Introduction

Numerous neuropathological studies of patients with hereditary ataxia have revealed heterogeneous lesions of the central and peripheral nervous systems, and clinicoanatomic correlation has been difficult. In light of recent progress in molecular genetics, it has become unnecessary to seek a classification on the basis of neuropathological observations. Nevertheless, traditional termssuchas ‘olivopontocerebellar atrophy’ or ‘cerebello-olivary atrophy’ will remain useful in anatomical descriptions. In the study of the hereditary ataxias, neuropathologists will have a new task. They must view their observations as a phenotype, similar to age at onset, disease duration, and age at death. They must also be familiar with the mutations that cause ataxia and correlate the complex structural abnormalities with data from molecular genetics. The findings include the length of the cytosine-adenine-guanine (CAG) trinucleotide repeats in various types of spinocerebellar ataxia (SCA), such as SCA1, SCA2, SCA3/Machado–Joseph disease, SCA6, and SCA7, the expanded GAA trinucleotide repeats in Friedreich's ataxia, and the matching abnormal or missing gene products. New names have appeared for gene products, e.g., frataxin in Friedreich's ataxia, and ataxin-1, ataxin-2, and ataxin-3 for SCA1, SCA2, and SCA3, respectively. Patients affected by SCA1, SCA2, and SCA3/Machado–Joseph disease biosynthesize normal and mutated ataxins, but the physiological roles of the unmutated polypeptides remain elusive. More is known about frataxin as an iron-carrying protein and the normal SCA6 gene product, an α1A-calcium channel protein. Qualitative and quantitative morphological analyses, and measurement of gene products will all be required to identify the true cause of ataxia.

The illustrations in this neuropathological review derive from the examination of genetically defined types of hereditary ataxia. In some cases, the genetic diagnosis was made by subsequent analysis of DNA in surviving relatives.