Enzyme deficiency disorders defects

Hereditary methemoglobinemia is classified into three types a red blood cell type (type I), a generalized type (type II), and a blood cell type (type HI). Enzyme deficiency of type I is limited to red blood cells, and these patients show only the diffuse, persistent, slate-gray cyanosis not associated with cardiac or pulmonary disease. In type II, the enzyme deficiency occurs in all cells, and patients of this type have a severe neurological disorder with mental retardation that predisposes them to early death. Patients with type III show symptoms similar to those of patients with type I. The precise nature of type III is not clear, but decreased enzyme activity is observed in all cells (M9). It is considered that uncomplicated hereditary methemoglobinemia without neurological involvement arises from a defect limited to the soluble cytochrome b5 reductase and that a combined deficiency of both the cytosolic and the microsomal cytochrome b5 reductase occurs in subjects with mental retardation. Up to now, three missense mutations in type I and three missense mutations, two nonsense mutations, two in-frame 3-bp deletions, and one splicing mutation in type n have been identified (M3, M8, M31). 

Bifunctional protein deficiency. The enzyme defect involves the D-bifunctional protein. This enzyme contains two catalytic sites, one with enoyl-CoA hydratase activity, the other with 3-hydroxyacyl-CoA activity [13]. Defects may involve both catalytic sites or each separately. The severity of clinical manifestations varies from that of a very severe disorder that resembles Zellweger s syndrome clinically and pathologically, to somewhat milder forms. Table 41-6 shows that biochemical abnormalities involve straight chain, branched chain fatty acids and bile acids. Bifunctional deficiency is often misdiagnosed as Zellweger s syndrome. Approximately 15% of patients initially thought to have a PBD have D-bifunctional enzyme deficiency. Differential diagnosis is achieved by the biochemical studies listed in Table 41-7 and by mutation analysis. 

Definition of porphyrias, their modes of genetic inheritance, and their treatment Porphyrias are caused by inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. Porphyrias are classified as erythropoietic or hepatic, depending where the enzyme deficiency occurs. With the exception of congenital erythropoietic porphyria, which is a genetically recessive disease, all the porphyrias are inherited as autosomal dominant disorders. All porphyrias result in a decreased synthesis of heme and, therefore, ALA synthase is dere-pressed. The severity of symptoms of the porphyrias can be diminished by intravenous injections of hemin. Because some porphyrias result in photosensitivity, avoidance of sunlight is helpful. 

For disorders characterized by an underlying enzyme deficiency (e.g., Gaucher disease, Fabry disease, Tay-Sachs, Hurler syndrome), assays of enzyme activity in blood and/or tissues is generally available (Meikle et al., 2004). Mutation analysis is also available, particularly for populations in whom the common disease alleles are known (e.g., mutations among Ashkenazi Jews for Gaucher, Tay-Sachs, Niemann-Pick type A, and mucolipidosis type IV Ostrer, 2001). In other cases, analysis of the gene defect responsible for rare subtypes is available through specialized laboratories. 

This section describes the red cell enzymes involved in the metabolic pathways of clinical importance in the human red cell and the disorders associated with defects in these pathways. In addition, diagnostic strategies and pitfalls of laboratory diagnostics for these enzyme deficiencies will be explained. The laboratory methods described have been... 

Deficient or defective apo C-II, the required activator for LPL, reduces the activity of this enzyme, impairs chylomicron catabolism, and increases plasma triglycerides (500 to 10,000 mg/dL). Those affected by this disorder have less than 10% of the normal concentration of apo C-II, the minimum amount necessary for normal LPL activity. Total cholesterol tends to vary considerably (150 to 890mg/dL) in these patients, but HDL and LDL cholesterol concentrations are below the 5th percentile. Furthermore, plasma apo A-I, A-II, and B-lOO concentrations are decreased, whereas apo C III and E concentrations are increased. 

Steroidgenic pathways in 1 lj8-hydroxylase CYPBl and CYPB2 deficiency. A CYPl IB 1 defect causes a deficiency of cortisol and the disorder congential adrenal hyperplasia (CAH). A CYPl 1B2 defect causes an aldosterone deficiency. Synthesis of steroids within the boxed areas is decreased and steroids outside the boxed area increased, respectively, for each enzyme deficiency. 

Often enzyme deficiencies are inherited as autosomal recessive disorders, so that both chromosomes are defective for the individual to be affected. 

Disorders of Red Blood Cells. For the red blood cell to survive and function properly in the body, it must maintain a proper membrane, possess structurally correct and appropriately functioning hemoglobin, and have properly working metabolic pathways. Problems or defects in any of these areas will result in the red blood cell having a shortened life. Anemia results when the circulating red blood cells are unable to provide an adequate supply of oxygen to the tissues of the body. The many causes of anemia can be classified as nutritional deficiency (vitamin B12 or folic acid deficiency), blood loss, accelerated red cell destruction, hemoglobin defects (hereditary or acquired), and enzyme deficiencies. 

The Sanfilippo syndrome, type A presents with severe and progressive mental retardation with sleep disturbances and behavioral problems as the most prominent features. The organ enlargement and joint stiffness seen in the other mucopolysaccharidoses is not present or occurs later in life. Diarrhea can be more severe and recurrent than in the other mucopolysaccharidoses. Onset of the disorder is usually between 1 and 6 years of age. Studies of the basic defect in Sanfilippo syndrome revealed that there are four separate disorders. The type of Sanfilippo syndrome is based on enzyme deficiency. The clinical symptoms in the four types overlap. The prevalence of Sanfilippo syndrome in the Netherlands is estimated at 1 in 24,000 for three of the four types [3]. However, using all four types of Sanfilippo syndrome, the study from Australia estimates the prevalence at 1 in 60,600, which is about 2.5 times lower than that in the Netherlands [2]. The Sanfilippo syndrome, type A, is estimated at 1 in 114,000 [2]. 

In the metabolism of L-leucine, the isovaleryl-CoA produced by the oxidative decarboxylation step is further metabolized by a series of enzyme-catalysed steps to acetoacetate and acetyl-CoA and thence into the tricarboxylic acid cycle. Specific enzyme deficiencies at every stage of this metabolic pathway are known and are described in Section 10.3. In contrast, only one disorder of L-isoleucine metabolism subsequent to the oxidative decarboxylation step has been recognized (Section 10.4), and no disorders of the L-valine pathway from isobutyryl-CoA have been described. This may be due to their relative rarity but possibly also to greater difficulty in their detection. The metabolism of valine and leucine is, however, of particular interest in the organic acidurias, since both are major precursors of propionyl-CoA and methylmalonyl-CoA, defects in the metabolism of which lead to propionic acidaemia and methylmalonic aciduria (Chapter 11). 

Isolated deficiencies of methylcobalamin or of 5 -deoxyadenosylcobalamin result in homocystinuria or methylmalonic aciduria respectively, whereas deficiencies in the earlier reductase steps result in combined disorders. Intrinsic factor deficiency also leads to combined methylmalonic aciduria and homocystinuria because of the low serum vitamin B12 levels, but the urinary concentrations recorded are only moderately increased in comparison to those encountered in methylmalonic aciduria due to primary enzyme deficiencies. Defects in vitamin B12 transport, TCI and TCII deficiency do not appear to produce abnormal organic or amino acidurias. Deficiencies of intrinsic factor or of ileal absorption of vitamin B12 respond clinically and biochemically to physiological doses (1-5 fig day ) of vitamin B12 given intravenously or intramuscularly, whereas deficiencies in transport proteins require pharmacological doses (>500 pg day ). The involvement of 5 -deoxyadenosylcobalamin in methylmalonate metabolism also suggests the possibility of vitamin Bi2-responsive primary methylmalonic aciduria, and this is discussed further below. 

Galactosialidosis is characterized by the simultaneous deficiencies of P-galactosidase and a-neuroaminidase. Clinical and pathological manifestations resemble those in GM1 gangliosidosis and like it show a range of severity. The underlying defect involves a protective protein, which stabilizes these two enzymes by a mechanism that is not understood. Curiously, the protective protein is itself a peptidase. The disorder is most common in Japan. The defective gene has been cloned and mutations have been identified. 

In view of the toxicity of ammonia, complete absence of any one of the enzymes of the cycle is fatal. Nonetheless, disorders of the cycle do occur, which are caused by a low activity of one of the enzymes or carbamoyl phosphate synthetase. In addition, defects in N-acetylglutamate synthase have been reported, but they are very rare. With the exception of ornithine transcarbamoylase, the deficiencies have an autosomal recessive mode of inheritance. The transcarbamoylase deficiency is inherited as an X-linked dominant trait, usually lethal in male patients. A deficiency of carbamoyl phosphate synthetase, ornithine transcarbamoylase or argininosuccinate synthetase results in accumulation and excretion of citrulline. A deficiency of argininosuccinate lyase results in the accumulation and excretion of argininosuccinate and arginine (Table 10.5). The abbreviations CPSD, OTCD, ASD, ALD and AD stand, respectively, for the deficiencies of these enzymes, where D stands for deficiency. 

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