Re-defining neurological syndromes: the genotype meets the phenotype.

Since time immemorial, generations of medical students and physicians have always been taught that a thorough and detailed history and examination is the foundation of the practice of good clinical medicine. This is particularly so in Neurology, in which the detection of an absent reflex or of focal weakness may assist in localisation of the lesion and, ultimately, in fixing the clinical diagnosis. While this age-old maxim still holds true and continues to play a vital role in our practice, recent advances in molecular science have threatened to challenge the classification of neurological syndromes based on clinical symptoms and signs, and to influence treatment options and patient management. Recognising the immense role that advances in molecular science, in particular human genetics, have played in the diagnosis and treatment of diseases, the Human Genetics Subcommittee of the Bioethics Advisory Committee published guidelines addressing a wide spectrum of pertinent issues in genetic testing and research. 1 In this light, I would like to highlight how recent advances in genetics have challenged the conventional classification of some neurodegenerative diseases, and the potential impact and challenges these discoveries have on clinical practice in this region. Most of us would have no problem in recognising a patient with cerebellar dysfunction, characterised by an unsteady gait, incoordination, dysmetria, dysarthria, and ocular movement abnormalities. For years, the diagnosis and categorisation of so-called idiopathic spinocerebellar ataxias (SCAs) have been based initially on Holmes's neuropathological classification and later Harding's clinical classification. 2 The discovery of an abnormal nucleotide repeat expansion (e.g trinucleotide or pentanucleotide) as a genetic cause for these familial (and also apparently sporadic) SCAs has changed clinical classifications and allow " marriage " of clinical syndromes previously thought to be of separate entities (such as Machado-Joseph disease and SCA3). 2-4 To date, 27 gene loci or causative mutation have been discovered for SCAs. Genotype-phenotype correlations of the various SCAs have alluded to a broad spectrum of neurological signs which overlaps with other neurological diseases, such as multiple system atrophy. Hence genetic testing for SCA in patients with ataxia alone or ataxia in combination with other neurological signs would enable us to confirm the exact diagnosis and may allow the early institution of genetic counseling. It can also assist in the selection of specific patients for pharmaceutical treatment trials, and ultimately could elucidate the pathogenesis and prognosis of the disease. While it is reasonable to consider sending a …