Friedreich's ataxia: pathology, pathogenesis, and molecular genetics

Abstract

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.

Published by Elsevier B.V.

Figures

Fig. 1

Ages of onset and death as a function of GAA trinucleotide repeat expansions (short alleles) in 30 patients with autopsy-confirmed FRDA (Table 2). (a) Age of onset vs. GAA trinucleotide repeats; (b) age of death vs. GAA trinucleotide repeats. The patient identified by the arrows (onset at 50, death at 83) was not diagnosed during life. An exponential trend line generated an R2=0.5087 for age of onset; a logarithmic trend line yielded R2=0.494 for age of death. Dürr et al. [19] reported an optimal fit between age of onset and GAA trinucleotide repeat expansion in the shorter allele in 140 patients (quadratic regression; R2=0.56). Filla et al. [20] obtained an R2=0.47 in 64 patients (linear regression).

Fig. 2

The thoracic spinal cord in FRDA. The transverse diameter of the spinal cord is less than 1 cm (bar). This view of the dorsal surface of the spinal cord shows thick white anterior roots (long arrows) that stand out in contrast to thin dorsal roots (short arrows).

Fig. 3

Gross appearance of the DN in FRDA. (a) FRDA; (b) normal control. The interrupted lines indicate the approximate location of the DN gray matter. The small size of the nucleus in FRDA is particularly apparent on a macrostain for iron (a). The normal DN shows the typical meandering gray matter ribbon (b). Iron reaction product does not co-localize with the gray matter but extends into the white matter of hilus and fleece.

Fig. 4

Gross appearance of the heart in FRDA. (a) Concentric cardiac hypertrophy and discoloration of the myocardium. In this case, the ventricles are narrowed. (b) Cardiac hypertrophy affecting only the left ventricular wall and interventricular septum. The right ventricle is dilated. Bars, 1 cm.

Fig. 5

Dorsal root ganglion in FRDA. (a)–(c), FRDA; (d)–(f), normal control. The hematoxylin-and-eosin stain (a; d) shows the overall size reduction of subcapsular nerve cells in the DRG and several residual nodules. The arrow (a) points to one nodule of Nageotte. Smaller size and frank destruction of neuronal cytoplasm are especially apparent after immunostaining for class-III-β-tubulin (arrows in [b]). Immunocytochemistry for S100α shows more prominent reaction product in satellite cells about smaller neurons in FRDA (c). Residual nodules are also S100α-positive (arrows in [c]). Bars: 50 μm.

Fig. 6

Ferritin in DRG of FRDA and a normal control. (a) Normal; (b) FRDA. In the normal state, immunocytochemistry of ferritin labels a few cells in the satellite layer around neurons (arrows in [a]). In FRDA, ferritin is present in a thicker layer of satellite cells (short arrow in [b]) and persists in residual nodules after complete neuronal atrophy (longer arrows in [b]). Bars, 20 μm.

Fig. 7

Dorsal spinal roots in FRDA. (a)–(b), FRDA; (c)–(d) normal control; (a) and (c), immunocytochemistry of phosphorylated neurofilament protein to visualize axons; (b) and (d), immunostain of myelin basic protein. Axons are present in normal abundance in FRDA (a) when compared to a normal control (c). In contrast, myelin sheaths in FRDA are much thinner (b) than in the normal control (d). Bars, 20 μm.

Fig. 8

Upper lumbar spinal cord in FRDA. (a)–(c), FRDA; (d)–(e), normal control. (a) and (d), immunostain of myelin basic protein; (b) immunostain of phosphorylated neurofilament protein in axons; (c) and (e), Cresyl Violet. The overall area of the spinal cord in FRDA ([a] and [b]) is greatly reduced in comparison with a normal control (d). In FRDA, the nucleus dorsalis of Clarke (c) is devoid of large round chromatin-rich neurons. Panel (e) illustrates the normal nucleus. Atrophy of the dorsal nuclei in FRDA is also apparent on low-power magnification of the spinal cord (arrows in [a] and [b]). In the normal spinal cord, dorsal nuclei show a distinct “bulge” (arrows in [d]). Bars: (a), (b), and (d), 1 mm; (c) and (d), 100 μm.

Fig. 9

The dentate nucleus in FRDA. (a) and (b), FRDA; (c) and (d), normal control. (a) and (c), immunocytochemistry of neuron-specific enolase (NSE); (b), inset in (b), and (d), glutamic acid decarboxylase (GAD). NSE-reaction product shows severe loss of large neurons while small neurons remain (arrows in [a]). GAD reaction product shows loss of corticonuclear terminals in the dentate nucleus of an FRDA patient (b) and grumose degeneration (inset in [b]). Small neurons display GAD-reaction product in their cytoplasm (arrows in [b]). In the normal dentate nucleus, the great abundance of GAD-positive terminals obscures the reactive cytoplasm in small neurons though one small GABA-ergic is visible (arrow in [d]). Bars: (a) and (c), 100 μm; (cb) and (d), 50 μm; inset in (b), 25 μm.

Fig. 10

The dentate nucleus in FRDA. (a)-(c), FRDA; (d)-(f), normal control. Double-label confocal immunofluorescence of synaptophysin ([a] and [d]; yellow-green; fluorescein isothiocyanate) and frataxin ([b] and [e]; red; Quantum dot 655); (c) and (f), merged images. In FRDA ([a]-[c]), synaptic terminals are modified to clusters of excessively large endings, representing grumose degeneration. Frataxin reaction product (b) is very sparse, and the merged images (c) show no co-localization of synaptophysin and frataxin. In the normal state ([d]–[f]), frataxin fluorescence is abundant in the cytoplasm of a nerve cell and in the rim of axosomatic terminals (e). The interrupted line in the lower panel ([d]–[f]) indicates the neuronal nucleus. Bars: 25 μm.

Fig. 11

The sural nerve in FRDA (autopsy specimens). (a)–(c), FRDA; (d)–(f), normal control. (a) and (e), immunostain of phosphorylated neurofilament protein; (b) and (e), immunostain of myelin basic protein; (c) and (f) electron microscopy. The main abnormality in FRDA is lack of myelin sheaths, especially those of larger diameter (b). Axons remain numerous in FRDA (a) though their overall size appears smaller in comparison with the normal state (e). Paucity of thicker myelin sheaths and greater abundance of unmyelinated fibers (c) are also apparent at the electron microscope level in FRDA (c) when compared to the normal state (f). umf, clusters of unmyelinated fibers. Bars: (a)–(b) and (d)–(e), 20 μm; (c) and (f), 5 μm.

Fig. 12

The histopathology of the heart in FRDA. (a) Hematoxylin and eosin; (b) iron histochemistry; (c) immunocytochemistry of cytosolic ferritin; (d) immunocytochemistry of mitochondrial ferritin; (e) and (f) electron microscopy after enhancement of ferritin by bismuth subnitrate [55]. For ultrastructural study, tissue samples were fixed by paraformaldehyde–glutaraldehyde mixtures and osmium tetroxide but other contrasting agents, such as lead citrate and uranyl acetate, were omitted. A cross-section of heart muscle (a) displays highly variable fiber sizes, excessive endomysium, and bizarre sarcoplasmic nuclei. The iron stain in (b) shows a single fiber with a collection of reactive granules. They are distributed in row-like manner, seemingly in parallel with muscle fibrils. Frequency and distribution of cytosolic (c) and mitochondrial ferritin (d) resemble the iron-containing granules in (b). The ultrastructural images were obtained from the heart of an FRDA patient with numerous iron deposits (as in [b]). The electron dense inclusions are thought to represent iron-laden mitochondria rather than lipofuscin granules. The arrow in (e) indicates partial involvement of a mitochondrion. Bars: (a)–(b), 50 μm; (c)–(d), 20 μm; (e)–(f), 1 μm.

Fig. 13

The endocrine pancreas in FRDA. (a)–(b) Diabetic patient; (c)–(d) non-diabetic patient; synaptophysin immunocytochemistry. In the diabetic patient, only few small islets remain (arrows in [a]). The interrupted line in (a) shows an islet that has lost most of its synaptophysin immunoreactivity. Normal islets are over 200 μm in diameter (c). Panel (b) suggests that in diabetic FRDA patients, β-cells lose their synaptophysin immunoreactivity as the disease progresses. The arrows in (c) and (d) show invaginations of normal exocrine pancreatic tissue into islets. They are synaptophysin-negative and must be distinguished from non-reactive cells in the diabetic patient (a). Bars, (a) and (c), 100 μm; (b) and (d), 20 μm.