Tumour necrosis factor in neonatal listeriosis: a case report

A newborn with fatal neonatal listeriosis developed septic shock, neutropenia, thrombocytopenia and profound hypoxaemia due to severe pulmonary hypertension. Tumour necrosis factor , interleukin-1- and interferon- serum concentrations were markedly elevated, suggesting the participation of these cytokines in the aetiopathogenesis of shock induced by Listeria monocytogenes in the neonate.Abbreviations IFN- interferon- - IFN- interferon- - IL-1 interleukin-1 - MPA monocytosis producing agent - TNF- tumour necrosis factor      

The unreliability of mean corpuscular volume and mean cellular hemoglobin determinations in the diagnosis of α-thalassemia in newborn infants

Mean corpuscular volume (MCV) and mean cellular hemoglobin (MCH) were determined by means of a Hemalog 8/90 electronic counter in 51 full-term newborn infants with -thalassemia-2 and 15 with -thalassemia-1, as well as in 150 normal newborn infants. The mean MCV and MCH values were 92 fl±06 and 33.26 pg±2.22 in the normal newborn infants, 82 fl±07 and 29.40 pg±2.60 in the -thalassemia-2 subjects, and 73 fl±06 and 26.07 pg±2.05 in the -thalassemia-1 subjects. Four of the 150 normal newborn infants had MCV's<79 fl and MCH's<29.00 pg whereas 5 of the -thalassemic subjects had MCV's>90 fl and MCH's>32.00 pg. We conclude that MCV and MCH determinations are unreliable in the diagnosis of -thalassemia in the neonatal period.     

Detection of late onset steroid 21-hydroxylase deficiency by capillary gas chromatographic profiling of urinary steroids in children and adolescents

Patients suffering from late onset 21-hydroxylase deficiency (LO-CAH) excreted only slightly higher amounts of 17-hydroxypregnanolone (17-OH-PO), pregnanetriol (PT) and 11-oxo-pregnanetriol (11-O-PT) than age-matched healthy controls. To discriminate between LO-CAH and virilization of unknown origin and precocious pubarche, we calculated the following ratios: (1) pregnanetriol to tetrahydrocortisone (PT/THE), (2) the sum of 17-OH-PO, PT and 11-O-PT (OHP-M) to the sum of THE, tetrahydrocortisol (THF) and allotetrahydrocortisol (a-THF) (C-M) and (3) 11-O-PT to C-M. The following patients were studied: 9 patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency-non-salt losing (CAH-NSL), never treated; 8 patients with CAH (NSL/SL: 3/5) off treatment; 10 patients with LO-CAH; 11 patients with virilization of unknown origin (prepubertal/pubertal: 5/6) and 9 patients with precocious pubarche. Healthy individuals and obligatory heterozygote carriers of comparable ages served as controls. LO-CAH showed increased ratios (median (range)) of PT/THE: 2.27, (1.15–9.09), OHP-M/C-M: 2.30, (1.24–8.15), and 11-O-PT/C-M: 0.24, (0.13–1.23) compared to healthy individuals and heterozygous carriers: PT/THE 0.28, (0.03–0.57), OHP-M/C-M 0.23, (0.06–0.46) and 11-O-PT/C-M<0.01, (<0.01–0.06), respectively. The calculation of ratios, rather than absolute amounts seems to allow the detection of LO-CAH in a single spontaneously voided urine specimen. The clinical and measurable hormonal manifestations of LO-CAH occur at the same time.Abbreviations LO-CAH late onset 21-hydroxylase deficiency - CAH congenital adrenal hyperplasia due to 21-hydroxylase deficiency - SL salt losing - NSL non-salt losing - p.p. prepubertal - p. pubertal - 17-OH-PO 17-hydroxypregnanolone (5-pregnane-3,17-diol-20-one) - PT pregnanetriol (5-pregnane-3,17,20-triol) - 11-O-PT 11-oxo-pregnanetriol (5-pregnane-3,17,20-triol-11-one) - THE tetrahydrocortisone (5-pregnane-3,17,21-triol-11,20-dione) - THF tetrahydrocortisol (5-pregnane-3,11,17,21-tetrol-20-one) - a-THF allotetrahydrocortisol (5-pregnane-3,11,17,21-tetrol-20-one) - OHP-M 17-OH-PO+PT+11-O-PT - C-M THE+THF+a-THF Dedicated to Prof. Enno Kleihauer, Ulm, on the occasion of his 60th birthday     

α-aminoadipic aciduria and persistence of fetal haemoglobin in an oligophrenic child

The case of a mentally retarded girl with a number of dysmorphic features, Raynaud's phenomenon, hypotonia and petit mal seizures is presented. Laboratory investigations showed -aminoadipic aciduria and a high level of fetal haemoglobin. Oral l-lysine loading resulted in a marked increase of -aminoadipic acid in blood and urine. After 3 months of pyridoxine medication the increase of -aminoadipic acid in blood and urine during the oral l-lysine loading test was less than in the test before treatment. A normal degradation rate of dl--amino [1-¹⁴C] adipic acid in fibroblasts of the patient, as measured by ¹⁴CO₂ production, did not indicate a primary enzyme defect in the -aminoadipic acid transamination or decarboxylation steps.The persistent HbF could be the result of stress on the erythropoiesis by a secondary induced defect in an early stage of haemoglobin synthesis in which -amino--ketoadipic acid, a structural analogue of -aminoadipic acid, is an intermediate.     

Age-dependency of alpha- and beta-adrenoceptors on thrombocytes and lymphocytes of asthmatic and nonasthmatic children

Among the possible mechanisms which may cause wheezing or asthmatic episodes a genetically determined -adrenoceptor blockade and a hyperresponsiveness of -andrenoceptors has been postulated. Evidence to support this hypothesis stems from an increased bronchial sensitivity to -blockers, a reduced formation of cyclic AMP in response to -adrenergic stimulation and enhanced -adrenergic responses in asthmatic subjects. The recent development of techniques for measuring the specific, high-affinity binding of radiolabeled -and -adrenergic antagonists made it possible to study - and -adrenoceptors in vitro. Based upon the assumption that a change in the number and/or affinity of adrenergic receptors might be a general phenomenon, we have performed - and -receptor binding studies on lymphocytes and platelets from wheezing infants and asthmatic children as well as of infants, children, and adults not suffering from these diseases.Using ¹²⁵[I]-cyanopindolol (ICYP) and ³[H]-yohimbine (HYOH) as highly specific ligands for - and -adrenoceptors, the following results were obtained: (1) Lymphocytes and platelets from control subjects and asthamatics bound similar amounts of ICYP and HYOH and thus showed no differences either in the number or the affinity of - and -adrenoceptors. Lymphocytes and platelets of wheezing and nonwheezing infants also bound the same amounts of the radioligands. (2) In asthmatic children receiving 4×2 puffs salbutamol -adrenoceptor were down-regulated and this may mimic -adrenoceptor blockade. (3) When subjects were divided into four categories according to age (0–5, 5–10, 10–20 years, adults) the number of -adrenoceptor binding sites showed an age-dependent increase. The number and affinity of -adreneceptor binding sites on platelets was neither influenced by age nor disease.It is concluded that the - and -adrenoceptors of wheezing infants and asthmatic children at least on blood cells are normal. However the -adrenoceptors show an age-dependent maturation process, which may account for an unresponsiveness to -adrenoceptor agonists in wheezing infants.Supported by a grant from the Ministerium für Wissenschaft und Forschung, NRWPresented at the 19th Workshop for Pediatric Research, University of Göttingen, March 10–11, 1983     

Increased expression of EGFR and TGF-α in segmental renal dysplasia in duplex kidney

Renal dysplasia (RD) is a disorganised development of renal parenchyma that results in a deficit of functional renal tissue. It is known that the epidermal growth factor (EGF) and the transforming growth factor- (TGF-) enhance renal cell proliferation, migration and differentiation during kidney development through binding to the same EGF receptor (EGFR). The aim of the study was to analyse the expression of TGF- and EGFR in the dysplastic kidney. The specimens of dysplstic upper poles duplex kidneys were surgically resected from 19 patients. Indirect immunohistochemistry was performed using the ABC method employing antibodies against EGFR and TGF-, and gene expression using primers specific to the human genes. There was absent or weak EGFR and TGF- immunoreactivity in normal kidney tissue. In dysplastic kidneys, there was strong TGF- and EGFR immunoreactivity in the epithelium of primitive tubules and strong EGFR immunoreactivity in the connective tissue around the primitive tubules. Our findings of markedly increased local expression of EGFR and TGF- in primitive tubules suggest that EGFR and TGF- may play an important role in altering renal morphogenesis resulting in renal dysplasia.     

Proliferation of intrahepatic bile-duct epithelium in biliary atresia

Proliferating cell nuclear antigen (PCNA) and transforming growth factor (TGF) are considered as markers of cell proliferation. The expression of PCNA and TGF was evaluated immunohistochemically using anti-PCNA antibody and TGF in 31 patients with biliary atresia (BA) (15 jaundice-free and 16 with persistent jaundice) and 6 control infants. The labeling indices (LI) for PCNA- and TGF-positive bile-duct epithelium in BA were 14.1±14.0% and 51.4±33.7%, respectively, which was significantly higher than in the controls (P <0.01). In BA, the number of PCNA-immunoreactive cells was higher in the peripheral bile ductules than in the central bile ducts of the portal tract (P <0.01). LI was not related to patient age at the time of hepatic portoenterostomy in two groups divided at the age of 60 days. Patients in the persistent jaundice group had greater expression of PCNA and TGF (21.7±16.0% and 76.9±20.7%, respectively) compared to those in the jaundice-free group (6.0±2.7% and 24.3±20.9%, P <0.001). PCNA and TGF expression in the bile-duct epithelium of the portal tract was closely related to prognosis in BA patients, and thus could be useful as a prognostic marker.     

Serum tumour necrosis factor in newborns at risk for infections

Tumour necrosis factor- (TNF-) is an important mediator in the pathogenesis of Gram-negative shock. In order to assess the role of TNF- as a marker of the severity of infections in the neonates, serum TNF- concentrations were determined at the time of septic work-up in 69 newborns (gestational age: 28–40 weeks). Nine patients had systemic infection (group A), four of them with signs of circulatory failure. Eleven patients had positive cultures of gastric aspiration or placental smears (group B) and 49 patients had completly negative septic work-up. Patients of group A had significantly more elevated serum TNF- levels than patients of group B and C. Within group A, patients with circulatory failure had mean serum TNF- concentration of 2165±817 pg/ml versus 27±8 pg/ml in newborns without shock. Serum TNF- concentrations of more than 15 pg/ml detected systemic infections in eight out of nine patients. The specificity was 98% (1 elevated TNF- concentration out of 60 non infected patients). These data indicate that premature neonates and term newborns are able to produce TNF- when they are infected. Highly elevated TNF- concentrations are found in severe systemic infections causing cardiovascular impairment.     

Alpha-Synuclein Expression in the Developing Human Brain

Alpha ()-synuclein is a presynaptic protein, abnormal expression of which has been associated with neurodegenerative and neoplastic diseases. It is abundant in the developing vertebrate central nervous system (CNS), but less is known about its developmental expression in the human CNS. Immunohistochemical expression of -synuclein was studied in 39 fetal, perinatal, pediatric, and adolescent brains. Perikaryal expression of -synuclein is observed as early as 11-wk gestation in the cortical plate. Several discrete neuronal groups in the hippocampus, basal ganglia, and brain stem express perikaryal -synuclein by 20-wk gestation, persisting through the first few years of life. In the cerebellum, -synuclein is present by 21-wk gestation and persists into adult life as a coarse granular neuropil reaction product in the internal granular layer, and as a diffuse neuropil blush in the molecular layer. The germinal matrix, glia, endothelial cells, external granular layer, Pukinje cells, and dentate neurons are consistently negative for -synuclein. We conclude that -synuclein is expressed very early in human gestation, and that its distribution and temporal sequence of expression varies in discrete neuronal groups. Perikaryal -synuclein starts disappearing from the neuronal cytosol in early childhood, and only the neuropil retains immunoreactivity into adulthood. The reappearance of -synuclein in the adult neuronal cytosol in certain disease processes may represent reemergence of cues from an earlier developmental stage as part of a stress response.     

Cholic acid,chenodeoxycholic acid,alpha-1-fetoprotein and alpha-1-antitrypsin serum concentrations in breast-fed infants with prolonged jaundice

Thirteen breast-fed one-month-old infants with prolonged jaundice not due to known causes were included in this study. All infants were investigated at one and twelve months of age. Serum concentrations of total (TB) and conjugated bilirubin (CB), aspartate (ASAT) and alanine aminotransferase (ALAT), alkaline phosphatase (AP), -1-antitrypsin (-1-AT), -1-fetoprotein (AFP) and the two primary bile acids; cholic (CA) and chenodeoxycholic acid (CDCA) were determined at both ages. The Pi-phenotype of -1-AT was determined at the age of twelve months. The serum concentrations of TB, CB, AP and AFP were elevated at the age of one month but were normal at the age of twelve months. No changes in the serum concentrations of ASAT or ALAT were observed between one and twelve months of age, and the values were within the reference ranges. The serum concentrations of -1-AT were within the reference range at both ages. Two infants were heterozygous for MZ, and they had normal serum -1-AT concentrations. The serum concentrations of CA and CDCA were elevated at the age of one month and were still significantly elevated at the age of twelve months indicating that the infants had slight cholestasis at the age of one month, and that the cholestasis had largely subsided by the end of the first year of life.     

Adrenoceptors and the lung: their role in health and disease

- and -Adrenoceptors have each been divided into two subgroups (₁, ₂, ₁ and ₂). The basic mechanisms underlying the adrenoceptor/effector coupling are complex and vary for the -, but not for the -subpopulations. Adrenoceptors of the bronchi and the lung show a special pattern of distribution and response, ensuring that the airway system works as a functionary unit. Dysfunctions of adrenoceptormediated effects have been suggested to contribute to some important paediatric disorders such as hyaline membrane syndrome, wet lung, bronchial asthma, cystic fibrosis, and pertussis. Drugs which act on the adrenergic system influence some of these disorders directly. Further studies applying modern techniques to receptor research are needed in order to clarify the basic mechanisms involved in receptor-mediated lung disorders and the activity of drugs in lung tissue.Abbreviations AC adenylate cyclase - ADP adenosine diphosphate - -R -adrenoceptor - cAMP cyclic adenosine monophosphate - CF cystic fibrosis - GDP guanosine diphosphate - GTP guanosine triphosphate - IAP islet activating protein     

Upregulated expression of EGF and TGF-α in the proximal respiratory epithelium in the human hypoplastic lung in congenital diaphragmatic hernia

Newborn infants with congenital diaphragmatic hernia (CDH) still have a high mortality rate. Epidermal growth factor (EGF) and transforming growth factor- (TGF-) are peptide growth factors involved in the fetal lung growth and development. The EGF and TGF- have been reported to promote pulmonary branching activity and alveolar type-II pneumocyte proliferation. Epidermal growth factor and TGF- immunoreactivity and mRNA expression in the bronchial and bronchiolar epithelium is maximal during early fetal life and barely detectable in the proximal airways of neonatal lung. The purpose of this study was to determine protein and gene expression of EGF and TGF- in CDH lung in order to elucidate the potential role of these growth factors in the pathogenesis of pulmonary hypoplasia in CDH. Lung tissue specimens were obtained from archival lung tissue from 11 patients with CDH and 5 controls. Indirect immunohistochemistry was performed using ABC method with anti-EGF and anti-TGF- antibodies. In situ hybridization was performed using EGF and TGF- specific digoxigenin-labeled oligonucleotide probes. The most striking difference between hypoplastic CDH lung and control lung was the strong EGF and TGF- mRNA expression and immunoreactivity in the bronchial and bronchiolar epithelium in CDH lung. The upregulated protein and gene expression of EGF and TGF- in the proximal airways in the CDH hypoplastic lung suggests persistence of fetal stage of pulmonary airway development in CDH.     

Sisters with α-mannosidosis and systemic lupus erythematosus

Alpha-mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal -mannosidase (LAMAN). Here, we report two sisters with -mannosidosis who developed systemic lupus erythematosus (SLE). The sisters were both homozygous for a one bp deletion within the LAMAN gene resulting in a truncated gene product. The coincidence of -mannosidosis and SLE are discussed with regard to both clinical and molecular findings. Conclusion:-mannnosidosis may contribute to the onset of systemic lupus erythematosus in predisposed patients.Abbreviations ACR American College of Rheumatology - LAMAN lysosomal -mannosidase - SLE systemic lupus erythematosus     

Fetal bile acids in congenital biliary atresia —production in the liver and clinical significance

The 1-hydroxy bile acids have been said to be fetal bile acids. These bile acids were evaluated in eight patients with congenital biliary atresia (CBA) using gas chromatography-mass spectrometry. At the time of operation 1,3,7,12-tetrahydroxy-5-cholan-24-oic acid (CA-1-ol) and 1,3,7-trihydroxy-5-cholan-24-oic acid (CDCA-1-ol) were 0.46 ± 34 g/ml and 0.72 ± 0.45 g/ml, respectively, which was significantly higher than in the control group. The percentage CA-1-ol of total bile acids showed a tendency to decrease as age advanced. The grade of hepatic fibrosis ranged from F₂ to F₃ and the values and percentages of CA-1-ol and CDCA-1-ol were relatively higher in F₂ than F₃ patients. The percentage of total bile acids gradually increased in patients without sufficient bile flow but fell sharply after Kasai's procedure in the patients with sufficient bile flow. It appears that fetal bile acids are produced in the livers of CBA patients in the same way as in fetal liver, and that production continues in patients without good bile secretion even after Kasai's procedure. These results suggest that these hydroxylases are reactivated in CBA patients.     

Hypocalcaemia induced by glucocorticoids in a child with hypoparathyroidism treated with 1-α-hydroxyvitamin D3

Glucocorticoids tend to lower the intestinal absorption of calcium, leading to a negative calcium balance. A 7-year-old girl with hypoparathyroidism was maintained as normocalcaemic on 1--hydroxyvitamin D₃ (1D₃) and calcium gluconate lactate. During an episode of aplastic anaemia she was treated with prednisolone, with a subsequent dramatic fall of serum calcium despite 1D₃ treatment and serum 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) in the high-normal range. Glucocorticoids seem to have interfered directly with cellular events reponsible for intestinal absorption of calcium.Abbreviations 1D₃ 1--hydroxyvitamin D₃ - 1,25(OH)₂D₃ 1,25-dihydroxyvitamin D₃ - PTH parathyroid hormone - PTE parathyroid extract - RIA radioimmunoassay - TRP tubular reabsorption of phosphorus     

Urinary excretion of 17-hydroxypregnanolones in patients with different forms of congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency

To improve diagnostic criteria in different (classical salt-wasting (SW), classical simple virilizing (SV) and non classical late onset (LO)) forms of congential adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency, we investigated the urinary excretion of 17-hydroxypregnanolones (17OH-PO(5) and (5), 15-hydroxypregnanolone(15OH-PO), pregnanetriol(PT) and 11-oxo-pregnanetriol (11-O-PT) compared to hydrocortisone metabolities During the 1st month of life newborn infants with CAH-SW excreted from barely detectable to very large amounts of 17OH-PO(5), 15OH-PO and PT, and, in 12 of 14 cases, also 11-O-PT in their urines. From the 1st to the 28th day of life, cortisol metabolites were virtually absent in urines of CAH-SW infants. This was in contrast of 36 healthy newborn infants. We measured the excretion of 17OH-PO(5) in children with CAH of whom 19 patients with CAH-SV had a median 17OH-PO(5) excretion of 1110 g/day (range: 152–5515). In 21patients with CAH-LO, median excretion of 17OH-PO(5) was 294g/day (range: 66–1273). Besides the conventional metabolites of 17-hydroxyprogesterone (17OH-PO(5), PT and 11-O-PT),no 17OH-PO(5) was detected in the urines of 14 patients with precocious pubarche, in 14 patients with virilization of unknown origin and in 94 healthy children of comparable age. The ratio of 17OH-PO(5) to tetrahydrocortisone (THE) discriminated between CAH-SV and CAH-LO from the 1st to the 18th year of age. The determination of urinary 17OH-PO(5) is an excellent diagnostic method in CAH-SV as well as CAH-LO.     

Lacticacidaemia due to pyruvate dehydrogenase deficiency,with evidence of protein polymorphism in the α-subunit of the enzyme

In three infants with neonatal lacticacidaemia, a deficiency in the E₁ (pyruvate dehydrogenase) component of the pyruvate dehydrogenase complex was demonstrated in skin fibroblast cultures. Residual activites of the pyruvate dehydrogenase complex in the activated state were 1.6%, 3.9% and 18.8% of control values, respectively. Immunoprecipitation of extracts of cultures skin fibroblasts grown on ³⁵S-methionine with anti-pyruvate dehydrogenase complex antibody revealed an abnormality in the E₁-component of these three patients when visualised after sodium dodecyl sulphate/polyacrylamide gel electrophoresis. This component appeared to have a slightly lower molecular weight than did this protein from control cell strains. Cell strains from other patients with a deficiency of the pyruvate dehydrogenase complex did not exhibit this defect. Three patients also showed dysmorphism and developmental abnormalities of the central nervous system.Abbreviations PDHC pyruvate dehydrogenase complex - -MEM -minimal essential medium     

Familiärer mangel und α 1

Zusammenfassung Es wird über zwei Kinder aus zwei Familien mit Mangel an ₁ berichtet. Homozygote Defektträger wiesen etwa 15–25%, heterozygote 50–75% des mittleren normalen Serumspiegels auf. Unter 100 Blutspendern fanden sich 5 mit erniedrigten ₁ wie bei heterozygoten Defektträgern.Klinische Auswirkungen des Gendefektes waren im Kindesalter nicht zu erkennen, insbesondere keine Enthemmung der Fibrinolyse.

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₁ deficiency in two families

Two children from two different families with ₁ deficiency are described. Deficient subjects had 15–25% of normal serum ₁ levels in case of homozygosity and 50–75% in case of heterozygosity. Among one hundred healthy blood donors five had serum ₁ levels below 150 mg% corresponding to the levels found in heterozygous deficiency carriers.In the two children described the gene defect had no clinical consequence; fibrinolysis, in particular was not increased.

     

Renal prostaglandins: Relationship to the development of blood pressure and concentrating capacity in pre-term and full term healthy infants

The relationships between urinary prostaglandins (PGs)E₂ and F₂ and the postnatal development of blood pressure and renal concentrating capacity were investigated in 14 pre-term and 32 full term healthy infants. Mean PGE₂ and PGF₂ excretion was 18.9 and 10.1 ng/h/1.73 m², respectively, in pre-term infants. In full term infants mean urinary PGE₂ was signifincantly lower (13.4 ng/h/1.73 m²) and PGF₂ significantly higher (22.2 ng/h/1.73 m²). The decrease of the PGE₂/PGF₂ ratio (P<0.001) was accompanied by an increase in blood pressure. High PGE₂ levels in pre-term infants were inversely correlated with urinary cAMP excretion. A decreasing PGE₂/PGF₂ ratio in full term infants was associated with increasing urinary osmolality. After intranasal administration of antidiuretic hormone (DDAVP) in 8 full term infants the increase in urinary osmolality and cAMP excretion was accompanied by a drop in PGE₂ excretion to less than half the basal values.These findings suggests that the postnatal changes in urinary PG excretion are associated with a concomittant increase in blood pressure and in the concentrating capacity of the neonatal kidney.Supported by Deutsche Forschungsgemeinschaft     

Recurrent,familial Reye-like syndrome with a new complex amino and organic aciduria

Five of 13 siblings from a Jewish-Ashkenazi family suffered from recurrent Reye-like episodes. During attacks, these patients excreted -keto-adipic, -hydroxy-adipic, and -aminoadipic acids, branched-chain keto acids and saccharopine in addition, to lactic, pyruvic, and dicarboxylic acids characteristic of Reye syndrome. The serum concentrations of citrulline and -aminoadipic acid were elevated and carnitine was at the upper limit of the normal range. Serum acetoacetate level was 4–5 times the -hydroxybutyrate level, but the pyruvate/lactate ratio was normal. Notably, plasma ketone bodies were lower than expected from the degree of catabolism. When the patients were symptom-free, no abnormal amino or organic acids in serum or urine were detected. These findings might be interpreted as a functional impairment at three different biochemical sites: fatty acid -oxidation, dehydrogenase complexes of the pyruvic, -ketoglutaric, -ketoadipic, and branched-chain keto acids, and pyruvate carboxylase. We suggest that in this hereditary disorder a toxic substance, exogenously or endogenously derived, interfered at multiple sites in different metabolic pathways.