Inborn errors of metabolism, also termed “inherited metabolic disorders,” are a group of inherited systemic conditions involving various types of chemical imbalances that cause disease and affect essentially all organs to a greater or lesser degree.1–9 Each of the diseases is characterized by a specific genetic defect that causes an abnormality of an enzyme necessary for the degradation of some chemical substance.2 The disruption of degradation leads to disease due to the deficiency of a substance or to the pathologic accumulation of a substance.2,5 The first inborn errors of metabolism were identified about a century ago. Sir Archibald Garrod coined the phrase in 1902.10 Today, there are over 500 inborn errors of metabolism identified.11
The diseases that comprise the inborn errors of metabolism are individually rare; however, taken together, they affect about 1 in 1000 people.2 The majority of the diseases making up the inborn errors of metabolism exhibit autosomal recessive inheritance; however, X-linked recessive inheritance occurs with some diseases, and, less commonly, autosomal dominant inheritance is seen.5 The majority of these diseases are pediatric; however, with the identification of attenuated variants, and with improved survival, they are today’s conditions that must be considered in patients of all ages.2 Tissue biopsy may be necessary for specific diagnosis; however, given that these disorders typically present with unexpected findings, high clinical suspicion and careful radiologic evaluation are usually the key to faster and more accurate diagnoses. Particularly as newer and more effective therapies being designed require earlier diagnoses, radiology plays a central role in diagnosis, and clinical–radiologic correlations are increasingly important.2 Although metabolic specialists with expertise in the various inborn errors of metabolism are present in large academic centers and tertiary care centers, pediatricians and primary care physicians are typically the first physicians to whom patients with these diseases present themselves.5
Some of the diseases that make up the inborn errors of metabolism can be placed into a few broad groups; these include disorders of amino acid metabolism, organic acidurias, urea cycle defects, disorders of ketogenesis and ketolysis, disorders of fatty acid oxidation, lysosomal storage disorders, and mitochondrial disease.2 While the lung is not typically a primary site of clinical disease in patients with inborn errors of metabolism, the lungs are involved with many inborn errors of metabolism, and in some diseases, clinically significant lung disease may occur.1,12 Of course, the lungs may be involved with infections as a secondary feature in many types of chronic diseases, including inborn errors of metabolism; however, this chapter focuses on several specific inborn errors of metabolism for which lung disease may be a clinically significant feature.
Acid Sphingomyelinase Deficiency (Niemann–Pick Disease Types A and B)
Acid sphingomyelinase (ASM) deficiency, an autosomal recessive condition, has a phenotype that occurs in a continuum, with severe, neuropathic ...