Neonatal defects

Fatal hereditary disorder that typically presents in the neonatal period. Clinical features include an array of hepatic, renal and neurological dysfunctions. Patients with Zellweger syndrome rarely survive the first year of life. The disease is caused by mutations in the Pex proteins leading to an defective import of peroxisomal matrix proteins and consequently to a loss of most peroxisomal metabolic pathways. 

This complex contains 11 polypeptide subunits of which only one is encoded by mtDNA. Defects of complex III are relatively uncommon and clinical presentations vary. Fatal infantile encephalomyopathies have been described in which severe neonatal lactic acidosis and hypotonia are present along with generalized amino aciduria, a Fanconi syndrome of renal insufficiency and eventual coma and death. Muscle biopsy findings may be uninformative since abnormal mitochondrial distribution is not seen, i.e., there are no ragged-red fibers. Other patients present with pure myopathy in later life and the existence of tissue-specific subunits in complex III has been suggested since one of these patients was shown to have normal complex 111 activity in lymphocytes and fibroblasts. 

Figure 30-12. Intermediates in tyrosine catabolism. Carbons are numbered to emphasize their ultimate fate. (a-KG, a-ketoglutarate Glu, glutamate PLP, pyridoxal phosphate.) Circled numerals represent the probable sites of the metabolic defects in type II tyrosinemia neonatal tyrosinemia alkaptonuria and 0 type I tyrosinemia, or tyrosinosis.

The probable metabohc defect in type I tyrosine-mia (tyrosinosis) is at himarylacetoacetate hydrolase (reaction 4, Figure 30-12). Therapy employs a diet low in tyrosine and phenylalanine. Untreated acute and chronic tyrosinosis leads to death from liver failure. Alternate metabolites of tyrosine are also excreted in type II tyrosinemia (Richner-Hanhart syndrome), a defect in tyrosine aminotransferase (reaction 1, Figure 30-12), and in neonatal tyrosinemia, due to lowered y>-hydroxyphenylpyruvate hydroxylase activity (reaction 2, Figure 30-12). Therapy employs a diet low in protein. 

Glutaric acidurias Type I Primary defect of glutarate oxidation Type II Defect of electron transfer flavoprotein Type I Severe basal ganglia/cerebellar disease with macrocephaly. Onset 1-2 years Type II Fulminant neurological syndrome of the neonate. Often with renal/hepatic cysts. Usually fatal Diet low in lysine and tryptophan Supplementation with coenzyme Q, riboflavin, carnitine... 

Nonketotic Defect of the glycine Intractable seizures in neonate. Usually fatal Diet low in glycine... 

Urea cycle defects Failure to convert ammonia to urea via urea cycle (Fig. 40-5). Coma, convulsions, vomiting, respiratoryfailure in neonate. Often mistaken for sepsis of the newborn. Mental retardation, failure to thrive, lethargy, ataxia and coma in the older child. Associated with hyperammonemia and abnormalities of blood aminogram Low protein diet Acylation therapy (sodium benzoate, sodium phenylacetate) Arginine therapy in selected syndromes Hepatic transplantation... 

Ornithine transcarbamylase deficiency. This is the most common of the urea cycle defects. Presentation is variable, ranging from a fulminant, fatal disorder of neonates to a schizophrenic-like illness in an otherwise healthy adult. Males characteristically fare more poorly than do females with this X-linked disorder because of random inactivation (lyonization) of the X chromosome. If inactivation affects primarily the X chromosome bearing the mutant OTC gene, then a more favorable outcome can be anticipated. Conversely, the unfavorably lyonized female has a more active disease. 

Defects of substrate utilization. Pyruvate dehydrogenase (PDH) deficiency can cause alterations of pyruvate metabolism, as can defects of pyruvate carboxylase, as discussed earlier. Over 200 patients have been described with a disturbance of the PDH complex (PDHC) [15,16]. The clinical picture includes several phenotypes ranging from a severe, devastating metabolic disease in the neonatal period to a benign, recurrent syndrome in older children. There is considerable overlap clinically and biochemically with other disorders (see below). 

Glutaric aciduria type II, which is a defect of P-oxida-tion, may affect muscle exclusively or in conjunction with other tissues. Glutaric aciduria type II, also termed multiple acyl-CoA dehydrogenase deficiency (Fig. 42-2), usually causes respiratory distress, hypoglycemia, hyperammonemia, systemic carnitine deficiency, nonketotic metabolic acidosis in the neonatal period and death within the first week. A few patients with onset in childhood or adult life showed lipid-storage myopathy, with weakness or premature fatigue [4]. Short-chain acyl-CoA deficiency (Fig. 42-2) was described in one woman with proximal limb weakness and exercise intolerance. Muscle biopsy showed marked accumulation of lipid droplets. Although... 

Pirenne-Ansart, H., et al. Defective cytokine expression but adult-type T-cell receptor, CD8, and p561ck modulation in CD3- or CD2-activated T cells from neonates, Pediatr. Res., 37, 64, 1995. 

Chelvarajan, R.L., et al. Defective macrophage function in neonates and its impact on unresponsiveness of neonates to polysaccharide antigens, J. Leukoc. Biol., 75, 982, 2004. 

Kim SS, Rhee GS, Kwack SJ et al (2003) Neonatal exposure to sumithrin shows estrogen-like effects in prepubertal rat development. Birth Defects Res Part A Clin Mol Teratol 67 350... 

Some animal studies with ozone or thetic photochemical smog have shown chromosomal defects in circulating lymphocytes, a more rapid appearance of benign pulmonary tumors, and an increase in neonatal mortality consistent with a mutagenic effect. 

Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor and ACE inhibitors should be avoided during pregnancy. ACE inhibitors may adversely affect fetal and neonatal blood pressure control and renal function. They may also cause neonatal skull defects. 

Children Caverject is not indicated for use in newborns or children. However, alprostadil Prostin VR Pediatric) is used in newborns to maintain the patency of the ductus arteriosus in neonates with congenital heart defects. 

Recent publications signal the continued interest in the function of this protein. It has been called a stress enzyme, involved in influenza virus infection (Tomas and Toparceanu, 1986). An explanation for Wilson s disease in terms of a genetic defect resulting in failure to convert from a neonatal (i.e., low) level of ceruloplasmin and copper to a normal adult level has been reported (Srai et al., 1986). Tissue specificity for the binding of ceruloplasmin to membranes was demonstrated in a study investigating the possible role of ceruloplasmin-specific receptors in the transfer of copper from ceruloplasmin to other copper-containing proteins (Orena et al, 1986). Ceruloplasmin has been shown to be effective in transferring copper to Cu,Zn-SOD in culture (Dameron and Harris, 1987), as has copper albumin. In view of the variable content of copper in this protein, it is not clear which copper is transferred. 

Reproductive Toxicology (mammalian) The study of the effects of chemicals on the adult reproductive and neuroendocrine systems, the embryo, foetus, neonate and prepubertal mammal. Reproductive Toxins Tire tenn refers to a specific target organ characterization of effect. These are chemicals which affect the reproductive capabilities including chromosomal damage (mutations) and effects on fetuses (teratogenesis). Signs and symptoms include birth defects sterility. Examples are lead and DBCP. 

Central and/or peripheral nervous system involvement is one of the most frequent features, often resulting in the neonatal period in drowsiness, poor sucking, severe hypotonia, abnormal movements, seizures, respiratory distress, and fatal keto-acidotic coma with lactic acidosis [3]. To these severe conditions echo late-onset diseases now frequently attributed to or associated with mitochondrial OXPHOS defects, such as Alzheimer s or Parkinsons disease [10]. Major neurological symptoms, in variable combinations, involve trunk hypotonia, cranial nerve and brainstem involvement (with abnormal eye movements, ophthalmoplegia, recurrent apneas), cerebellar ataxia, myoclonia, seizures, pyramidal syndrome, peripheral neuropathy, poliodystrophy, and leukodystrophy infections [27,28]. A diffuse impairment of the cerebral white matter (leukodystrophy) mostly results in motor disturbance with mental retardation and low incidence of seizures. 

Polarographic studies can also be used to screen for much more specific defects suspected in some patients, such as impaired mitochondrial glutamate transport in cultured skin fibroblasts from patients presenting with neonatal myoclonic epilepsy [64]. 

The initial steps in BA synthesis are characterised by the introduction of a hy-droxylic group in the la position, or in position 27, followed by another in the la position into the cholesterol nucleus. Both synthetic pathways (the neutral and the acidic pathways) possess a distinct microsomal 7-oxysterol hydroxylase, which is regulated by different genes. The most recently described disorder of BA synthesis is cholesterol 7a-hydroxylase deficiency, in which their decreased production through the classical pathway is partially balanced by activation of the alternative pathway. Cholesterol levels increase in the liver, with a consequent low-density lipoprotein hypercholesterolemia, and cholesterol gallstones may result, although there is no liver disease. In contrast, a defect in the conversion of 27-hydroxy-cholesterol to la,27-dihydroxy-cholesterol due to deficiency of the oxysterol 7a-hydroxylase specific for the alternate pathway, causes severe neonatal liver disease [8]. 

Peroxisomal disorders (Zellweger syndrome, Refsum s disease, neonatal adre-noleukodystrophy) are characterised by defective peroxisome biogenesis, or, being present, peroxisomes lacking / -oxidative enzymes. In the BA biosynthetic pathway, dihydroxycoprostanic acid (DHCA) and trihydroxycoprostanic acid (THCA) are /1-oxidised in peroxisomes to produce CA and CDCA, respectively, whereas peroxisomal disorders cause a defective oxidation of the BA precursor side chain, which leads to an accumulation of C27 bile acids, notably 3 ,7 -dihydroxy-5/3-cholesta-noic acid (DHCA) and 3a,7a,12a-trihydroxy-5/l-cholestanoic acid (THCA), in the plasma and urine of affected patients. 

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