Friedreich's ataxia overview
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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.[3]
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.
Diagnosis
Diagnosis study of choice
Triplet Repeat Primed PCR (TP PCR) is the gold standard test for the diagnosis of Friedreich’s Ataxia. The following finding on performing genetic testing is confirmatory for Friedreich’s Ataxia: GAA trinucleotide repeat in the first intron of the frataxin gene on chromosome 9q13. The TP PCR must be performed when: The patient presented with symptoms of Friedreich’s Ataxia. History of neuromuscular disorders in a family because the Friedreich’s Ataxia is an autosomal recessive disease and some heterozygous traits may be asymptomatic.
History and Symptoms
The hallmark of Friedreich’s Ataxia is progressive ataxia. The most common symptoms of Friedreich’s Ataxia include: Balance problems and coordination problems. Common symptoms of Friedreich’s Ataxia include: Balance problems, coordination problems (leading to difficulties in writing, as well as in many other daily activities), Slurred speech, hearing problems, vision problems and wallowing problems.
Physical Examination
HEENT examination of patients with Friedreich’s ataxia may be remarkable for: Nystagmus, dysarthria, abnormal extra-ocular movements of the eyes, decreased visual acuity and diffuse optic nerve pallor in the ophthalmoscopic exam. Hearing acuity also may be reduced. Most patients with advanced Friedreich's ataxia suffer from a restrictive pulmonary syndrome of scoliotic origin. Some of the findings in the lung examination of the patients with Friedeich's ataxia may be due to heart failure.Some of the findings in the lung examination of the patients with Friedeich's ataxia may be due to heart failure. Cardiovascular examination of patients with examination of patients with Friedreich’s ataxia may be remarkable for: Harsh systolic murmurs, signs of ventricular hypertrophy, added heart sounds and loud S4. Back examination of patients with examination of patients with Friedreich’s ataxia may be remarkable for: Scoliosis, hyperkyphosis and pelvic obliquity. Neuromuscular examination of patients with Friedreich’s ataxia may be remarkable for: Spasticity, Gait ataxia, Dysmetria of arms and legs, head titubation, atrophy and weakness of the distal extremities, absence of muscle stretch reflexes, loss of joint and vibratory senses, superimposed stocking-and-glove type sensory neuropathy, Dysarthria, Dyspraxia, Foot deformity (pes cavus), Hyperreflexia / hyporeflexia / areflexia, positive (abnormal) Babinski reflex bilaterally and Muscle rigidity.
Laboratory Findings
Some patients with Friedreich's ataxia may have an abnormal laboratory findings such as: Decreased serum ceruloplasmin activity, elevated serum transaminases and LDH, elevated aldolase, decrease in serum and CSF albumins as well as a significant increase in CSF B-globulins, increase in amounts of chylomicrons, low serum cholesterol and beta-lipoproteins and absence of acanthocytosis.
Electrocardiogram
An ECG may be helpful in the diagnosis of Friedreich's ataxia. Findings on an ECG suggestive of Friedreich's ataxia include: T-wave repolarization abnormalities especially in the inferior and lateral leads, Bundle branch blocks, ventricular hypertrophy, right axis deviation, short PR interval, interatrial block, left atrial enlargement and right atrial enlargement.
X-ray
An x-ray may be helpful in the diagnosis of Friedreich's ataxia. Findings on an x-ray suggestive of Friedreich's ataxia include distorted cardiac silhouette by scoliokyphosis.
Echocardiography and Ultrasound
Echocardiography may be helpful in the diagnosis of Friedreich's ataxia. Findings on an echocardiography suggestive of Friedreich's ataxia include: Varying degrees of septal hypertrophy in approximately 81% of cases, left ventricular free wall hypertrophy in approximately 61% of cases, slight reduction of left ventricular internal dimension in approximately 57% of cases and systolic anterior motion of the mitral valve in approximately 14 % of cases.
CT scan
Brain CT scan may be helpful in the diagnosis of Friedreich's ataxia. Findings on CT scan suggestive of Friedreich's ataxia include: Moderate cerebellar atrophy and an increase in the surface area of the fourth ventricle in two-thirds of the patients, atrophy of the number and width of cerebellar sulci, olivopontocerebellar atrophy with or without supratentorial atrophy, atrophy of the Fourth ventricle, brainstem ratio and cerebellopontine angle cistern and increased Evans' index.
MRI
Brain MRI may be helpful in the diagnosis of Friedreich's ataxia. Findings on MRI suggestive of Friedreich's ataxia include: Cerebellar hemisphere atrophy in approximately 50% of patients, atrophy of the vermis in approximately 67% of patients, atrophy of the medulla and supratentorial cerebral atrophy in approximately 17% of patients.
Other Diagnostic Studies
X-ray fluorescence (HDXRF) may be helpful in the diagnosis of Friedreich's ataxia. Findings on an HDXRF suggestive of Friedreich's ataxia include: Clusters of iron-rich hot-spots with similar mass fractions and significant decrease in zinc concentration in the cytoplasm of fibroblasts of patients with friedreich's ataxia.
Treatment
Medical Therapy
Pharmacologic medical therapy is recommended among patients with Friedreich's ataxia but their affect in decrease the symptoms of Friedreich's ataxia is not significant. Pharmacologic medical therapies for Friedreich's ataxia include Physostigmine, Riluzole and Amantadine. The rationale for evaluating physostigmine in ataxia, including Friedreich's ataxia, is its inhibition of acetylcholinesterase, which prolongs central and peripheral effects of acetylcholine. The mechanism of action of Riluzole may be related to the small conductance calcium-activated potassium channels that appear to regulate excitability in neurons found within deep cerebellar nuclei. Amantadine may be helpfull in the treatment of the patients with Freidreich's ataxia.
Surgery
Surgery is usually used for patients with either: Scoliosis, progressive equinovarus deformity, progressive severe dysphagia with endoscopic gastrostomy and progressive severe cardiac failure with cardiac transplantation.
Primary Prevention
There are no established measures for the primary prevention of Friedreich's ataxia.
Secondary Prevention
There are no established measures for the primary prevention of Friedreich's ataxia.