Friedreich Ataxia and AVED

ABSTRACT

In 1863, Nicholaus Friedreich, Professor of Medicine in Heidelberg, described a “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 cardiopathy.^1,2 Not until the late 1970s were large series of patients analyzed to establish clear diagnostic criteria.^3,4 Recessive inheritance was firmly established as an essential feature of Friedreich ataxia (FRDA).^3-6 The Québec Collaborative Group identified the clinical features of typical FRDA and proposed them as diagnostic criteria.³ They were, however, too strict for the diagnosis of early cases. Harding distinguished the early signs and symptoms from those that may not be present at the onset, but that have to manifest as the disease evolves⁴ (Table 281-1). These studies, as well as more recent ones,^7,8 identified an important degree of clinical variability, both among and within the families. Atypical FRDA, including adult-onset Friedreich ataxia (LOFA)^9,10 (MIM 229300), and Friedreich ataxia with retained reflexes (FARR), a variant in which tendon reflexes in the lower limbs are preserved,¹¹ were recognized by genetic linkage studies to be part of the same entity. The identification of the most common FRDA mutation, an unstable hyperexpansion of a GAA triplet repeat polymorphism,¹² clarified the origin and mechanism of the clinical variations.

Onset is usually around puberty, but wide variations are observed, ranging from 2 to 50 years (mean and standard deviation are 15±8 years).¹³ “Typical” FRDA patients have onset before age 20.³ Age of onset is more variable among families than within families.^4,14 Gait instability (65 percent) or generalized clumsiness (25 percent) is the usual initial symptom. Occasionally, nonneurologic manifestations, such as as scoliosis (5 percent) or cardiomyopathy (5 percent), precede the onset of ataxia.¹⁵

The cardinal neurologic feature of FRDA is a progressive, unremitting, mixed cerebellar-sensory ataxia. Most commonly, it begins with clumsiness in gait and frequent falls (truncal ataxia). Limb incoordination, dysmetria, and intention tremor then follow. Speech becomes slow and jerky with sudden utterances (dysarthria) within 5 years after onset.^3,4,7,8...