ATASSIA DI FRIEDREICH PDF

Friedreich ataxia is the most common hereditary progressive ataxia. There is no recognized gender predilection. Typically present in childhood to adolescence Friedreich ataxia carries an autosomal recessive inheritance 1.

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NCBI Bookshelf. Friedreich ataxia FRDA is characterized by slowly progressive ataxia with onset usually before age 25 years mean age at onset: yrs.

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 for an abnormally expanded GAA repeat in the disease-causing range on one allele and another intragenic pathogenic variant on the other allele.

Treatment of manifestations: 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; dietary 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 to 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. Surveillance: 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.

FRDA is inherited in an autosomal recessive manner. Carrier testing of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing 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. Note: 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. Allele sizes. 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 interrupted 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. Note: 1 Molecular genetic testing does not determine presence or absence of nucleotide interruptions of the GAA tract. 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. Note: 1 The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. For an introduction to multigene panels click here.

More detailed information for clinicians ordering genetic tests can be found here. View in own window. See Table A. 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 significance , likely 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 the GAA repeat region.

Nonsense, missense , frameshift, and splicing defect variants have been identified see Molecular Genetics. Methods used may include quantitative PCR , long-range PCR, multiplex ligation-dependent probe amplification MLPA , and a gene -targeted microarray designed to detect single- exon deletions or duplications. See Molecular Genetics. However, no other loci have been convincingly linked to the FRDA phenotype.

Neurologic manifestations. 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 proprioception , is 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. Electrodiagnostic findings. 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: mild dysarthria, increased velopharyngeal involvement manifest as hypernasality, and increased laryngeal dysfunction manifest as increased strained-strangled vocal quality [ Folker et al ].

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 breathiness , increased strain, and altered pitch variability is also seen [ Vogel et al ].

Dysphagia in FRDA relates to oropharyngeal incoordination, weakness, and spasticity. 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 than concentric [ Dutka et al , Bit-Avragim et al , Koc 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 [ Dutka et al , Mottram 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 allele. 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 T wave inversion, left axis deviation, and repolarization abnormalities being most commonly seen [ Dutka et 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 in the later stages of the disease and are the most common cause of mortality [ Tsou et al ]. Urinary issues. Of 28 who underwent urodynamic studies, all had normal serum creatinine and four had upper urinary tract dilatation. Sleep-disordered breathing. Sleep-disordered breathing and sleep apnea are more prevalent in those with FRDA than in the healthy population.

Non-diabetic individuals with FRDA demonstrate high insulin responsiveness to oral glucose testing and low insulin sensitivity [ Isaacs et al ].

Ophthalmic manifestations. Progressive diminution 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. Hearing loss. Auditory neuropathy may occur and difficulty hearing in background noise is common [ Rance et al ].

Cognitive skills. While cognition is generally not impaired in FRDA, motor and mental reaction times can be significantly slowed [ Wollmann et al , Corben et al ]. Motor planning is markedly impaired [ Corben et al , Corben 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 ]. Bone mineral density. A 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 al , Tai et al , Patel 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 ].

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Alternative titles; symbols. Other entities represented in this entry:. The most common molecular abnormality is a GAA trinucleotide repeat expansion in intron 1 of the FXN gene: normal individuals have 5 to 30 GAA repeat expansions, whereas affected individuals have from 70 to more than 1, GAA triplets Al-Mahdawi et al. Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in the first or second decade, before the end of puberty. It is one of the most common forms of autosomal recessive ataxia, occurring in about 1 in 50, individuals.

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Friedreich's ataxia

We'd like to understand how you use our websites in order to improve them. Register your interest. We report on a year-old woman with advanced FA who achieved a successful pregnancy. The neurological and cardiological features of the disease remained unchanged during and after pregnancy.

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A case of successful pregnancy in a woman with Friedreich ataxia

We'd like to understand how you use our websites in order to improve them. Register your interest. Eighteen patients with the presumptive diagnosis of Friedreich's ataxia were studied. Clinical, neurophysiological and biochemical data were concordant in 14 patients and led to the diagnosis of typical Friedreich's ataxia in this group of patients: the remaining 4 patients differed from the typical patients in several respects but mainly in the cardiological findings. It is concluded that so far no single clinical or laboratory finding is typical of F. Multidisciplinary approaches are essential to the diagnosis of Friedreich's ataxia.

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