Friedreich's ataxia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2], Mohamadmostafa Jahansouz M.D
Overview
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. Conditions associated with friedreich’s ataxia include: Hypertrophic cardiomyopathy, diabetes mellitus, scoliosis, distal wasting, optic atrophy, sensorineural deafness, sleep apnea and pes cavus in 55% to 75% of cases. 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, thin and gray dorsal spinal roots, smallness and gray discoloration of the dorsal column, thin and gray gracile and cuneate fasciculi and 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 and "marble”-like discoloration of the myocardium. On microscopic histopathological analysis, involvement of spinal cord, cerebellum, heart and pancreas are characteristic findings of Friedreich's ataxia. 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 and increased ferritin immunoreactivity in satellite cells. 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 and Frataxin-deficient mitochondria. 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 and myocardial fiber necrosis and an inflammatory reaction in the severe cases of cardiomyopathy. Cell stains in samples of pancreas reveal: Lose of the sharp demarcation of the synaptophysin-positive islets of pancreas and the “fade” appearance of the β-cells into the surrounding exocrine pancreas.
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.[4]
- Friedreich’s ataxia is transmitted in autosomal recessive pattern.[5]
- 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.[2] These functions include:[6][7][8][2]
- 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[9]
- Diabetes mellitus[10]
- Scoliosis[11]
- Distal wasting[12]
- Optic atrophy[12]
- Sensorineural deafness[12]
- Sleep apnea[13]
- Pes cavus in 55% to 75% of cases[14]
Gross Pathology
On gross pathology involvement of spinal cord, cerebellum, and heart are characteristic findings of Friedreich's ataxia.
Spinal cord lesions include:[2][15]
- 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[16]
Heart findings include:
- Increased heart weight[17]
- Increased thickness of left and right ventricular walls and interventricular septum[18]
- Dilatation of the ventricles[18]
- “Marble”-like discoloration of the myocardium[2]
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.[19]
- Cell stains in samples of DGN reveal:[2][15][20][21]
- 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[22]
- Cell stains in samples of cerebellum reveal:
- The absence of very large neurons[2]
- Severe loss of γ-aminobutyric acid (GABA)-containing terminals in the immunostaining with an antibody to glutamic acid decarboxylase (GAD)[23]
- Grumose degeneration in the immunostaining with anti-GAD[2]
- Punctate reaction product in areas known to be rich in mitochondria, namely, neuronal cytoplasm and synaptic terminals[2]
- Frataxin-deficient mitochondria[24]
Heart
- Cell stains in samples of heart reveal:[2]
- 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:[2]
- 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.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 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.
- ↑ Martino D, Stamelou M, Bhatia KP (June 2013). "The differential diagnosis of Huntington's disease-like syndromes: 'red flags' for the clinician". J. Neurol. Neurosurg. Psychiatry. 84 (6): 650–6. doi:10.1136/jnnp-2012-302532. PMC 3646286. PMID 22993450.
- ↑ Koeppen AH, Mazurkiewicz JE (February 2013). "Friedreich ataxia: neuropathology revised". J. Neuropathol. Exp. Neurol. 72 (2): 78–90. doi:10.1097/NEN.0b013e31827e5762. PMC 3817014. PMID 23334592.
- ↑ 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.
- ↑ Napoli E, Taroni F, Cortopassi GA (2006). "Frataxin, iron-sulfur clusters, heme, ROS, and aging". Antioxid. Redox Signal. 8 (3–4): 506–16. doi:10.1089/ars.2006.8.506. PMC 1805116. PMID 16677095.
- ↑ Isaya G, O'Neill HA, Gakh O, Park S, Mantcheva R, Mooney SM (May 2004). "Functional studies of frataxin". Acta Paediatr Suppl. 93 (445): 68–71, discussion 72–3. PMID 15176725.
- ↑ Schagerlöf U, Elmlund H, Gakh O, Nordlund G, Hebert H, Lindahl M, Isaya G, Al-Karadaghi S (April 2008). "Structural basis of the iron storage function of frataxin from single-particle reconstruction of the iron-loaded oligomer". Biochemistry. 47 (17): 4948–54. doi:10.1021/bi800052m. PMC 3932613. PMID 18393441.
- ↑ Weidemann F, Störk S, Liu D, Hu K, Herrmann S, Ertl G, Niemann M (August 2013). "Cardiomyopathy of Friedreich ataxia". J. Neurochem. 126 Suppl 1: 88–93. doi:10.1111/jnc.12217. PMID 23859344.
- ↑ Gudowski G, Grossmann P, Robbe K (October 1967). "[The prednisolone provocation test in chronic pyelonephritis in children]". Kinderarztl Prax (in German). 35 (10): 441–5. PMID 5602235.
- ↑ Milbrandt TA, Kunes JR, Karol LA (March 2008). "Friedreich's ataxia and scoliosis: the experience at two institutions". J Pediatr Orthop. 28 (2): 234–8. doi:10.1097/BPO.0b013e318164fa79. PMID 18388721.
- ↑ 12.0 12.1 12.2 Hofstetter JR, Chevaux F, Fontolliet C (September 1980). "[Alcoholic hepatitis]". Schweiz Med Wochenschr (in German). 110 (38): 1370–5. PMID 6106966.
- ↑ Reddy PL, Grewal RP (February 2007). "Friedreich's ataxia: a clinical and genetic analysis". Clin Neurol Neurosurg. 109 (2): 200–2. doi:10.1016/j.clineuro.2006.09.003. PMID 17049722.
- ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Bidichandani SI, Delatycki MB. PMID 20301458. Vancouver style error: initials (help); Missing or empty
|title=(help) - ↑ 15.0 15.1 Nath P, Getzenberg R, Beebe D, Pallansch L, Zelenka P (March 1987). "c-myc mRNA is elevated as differentiating lens cells withdraw from the cell cycle". Exp. Cell Res. 169 (1): 215–22. PMID 3817014.
- ↑ Mian N, Pover WF (May 1974). "Loss of cellular material from suspensions of isolated epithelial cells of guinea pig small intestine". Biomedicine. 20 (3): 186–91. PMID 4215469.
- ↑ Howdle PD, Hanson DG, Trejdosiewicz LK, Ciclitira PJ, Smart CJ, Walker WA (1989). "Responses of antigen-specific long-term murine T cell lines to wheat gliadin fractions". Int. Arch. Allergy Appl. Immunol. 89 (2–3): 269–74. PMID 2474513.
- ↑ 18.0 18.1 Churkina LN, Vasiurenko ZP, Smirnov VV, Kiprianova EA, Garagulia AD (July 1983). "[Effect of antibiotic AL-87 on the fatty acid composition of microorganisms in different taxonomic groups]". Antibiotiki (in Russian). 28 (7): 489–94. PMID 6354072.
- ↑ Koeppen AH, Morral JA, Davis AN, Qian J, Petrocine SV, Knutson MD, Gibson WM, Cusack MJ, Li D (December 2009). "The dorsal root ganglion in Friedreich's ataxia". Acta Neuropathol. 118 (6): 763–76. doi:10.1007/s00401-009-0589-x. PMID 19727777.
- ↑ Kono R (June 1967). "[Suspected human hepatitis virus]". Saishin Igaku (in Japanese). 22 (6): 1334–7. PMID 4294979.
- ↑ Wykle RL, Schremmer JM (March 1974). "A lysophospholipase D pathway in the metabolism of ether-linked lipids in brain microsomes". J. Biol. Chem. 249 (6): 1742–6. PMID 4855486.
- ↑ Koeppen AH, Michael SC, Knutson MD, Haile DJ, Qian J, Levi S, Santambrogio P, Garrick MD, Lamarche JB (August 2007). "The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins". Acta Neuropathol. 114 (2): 163–73. doi:10.1007/s00401-007-0220-y. PMID 17443334.
- ↑ Koeppen AH, Davis AN, Morral JA (September 2011). "The cerebellar component of Friedreich's ataxia". Acta Neuropathol. 122 (3): 323–30. doi:10.1007/s00401-011-0844-9. PMC 4890974. PMID 21638087.
- ↑ Broghammer H (1969). "Therapeutic effect of gelatin plasma substitutes in experimental shock". Bibl Haematol. 33: 223–31. PMID 5383992.