ATASSIA DI FRIEDREICH PDF

Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia Buyse G, Mertens L, Di Salvo G, Matthijs I, Weidemann F, Eyskens B. A number sign (#) is used with this entry because one form of Friedreich ataxia ( FRDA1) is caused by mutation in the gene encoding frataxin (FXN; ). Ultime notizie sull’atassia di Friedreich. Treatment with histone deacetylase inhibitors (HDACi) can restore the cellular pathways that become impaired upon loss.

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University of Washington, Seattle; December 18, ; Last Update: Friedreich ataxia FRDA is characterized by slowly progressive ataxia with onset usually before age 25 years mean age at onset: FRDA is typically associated with dysarthria, muscle weakness, spasticity particularly in the lower limbs, scoliosis, bladder dysfunction, absent lower limb reflexes, and loss of position and vibration sense. The remaining individuals with FRDA are compound heterozygotes rriedreich an abnormally expanded GAA repeat in the disease-causing range on one allele and another intragenic pathogenic variant on the other allele.

Clinical management guidelines have been published. Prostheses; walking aids and wheelchairs for mobility; speech, occupational, and physical therapy; pharmacologic agents for spasticity; orthopedic interventions for scoliosis and foot deformities; hearing devices for auditory involvement; dietary modifications and placement of a nasogastric tube or gastrostomy for dysphagia; antiarrhythmic agents, anti-cardiac failure medications, anticoagulants, and pacemaker for cardiac disease; atadsia modification, oral hypoglycemic agents or insulin for diabetes mellitus; antispasmodics for bladder dysfunction; continuous positive pressure for obstructive sleep apnea; psychological support, both pharmacologic and counseling.

Prevention of secondary manifestations: Active management of spasticity atasssia prevent permanent contractures; aggressive treatment of scoliosis to prevent cardiopulmonary complications; treatment of diabetes to avoid complications related to inadequate treatment; treatment of cardiac complications to avoid arrhythmias; treatment of sleep apnea to present neurologic and cardiopulmonary complications of untreated sleep apnea.

At least annual assessment of overall status; examination for complications including spasticity, scoliosis, and foot deformity; annual ECG, echocardiogram, and fasting blood sugar to monitor for diabetes mellitus; hearing assessment every two to three years; a low threshold for sleep study to investigate for obstructive sleep apnea. Environments that place ahassia individual at risk for falls such as rough surfaces for ambulant individuals; excessive use of alcohol, which can increase ataxia; medications e.

FRDA is inherited in an autosomal recessive manner. Carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if both FXN pathogenic variants have been identified in an affected family member.

Friedrich ataxia FRDA should be suspected in individuals with a combination of the following clinical features and family history:. Family history consistent with autosomal recessive inheritance. Absence of a family history of autosomal recessive inheritance does not preclude the diagnosis.

The diagnosis of Friedreich ataxia is established in a proband by detection of biallelic pathogenic variants in FXN see Table 1.

Friedreich’s ataxia – Wikipedia

Rare alleles of variant structure. In contrast to the alleles discussed above in which the GAA trinucleotides are perfect repeats, in rare pathogenic alleles the GAA repeats are not in perfect tandem order but rather are atadsia by other nucleotides. Such “interrupted FXN alleles” differ in length and types of nucleotides in the interruption, but they are typically close to the 3′ end of the GAA repeat tract see Molecular Genetics.

Interpretation of test results.

The exact demarcation between normal and full- penetrance alleles remains poorly defined. While the risk for phenotypic expression with borderline alleles is increased, it is not possible to offer precise risks. Therefore, the interpretation of test results in an individual with a large GAA expanded allele of full penetrance and a second allele of fewer than GAA repeats may be difficult. Molecular genetic testing approaches can include single- gene testing and use of a multigene panel.

A multigene panel that includes FXN and other genes of interest see Differential Diagnosis may also be considered. While this is not recommended as a first-line strategy in typical cases, it may help identify some affected individuals with atypical presentations. To date, next-generation sequencing strategies cannot identify expanded repeats and therefore will not diagnose the majority of individuals with FRDA. For an introduction to multigene panels click here.

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More detailed information for clinicians ordering genetic tests can be found here. View in own window. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

The remainder of individuals with FRDA have an abnormally expanded GAA repeat in the disease-causing range in one FXN allele and another intragenic pathogenic variant in the other allele. Sequence analysis detects variants that are benign, likely benign, of uncertain significancelikely pathogenic, or pathogenic.

For issues to consider in interpretation of sequence analysis results, click here. Sequence analysis of exons and flanking regions will identify FXN pathogenic variants located outside of the GAA repeat region. Nonsense, missenseframeshift, and splicing defect variants have been identified see Molecular Genetics. Methods that may be used include: However, no other loci have been convincingly linked to the FRDA phenotype.

Individuals with typical Friedreich ataxia FRDA develop progressive ataxia with onset from early childhood through to early adulthood, starting with poor balance when walking, followed by slurred speech and upper-limb ataxia. The mean age at onset of symptoms is ten to 15 years [ Delatycki et al b ]; onset can be as early as age two years and as late as the eighth decade.

Gait ataxia, caused by a combination of spinocerebellar degeneration and loss of joint-position sense proprioceptionis the earliest symptom in the vast majority.

The poor balance is accentuated when visual input is eliminated, such as in darkness or when the eyes are closed Romberg sign. Ankle and knee jerks are generally absent, and plantar responses are up-going. Involvement of peripheral sensory and motor neurons results in a mixed axonal peripheral neuropathy. Muscle weakness is often present and is most prominent in hip extensors and abductors; as disease advances, distal limb muscle weakness and wasting become evident.

Spasticity in the lower limbs is common and can be significant, affecting foot plantar flexors and inverters to a greater extent than dorsiflexors and everters. A study found that 49 of 77 individuals with FRDA had scoliosis; ten were treated with a brace and 16 required spinal surgery [ Milbrandt et al ]. Autonomic disturbance becomes more common with disease progression. The most common manifestations are cold, cyanosed feet; bradycardia is less common.

Central motor conduction time is abnormal after transcranial magnetic stimulation [ Brighina et al ]. Dysarthria, present in the majority of individuals with FRDA, is generally of three types: Dysarthria becomes worse as the disease progresses with the main changes seen over time being in speaking rate and utterance duration [ Rosen et al ]. Mild dysphonia characterized by hoarseness combined roughness and breathinessincreased strain, and altered pitch variability is also seen [ Vogel et al ].

Dysphagia in FRDA relates to oropharyngeal incoordination, weakness, and spasticity.

Friedreich’s ataxia

Hypertrophic cardiomyopathy, defined as increased thickness of the interventricular septum, is present in about two thirds of individuals with FRDA [ Delatycki et al a ]. Echocardiographic evaluation may reveal left ventricular hypertrophy that is more commonly asymmetric friedrelch concentric [ Dutka et alBit-Avragim et alKoc et al ].

When more subtle cardiac involvement is sought by methods such as tissue Doppler echocardiography, an even larger percentage of individuals have detectable abnormalities [ Vi et alMottram et al ].

Later in the disease course, the cardiomyopathy may become dilated.

Progressive systolic dysfunction is common [ Kipps et al ] and reduction in left ventricular wall thickness is often seen as the disease progresses [ Rajagopalan et al ]. Those in the “high risk” group had longer GAA expansions on the shorter friefreich. The degree of neurologic impairment did not predict whether an affected individual would have stable or rapid progression of cardiomyopathy. Electrocardiography ECG is abnormal in the vast majority, with Agassia wave inversion, left axis deviation, and repolarization abnormalities being ahassia commonly seen [ Dutka atassoa al ].

Quercia et al [] established the diagnosis of FRDA in a young child evaluated for sudden death. Arrhythmias especially atrial fibrillation and congestive heart failure frequently occur ataszia the later stages of the disease and are the most common cause of mortality [ Tsou et al ]. Of 28 who underwent urodynamic studies, all had normal serum creatinine and four had upper urinary tract dilatation. Sleep-disordered breathing and sleep apnea are more prevalent in those with FRDA than in the healthy population.

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Non-diabetic individuals with FRDA demonstrate high insulin responsiveness to oral glucose testing and low insulin sensitivity [ Isaacs et al ]. Progressive friedrejch of contrast acuity is typical with disease progression [ Seyer et al ].

Abnormal extraocular movements include irregular ocular pursuit, dysmetric saccades, saccadic latency, square wave jerks, ocular flutter, and marked reduction in vestibulo-ocular reflex gain and increased latency [ Fahey et al ].

Horizontal and vertical gaze palsy does not occur. Auditory neuropathy may occur and difficulty hearing in background noise is common [ Rance et al ].

While cognition is generally not impaired atasxia FRDA, motor and mental reaction times can be significantly slowed [ Wollmann et alCorben et al ]. Motor planning is markedly impaired [ Corben et alCorben et al ]. The intelligence profile of individuals with FRDA is characterized by concrete thinking and poor capacity in concept formation and visuospatial reasoning with reduced speed of information processing [ Mantovan et al ].

Problems with attention and working memory have also been demonstrated [ Klopper et al ]. Those with earlier onset and larger FXN intron 1 GAA repeats tend to have more severe cognitive difficulties than those with later onset and smaller GAA repeats [ Nachbauer et al ].

Aassia study of 28 individuals with FRDA identified that six There was a negative correlation between disease severity and femoral neck bone density.

Females were more likely to have clinical fractures than males but no association was found between bone mineral density and fracture occurrence. In fact, all fractures occurred in those with a Z-score better than Inflammatory bowel disease and growth hormone deficiency are more common in individuals with FRDA than the general community [ Shinnick et al ].

The rate of progression of FRDA is variable. A number of studies have found that progression is more rapid in those with earlier disease onset [ Reetz et alTai et alPatel et al ]. In a large study conducted in the early s, the average age at death was 37 years [ Harding ].

In a more recent study, the mean and median age of death was Survival into the sixth and seventh decades has been documented. A study of 65 pregnancies in 31 women with FRDA found no increase in the rate of spontaneous miscarriage, preeclampsia, prematurity, or cesarean section delivery [ Friedman et al ].

Worsening, improving, or unchanged symptoms during pregnancy were each reported by approximately one third of women with FRDA.

With advanced disease, atrophy of the cervical spinal cord and cerebellum may be observed [ Bhidayasiri et al ]. Atrophy of the superior cerebellar peduncle, the main outflow tract of the dentate nucleus, may also be seen [ Akhlaghi et al ]. Cervical spinal cord size correlates with disease severity as measured by the Friedreich Ataxia Rating Scale [ Chevis et al ].

A voxel-based morphometry study showed a symmetric volume loss in the dorsal medulla, infero-medial portions of the cerebellar hemispheres, rostral vermis, and dentate region [ Della Nave et al ]. No volume loss in cerebral hemispheres was observed. Lower fractional anisotropy, higher mean diffusivity, and increased radial diffusivity compared to controls have been found in the dentatorubral, dentatothalamic, and thalamocortical tracts in individuals with FRDA [ Akhlaghi et al ].

Reduced N-acetylaspartate in the cerebellum has been demonstrated by 1 H-MRS [ Iltis et al ] and increased diffusion weighted imaging may be present in a number of brain white matter tracts [ Rizzo et al ]. The oldest reported age of onset among individuals homozygous for the GAA expansion is 80 years [ Alvarez et al ]. A study of 44 individuals with LOFA and froedreich individuals with VLOFA found that dysarthria, absent tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, ganglionopathy, cerebellar atrophy, scoliosis, cardiomyopathy, and driedreich disability were milder, and GAA expansion on the smaller allele shorter, than in individuals with typical-onset FRDA [ Lecocq et al ].