Friedreich's ataxia pathophysiology: Difference between revisions
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===Pathogenesis and genetics=== | ===Pathogenesis and genetics=== | ||
*It is understood that Friedreich’s ataxia is the result of a [[homozygous]] [[guanine]]-[[adenine]]-[[adenine]] (GAA) [[Trinucleotide repeat expansion disorders|trinucleotide repeat expansion]] on chromosome 9q13 that causes a transcriptional defect of the [[frataxin]] gene.<ref name="pmid11269509">{{cite journal |vauthors=Bit-Avragim N, Perrot A, Schöls L, Hardt C, Kreuz FR, Zühlke C, Bubel S, Laccone F, Vogel HP, Dietz R, Osterziel KJ |title=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 |journal=J. Mol. Med. |volume=78 |issue=11 |pages=626–32 |date=2001 |pmid=11269509 |doi= |url=}}</ref> | *It is understood that Friedreich’s ataxia is the result of a [[homozygous]] [[guanine]]-[[adenine]]-[[adenine]] (GAA) [[Trinucleotide repeat expansion disorders|trinucleotide repeat expansion]] on chromosome 9q13 that causes a transcriptional defect of the [[frataxin]] gene.<ref name="pmid11269509">{{cite journal |vauthors=Bit-Avragim N, Perrot A, Schöls L, Hardt C, Kreuz FR, Zühlke C, Bubel S, Laccone F, Vogel HP, Dietz R, Osterziel KJ |title=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 |journal=J. Mol. Med. |volume=78 |issue=11 |pages=626–32 |date=2001 |pmid=11269509 |doi= |url=}}</ref> | ||
*[[Frataxin]] is a small mitochondrial protein and deficiency of [[frataxin]] is responsible for all clinical and morphological manifestations of Friedreich’s ataxia.<ref name=" | *[[Frataxin]] is a small mitochondrial protein and deficiency of [[frataxin]] is responsible for all clinical and morphological manifestations of Friedreich’s ataxia.<ref name="pmid21315377">{{cite journal |vauthors=Koeppen AH |title=Friedreich's ataxia: pathology, pathogenesis, and molecular genetics |journal=J. Neurol. Sci. |volume=303 |issue=1-2 |pages=1–12 |date=April 2011 |pmid=21315377 |pmc=3062632 |doi=10.1016/j.jns.2011.01.010 |url=}}</ref> | ||
*The severity of the disease is directly related to the length of the [[Trinucleotide repeat expansion disorders|trinucleotide repeat expansion]] and long expansions lead to early onset, severe clinical illness, and death in young adult life.<ref name="pmid3913379">{{cite journal |vauthors=Lilja M, Ikäheimo M, Mattila MJ, Jounela AJ |title=Haemodynamic effects of prazosin combinations during dynamic and isometric exercise |journal=Ann. Clin. Res. |volume=17 |issue=6 |pages=316–22 |date=1985 |pmid=3913379 |doi= |url=}}</ref> | *The severity of the disease is directly related to the length of the [[Trinucleotide repeat expansion disorders|trinucleotide repeat expansion]] and long expansions lead to early onset, severe clinical illness, and death in young adult life.<ref name="pmid3913379">{{cite journal |vauthors=Lilja M, Ikäheimo M, Mattila MJ, Jounela AJ |title=Haemodynamic effects of prazosin combinations during dynamic and isometric exercise |journal=Ann. Clin. Res. |volume=17 |issue=6 |pages=316–22 |date=1985 |pmid=3913379 |doi= |url=}}</ref> | ||
*Patients with short [[Trinucleotide repeat expansion disorders|trinucleotide repeat expansion]] have a later onset and a more benign course and even some of them are not diagnosed during life.<ref name="pmid3913379">{{cite journal |vauthors=Lilja M, Ikäheimo M, Mattila MJ, Jounela AJ |title=Haemodynamic effects of prazosin combinations during dynamic and isometric exercise |journal=Ann. Clin. Res. |volume=17 |issue=6 |pages=316–22 |date=1985 |pmid=3913379 |doi= |url=}}</ref> | *Patients with short [[Trinucleotide repeat expansion disorders|trinucleotide repeat expansion]] have a later onset and a more benign course and even some of them are not diagnosed during life.<ref name="pmid3913379">{{cite journal |vauthors=Lilja M, Ikäheimo M, Mattila MJ, Jounela AJ |title=Haemodynamic effects of prazosin combinations during dynamic and isometric exercise |journal=Ann. Clin. Res. |volume=17 |issue=6 |pages=316–22 |date=1985 |pmid=3913379 |doi= |url=}}</ref> | ||
| Line 31: | Line 31: | ||
On gross pathology involvement of spinal cord, [[cerebellum]], and heart are characteristic findings of Friedreich's ataxia. | On gross pathology involvement of spinal cord, [[cerebellum]], and heart are characteristic findings of Friedreich's ataxia. | ||
'''Spinal cord''' lesions include:<ref name=" | '''Spinal cord''' lesions include:<ref name="pmid21315377">{{cite journal |vauthors=Koeppen AH |title=Friedreich's ataxia: pathology, pathogenesis, and molecular genetics |journal=J. Neurol. Sci. |volume=303 |issue=1-2 |pages=1–12 |date=April 2011 |pmid=21315377 |pmc=3062632 |doi=10.1016/j.jns.2011.01.010 |url=}}</ref><ref name="pmid3817014">{{cite journal |vauthors=Nath P, Getzenberg R, Beebe D, Pallansch L, Zelenka P |title=c-myc mRNA is elevated as differentiating lens cells withdraw from the cell cycle |journal=Exp. Cell Res. |volume=169 |issue=1 |pages=215–22 |date=March 1987 |pmid=3817014 |doi= |url=}}</ref> | ||
*Decreased transverse diameter of the [[spinal cord]] at all levels | *Decreased transverse diameter of the [[spinal cord]] at all levels | ||
**The thinning is especially evident in the thoracic region | **The thinning is especially evident in the thoracic region | ||
| Line 44: | Line 44: | ||
*Increased thickness of left and right ventricular walls and [[interventricular septum]]<ref name="pmid6354072">{{cite journal |vauthors=Churkina LN, Vasiurenko ZP, Smirnov VV, Kiprianova EA, Garagulia AD |title=[Effect of antibiotic AL-87 on the fatty acid composition of microorganisms in different taxonomic groups] |language=Russian |journal=Antibiotiki |volume=28 |issue=7 |pages=489–94 |date=July 1983 |pmid=6354072 |doi= |url=}}</ref> | *Increased thickness of left and right ventricular walls and [[interventricular septum]]<ref name="pmid6354072">{{cite journal |vauthors=Churkina LN, Vasiurenko ZP, Smirnov VV, Kiprianova EA, Garagulia AD |title=[Effect of antibiotic AL-87 on the fatty acid composition of microorganisms in different taxonomic groups] |language=Russian |journal=Antibiotiki |volume=28 |issue=7 |pages=489–94 |date=July 1983 |pmid=6354072 |doi= |url=}}</ref> | ||
*Dilatation of the [[ventricles]]<ref name="pmid6354072">{{cite journal |vauthors=Churkina LN, Vasiurenko ZP, Smirnov VV, Kiprianova EA, Garagulia AD |title=[Effect of antibiotic AL-87 on the fatty acid composition of microorganisms in different taxonomic groups] |language=Russian |journal=Antibiotiki |volume=28 |issue=7 |pages=489–94 |date=July 1983 |pmid=6354072 |doi= |url=}}</ref> | *Dilatation of the [[ventricles]]<ref name="pmid6354072">{{cite journal |vauthors=Churkina LN, Vasiurenko ZP, Smirnov VV, Kiprianova EA, Garagulia AD |title=[Effect of antibiotic AL-87 on the fatty acid composition of microorganisms in different taxonomic groups] |language=Russian |journal=Antibiotiki |volume=28 |issue=7 |pages=489–94 |date=July 1983 |pmid=6354072 |doi= |url=}}</ref> | ||
*“Marble”-like discoloration of the [[myocardium]]<ref name=" | *“Marble”-like discoloration of the [[myocardium]]<ref name="pmid21315377">{{cite journal |vauthors=Koeppen AH |title=Friedreich's ataxia: pathology, pathogenesis, and molecular genetics |journal=J. Neurol. Sci. |volume=303 |issue=1-2 |pages=1–12 |date=April 2011 |pmid=21315377 |pmc=3062632 |doi=10.1016/j.jns.2011.01.010 |url=}}</ref> | ||
==Microscopic Pathology== | ==Microscopic Pathology== | ||
| Line 51: | Line 51: | ||
'''<big>Spinal cord</big>''' | '''<big>Spinal cord</big>''' | ||
*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.<ref name="pmid19727777">{{cite journal |vauthors=Koeppen AH, Morral JA, Davis AN, Qian J, Petrocine SV, Knutson MD, Gibson WM, Cusack MJ, Li D |title=The dorsal root ganglion in Friedreich's ataxia |journal=Acta Neuropathol. |volume=118 |issue=6 |pages=763–76 |date=December 2009 |pmid=19727777 |doi=10.1007/s00401-009-0589-x |url=}}</ref> | *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.<ref name="pmid19727777">{{cite journal |vauthors=Koeppen AH, Morral JA, Davis AN, Qian J, Petrocine SV, Knutson MD, Gibson WM, Cusack MJ, Li D |title=The dorsal root ganglion in Friedreich's ataxia |journal=Acta Neuropathol. |volume=118 |issue=6 |pages=763–76 |date=December 2009 |pmid=19727777 |doi=10.1007/s00401-009-0589-x |url=}}</ref> | ||
*Cell stains in samples of DGN reveal:<ref name=" | *Cell stains in samples of DGN reveal:<ref name="pmid21315377">{{cite journal |vauthors=Koeppen AH |title=Friedreich's ataxia: pathology, pathogenesis, and molecular genetics |journal=J. Neurol. Sci. |volume=303 |issue=1-2 |pages=1–12 |date=April 2011 |pmid=21315377 |pmc=3062632 |doi=10.1016/j.jns.2011.01.010 |url=}}</ref><ref name="pmid3817014">{{cite journal |vauthors=Nath P, Getzenberg R, Beebe D, Pallansch L, Zelenka P |title=c-myc mRNA is elevated as differentiating lens cells withdraw from the cell cycle |journal=Exp. Cell Res. |volume=169 |issue=1 |pages=215–22 |date=March 1987 |pmid=3817014 |doi= |url=}}</ref><ref name="pmid4294979">{{cite journal |vauthors=Kono R |title=[Suspected human hepatitis virus] |language=Japanese |journal=Saishin Igaku |volume=22 |issue=6 |pages=1334–7 |date=June 1967 |pmid=4294979 |doi= |url=}}</ref><ref name="pmid4855486">{{cite journal |vauthors=Wykle RL, Schremmer JM |title=A lysophospholipase D pathway in the metabolism of ether-linked lipids in brain microsomes |journal=J. Biol. Chem. |volume=249 |issue=6 |pages=1742–6 |date=March 1974 |pmid=4855486 |doi= |url=}}</ref> | ||
**An overall reduction in the size of [[ganglion cells]] | **An overall reduction in the size of [[ganglion cells]] | ||
**The absence of very large [[Neuron|neurons]] and large [[Myelinated|myelinated fibers]] | **The absence of very large [[Neuron|neurons]] and large [[Myelinated|myelinated fibers]] | ||
| Line 62: | Line 62: | ||
*Friedreich’s ataxia mostly affects the [[dentate nucleus]] of [[cerebellum]]<ref name="pmid17443334">{{cite journal |vauthors=Koeppen AH, Michael SC, Knutson MD, Haile DJ, Qian J, Levi S, Santambrogio P, Garrick MD, Lamarche JB |title=The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins |journal=Acta Neuropathol. |volume=114 |issue=2 |pages=163–73 |date=August 2007 |pmid=17443334 |doi=10.1007/s00401-007-0220-y |url=}}</ref> | *Friedreich’s ataxia mostly affects the [[dentate nucleus]] of [[cerebellum]]<ref name="pmid17443334">{{cite journal |vauthors=Koeppen AH, Michael SC, Knutson MD, Haile DJ, Qian J, Levi S, Santambrogio P, Garrick MD, Lamarche JB |title=The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins |journal=Acta Neuropathol. |volume=114 |issue=2 |pages=163–73 |date=August 2007 |pmid=17443334 |doi=10.1007/s00401-007-0220-y |url=}}</ref> | ||
*Cell stains in samples of [[cerebellum]] reveal: | *Cell stains in samples of [[cerebellum]] reveal: | ||
**The absence of very large [[Neuron|neurons]]<ref name=" | **The absence of very large [[Neuron|neurons]]<ref name="pmid21315377">{{cite journal |vauthors=Koeppen AH |title=Friedreich's ataxia: pathology, pathogenesis, and molecular genetics |journal=J. Neurol. Sci. |volume=303 |issue=1-2 |pages=1–12 |date=April 2011 |pmid=21315377 |pmc=3062632 |doi=10.1016/j.jns.2011.01.010 |url=}}</ref> | ||
**Severe loss of [[γ-aminobutyric acid]] (GABA)-containing terminals in the immunostaining with an antibody to [[glutamic acid decarboxylase]] (GAD)<ref name="pmid21638087">{{cite journal |vauthors=Koeppen AH, Davis AN, Morral JA |title=The cerebellar component of Friedreich's ataxia |journal=Acta Neuropathol. |volume=122 |issue=3 |pages=323–30 |date=September 2011 |pmid=21638087 |pmc=4890974 |doi=10.1007/s00401-011-0844-9 |url=}}</ref> | **Severe loss of [[γ-aminobutyric acid]] (GABA)-containing terminals in the immunostaining with an antibody to [[glutamic acid decarboxylase]] (GAD)<ref name="pmid21638087">{{cite journal |vauthors=Koeppen AH, Davis AN, Morral JA |title=The cerebellar component of Friedreich's ataxia |journal=Acta Neuropathol. |volume=122 |issue=3 |pages=323–30 |date=September 2011 |pmid=21638087 |pmc=4890974 |doi=10.1007/s00401-011-0844-9 |url=}}</ref> | ||
**Grumose degeneration in the immunostaining with anti-GAD<ref name=" | **Grumose degeneration in the immunostaining with anti-GAD<ref name="pmid21315377">{{cite journal |vauthors=Koeppen AH |title=Friedreich's ataxia: pathology, pathogenesis, and molecular genetics |journal=J. Neurol. Sci. |volume=303 |issue=1-2 |pages=1–12 |date=April 2011 |pmid=21315377 |pmc=3062632 |doi=10.1016/j.jns.2011.01.010 |url=}}</ref> | ||
**Punctate reaction product in areas known to be rich in [[Mitochondrion|mitochondria]], namely, neuronal cytoplasm and synaptic terminals<ref name=" | **Punctate reaction product in areas known to be rich in [[Mitochondrion|mitochondria]], namely, neuronal cytoplasm and synaptic terminals<ref name="pmid21315377">{{cite journal |vauthors=Koeppen AH |title=Friedreich's ataxia: pathology, pathogenesis, and molecular genetics |journal=J. Neurol. Sci. |volume=303 |issue=1-2 |pages=1–12 |date=April 2011 |pmid=21315377 |pmc=3062632 |doi=10.1016/j.jns.2011.01.010 |url=}}</ref> | ||
**[[Frataxin]]-deficient [[mitochondria]]<ref name="pmid5383992">{{cite journal |vauthors=Broghammer H |title=Therapeutic effect of gelatin plasma substitutes in experimental shock |journal=Bibl Haematol |volume=33 |issue= |pages=223–31 |date=1969 |pmid=5383992 |doi= |url=}}</ref> | **[[Frataxin]]-deficient [[mitochondria]]<ref name="pmid5383992">{{cite journal |vauthors=Broghammer H |title=Therapeutic effect of gelatin plasma substitutes in experimental shock |journal=Bibl Haematol |volume=33 |issue= |pages=223–31 |date=1969 |pmid=5383992 |doi= |url=}}</ref> | ||
'''<big>Heart</big>''' | '''<big>Heart</big>''' | ||
*Cell stains in samples of heart reveal:<ref name=" | *Cell stains in samples of heart reveal:<ref name="pmid21315377">{{cite journal |vauthors=Koeppen AH |title=Friedreich's ataxia: pathology, pathogenesis, and molecular genetics |journal=J. Neurol. Sci. |volume=303 |issue=1-2 |pages=1–12 |date=April 2011 |pmid=21315377 |pmc=3062632 |doi=10.1016/j.jns.2011.01.010 |url=}}</ref> | ||
**Collections of tiny reactive inclusions in a small percentage of [[Cardiomyocyte|cardiomyocytes]] that are arranged in parallel with [[myofibrils]] in the iron stains | **Collections of tiny reactive inclusions in a small percentage of [[Cardiomyocyte|cardiomyocytes]] that are arranged in parallel with [[myofibrils]] in the iron stains | ||
**Electron-dense inclusions in [[Mitochondrion|mitochondria]] | **Electron-dense inclusions in [[Mitochondrion|mitochondria]] | ||
**[[Myocardial]] fiber necrosis and an inflammatory reaction in the severe cases of [[cardiomyopathy]] | **[[Myocardial]] fiber necrosis and an inflammatory reaction in the severe cases of [[cardiomyopathy]] | ||
'''<big>Pancreas</big>''' | '''<big>Pancreas</big>''' | ||
*Cell stains in samples of [[pancreas]] reveal:<ref name=" | *Cell stains in samples of [[pancreas]] reveal:<ref name="pmid21315377">{{cite journal |vauthors=Koeppen AH |title=Friedreich's ataxia: pathology, pathogenesis, and molecular genetics |journal=J. Neurol. Sci. |volume=303 |issue=1-2 |pages=1–12 |date=April 2011 |pmid=21315377 |pmc=3062632 |doi=10.1016/j.jns.2011.01.010 |url=}}</ref> | ||
**Lose of the sharp demarcation of the [[synaptophysin]]-positive [[Islets of Langerhans|islets]] of [[pancreas]] | **Lose of the sharp demarcation of the [[synaptophysin]]-positive [[Islets of Langerhans|islets]] of [[pancreas]] | ||
**The “fade” appearance of the β-cells into the surrounding exocrine [[pancreas]] | **The “fade” appearance of the β-cells into the surrounding exocrine [[pancreas]] | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D
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.[2] These functions include:[5][6]
- 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[7]
- Diabetes mellitus[8]
- Scoliosis[9]
- Distal wasting[10]
- Optic atrophy[10]
- Sensorineural deafness[10]
- Sleep apnea[11]
- Pes cavus in 55% to 75% of cases[12]
Gross Pathology
On gross pathology involvement of spinal cord, cerebellum, and heart are characteristic findings of Friedreich's ataxia.
Spinal cord lesions include:[2][13]
- 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[14]
Heart findings include:
- Increased heart weight[15]
- Increased thickness of left and right ventricular walls and interventricular septum[16]
- Dilatation of the ventricles[16]
- “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.[17]
- Cell stains in samples of DGN reveal:[2][13][18][19]
- 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[20]
- 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)[21]
- 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[22]
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.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 10.0 10.1 10.2 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) - ↑ 13.0 13.1 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.
- ↑ 16.0 16.1 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.