Clinical Features and Pathology

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Friedreich ataxia (FA) is the most common of the early-onset hereditary ataxias in Indo-European and North African populations. The disease was first described in 1863 by Nickolaus Friedreich, Professor of Medicine at Heidelberg. Although Friedreich's papers described the essential clinical and pathological features of the disease as "degenerative atrophy of the posterior columns of the spinal cord" leading to progressive ataxia, sensory loss and muscle weakness, often associated with scoliosis, foot deformity and heart disease, subsequent descriptions of atypical cases and of clinically similar diseases clouded classification for many years. Diagnostic criteria were established in the late 1970s, after a renewed interest in the disease prompted several rigorous clinical studies (Geoffroy et al. 1976; Harding 1981). The following clinical features were considered essential to establish the diagnosis: (1) autosomal recessive inheritance, (2) onset before 25 years of age, (3) progressive limb and gait ataxia, (4) absent tendon reflexes in the legs, (5) electrophysiologic evidence of axonal sensory neuropathy, followed within 5 years of onset by (6) dysarthria, (7) areflexia at all four limbs, (8) distal loss of position and vibration sense, (9) extensor plantar responses, and (10) pyramidal weakness of the legs. The associated neuropathology is characterized by atrophy of the sensory pathways, with early loss of large neurons in the dorsal root ganglia (DRG), sensory axonal neuropathy, and degeneration of the posterior columns of the spinal cord. The cerebellum shows atrophy of the deep dentate nucleus, but its cortex is relatively preserved (Koeppen 2003).

The eventual identification of the FA gene (FRDA) and its most common mutation, the unstable hyperexpansion of a d(GAA) triplet repeat sequence (Campuzano et al. 1996), has allowed the clinical and pathological spectrum of the disease to be defined better. While the aforementioned criteria certainly identify the typical cases of FA, it is now clear that the disease shows a remarkable clinical variability, sometimes even within the same sibship, a rather uncommon finding for recessive disorders. Variability involves age of onset, rate of progression, and overall severity (Dürr et al. 1996; Monter-mini et al. 1997a). Cardiomyopathy, kyphoscoliosis, pes cavus, optic atrophy, hearing loss and diabetes mellitus only occur in some patients. Atypical cases with an overall FA-like phenotype but missing some of the essential diagnostic features can be identified. These include late-onset FA, which develops after the age of 25, sometimes as late as the sixth decade, and FA with retained tendon reflexes. The molecular basis for such a variability is only partially understood. Germ-line and somatic instability of the d(GAA) triplet repeat sequence certainly plays a role (Montermini et al. 1997a), but additional genetic and environmental factors are clearly involved. One example of a possible modifier genetic factor is the effect of mitochondrial DNA hap-logroups (Giacchetti et al. 2004).

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