Friedreich's ataxia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief:
Overview
Pathophysiology
Pathogenesis and genetics
It is understood that Friedreich’s ataxia is the result of a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion on chromosome 9q13 that causes a transcriptional defect of the frataxin gene. Frataxin is a small mitochondrial protein and deficiency of frataxin is responsible for all clinical and morphological manifestations of Friedreich’s ataxia. The severity of the disease is directly related to the length of the trinucleotide repeat expansion and long expansions lead to early onset, severe clinical illness, and death in young adult life. Patients with short trinucleotide repeat expansion have a later onset and a more benign course and even some of them are not diagnosed during life. Friedreich’s ataxia is transmitted in autosomal recessive pattern. Because the frataxin protein has multiple functions in the normal state, the exact role of frataxin deficiency in the pathogenesis of Friedreich's ataxia is still unclear. These functions include: Biogenesis of iron-sulfur clusters Iron chaperoning Iron storage Control of iron-mediated oxidative tissue damage
Associated Conditions
Conditions associated with friedreich’s ataxia include:
Hypertrophic cardiomyopathy Diabetes mellitus Scoliosis Distal wasting Optic atrophy Sensorineural deafness Sleep apnea Pes cavus in 55% to 75% of cases
Gross Pathology
On gross pathology involvement of spinal cord, cerebellum, and heart are characteristic findings of Friedreich's ataxia.
Spinal cord lesions include:
Decreased transverse diameter of the spinal cord at all levels The thinning is especially evident in the thoracic region Thin and gray dorsal spinal roots Smallness and gray discoloration of the dorsal column Thin and gray gracile and cuneate fasciculi Fiber loss in the anterolateral fields corresponding to spinocerebellar and corticospinal tracts
Cerebellum lesions include:
Atrophy of the dentate nuclei and its efferent fibers
Heart findings include:
Increased heart weight Increased thickness of left and right ventricular walls and interventricular septum Dilatation of the ventricles “Marble”-like discoloration of the myocardium
Microscopic Pathology
On microscopic histopathological analysis, involvement of spinal cord, cerebellum, heart and pancreas are characteristic findings of Friedreich's ataxia.
Spinal cord
Friedreich’s ataxia mostly affects the dorsal root ganglia (DRG) of the spinal cord. It affects the entire DGR but is most prominent in subcapsular regions. Cell stains in samples of DGN reveal: An overall reduction in the size of ganglion cells The absence of very large neurons and large myelinated fibers Clusters of nuclei representing “residual nodules” that indicate an invasion-like entry of satellite cells into the cytoplasm of neurons. Progressive destruction of neuronal cytoplasm in cytoskeletal stains, such as for class-III-β-tubulin Greatly thickened satellite cells Residual nodules remain strongly reactive with anti-S100α in the satellite cells Increased ferritin immunoreactivity in satellite cells
Cerebellum
Friedreich’s ataxia mostly affects the dentate nucleus of cerebellum Cell stains in samples of cerebellum reveal: The absence of very large neurons Severe loss of γ-aminobutyric acid (GABA)-containing terminals in the immunostaining with an antibody to glutamic acid decarboxylase (GAD) Grumose degeneration in the immunostaining with anti-GAD Punctate reaction product in areas known to be rich in mitochondria, namely, neuronal cytoplasm and synaptic terminals Frataxin-deficient mitochondria
Heart
Cell stains in samples of heart reveal: Collections of tiny reactive inclusions in a small percentage of cardiomyocytes that are arranged in parallel with myofibrils in the iron stains Electron-dense inclusions in mitochondria Myocardial fiber necrosis and an inflammatory reaction in the severe cases of cardiomyopathy
Pancreas
Cell stains in samples of pancreas reveal: Lose of the sharp demarcation of the synaptophysin-positive islets of pancreas The “fade” appearance of the β-cells into the surrounding exocrine pancreas