Clinical laboratory testing should begin with tests that are available in most hospital clinical laboratories. Care in the collection and handling of laboratory specimens is crucial to obtaining accurate results. Plasma measurements oflactate and ammonia are particularly subject to spuriousresults if not handled correctly. Significant ketosis in theneonate is unusual and suggests an organic acid disorder.Ketosis out of proportion to fasting status in an older child occurs in disorders of ketone usage. Lack of severe ketosis in an older child under conditions of metabolic stress is a
Arterial blood gas Glucose Electrolytes—anion gap pH Glucose Ketones Ammonia Reducing substances Liver enzymes Organic acids Complete blood count, differential,† Acylglycines and platelet count Orotic acid Lactate, pyruvate Organic acids Amino acids Acylcarnitines Carnitine *Organ-specific evaluation is indicated for specific symptoms (e.g., cranial if nonketotic hyperglycemia is suspected).
†Thrombocytopenia and neutropenia are seen in organic acidurias; vacuolated lymphocytes and metachromatic granules are seen in lysosomal disorders.
feature of fatty acid oxidation disorders. In some disorders,such as urea cycle disorders, ketone utilization disorders,milder forms of fatty acid oxidation defects, and intermittent maple syrup urine disease, the laboratory abnormalitiesmay be present only during an acute presentation. Therefore,normal testing in the well state does not rule out a metabolicdisorder.
Mechanisms of Inheritance
Although all of the classic mechanisms of inheritance are represented, most inborn errors of metabolism are autosomal recessive. Isolation or founder effect may make a specific recessive condition common in some populations (e.g., maple syrup urine disease in the Old Order Mennonite population in Pennsylvania). X-linked conditions exhibit increased presentation in males. In general, carriers of recessive or X-linked (females) diseases are asymptomatic. However, in ornithine transcarbamylase deficiency, females can be symptomatic if they have a low proportion of normal cells in the liver. Most mitochondrial disorders in children are a result of mutations in autosomal genes, although there are X-linked forms. Mutations in the mitochondrial DNA also lead to mitochondrial disease. In this situation the type and severity of the presentation depend on the specific defects and the tissue specific ratio of normal to abnormal copies of the mitochondrial DNA (the degree of heteroplasmy).
Identification of Molecular Pathology
If the molecular basis of an inborn error of metabolism is known (i.e., the gene or genes have been mapped and mutations defined), specific genetic testing may be clinically available. In some disorders, there is a good correlation between specific mutations and clinical outcome. Genetic testing in other at-risk family members can provide important genetic information for them, enabling decision making throughout the rest of the family.
Table 51-8 Disorders Identified by Newborn Screening Programs in the United States DISORDER METHODS CONFIRMATORY TESTING AMINO ACID Phenylketonuria (PKU) Guthrie*, MS/MS Plasma phenylalanine, mutation testing
Tyrosinemia Guthrie, MS/MS Plasma amino acid profile, urine succinylacetone
Maple syrup urine disease (MSUD) Guthrie, MS/MS Plasma amino acid profile, look for alloisoleucine ORGANIC ACID
Methylmalonic acidemias MS/MS Urine organic acid profile, plasma amino acid profile, plasma homocysteine
Biotinidase deficiency Enzyme measurement Quantitative biotinidase measurement, DNA mutations
Medium-chain acyl-CoA dehydrogenase MS/MS Urine organic acid profile, urine acylglycine profile, plasma deficiency (MCAD)