Defining neurogenetic phenotypes (or how to compare needles in haystacks)

Abstract

Accurate diagnosis is the foundation of clinical neurology, providing both the physician and the patient with a guide to the future, hopefully leading to a treatment, and sometimes pointing towards a cure. Unlike many other clinical disciplines, the day-to-day practice of neurology involves a pantheon of symptoms and long lists of differential diagnoses. The challenge is to spot the rarities, especially if this is going to influence clinical management. This should be much easier in 2010, given recent advances in the routine diagnostic armamentarium; but paradoxically it seems more difficult, as we continue to dissect sub-categories of common disorders and overlapping clinical spectrums expand. So what are the distinguishing features of a particular disorder, and how can we reliably define them? This is particularly difficult if they are exceptionally rare ‘once in a lifetime’ diagnoses. Two papers in this edition of Brain tackle this issue for two important genetic neurometabolic disorders (Jinnah et al. , 2010; Leen et al. , 2010), illustrating an emerging approach to this thorny topic. In 1964, the medical student Michael Lesch and the paediatrician Bill Nyhan published the classic description of two brothers, aged 4 and 8, with a new familial disorder of uric acid metabolism and central nervous system dysfunction (Lesch and Nyhan, 1964). The primary biochemical defect was defined within a few years, affecting the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) (Seegmiller et al. , 1967), ultimately leading to the identification of recessive mutations in the X-chromosomal disease gene HPRT1 . After a normal pregnancy and birth, Lesch–Nyhan disease typically presents with developmental delay in the first year of life, most noticeably affecting the motor system, and leading to delayed sitting, crawling and walking. Involuntary movements develop before school age, with dystonia and choreoathetosis, leading on to spasticity that prevents affected boys from walking …