The pathogenic mutation in Friedreich’s ataxia (FRDA) is a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion on chromosome 9q13 that causes a transcriptional defect of the frataxin gene. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. This autosomal recessive disease affects central and peripheral nervous systems, heart, skeleton, and endocrine pancreas. Long expansions lead to early onset, severe clinical illness, and death in young adult life. Patients with short expansions have a later onset and a more benign course. Some are not diagnosed during life. The neurological phenotype reflects lesions in dorsal root ganglia (DRG), sensory peripheral nerves, corticospinal tracts, and dentate nuclei (DN). Most patients succumb to cardiomyopathy, and many become diabetic during the course of their disease. This review seeks to reconcile the diverse clinical features with pathological and molecular data. In the pathogenesis of the lesion in DRG, dorsal spinal roots, and sensory peripheral nerves, developmental defects and atrophy occur in combination. The progressive lesion of the DN lacks a known developmental component. Destruction of the DN, optic atrophy, and degeneration of the corticospinal tracts are intrinsic central nervous system lesions. Fiber loss in dorsal columns and spinocerebellar tracts, and atrophy of the neurons in the dorsal nuclei of Clarke are secondary to the lesion in DRG. The role of frataxin deficiency in the pathogenesis of FRDA is still unclear because the protein has multiple functions in the normal state, including biogenesis of iron–sulfur clusters; iron chaperoning; iron storage; and control of iron-mediated oxidative tissue damage.

Friedreich ataxia is an autosomal recessive disorder that affects children and young adults. The mutation consists of a homozygous guanine-adenine-adenine trinucleotide repeat expansion that causes deficiency of frataxin, a small nuclear genome–encoded mitochondrial protein. Low frataxin levels lead to insufficient biosynthesis of iron-sulfur clusters that are required for mitochondrial electron transport and assembly of functional aconitase, and iron dysmetabolism of the entire cell. This review of the neuropathology of Friedreich ataxia stresses the critical role of hypoplasia and superimposed atrophy of dorsal root ganglia. Progressive destruction of dorsal root ganglia accounts for thinning of dorsal roots, degeneration of dorsal columns, transsynaptic atrophy of nerve cells in Clarke column and dorsal spinocerebellar fibers, atrophy of gracile and cuneate nuclei, and neuropathy of sensory nerves. The lesion of the dentate nucleus consists of progressive and selective atrophy of large glutamatergic neurons and grumose degeneration of corticonuclear synaptic terminals that contain γ-aminobutyric acid (GABA). Small GABA-ergic neurons and their projection fibers in the dentato-olivary tract survive. Atrophy of Betz cells and corticospinal tracts constitute a second intrinsic CNS lesion. In light of the selective vulnerability of organs and tissues to systemic frataxin deficiency, many questions about the pathogenesis of Friedreich ataxia remain.

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Autosomal dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative disorders clinically characterized by late-onset ataxia and variable other manifestations. Genetically and clinically, SCA is highly heterogeneous. Recently, CAG repeat expansions in the gene encoding TATA-binding protein (TBP) have been found in a new form of SCA, which has been designated SCA17. To estimate the frequency of SCA17 among white SCA patients and to define the phenotypic variability, we determined the frequency of SCA17 in a large sample of 1,318 SCA patients. In total, 15 patients in four autosomal dominant SCA families had CAG/CAA repeat expansions in the TBP gene ranging from 45 to 54 repeats. The clinical features of our SCA17 patients differ from other SCA types by manifesting with psychiatric abnormalities and dementia. The neuropathology of SCA17 can be classified as a "pure cerebellar" or "cerebello-olivary" form of ataxia. However, intranuclear neuronal inclusion bodies with immunoreactivity to anti-TBP and antipolyglutamine were much more widely distributed throughout the brain gray matter than in other SCAs. Based on clinical and genetic data, we conclude that SCA17 is rare among white SCA patients. SCA17 should be considered in sporadic and familial cases of ataxia with accompanying psychiatric symptoms and dementia.

Six forms of spinocerebellar ataxia (SCA) are caused by pathological cytosine-adenine-guanine (CAG) trinucleotide repeat expansions in the coding region of the mutated genes. The translated proteins contain abnormally long polyglutamine stretches, and SCA-1, SCA-2, SCA-3/Machado-Joseph disease (MJD), SCA-6, SCA-7, and SCA-17 are "polyglutamine diseases". Despite their clinical and genetic heterogeneity, the ataxia-causing lesions in the brain invariably affect the "cerebellar module" that is defined as a reciprocal circuitry between the cerebellar cortex, the dentate nuclei, and the inferior olivary nuclei. While the neurons of the basis pontis do not properly belong to this module, pontine atrophy is an important additional lesion in SCA-1, SCA-2, and SCA-7. The descriptive term olivopontocerebellar atrophy (OPCA) applies to these forms whereas SCA-6 is the prototype of "pure" cerebellar cortical or cerebello-olivary atrophy. Purkinje cells have an elaborate dendritic tree, and atrophy of these most remarkable cells has captured the attention of many morphologists. Almost invariably, the loss of Purkinje cells entails retrograde neuronal degeneration in the inferior olivary nuclei. However, SCA-6 is an exception, and many olivary neurons survive. Similarly, stellate, basket, and granule cells do not undergo commensurate retrograde atrophy when Purkinje cells disappear. The dentate nucleus displays "grumose" degeneration in SCA-3/MJD while the cerebellar cortex and the inferior olivary nuclei remain largely unaffected. The role of polyglutamine-containing intranuclear and cytoplasmic inclusion bodies in SCA remains unknown but protein aggregation may be the common step in the pathogenesis of these otherwise rather heterogeneous disorders.