Clinical biochemical genetics deficiencies

Acylcarnitine profiles are dependent on the clinical status of the patient at the time of sample collection [56, 57]. It is therefore important to provide the biochemical genetics laboratory with information regarding the clinical context during which the sample was collected. The laboratory must be conscientious of the fact that carnitine deficiency states can be associated with acylcarnitine profiles that lack any acylcarnitine species that are elevated above the reference range. Therefore, it is essential that the complete profiles are reviewed and even borderline elevated acylcarnitines should prompt further follow up in the presence of abnormally low free acetylcar-nitine (Fig. 3.2.2). If clinically indicated, a repeat sample should be collected at least 24 h after L-carnitine supplementation. 

Schaefer EJ. Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis 1984 4 303-22. 

At least four cases of PDC deficiency have been described in which the intrinsic defect lay not in the complex per se but in one of the two genetically distinct isozymes required to dephospho-rylate the serine residues of the El a subunit. The clinical signs of PDP deficiency do not distinguish it from primary defects of Ela, El(3, E2, E3, or BE The most telling biochemical abnormality reported to date has been the inability to activate PDC in cells cultured with DCA. However, neither direct measurements of PDP activity nor mutations in the PDP gene have been reported for any published case of phosphatase deficiency. 

Most early clinical descriptions of apparent thiamine-responsive PDC deficiency were not characterized biochemically to ascertain true thiamine dependence. In subsequent reports, immunochemical analyses have demonstrated varied patterns of a- and P-subunit expression, and in vitro studies of cultured cells have sometimes found altered El enzyme kinetics (high Km, low Vmax) for TPP. When molecular genetic analyses have been undertaken, different mutations have been identified within the conserved TPP-binding motif that are considered to lead to diminished binding affinity for TPP or to decreased stability of the oc2P2 tetramer. 

Okajima K, Mewhort LZ, Lusk MM, et al. Relationships of clinical and biochemical manifestations to genotype analysis in patients with pyruvate dehydrogenase complex deficiency. Molecular Genetics and Metabolism 84 232-33, 2005. 

The leukocyte response is inadequate in a great number of clinical conditions. Most of the disorders described have been associated with an increased susceptibility to infections. However, the biochemical or molecular level of the various defects have not been clearly established, except for some genetically determined deficiencies. A few examples of neutrophil abnormalities will be given in the two subsequent sections, but for a more complete insight into PMN phagocytic disorders, general reviews and monographs are available (K2, B2, Wl, W3, K3). 

The terms hypermethioninemia, homocystinuria (or -emia), and cystathionin-uria (or -emia) designate biochemical abnormalities and are not specific clinical diseases. Each may be caused by more than one specific genetic defect. For example, at least seven distinct genetic alterations can cause increased excretion of homocystine in the urine. A deficiency of cystathionine (3-synthase is the most common cause of homocystinuria more than 600 such proven cases have been studied. 

The term phenocopy refers to an environmentally induced variation that closely resembles a genetically determined variation. For example, dietary vitamin B deficiency is a phenocopy of the inherited disorder, methylmalonic acidemia and homocystinuria due to cobalamin C disease. Both dietary vitamin B,2 deficiency and cobalamin C disease have the biochemical findings of elevated plasma methylmalonic acid and homocysteine levels. Awareness of phenocopies is important as they provide an alternative explanation for clinical findings. For example, in the case of elevated... 

Gallant NM, et al. Biochemical, molecular, and clinical characteristics of children with short chain acyl-CoA dehydrogenase deficiency detected by newborn screening in California. Mol Genet Metab. 2012 106(1) 55-61. 

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