An Approach to Inborn Errors of Metabolism

Many childhood conditions are caused by single-gene mutations that encode specific proteins. These mutations can change primary protein structure or the amount of protein synthesized. The function of a protein, whether it is an enzyme, receptor, transport vehicle, membrane component, transcriptional co-regulator, or structural element, may be compromised or abolished. Hereditary diseases that disrupt normal biochemical processes are termed inborn errors of metabolism or inherited metabolic diseases .

Most genetic changes are clinically inconsequential and represent benign variants . However, pathogenic variants produce diseases that range in severity of presentation and time of onset. Severe metabolic disorders usually become clinically apparent in the newborn period or shortly thereafter, whereas milder forms may present later in childhood and even in adulthood. With some exceptions, the presenting symptoms of most metabolic conditions lack the specificity to enable a definitive diagnosis without further evaluation. The combination of low specificity of presenting symptoms and low prevalence of metabolic disorders makes determination of the diagnosis difficult. Progressive symptoms, the lack of plausible non-genetic diagnosis after detailed evaluation, history of overlapping symptoms in patient's relatives, or consanguinity should alert a pediatrician to seek a consultation with a geneticist and consider metabolic testing early in the evaluation.

Correct diagnosis is often only the beginning of a long medical journey for most families affected by metabolic conditions (see Chapter 95 ). Although each inherited metabolic disorder is individually rare, improved diagnosis and increasing survival of patients with metabolic conditions virtually ensure that a pediatrician will encounter and provide care to affected patients. Pediatricians can play a critical role in establishing the continuity of care, managing some aspects of treatment, fostering adherence, and delivering routine pediatric interventions such as immunizations, referrals to specialists, and elements of genetic counseling (see Chapter 94.1 ).

The greater awareness of metabolic conditions, wider availability of biochemical laboratories, global metabolomic analysis, and routine application of exome sequencing dramatically increased the detection rate of the known disorders and contributed to the discovery of new metabolic disorders. Nonetheless, collection and analysis of family history remains a critical screening test that a healthcare provider can use to identify an infant or child at risk for a metabolic disorder. The identification of consanguinity or a particular ethnic background with an unusually high incidence of inborn errors of metabolism can be important to direct further studies. For example, tyrosinemia type 1 is more common among French-Canadians of Quebec, maple syrup urine disease is seen with higher frequency in the U.S. Amish population, and Canavan disease in patients of the Ashkenazi Jewish ancestry.