Refining the phenotype of inborn errors of metabolism
In the early twentieth century, knowledge of metabolic disorders was confined to a handful of ‘orphan’ diseases. Phenylketonuria was the first of these inborn errors of metabolism to be unravelled and identified as being caused by an enzyme deficit, which then could be managed with a low protein diet. Since that time many of these conditions have subsequently been recognised as having a single-gene origin. However, as is common for conditions initially defined on the basis of a rigid clinical phenotype, ‘forme frustes’ are identified when definitive genetic testing becomes more widely available. As a result there is often a later expansion of the initial phenotype, underlining the importance of careful clinical description and directed ancillary investigations in the diagnosis of these disorders. Unfortunately, the rarity of inborn errors of metabolism militates against large-scale studies of these conditions resulting in a paucity of evidence-based medicine to provide guidance in the diagnosis and management of these conditions. The three studies in this month’s journal club take different approaches to surmount the challenge posed by low disease frequency including careful and thorough clinical phenotyping and the development of a large recruitment base. Three uncertainties are addressed: clarification of the phenotype of a subset of Neuronal Ceroid Lipofuscinosis patients; a clinical description of Unverricht–Lundborg disease with an answer to the debate over correlation of repeat length expansions and disease severity; and finally, development of a radiological algorithm in diagnosing adult onset inherited white matter disease.