The Biochemical Abnormality

We may now inquire as to the biochemical basis of the adaptive response and the biochemical defects responsible for the failure of adaptation to environmental factors, i.e., the defects that lead to abnormal structure or amounts of enzymes and nonenzymatic proteins. Fig. 5 depicts in simplified fashion the mechanism of protein biosynthesis. 

It might seem possible that defects in protein synthesis could occur as a result of a defective gene that encodes a specific messenger ribonucleic acid (mRNA), ribosomal ribonucleic acid (rRNA), or transfer ribonucleic acid (tRNA). Flowever, upon reflection, it can be seen that the genes for rRNA and tRNA cannot be defective, since rRNA and tRNA are common to all protein synthesis. A significant defect in the 

We cannot implicate the genes for DNA-dependent RNA polymerase (types I, II and III), for ribosomal proteins, for enzymes that process rRNA and tRNA precursors, or for enzymes that activate amino acids. All of these genes encode products that are utilized for all protein synthesis. A significant defect in any of these genes would lead to a general failure of protein synthesis (see Fig. 5). Again, we are compelled to conclude that defects in protein synthesis result from a defect in the structural gene or its controls for the specific protein that contains the abnormality. 

A number of abnormalities of protein synthesis are known in terms of defects of the structural gene. Specific abnormalities of the regulatory genes in mammalian cells have not been demonstrated. One can only speculate at this time about the consequences of defects in the promoter and operator. 

Despite the uncertainties, we can use the model depicted in Fig. 5 to examine the known defects in protein synthesis in a variety of disease entities. Table 3 summarizes some of the known defects in the structural gene which give rise to defects in protein synthesis, and lists some of the hypothetical consequences of defects in the control portions of the structural gene which might be predicted if such regions exist. 

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The function of the ALD protein is not fully understood, and knockout mice lacking it do not exhibit the severe CNS neurological deficits commonly associated with the human disease despite a similar accumulation of VLCFAs [26], Furthermore, the clinical variability in human patients cannot be accounted for by the severity of the biochemical abnormality or the nature of the gene defect. These observations, plus other data from mice with defects in VLCFA metabolism, raise the issue of whether the accumulation of VLCFAs in myelin is crucial to the pathological mechanisms or is an epiphenomenon. Unlike most other lipid-storage diseases, active ALD brain lesions are characterized by perivascular accumulation of lymphocytes. For this reason, it has been hypothesized that the severity of CNS pathology may relate to an autoimmune reaction that varies from patient to patient and... 

The treatment goals for hypothyroidism are to normalize thyroid hormone concentrations in tissue, provide symptomatic relief, prevent neurologic deficits in newborns and children, and reverse the biochemical abnormalities of hypothyroidism. 

One reason for this was that some of the conditions had relatively trivial consequences for the patients. In other cases, like porphyria or hemophilia, it would be another 20 to 30 years before the biochemical abnormality could be identified. Furthermore clinical interests at the time largely focused on diseases with extrinsic origins—bacterial or viral infections—when constitutional idiosyncracies appeared of little relevance. 

F. Role in therapy According to Micromedex, the goal of therapy with Adagen is to correct immune function by reversal of the biochemical abnormalities caused by adenosine deaminase deficiency. Adagen s role in therapy at this time would appear to be as an alternative when bone marrow transplantation is not feasible or has been unsuccessful. It may also be considered in lieu of transplantation in milder cases of adenosine deaminase deficiency. Adagen is preferable to red cell transfusions in these patients. While regular administration of Adagen can improve immune function and reduce the incidence of opportunistic infections in patients with ADA-deficient SCID, it is of no value in patients with immunodeficiency due to other causes. 

In one patient with acute valproate-associated encephalopathy associated with biochemical evidence of severe carnitine deficiency and a defect in valproate metabolism, L-carnitine substitution corrected the biochemical abnormalities, but the patient died (SED-13, 150) (1186). 

Desipramine has been used as part of the treatment of alcoholism. Because depression has led to relapsed drinking in people suffering from alcoholism who are striving to maintain sobriety, treatment with antidepressants may reverse or prevent these depressive symptoms. They may also correct the biochemical abnormalities hypothesized to underlie both depression and alcoholism, thus helping to ensure abstinence in recovering alcoholics. 

Biotinidase activity in cerebrospinal fluid and the brain is very low. This suggests that the brain may not recycle biotin effectively and depends on biotin transported across the blood-brain barrier. Several symptomatic children who have failed to exhibit peripheral lactic acidosis or organic aciduria have had elevated lactate or organic acids in their cerebrospinal fluid. This compartmentalization of the biochemical abnormalities may explain why the neurological symptoms usually appear before other symptoms. Peripheral metabolic ketoacidosis and organic aciduria subsequently occur with prolonged metabolic compromise. 

If the child with profound biotinidase deficiency is symptomatic, then the biochemical abnormalities and seizures resolve rapidly after biotin treatment. This is usually followed by improvement of the cutaneous abnormalities. Hair growth returns over a period of weeks to months in the children with alopecia. Optic atrophy and hearing loss are usually resistant to therapy, especially if several months have elapsed between the time of diagnosis and the initiation of treatment. Some treated children have rapidly regained lost developmental milestones, whereas others have continued to show deficits. 

Marfan syndrome is caused by mutations in the fibrillin-1 gene located on chromosome 15. Fibrillin is a protein that plays a role in the characteristically elastic properties of connective tissne. The biochemical abnormality that leads to Marfan syndrome is not well under-... 

Hjq)onatremia is rare, and persistent hyponatremia very rare in patients taking cisplatin (162). In a detailed description of the biochemical abnormalities that can result from renal tubular dysfunction after cisplatin therapy, it was noted that hypocalciuria is more common than hypomagnesemia, and that there tends to be a state of reduced serum bicarbonate. The most severe renal tubular damage caused by cisplatin is characterized by hypocalciuria, total body magnesium deficiency, and hypokalemic metabolic alkalosis (163). 

The low Tj syndrome observed after major trauma may also be related to changes in selenium status affecting the activity of iodothyronine deiodinase, with selenium supplements reversing most of the biochemical abnormalities found in thyroid function tests. ... 

Physicians and laboratory scientists are occasionally confronted with isolated high or low serum alkaline phosphatase values which remain unexplained even after thorough investigation (B42). Such high or low activities may persist for prolonged periods of time (Mc3). Wilson (W28) described several members of a family with gross hyperphosphatasemia in the absence of demonstrable disease. The biochemical abnormality appeared to be inherited as an autosomal dominant trait. 

Walsh and Kissane (W5) reported six patients with hypernephroma and hyperphosphatasemia. The biochemical abnormality disappeared after nephrectomy. It has been suggested (D19) that this syndrome is due to the synthesis of alkaline phosphatase by the tumor. 

Of the biochemical abnormalities seen in lead-treated animals, the most important is the alteration in oxidative metabolism. These have been shown at high levels, but more relevantly, at lower levels of lead exposure in both adult rats (Sterling et al., 1982) and neonates (Bull et al., 1979). These have... 

Increased urinary formiminoglutamic acid in the absence of folic acid deficiency or cobalamine C disease is indicative of formiminotransferase deficiency. Accumulation of imidazolonepropionic acid is not observed, but there is an abnormal excretion of its oxidation product, hydantoin-5-pro-pionic acid. Loading tests with histidine will enhance the excretion. Confirmation of the defect is made by enzyme analysis probably the liver is the only suitable tissue. Affected patients were mentally retarded and/or had convulsions however, a number of healthy siblings with the biochemical abnormality have been described. 

With the exception of glutaric aciduria type I and hyperornithinemia there is no or a very doubtful causal relationship between the biochemical abnormality and the symptoms of psychomotor/neurological impairment. 

In addition to the types mentioned in this chapter, there are at least five more groups of neuronal ceroid Upofuscinosis where the biochemical abnormality has not been determined although the genes linked to the disorders have been identified [5]. 

The introduction gives a brief overview of the clinical conditions described in the chapter and relates them to the biochemical abnormalities. Key references for further reading are given here. 

This disorder therefore appears associated with moderate to severe mental retardation, unlike most of the patients with other forms of methylmalonic aciduria. The biochemical abnormalities in these patients may be explained on the basis of defects in the biosynthesis of both of the cobalamin coenzymes and hence in the early stages of Co (III) reduction in the cell (Willard and Rosenberg, 1979). Activities of methionine synthetase and methylmalonyl-CoA mutase in cultured skin fibroblasts could be augmented in the presence of 5 -deoxyadenosylcobalamin and/or methylcobalamin (Mudd etal., 1970) and... 

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