Friedreich's ataxia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[[2]]
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.[1]
- Frataxin is a small mitochondrial protein and deficiency of frataxin is responsible for all clinical and morphological manifestations of Friedreich’s ataxia.[2]
- 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.[3]
- 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.[3]
- Friedreich’s ataxia is transmitted in autosomal recessive pattern.[4]
- 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.[5] These functions include:[6]
- Biogenesis of iron-sulfur clusters[7]
- 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
References
- ↑ Bit-Avragim N, Perrot A, Schöls L, Hardt C, Kreuz FR, Zühlke C, Bubel S, Laccone F, Vogel HP, Dietz R, Osterziel KJ (2001). "The GAA repeat expansion in intron 1 of the frataxin gene is related to the severity of cardiac manifestation in patients with Friedreich's ataxia". J. Mol. Med. 78 (11): 626–32. PMID 11269509.
- ↑ Marcus AJ, Safier LB, Ullman HL, Islam N, Broekman MJ, Falck JR, Fischer S, von Schacky C (1988). "Cell-cell interactions in the eicosanoid pathways". Prog. Clin. Biol. Res. 283: 559–67. PMID 3062632.
- ↑ Jump up to: 3.0 3.1 Lilja M, Ikäheimo M, Mattila MJ, Jounela AJ (1985). "Haemodynamic effects of prazosin combinations during dynamic and isometric exercise". Ann. Clin. Res. 17 (6): 316–22. PMID 3913379.
- ↑ Payne RM (May 2011). "The Heart in Friedreich's Ataxia: Basic Findings and Clinical Implications". Prog. Pediatr. Cardiol. 31 (2): 103–109. doi:10.1016/j.ppedcard.2011.02.007. PMC 3117664. PMID 21691434.
- ↑ Koeppen AH (April 2011). "Friedreich's ataxia: pathology, pathogenesis, and molecular genetics". J. Neurol. Sci. 303 (1–2): 1–12. doi:10.1016/j.jns.2011.01.010. PMC 3062632. PMID 21315377.
- ↑ Gold MI (March 1989). "Preoxygenation". Br J Anaesth. 62 (3): 241–2. PMID 2930671.
- ↑ Holzman IR (April 1985). "A method to maintain infant temperature". Am. J. Dis. Child. 139 (4): 390–2. PMID 3976629.