Chapter 232

## 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 232-1). 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 Deep sensory loss is another cardinal manifestation of FRDA. Loss of position and vibration sense is commonly found at onset and invariably after 2 years. Perception of light touch, pain, and temperature are initially normal, but tend to decrease in most patients with advanced disease. Also a consequence of sensory axonal neuropathy, the loss of tendon reflexes, at least in the lower limbs, has been considered an obligatory feature that needs to be present at onset to establish the diagnosis.3,4 Extensor plantar response was also considered an obligatory sign. However, exceptions exist. Other pyramidal signs (spasticity) are usually absent, obscured by the predominant loss of tendon reflexes and decrease of muscle tone.15 Muscle weakness is common and progressive, particularly at the lower limbs, usually affecting the proximal muscles first.16 Atrophy of distal lower limb muscles and of small hand muscles is sometimes observed, even early in the course of the disease.4 The most common abnormality of ocular movements in FRDA is fixation instability.17 Ophthalmoparesis is not observed and nystagmus is uncommon. About 30 percent of the patients develop optic atrophy, with or without visual impairment, particularly in the later stages of disease.15 Sensorineural hearing loss, more common with advanced disease, affects about 20 percent of the patients.18,19 Neuropathologic studies show an invariable loss of the large primary sensory neurons of the dorsal root ganglia (DRG).20 Atrophy of the central branches of the corresponding axons causes thinning of the dorsal roots, particularly at the lumbosacral level, and atrophy of the peripheral branches causes loss of large myelinated fibers from peripheral nerves. The fine unmyelinated fibers are well preserved, and interstitial connective tissue is increased. The motor component of peripheral nerves is well preserved. Degeneration of the posterior columns of the spinal cord is the hallmark of the disease.20 The posterior columns contain the central axonal branches of the large sensory neurons. As for the DRG, the fibers originating more caudally are more severely affected. Atrophy is also observed in the spinocerebellar tracts, the dorsal being more affected than the ventral. Clarke columns, where the spinocerebellar tracts originate, show severe loss of neurons. Therefore, the sensory systems providing information to the brain and cerebellum about the position and speed of body segments, particularly the lower limbs, are severely compromised in FRDA. Motor neurons in the ventral horns are well preserved, but the long crossed and uncrossed corticospinal motor tracts are atrophied, explaining the pyramidal signs. The pattern of atrophy of the corticospinal tracts suggests a “dying back” process.21 In the brain stem, trans-synaptic degeneration can be observed in the gracile and cuneate nuclei where the dorsal column tracts terminate, and in the medial lemnisci that continue the central sensory pathway above these nuclei.20 Sensory cranial nerves also show myelin pallor and loss of fibers. The cerebellar cortex shows only mild loss of Purkinje cells late in the disease course. This pattern of involvement contrasts with other inherited degenerative ataxias,22 in particular with the group of early onset ataxias with retained reflexes (EOCA), where the cerebellum is much more atrophic than the cervical spinal cord. The deep cerebellar nuclei, where cerebellar efferents originate, are severely affected with marked neuronal loss and gliosis in the dentate nucleus.20 As a consequence, the superior cerebellar pedunculi appear markedly atrophic. Other cerebral structures do not appear to be directly involved by the disease, with the exception of a loss of large pyramidal cells in the primary motor areas. Cardiomyopathy is a frequent nonneurologic finding in FRDA. Cardiac involvement is more often observed in patients with an earlier age of onset. The most common complaints are shortness of breath (40 percent of patients) and palpitations (11 percent).4 Enlargement of the heart is the typical finding, with thickening of ventricular walls and/or interventricular septum,23,24 which is best evidenced by echocardography.4,25 Electrocardiographic abnormalities include widespread T-wave inversions and signs of ventricular hypertrophy. About 10 percent of FRDA patients have diabetes mellitus, and an additional 20 percent have carbohydrate intolerance. A detailed study of glucose and insulin metabolism in FRDA patients revealed a deficiency in arginine-stimulated insulin secretion in all cases, including normotolerant individuals,26 suggesting that beta cells are invariably affected by the primary genetic defect of FRDA. The pancreas of patients with diabetes mellitus show a loss of islet cells without sign of autoimmune inflamation.27 Most patients have skeletal abnormalities even in the early phase of the disease. Kyphoscoliosis affects over 85 percent of patients and may be severe in 10 percent, particularly when onset is before puberty.3 It may cause pain and cardiorespiratory problems. Pes cavus and pes equinovarus, although found in more than 50 percent of patients, are not typical of FRDA, being even more common in other neuropathic diseases as Charcot-Marie-Tooth disease (CMT). Electromyographic and electroneurographic studies in FRDA reveal the underlying dying-back axonal sensory neuropathy. Sensory action potentials (SAPs) in peripheral nerves are severely reduced or absent, even early in the course of the disease.28–30 Motor and sensory nerve conduction velocities (NCVs) are within or just below the normal range, a feature that helps distinguishing an early case of FRDA from a case of demyelinating hereditary sensorimotor neuropathy, as CMT.

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