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==Overview== | ==Overview== | ||
Revision as of 17:33, 21 May 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: {{MMJ}]
Overview
Historical Perspective
Friedreich’s ataxia was first discovered by Nikolaus Friedreich, a German pathologist and neurologist, in 1863. The association between hereditary inheritance and Friedreich’s ataxia was made first time by Nikolaus Friedreich. In 1996, the association between a GAA repeat expansion on chromosome 9 and the development of Friedreich's ataxia was discovered for the first time. Geraint Williams who had Friedreich's ataxia is known for scaling Mount Kilimanjaro in an adaptive wheelchair known as a Mountain Trike.
Classification
There is no established system for the classification of Friedreich's ataxia.
Pathophysiology
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.
Causes
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.
Differentiating Friedreich’s ataxia from Other Diseases
As Friedreich’s ataxia manifests in a variety of clinical forms and different ages, differentiation must be established in accordance with the manifestations of the disease and onset of the symptoms. The main and most prominent symptom of the Friedreich’s ataxia is ataxia that worsens over time and it must be differentiated from other diseases that cause progressive ataxia such as: spinocerebellar ataxias (SCA), dentato-rubro-pallido-luysian atrophy, Episodic ataxia, Spastic ataxia, abetalipoproteinemia, Refsum disease, hypomyelinating leukoencephalopathy (Hypomyelination, basal ganglia atrophy, rigidity, dystonia, chorea), pure cerebellar ataxia, progressive cerebellar atrophy with epileptic encephalopathy: Infantile seizures, intellectual deficits, microcephaly, rapid-onset ataxia: Cerebellar atrophy and CAPOS mutation: (Cerebellar ataxia, areflexia, Pes cavus, optic atrophy, sensorineural hearing loss, and alternating hemiplegia).
Epidemiology and Demographics
The incidence of Friedreich’s ataxia is approximately 2-4 per 100,000 individuals worldwide. The prevalence of Friedreich’s ataxia is approximately 2-4 per 100,000 individuals worldwide. Friedreich’s Ataxia commonly affects individuals from early childhood through to early adulthood, starting with poor balance when walking, followed by slurred speech and upper-limb ataxia. Friedreich’s Ataxia is usually first diagnosed at age 10 to 15 years but onset of disease may be as early as age 2 years and as late as the 8th decade. The GAA triplet repeat expansion that causes Friedreich’s Ataxia usually affects only individuals of the European, North African, Middle Eastern, or Indian origin (Indo-European and Afro-Asiatic speakers). Sub-Saharan Africans, Amerindians, and individuals from China, Japan, and Southeast Asia are less likely to develop Friedreich’s Ataxia. Friedreich’s Ataxia affects men and women equally. Female are more commonly affected by clinical fractures than male.
Risk Factors
Because Friedreich’s Ataxia is a genetic diseases transmitted by autosomal recessive pattern, the most potent risk factor in the development of Friedreich’s Ataxia is strong family history. Other risk factors are unknown. The risk factors for developing associated clinical conditions of Friedreich's ataxia include: GAA1 length and age of diagnosis.
Screening
There is insufficient evidence to recommend routine screening for Friedreich’s Ataxia.
Natural History, Complications, and Prognosis
The symptoms of Friedreich’s Ataxia usually develop in the second decade of life but the onset of disease may be as early as age 2 years and as late as the 8th decade, and start with progressive ataxia. Common complications of Friedreich’s Ataxia include: Aspiration pneumonia, hypertrophic cardiomyopathy, diabetic coma, embolic stroke, cerebral haemorrhage, trauma sequelae and renal failure. The presence of diabetes and dilated cardiomyopathy has a negative impact on survival of patients with Friedreich’s Ataxia. The average age of death of patients with Friedreich’s Ataxia is at 37.5 years. Depending on the extent of the disease progression at the time of diagnosis, the prognosis may vary. The presence of hypertrophic cardiomyopathy is associated with a particularly poor prognosis among patients with Friedreich’s Ataxia.