growth and psychomotor development. An elevated plasma phytanic acid concentration and a deficient phytanic acid oxidase activity in fibroblasts were found with an accumulation of very long chain fatty acids in plasma and fibroblasts. There were elevated pipecolic acid levels in plasma, urine and CSF, and abnormal bile acid metabolites in plasma. Deficient activity of acylCoA: dihydroxyacetone phosphate acyl transferase was found in thrombocytes and fibroblasts of these patients as well as an impairedde novo plasmalogen biosynthesis in fibroblasts. These biochemical abnormalities, previously described in the Zellweger syndrome, suggest multiple peroxisomal dysfunction in our patients.

3-Hydroxy-3-methylglutaryl-coenzyme a lyase deficiency: a review.

Abstract: Children with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG-CoA-LD; McKusick 24645), have inherited two areas of metabolic weakness. Firstly, they are unable to metabolize fully the carbon skeleton of leucine, and secondly, they cannot make ketone bodies in response to prolonged fasting. In the first year of life infants with HMG-CoA-LD run a high risk of developing severe hypoglycaemia which can lead to death if prompt intervention does not occur. The metabolic crisis develops when the infant is first introduced to dietary protein soon after birth, or later, when a reduced intake of glucose, often during a viral infection, results in a drain on the infant's circulating glucose levels. However, where diets are adequately adjusted to limit protein and fat intake, the metabolic handicaps of individuals with HMG-CoA-LD are not exposed and they are virtually symptomless. As children with HMG-CoA-LD grow older the incidence of hypoglycaemic attacks diminishes and they usually develop normally. This article reviews literature on cases of HMG-CoA-LD and interprets data on altered metabolism in these children.

Gonadal function in patients with galactosaemia

Abstract: Gonadal function was followed in 26 females and 12 males with galactosaemia due to deficiency of the enzyme galactose-1-phosphate (Gal-1-P) uridyl transferase over a 4 year period. Gonadal function was normal in males, but all females except two had evidence of acquired ovarian failure. Twelve females with ovarian failure documented at the beginning of this study continued to have either primary or secondary amenorrhoea on follow-up. Five of six patients, who previously had normal gonadal function developed either hypergonadotrophic hypogonadism or an abnormal response to gonadotrophin-releasing hormone (LRH) indicative of acquired ovarian damage. Seven of eight female patients, 1-12 years of age, who were evaluated for the first time had an exaggerated release of gonadotrophins during LRH stimulation tests diagnostic of gonadal insufficiency. The pathogenesis of ovarian failure remains unknown, but it appears likely that galactose or Gal-1-P is toxic to the ovary. The source of galactose metabolites, which may begin to accumulate prenatally and continue to damage the gonad in the postnatal period, is likely to be derived from the diet and from the endogenous synthesis of Gal-1-P from glucose via a variety of metabolic pathways. The testis appears to be relatively resistant to the effects of abnormal galactose metabolism.

Peroxisomal Abnormalities in Rhizomelic Chondrodysplasia Punctata

Abstract: The rhizomelic type of chondrodysplasia punctata (RCDP), an autosomal recessive disorder, is clinically characterized by a disproportionally short stature affecting primarily the proximal parts of the extremities, typical facial appearance, congenital cataracts, joint contractures, characteristic ocular involvement and severe mental retardation (Spranger et al, 1971). Radiological studies reveal shortening, metaphyseal cupping and disturbed ossification of humeri and/or femora, together with epiphyseal and extraepiphyseal calcifications (Spranger et al., 1971). No biochemical abnormalities have been described so far.

Disorders of the Pyruvate Dehydrogenase Complex

Abstract: Pyruvate dehydrogenase deficiency may be a non-specific consequence of many different neurological degenerative disorders. There are also serious methodological problems in estimating the activity of this enzyme complex.

Treatment of chronic congenital lactic acidosis by oral administration of dichloroacetate

Abstract: Sodium dichloroacetate (DCA) was administered orally at a dose of 50 mg per kg body weight twice or three times per day to a newborn infant with lactic acidosis of unknown cause (patient 1) and to a 15-year-old boy with mitochondrial encephalomyopathy associated with lactic acidosis (patient 2). In patient 1, during treatment with DCA, DCA accumulated in the blood judging from the findings that the urinary excretion of DCA increased cumulatively and the blood lactate level rapidly decreased to the normal range. In patient 2, the blood DCA level gradually increased during treatment to a concentration of 250 µgml−1 and the blood lactate level decreased and was maintained within the normal range. DCA was detected in the brain (25 µg g tissue−1) and the liver, kidney and muscle (33.8, 33.8 and 26.3 µg g tissue−1, respectively) obtained at autopsy of patient 1, and in the cerebrospinal fluid of patient 2 at a concentration of 125 µg ml−1 when the blood concentration was 250 µg ml−1. The lactate levels in the cerebrospinal fluid decreased from 7 and 4mmoll−1 to 2.4 and 2.6 mmoll−1 in patients 1 and 2, respectively. Thus DCA may be useful in clinical treatment of chronic congenital lactic acidosis because it seems to cross the blood-brain barrier. However, it must be given at non-toxic doses, determined by monitoring the concentrations of lactate and DCA in the blood, because orally administered DCA tends to accumulate in tissues.

Enzyme activities and phospholipid storage patterns in brain and spleen samples from Niemann-Pick disease variants: a comparison of neuropathic and non-neuropathic forms.

Abstract: Phospholipid levels and enzyme activities were measured in brain and spleen samples from patients with the three major variants of Niemann-Pick disease. Accumulations of sphingomyelin and bis(monoacylglycero)phosphate were demonstrated in spleen from types A and B and group C Niemann-Pick disease, whereas only in type A Niemann-Pick brain was the sphingomyelin concentration increased. Sphingomyelinase activity was markedly deficient in type A Niemann-Pick brain and spleen but residual activity of approximately 12% of control was measured in type B Niemann-Pick brain. Normal or raised sphingomyelinase and β-glucosidase activities were measured in group C Niemann-Pick brain and spleen. Significant (17% of control) residual β-glucosidase activity was also measured in non-neuropathic Gaucher brain. Normal levels of neutral sphingomyelinase activity were measured in brain samples from the three variants of Niemann-Pick disease. Acid sphingomyelinase activity in group C Niemann-Pick brain appeared normal with respect to enzyme extraction, pH optimum (pH5.0) and apparentK m (approximately 0.4 mmol/L). Isoelectric focusing of brain sphingomyelinase revealed a degree of heterogeneity with activity peaks between pI 4.5 and 6.5. No defect was observed in group C Niemann-Pick brain and, although attenuated, all peaks were present in type B Niemann-Pick brain.

Peroxisomes in infantile phytanic acid storage disease: a cytochemical study of skin fibroblasts.

Abstract: Cultured skin fibroblasts from six patients demonstrating clinical signs and biochemical characteristics of infantile phytanic acid storage disease (IPSD) were examined by electron microscopy, using cytochemical procedures for the demonstration of peroxisomal catalase activity. In four of the six fibroblast cell lines peroxisomes strongly reactive for catalase were present in numbers similar to those found in normal fibroblasts. Liver biopsy tissue from one of these patients showed no typical hepatic peroxisomes, but did show small, marginally reactive bodies. In two other IPSD fibroblast cell lines peroxisomes with appreciable cytochemical reactivity were rare or absent. It seems, therefore, that infantile phytanic acid storage disease is heterogeneous with respect to the presence of cytochemically recognizable peroxisomes, at least in the cases studied here. Furthermore, peroxisomes may be markedly affected in one cell type — liver — and yet not affected in another — skin fibroblasts — within a single individual.

Incidence of Phenylketonuria and Hyperphenylalaninaemia in a Sample of the Turkish Newborn Population

Abstract: The incidence of hereditary aminoacidopathies has been determined and nationwide programmes focussed on the most common diseases have been set up in the USA and most of the European countries. Specifically, the programme for phenylketonuria (PKU, McKusick 26160) has been successful and has served as a model for the detection and preventive treatment of genetic diseases.

Age-related differences in plasmalogen content of erythrocytes from patients with the cerebro-hepato-renal (Zellweger) syndrome: implications for postnatal detection of the disease.

Abstract: Phosphatidylethanolamine plasmalogen levels were determined in erythrocytes from controls and 13 patients with the cerebro-hepato-renal (Zellweger) syndrome. It was found that in Zellweger patients 20 weeks of age or younger, erythrocyte phosphatidylethanolamine plasmalogen levels were lowered whereas in older patients (except in one) normal levels were found. The results obtained suggest a close relationship between the age of the patients at sampling and the phosphatidylethanolamine plasmalogen levels in their erythrocytes. A possible explanation for these findings and the implications for the postnatal detection of Zellweger syndrome are discussed.

A new case of C6–C14 dicarboxylic aciduria with favourable evolution

Abstract: Acyl-CoA dehydrogenation deficiencies and carnitine deficiencies result in several biochemical disturbances with no specific organic acid profile and similar symptoms (Duran et al., 1984). We present here a case of C6–C14dicarboxylic aciduria with an unusual major peak, eluting just before adipic acid, which is currently under investigation. The patient responded to treatment with carnitine, riboflavin and a high carbohydrate, low fat diet with frequent intakes.

Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like Episodes Syndrome and NADH-CoQ Reductase Deficiency

Abstract: M. KOBAYASHI 1, H. MORISHITA 1, N. SUGIYAMA 1, K. YOKOCHI 1, M. NAKANO 1, Y. WADA 1, Y. HOTTA 2, A. TERAUCHI 3 and I. NONAKA 4 1Department of Paediatrics and ~First Department of Anatomy, Medical School, Nagoya City University, Kawasumi-cho, Mizuho-ku, Nagoya 467, Japan 3Higashimatsumoto National Sanatorium, Matsumoto 399-65, Nagano, Japan 4National Centre for Nervous, Mental and Muscular Disorders, Kodaira 187, Tokyo, Japan

Pregnancy in and incidence of xanthine oxidase deficiency.

Abstract: Our patient was found to be hypouricaemic, 31/~molL -a (normal 100425/lmolL -1) during a survey of 1000 consecutive pregnant women. At 16 weeks (w) gestation her urinary urate was low, 0.3mmo124h -1 (normal 2.14.4mmo124h -1) and plasma xanthine (xan) was high at 9/~molL -1 (normal <2/imol L-i) , confirming a diagnosis of xanthine oxidase deficiency (McKusick 27830). Normal pregnancy ended in the spontaneous onset of labour at 41w, and a normal vaginal delivery of a fit 3.39 kg girl who was breastfed. Maternal plasma urate (/~mol L -1) rose to 47 at 27w, 54 at 31w and 120 in labour at 41w, and fell after delivery to 25-35. Maternal plasma xan concentrations (/lmolL -i) rose slightly in pregnancy from 9 at 16w to 12 at 31w and returned to 10 six weeks after delivery. In the 2 days after delivery xan concentrations fell from 30 to 23. Plasma hypoxanthine (hyp) concentrations (/~mol L -~) were at the upper limits of the normal range, being 4 at 16w and 5 at 31W. Labour markedly raised concentrations of hyp to 20 and of xan to 21; the hyp elevation is greater than the normal approximate doubling of concentration during labour to a mean (SD) 3.5 (1.6), n = 12. Six weeks after delivery plasma hyp had returned to a normal value of 3. After delivery the mixed cord blood (fetal) concentrations (/lmol L -i) of hyp were 25 (normal <10) and ofxan were 7 (normal <4). Amniotic fluid concentrations (/~molL -i) of hyp were 11 and of xan were 14 (normal after labour <10)o Maternal renal excretion of xan (nmol per h per kg body weight) rose from 580 at 16w to 1020 at 31w and 990 at 41w, falling to 490 six weeks after delivery with no systematic change in hyp excretion (107-180 nmol per h per kg body weight). Maternal weight was 73.5kg. Hyp would be efficiently recycled by the mother despite her inability to metabolize xan. No rise in urinary excretion of urate was detected. Calculated renal clearances for hyp and xan were similar to previous values (Harkness et al., 1983) although creatinine outputs were low. The minimal urinary excretion values suggest a transfer of purines hyp and xan from fetus to mother throughout the last 3 months of pregnancy. The rises in plasma urate are also consistent with such a transfer of urate and agree with previous results in 4 pregnancies (Uzan et al., 1980, Simmonds et aI., 1982). The fetus and infant had normal xanthine oxidase activity since urate concentrations (/lmolL -~) of 204 in amniotic fluid (normal range 200-520), and of 192 in cord blood plasma were normal and were higher than the urate concentration of 120 in maternal blood plasma at delivery; in addition, the infant's excretions (nmol per h per kg body weight) of hyp, 8, and xan, 10, were normal. However, fetal (cord) blood plasma concentrations of hyp and of xan were more than twice the 1Division of Inherited Metabolic Diseases, MRC Clinical Research Centre and 3Department of Obstetrics, Northwick Park Hospital, Watford Road, Harrow HA1 3U J, UK 2Department of Clinical Chemistry, University of Edinburgh, Edinburgh EH3 9YW, UK.

Protein-bound plasma homocyst(e)ine and identification of heterozygotes for cystathionine-synthase deficiency.

Abstract: We measured protein-bound plasma homocyst(e)ine in 15 normal adult subjects and nine heterozygotes for homocystinuria due to cystathionine β-synthase deficiency. The mean (±SD) concentrations obtained in the two groups of subjects were 4.35±1.50 and 9.16±3.40 µmoll−1, respectively. The mean values were significantly different, although the levels of three heterozygotes overlapped those of the control range. This method allows preliminary screening of the heterozygotes for homocystinuria and can be carried out by laboratories that have only facilities for amino acid analysis.

Molecular basis of α1-antitrypsin deficiency and its potential therapy by gene transfer

Abstract: The gene for α1-antitrypsin, a serum anti-protease, has been cloned and sequenced. The underlying mutation in the PiZ allele has been identified as a G to A conversion giving rise to the substitution of glu by lys at position 342. Preparation of specific probes has allowed prenatal diagnosis. Recombinant retroviruses containing the normal human α1-antitrypsin gene have been constructed and used to infect NIH3T3 cells. Analysis of DNA, RNA and protein indicate that successful incorporation of the α1-antitrypsin was achieved and that the gene was capable of being expressed. The feasibility of genetic replacement therapy has been demonstrated and further experiments justified.

DNA Analysis for Ornithine Transcarbamylase Deficiency

Abstract: We have utilized the Southern blotting technique to analyse genomic DNA from males with ornithine transcarbamylase (OTC) deficiency and their families. Using a nearly full-length human cDNA probe, we have identified 3 patients with deletions at this locus and have characterized 4 different restriction fragment length polymorphisms that can be used as linkage markers for the OTC mutation. These polymorphisms occur at sufficiently high frequencies so as to enable us to distinguish the two X-chromosomes in approximately 80% of OTC carriers. As a direct consequence of these findings, prenatal diagnosis and carrier assessment can be offered to a large fraction of families at risk for OTC deficiency.

Biochemical aspects of congenital adrenal hyperplasia.

Abstract: The assay of 17α-hydroxyprogesterone in blood spots on filter paper forms the basis of neonatal screening programmes to detect congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The blood concentrations of this hormone in the neonate varies with gestation age (term v preterm), age after birth, time of day and illness. Broad reference ranges for blood spot 17a-hydroxyprogesterone concentrations are therefore quoted for healthy term infants and these ranges are not appropriate for the interpretation of values in preterm and sick newborns. There is a risk of a false-negative or of a false-positive diagnosis. Many of the above difficulties may result from variations in assay performance due to changes in the pattern of steroids produced by the adrenal gland which in turn relate to morphological changes in the adrenal cortex at this age. The purpose of this presentation is to define the complex steroid milieu of the newborn human and briefly to review the factors which determine the function of the adrenal gland, since these influence the extent to which an assay for this steroid needs to be evaluated before application to neonatal screening for CAH. The data to be presented derive from the capillary column gas chromatographic analysis (GC) of steroids in urine since this provides the best method to display the overall steroid production of the organism. The GC method has itself been refined so that CAH can now be reliably diagnosed using this method, but the information from this work will also be judged for its relevance to the problems encountered in the neonatal screening for CAH by blood spot analysis.

Presentation of the data of the Italian registry for oculocutaneous tyrosinaemia

Abstract: Hereditary type II tyrosinaemia (McKusick 27660) is an autosomal recessive disorder characterized by hypertyrosinaemia and tyrosyluria, without signs of hepatic and renal damage. The patients have a dendritic keratopathy, painful hyperkeratosis of the palms and soles and sometimes mental retardation. Hypertyrosinaemia with values ranging from 14 to 62mgdl−1, tyrosinuria and tyrosyluria are found. A defect of hepatic tyrosine aminotransferase (EC 2.6.1.5) in the cytosol is considered to be the molecular abnormality (Kennaway and Buist, 1971; Goldsmith et al., 1979).

A new case of arginase deficiency in a Spanish male.

Abstract: A new case of arginase deficiency is reported in a male newborn from Spain. In contrast with the majority of the earlier cases, this infant showed severe protein intolerance of early onset. The diagnosis was based on the assay of the urea cycle enzymes in a postmortem liver sample. Levels of erythrocyte arginase were also determined in the parents and in a sister of the patient, and were consistent with heterozygosity. From a study of the pedigree it appears that arginase deficiency in this family presents a dramatic course.

Human DNA Repair Defects

Abstract: A number of human genetic diseases have come to be described as being defective in DNA repair. The minimum criterion on which this assignment is based is hypersensitivity to the clastogenic or lethal action of specific DNA damaging agents. In one disease, xeroderma pigmentosum, the molecular evidence for a defect in DNA repair is unequivocal. This condition then acts as a model for dissecting others. For the other diseases the formal evidence for defects in repair is less secure or even lacking. The evidence for repair in each disease is assembled together with any methods that have been used to support the differential diagnosis or for prenatal diagnosis. Attempts to clone human DNA repair genes are in hand and may provide the necessary evidence to decide if all the putative DNA repair defective diseases are genuine.

Lymphoid cell lines as a model system for the study of Wolman's disease: Enzymatic, metabolic and ultrastructural investigations

Abstract: Epstein-Barr virus (EBV) transformed lymphoid cell lines (LCL) were established from blood lymphocytes of a patient affected with Wolman's disease (WD) and from her parents. These LCL showed a severe deficiency in acid lipase activity using every substrate in comparison to LCL from normal subjects, in which acid lipase activity was similar to that in blood lymphocytes. In the LCL from Wolman's disease a major accumulation of neutral lipids was observed, mainly cholesteryl esters, CE (amount around 7 times higher than in normal cells and ratio of esterified/free cholesterol increased by 10 times) and to a lesser extent triglycerides, TG (amount increased by 1.5 times). Electron microscopy showed the storage vacuoles of neutral lipids quite characteristic of this lysosomal disease. The reported data demonstrated the validity of transformed LCL as a cellular model system in culture for experimental studies of Wolman's disease and for investigating the lysosomal metabolism of neutral lipids.

Tetrahydrobiopterin non-responsiveness in dihydropteridine reductase deficiency is associated with the presence of mutant protein.

Abstract: Correlation of the response to a load of tetrahydrobiopterin (BH4) in dihydropterin reductase (DHPR) deficient patients to the type of mutation in these patients has led to the conclusion that 4 patients without mutant DHPR molecules in their cells respond to the BH4 load, whereas 3 patients with mutant DHPR in their cells do not respond. Intravenous injection of BH4 in 1 of the cases not responding to BH4 again showed no response.

Molecular genetics of PKU.

Abstract: This review summarizes the isolation of rat phenylalanine hydroxylase mRNA and its use in the synthesis of its cDNA. As rat cDNA cross-hybridized with human phenylalanine hydroxylase mRNA, the rat cDNA probe was used to screen a human liver cDNA library. A partial length cDNA human phenylalanine hydroxylase probe was obtained which showed restriction fragment length polymorphism (RFLP) with 3 restriction enzymes and was successfully used to trace the transmission of the mutant gene in PKU families with one or more affected children. Recently the partial-length cDNA probe has been used to isolate a full-length cDNA probe for human phenylalanine hydroxylase. Gene transfer experiments with the full-length cDNA have led to expression of human phenylalanine hydroxylase in eukaryotic cultured cells and in recombinant bacteria which normally do not express phenylalanine hydroxylase activity. The full-length cDNA of human phenylalanine hydroxylase has been sequenced, uncovering the nucleic acid sequence of the exons of the human phenylalanine hydroxylase gene, as well as the most likely amino acid structure of the human phenylalanine hydroxylase enzyme. The full-length cDNA probe has 10 identifiable binding sites for restriction enzymes that show RFLP. These additional RFLPs have enabled haplotype analyses of the normal and mutant phenylalanine hydroxylase genes in PKU families. Haplotype analyses in Danish PKU families revealed 12 different haplotypes. However, of 132 chromosomes analysed from 66 obligate hetero- zygotes, 59 out of 66 PKU genes were associated with only 4 haplotypes.

Family studies of the Lesch-Nyhan syndrome: the use of a restriction fragment length polymorphism (RFLP) closely linked to the disease gene for carrier state and prenatal diagnosis.

Abstract: We have investigated the usefulness of a full-length cDNA probe for the hypoxanthine phosphoribosyltransferase, HPRT gene in the diagnosis of the carrier state for the Lesch-Nyhan syndrome in 13 families. The products of DNA digestion by 21 different restriction enzymes were examined by Southern analysis. The only useful polymorphism detected was a three allele polymorphism withBam HI; others were found withMsp I andHind III but they were not linked to the disease. None of the boys with the Lesch-Nyhan syndrome had a unique polymorphism and therefore a detectable gene deletion or other major structural alteration. A DNA polymorphism capable of giving additional diagnostic information with respect to carrier status was present in 8 of the 13 families, but not for all of the family members at risk. The cDNA probe and restriction enzyme analysis gave anunequivocal diagnosis to 20 women out of 28 who might have been carriers and for whom it would not have been available on the basis of pedigree analysis and biochemical tests alone. If a linked polymorphism is to be useful for carrier detection it must be present in only one of the mother's X-chromosomes (i.e. the mother must carry a different allele on each X-chromosome). Although this polymorphism is detected by an HPRT probe it is not at the site of the specific gene lesion. In spite of considerable genetic heterogeneity, most cases of the Lesch-Nyhan syndrome appear to be due to either single base substitutions or small deletions which are not detectable by Southern analysis. None of the propositi in these families was due to a new mutation arising in the maternal germ line. One family was identified in which the evidence was compatible with a mutation having arisen in the X-chromosome which the mother of the propositus inherited from her father, and in another family the mutation arose in the maternal grandmother. A case illustrating the application of this restriction fragment length polymorphism to the first trimester prenatal diagnosis of the Lesch-Nyhan syndrome is also reported. This study illustrates the limitations as well as the value of using a linked DNA polymorphism for carrier state diagnosis in X-linked diseases.

Liver Transplantation in a 23-year-old Tyrosinaemia Patient: Effects on the Renal Tubular Dysfunction

Abstract: Orthotopic liver transplantation was performed on a 23-year-old female with hereditary tyrosinaemia. The disorder was diagnosed at 7 years of age due to severe rickets, and the patient was treated with a diet restricted in phenylalanine and tyrosine. Nineteen months before the transplantation she had an acute episode of diffuse gastrointestinal bleeding due to portal hypertension. Three subsequent bleeding episodes with accompanying ascites and signs of encephalopathy were considered life-threatening.

A new variant of sphingomyelinase deficiency (Niemann-Pick): visceromegaly, minimal neurological lesions and low in vivo degradation rate of sphingomyelin.

Abstract: Three males (aged 10 years, 3 years 9 months and 2 years 8 months) with profound sphingomyelinase deficiency are presented. The sphingomyelin storage in the liver biopsies attained 30-fold, 65-fold and 16-fold increases against controls, respectively. Levels of bis(monoacylglyceryl) phosphate were also increased. In two cases the bone marrow contained foam cells with liquid crystals of sphingomyelin. Besides the visceral involvement dominated by hepatosplenomegaly, all three cases showed discrete, so far stationary (8 years, 42 months and 28 months) neuropathic features and retinal lesions resembling the classical cherry-red spot. Electrophysiological examinations showed a variable reduction of peripheral nerve conduction velocity and prolongation of the latencies of somatosensory, visual and auditory evoked potentials. Ultrastructural examination of skin nerves showed a slight storage, mainly in Schwann cells. In some myelinated fibres there were pseudomyelinic ovoids. The cases therefore displayed features of both A and B types of sphingomyelinase deficiency and should be conventionally classified as intermediate. However, the very low levels ofin vivo sphingomyelin hydrolysis (not exceeding 6%, against 30±10% in type B and 77±5% in controls) were clearly within the range of type A values (5±2%). Accordingly, we suggest that the cases may be biochemically classified as variants of type A disease.

GM2 Gangliosidosis with Hexosaminidase A and B Defect: Report of a Family with Motor Neuron Disease-like Phenotype

Abstract: GM2 Gangliosidosis is an inherited dysmetabolic disease, characterized by accumulation of GM2 and GA2 gangliosides in neuronal as well as in non-neuronal tissues. Biochemically the disorder can be due either to a deficiency of hexosaminidase isoenzyme A (Tay-Sachs form) or isoenzymes A and B (Sandhoff variant) or to absence of the activator protein of the enzyme (Sandhoff and Christomanov, 1979). Infantile, juvenile and adult phenotypes are known. Recently patients with late-onset disease with amyotrophic lateral sclerosis-like or Kugebelg-Welander phenotypes or spinocerebellar ataxia have been described, and a large heterogeneity is increasingly being discovered (Johnson, 1981; Federico, in press).

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency.

Abstract: In 1979 we reported a patient who presented at the age of 9 months with clinical and biochemical features of Reye's syndrome. 3-Hydroxyisovaleric, 3-methylglutaric, 3methylglutaconic and 3-hydroxy-3-methylglutaric acids were found in the urine on GLC analysis for organic acids (Leonard et aI., 1979a). Echovirus 11 was isolated from CSF, nose and throat swabs and from tracheal aspirates (Leonard et al., 1979b). Following her recovery from the initial illness she started on a leucine, protein and fat restricted diet. This required several modifications before weight gain and growth were acceptable. Progressive restriction in dietary fat from 3 .2gkgld -1 to 1 .7gkgld -1 was paralleled by a fall in urinary excretion of 3hydroxy-3-methylglutaric acid (1603 to 349 mmol (tool creatinine) -1) and 3-methylglutaconic acid (2800 to 785 mmol (tool creatinine) -I) despite a concomitant increase in leucine intake from 50 to 150mgkg -1 d -1. 3-Hydrox~sovaleric and 3methylgtutaric acid were less affected by dietary changes, urinary excretion falling from 1053 to 575, and 257 to 108retool (tool creatinine) -I respectively. All four of these organic acids persisted in the urine, 3-hydroxy-3-methylglutaric acid excretion remaining greater than 250 mmol (tool creatinine)1. HMG-CoA lyase (EC 4.1.3.4) activity was assayed (Clinkenbeard et al., 1975) in white cell pellets from the patient and her parents (by Dr R. Schutgens, University Hospital, Amsterdam). No activity was detectable in the case of the patient, and both her parents had activities lower than 5 of the 6 controls, suggesting that they were heterozygous for the condition. (Results in nmolmin t (mgprotein)-l: father, 5.1; mother, 6.8). The patient sustained severe neurological damage with her first illness. She remained severely retarded, microcephalic and visually impaired, with evidence of cerebral atrophy on CT scan. Although subject to recurrent upper respiratory tract infections she had no further episodes of hypoglycaemia, hyperammonaemia or encephalopathy. Infections were managed at home with frequent drinks of glucose polymer. Hospital admissions were only required for control of her epilepsy or for social reasons. At the age of 5 years and 9 months, after a 16-hour fast, the plasma concentration of 3-hydroxybutyrate remained undetectable (<0.1mmolL -1) but there was no hypoglycaemia (blood glucose 3.6mmolL-l) . In 1985 while on holiday in Pakistan she died from what was described as 'sickness and diarrhoea'. No other details were available.

Neutrophil metabolic dysfunction in genetically heterogeneous patients with glycogen storage disease type 1b.

Abstract: Recent reports have described neutropenia, neutrophil dysfunction and the resulting episodes of recurrent infection as distinctive features of glycogen storage disease (GSD) type lb (McKusick 23222) (Beaudet et aI., 1980; Gahr and Heyne, 1983; Seger et al., 1984). GSD lb has been attributed to a defect of the microsomal glucose-6-phosphate (G6P) translocase (Narisawa et al., 1978; Lange et al., 1980). The interest of many investigators was focussed on the relationship between metabolic abnormalities in the neutrophil and the defect of G6P translocase. However, the ~ etiology for the abnormalities in the neutrophil is not fully understood. This paper reports an investigation of the neutrophil metabolic function in three patients with GSD lb and the heterogeneity of neutrophil dysfunction within GSD lb.