Enzyme deficiency disorders

Enzyme Deficiency (Disorder) Symptoms Lab Tests Comments... 

Pyruvate kinase and other enzyme deficiency disorders of the erythrocyte, W. N. Valentine, K. R. Tanaka and D. 

There are important methodologic considerations which apply to the use of cultured amniotic fluid cells for the detection of biochemical disorders. The first is that the enzymes which can be sampled are those which are usually present in fibroblasts or fibroblast-like cells. Therefore, conditions such as phenylketonuria and glycogen storage disease type I, which are associated with deficiencies of enzymes present only in liver and kidney, are not amenable to this approach. The same also pertains to enzyme deficiencies affecting other specific tissues. 

Enzyme Deficiencies Associated with Immunological Disorders. 33... 

Hereditary Nonhemolytic Blood Disorders Associated with Red Blood Cell Enzyme Deficiency... 

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). 

Adenine phosphoribosyltransferase (APRT) deficiency is an inherited disorder of purine metabolism and is inherited in an autosomal recessive manner (K18, V7). This enzyme deficiency results in an inability to salvage the purine base adenine, which is oxidized via the 8-hydroxy intermediate by xanthine oxidase to 2,8-di-hydroxyadenine (2,8-DHA). This produces crystalluria and the possible formation of kidney stones due to the excretion of excessive amounts of this insoluble purine. Type I, with virtually undetectable enzyme activity, found predominantly in Caucasians, is found in homozygotes or compound heterozygotes for null alleles. Type II, with significant APRT activity, found only in Japan, is related to a missense mu-... 

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. 

In 1955, Fritz determined that carnitine plays an essential role in fatty acid -oxidation (FAO), and in 1973 the first two clinically relevant disorders affecting this pathway were described primary carnitine deficiency by Engel and Angelini, and carnitine palmitoyltransferase (CPT) type II (CPT-II) deficiency by DiMauro and DiMauro [6, 7]. To date, more than 20 different enzyme deficiency states affecting fatty acid transport and mitochondrial / -oxidaLion have been described [8] and additional enzymes involved in this pathway are still being discovered [9, 10]. 

Galactokinase is the enzyme deficient in galactokinase deficiency (MIM 230 200). This disorder is caused by impairment of the pathway step from galactose to galactose-1 -phosphate. 

Isomaltase-sucrase deficiency This enzyme deficiency results in an intolerance of ingested sucrose. This disorder is found in about ten percent of Greenland s Eskimos, whereas two percent of North Americans are heterozygous for the deficiency. Treatment is to withhold dietary sucrose. 

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. 

There are over 40 lysosomal storage disorders (LSDs) characterized by the specific enzyme deficiency and accumulated substrate. Pathologies associated with LSDs are multisystemic and variable including CNS, skeletal, cardiovascular, renal, and ocular system involvement. The aggregate incidence is estimated to approach 1 in 7000 live births (Ellinwood et al., 2004). Inheritance for LSDs is primarily autosomal recessive with the exception of two X-linked diseases (Fabry and mucopolysaccharidosis (MPS) II). Treatment for LSDs relies on providing functional enzyme to the lysosomes of affected cells and has traditionally been confined to bone marrow transplantation, and enzyme replacement therapy (ERT). 

Andrea suffered from various allergies during her entire life. As a baby she already had problems with breast milk, for example. Due to enzyme deficiencies she developed a muscle disorder. From the age of twenty onwards the condition left her more and more disabled, until she became dependent on a wheelchair at the age of twenty-nine. Allergies were common on both sides of her family and she herself was sensitive to many substances, especially foods (including all kinds of cereals). She had to feed herself liquid foods using a stomach tube and relied on a diet entirely adjusted to her allergies. She had to adhere to a strict rotary diet, so she could still eat certain vegetables, for example. 

Disorder Incidence per live births Catabolic pathway involved Enzyme deficiency... 

Biochemically, I-cell disease is characterized by excessive secretion of newly synthesized lysosomal enzymes into body fluids and concomitant loss of respective intracellular activities in fibroblasts. Shown in Table 17-1 are representative lysosomal enzyme activity levels in serum from patients with I-cell disease and those with the closely related disorder pseudo-Hurler poly dystrophy, indicating significantly increased levels of lysosomal enzyme activity. Germane to the biochemical diagnosis is the characteristic pattern of lysosomal enzyme deficiency in cultured fibroblasts, that is, an increase in the ratio of extracellular to intracellular enzyme activity (Table 17-2). It is interesting to note that not all lysosomal (i.e. intracellular)... 

Mass spectrometry has become an indispensable method for the analysis of bile acids by virtue of its power to identify, assign structure and quantify free or conjugated bile acids, either pure or in mixtures. It is useful not only to study the metabolism of bile acids but also for the detection and diagnosis of metabolic diseases. Indeed, numerous metabolic diseases resulting from an alteration of the conversion of cholesterol to bile acids have been described, including peroxisomal disorders resulting in a block of (3-oxidation of the lateral chain and other enzyme deficiencies interfering with the biochemistry of the side chain or the steroid nucleus. 

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. 

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