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Friedreich Ataxia

FA

Friedreich ataxia is an autosomal recessive disorder resulting in progressive neurologic and cardiac sequelae. It leads to significant morbidity as well as death.


Presentation

While the age of onset varies from one individual to another, it usually occurs around puberty [4]. However, there are individuals in which FA presents much earlier or later [5] [8]. Cases with early onset are associated with larger triplet nucleotide expansions. These patients exhibit rapid deterioration and manifest with cardiac involvement, diabetes, scoliosis and pes cavus [9]. However, those with later onset exhibit less GAA expansions and undergo slower progression [9]. 

The earliest feature of the disease is typically the gait ataxia, which results from poor muscle coordination. Both extremities are equally affected. Furthermore, patients with initial unilateral involvement eventually develop generalized ataxia. Some will experience a febrile illness prior to the onset of ataxia. The gait instability is characterized by a wide gait, difficulty with maintaining balance, slow ambulation, and trouble with running and standing. Additionally, patients with steppage gait exhibit uneven contact between the feet and the floor.

Progression of the condition results in extremity and trunk involvement. With ataxia of the arms, action and intention tremors occur. Furthermore, lower extremities become weaker and fatigued, especially in advanced disease states. Abnormal curvature of the spine and foot deformities also occur. Ultimately, patients will require a wheelchair for mobility. Affected facial and buccal muscles produce tremors and choreiform movements. Moreover, an involvement of the muscles in mouth and throat features difficulty with speech and swallowing. Over 50% of FA patients will develop cardiomyopathy and other sequelae such as cardiac arrhythmias and diabetes

Atypical presentation

Almost 25% of patients will develop FA after the age of 25. These individuals display an atypical clinical picture consisting of slow progression. Late onset FA occurs between 26 to 39 years while the very late onset presents after 40 years of age. Older onset patients are frequently associated with a subtype called Friedrich ataxia with retained reflex (FARR), in which the tendon reflexes are preserved for up to a decade after onset. FARR a is observed in 12% of FA cases. 

Falling
  • Although the patient's gait remained significantly impaired, extended use of the U-Step Walking Stabilizer modestly improved her gait performance, and her rate of falls decreased from 10 to 3 per month.[ncbi.nlm.nih.gov]
  • Disease-related falls, mobility restrictions, and wheelchair-dependency in later disease stages might additionally compromise bone structure in FRDA.[ncbi.nlm.nih.gov]
  • […] particularly color vision Decrease in ability to feel vibrations in lower limbs Foot problems, such as hammer toe and high arches Hearing loss, this occurs in about 10% of people Jerky eye movements Loss of coordination and balance, which leads to frequent falls[nlm.nih.gov]
  • Balance Exercises Patients may tremble/wobble with static standing and may report frequent falls. Balance exercises may assist with improving or maintaining balance and stability during sitting, standing, walking and moving.[web.archive.org]
  • He is thinking about quitting his soccer team since he is embarrassed by his frequent falls when his legs sometimes “give out” under him. He was diagnosed with scoliosis by his school nurse last month.[osmosis.org]
Congestive Heart Failure
  • Congestive heart failure usually is a terminal event.[ncbi.nlm.nih.gov]
  • Congestive heart failure was recently reported as the most frequent cause of Friedreich ataxia mortality.[ncbi.nlm.nih.gov]
  • Clinical manifestations include GAIT ATAXIA , pes cavus, speech impairment, lateral curvature of spine, rhythmic head tremor, kyphoscoliosis, congestive heart failure (secondary to a cardiomyopathy), and lower extremity weakness.[hon.ch]
  • Clinical manifestations include GAIT ATAXIA , pes cavus , speech impairment, lateral curvature of spine , rhythmic head tremor , kyphoscoliosis, congestive heart failure (secondary to a cardiomyopathy ), and lower extremity weakness.[expertscape.com]
  • Cardiac complications such as congestive heart failure and arrhythmias account for the latter. The age of onset is typically around puberty but ranges from 8 to 15 years.[symptoma.com]
Difficulty Walking
  • Specific symptoms include Difficulty walking Muscle weakness Speech problems Involuntary eye movements Scoliosis (curving of the spine to one side) Heart palpitations, from the heart disease which can happen along with Friedreich's ataxia People with[medlineplus.gov]
  • Difficulty walking The legs can be affected in different ways by Friedreich’s ataxia, including muscle weakness, weak or lack of leg reflexes, poor coordination and balance, foot deformities, and not being able to sense vibrations in the lower limbs,[friedreichsataxianews.com]
  • The illness typically begins with difficulty walking. People with Friedreich's ataxia develop clumsy, shaky movements of the legs (called gait ataxia) during childhood or early adolescence.[drugs.com]
  • Friedreich’s ataxia is a rare genetic disease that causes difficulty walking, a loss of sensation in the arms and legs, and impaired speech. It’s also known as spinocerebellar degeneration.[healthline.com]
Foot Deformity
  • In addition to neuropathological disabilities such as ataxia, sensory loss, and muscle weakness, common signs are scoliosis, foot deformity, and hypertrophic cardiomyopathy. Approximately 10 % of patients with FRDA develop diabetes.[ncbi.nlm.nih.gov]
  • Apart from predominant neurological features an involvement of the skeletal system in terms of scoliosis and foot deformities is frequent.[ncbi.nlm.nih.gov]
  • There was also plenty abuzz on Twitter as a reaction to that second analysis: RETA let's take out foot deformity so that people think we beat placebo by more than 2 points! Ground breaking science ![raredr.com]
  • The hallmark clinical features of FRDA include progressive afferent and cerebellar ataxia, dysarthria, impaired vibration sense and proprioception, absent tendon reflexes in lower limbs, pyramidal weakness, scoliosis, foot deformity and cardiomyopathy[ncbi.nlm.nih.gov]
  • Scoliosis and foot deformities (pes cavus and talipesequinovarus) can be mild or debilitating. Spasticity, seen later in the disease course, can lead to discomfort, pain, positioning problems and contractures in some.[orpha.net]
Muscular Atrophy
  • atrophy and related syndromes G12.0 Infantile spinal muscular atrophy, type I [Werdnig-Hoffman] G12.1 Other inherited spinal muscular atrophy G12.2 Motor neuron disease Reimbursement claims with a date of service on or after October 1, 2015 require the[icd10data.com]
  • DYCK P J & LAMBERT E H - Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. Arch Neurol 1968; 18 :619-625. [ Links ] 13.[scielo.br]
Ataxia
  • […] scoliosis due to Friedreich's ataxia Occipitoatlantoaxial scoliosis in Friedreichs ataxia Spinocerebellar ataxia Thoracic neuromuscular scoliosis due to Friedreichs ataxia Thoracic neuromuscular scoliosis due to Friedreich's ataxia Thoracic scoliosis[icd9data.com]
  • From Wikidata Jump to navigation Jump to search Human disease Friedreich ataxia 1 Friedreich's tabes Friedreich's ataxia Friedreich Ataxia type 1 FA Hereditary spinal ataxia FRIEDREICH ATAXIA 1; FRDA Spinocerebellar ataxia, Friedreich Hereditary spinal[wikidata.org]
  • Abstract Friedreich ataxia is the most common inherited ataxia, with a wide phenotypic spectrum.[doi.org]
  • Abstract Friedreich ataxia is the most frequent hereditary ataxia, with an estimated prevalence of 3–4 cases per 100,000 individuals.[doi.org]
  • Research into Friedreich ataxia has been hampered by low availability of study participants.[doi.org]
Dysarthria
  • Abstract Patterns of dysarthria in spinocerebellar ataxias (SCAs) and their discriminative features still remain elusive. Here we aimed to compare dysarthria profiles of patients with (SCA3 and SCA6 vs.[ncbi.nlm.nih.gov]
  • BACKGROUND: Friedreich Ataxia (FRDA) is the most common hereditary ataxia, with dysarthria as one of its key clinical signs.[ncbi.nlm.nih.gov]
  • Abstract The classic phenotype of Friedreich ataxia is characterized by dysarthria, progressive limb and trunk ataxia, loss of reflexes, and gait disturbance with the onset of disease before the second decade.[ncbi.nlm.nih.gov]
  • Acoustic analysis revealed participants with FRDA had greater nasality than controls (p KEYWORDS: Ataxia; dysarthria; hypernasality; hyponasality[ncbi.nlm.nih.gov]
  • PATIENTS AND METHODS: A previously healthy 10-year-old Malaysian boy, presented with fever, lethargy, headaches, dysarthria, dysphagia, vertigo and ataxia which developed over a one week period.[ncbi.nlm.nih.gov]
Cerebellar Ataxia
  • We have investigated this mutation in five Brazilian patients: four with typical FRDA findings and one patient with atypical manifestations, who was considered to have some other form of cerebellar ataxia with retained reflexes.[ncbi.nlm.nih.gov]
  • Both the number of GAA repeats and the duration of disease affect, in varying proportions, the signs associated with cerebellar ataxia.[doi.org]
  • Equistasi may improve limb and gait ataxia – a loss of control of voluntary muscular movement – in patients with hereditary cerebellar ataxia, such as Friedreich’s ataxia, although more studies are necessary to confirm these findings.[equistasi.com]
  • KEYWORDS: Cerebro-cerebellar connectivity; Cerebrum; Diffusion tensor imaging (DTI); Friedreich ataxia; Functional magnetic resonance imaging (fMRI); Magnetic resonance imaging (MRI); Neurodegenerative disorder; Neuroimaging; Spino-cerebellar ataxia[ncbi.nlm.nih.gov]
Nystagmus
  • The clinical picture consisted of progressive spastic gait, truncal and limb ataxia, dysarthria, nystagmus, hyperreflexia with knee and ankle clonus and extensor plantar response, and mild hypopallesthesia. Ages at present vary between 50 and 59.[ncbi.nlm.nih.gov]
  • Physical examination is notable for an ataxic gait, nystagmus, and mild dysarthria. You also observe the findings in Figure A on musculoskeletal examination.[step1.medbullets.com]
  • Differential Diagnosis Ataxia-telengiectasia - autosomal dominant, click HERE for a video of the nystagmus seen in this disorder.[pedclerk.bsd.uchicago.edu]
  • Oculomotor manifestations present early and include fixation instability (square wave jerks) and nystagmus. Visual loss may occur later. Auditory neuropathy (8-39% of cases), leads to hearing difficulties. Intelligence seems unaffected.[orpha.net]
  • Choreiform movements Associated impaired proprioception , vibration sense ( pallhypesthesia ), and loss of deep tendon reflexes Dysarthria and dysphagia (may be accompanied by uncoordinated breathing) Bladder dysfunction Hearing loss Impaired vision and nystagmus[amboss.com]
Tremor
  • Clinical manifestations include GAIT ATAXIA , pes cavus, speech impairment, lateral curvature of spine, rhythmic head tremor, kyphoscoliosis, congestive heart failure (secondary to a cardiomyopathy), and lower extremity weakness.[hon.ch]
  • Clinical manifestations include GAIT ATAXIA , pes cavus , speech impairment, lateral curvature of spine , rhythmic head tremor , kyphoscoliosis, congestive heart failure (secondary to a cardiomyopathy ), and lower extremity weakness.[expertscape.com]
  • Progressive ataxia (muscle weakness and impaired coordination) of all limbs Bilateral lower limbs equally affected Wide-based steppage gait with dysmetria and frequent falling Titubation while standing or sitting Torso and arms Action and intention tremors[amboss.com]
  • Affected facial and buccal muscles produce tremors and choreiform movements. Moreover, an involvement of the muscles in mouth and throat features difficulty with speech and swallowing.[symptoma.com]
  • Alongside the usual walking problems, the hand tremors and the difficulties in hearing, this was one more thing to deal with. I have been 'different' since I was six.[dailymail.co.uk]

Workup

The workup consists of a thorough history, physical exam, genetic testing, imaging modalities, and nerve conduction studies. Genetic testing will affirm the diagnosis by locating the FXN gene mutation. MRI of the brain and spinal cord is the test of choice, as it assesses the atrophy observed in FA. Additionally, transcranial sonography is a noninvasive evaluation of cerebellar and other abnormalities. It reveals echogenicity of the dentate in FA patients [10]. 

Regarding cardiac studies, echocardiography demonstrates concentric ventricular hypertrophy in FA patients with cardiac involvement. Also, EKG may display ventricular hypertrophy and T wave inversion

Nerve conduction tests are useful in diagnosing FA. Nerve conduction velocity (NCV) is normal or slightly decreased in these patients. Furthermore, sensory nerve action potentials (SNAP) are nonexistent in over 90% of cases while the remainder exhibit a decrease in the amplitude of potentials. Another study, brainstem auditory evoked responses, are abnormal as well. This reflects the involvement of the auditory pathways. 

Treatment

The therapy of FA is symptomatic and supportive. The multidisciplinary approach focuses on the systems involved. In patients with cardiac manifestations, antiarrhythmics, and drugs geared toward improving heart failure are useful. For those with diabetes, glycemic control through dietary modifications and medications such as oral hypoglycemic drugs and insulin may be appropriate. Patients with a physical handicap may benefit from physical therapy, wheelchairs, prosthesis, and walking aids. Those with scoliosis and foot abnormalities may require surgical intervention. Importantly, consultation with a neurologist and an orthopedic surgeon can guide the medical decision-making process.

For individuals with visual and hearing impairments, corrective devices and medications may be helpful. Speech and swallowing therapy may be indicated in certain patients. Finally, other supportive measures include psychological counseling.

Surveillance is important for all FA patients since they are at risk of developing complications such as heart disease and diabetes. Genetic counseling is recommended for patients and their family members. This service offers information about the inheritance pattern, the probability of having further affected offspring, and genetic testing. 

Prognosis

This progressive disorder is associated with poor prognosis. Specifically, patients typically survive until 25 to 30 years of age. Those that live beyond do not have cardiac involvement. In fact, approximately two-thirds of individuals with FA die from cardiac causes such as congestive heart failure and arrhythmias. Therefore, all individuals with FA should be monitored for cardiac manifestations [7]. The quality of life is affected by severe disability and morbidity. Within 15 years of onset, the patients suffer from ambulation difficulties. In particular, almost all become wheelchair bound by the age of 45 years.  

Etiology

FA occurs secondary to an expanded trinucleotide repeat located in the FXN gene. Hence, the impaired gene transcription causes a deficiency in the FXN protein [1] [2], which results in iron overload and mitochondrial dysfunction.

This mutation is inherited through an autosomal recessive pattern. Consanguineous unions are associated with a high risk of producing offspring with this recessive disorder. Furthermore, an affected parent (who is not in a consanguineous relationship) exhibits a risk of 1 in 200.

Epidemiology

FA is the most common ataxia attributed to recessive inheritance. In fact, it is responsible for half of all cases of inherited ataxia. With regards to the incidence, the estimates range from 1 in 22,000 to 1 in 50,000. The prevalence is 1 in 40,000. The patient demographics reflect a race preference. FA is more common in Europeans and North Americans with European ancestry. It does not occur in black Africans or Asians.

The age of onset is also significant. Specifically, FA manifests in ages ranging from 8 to 15 years of age with the mean age reported as 10.5 plus or minus 7 years [3]. In fact, the nature of the mutation decides when the disease presents [4] [5]. There is no gender preference. 

Sex distribution
Age distribution

Pathophysiology

The pathogenesis of FA exhibits the "dying back phenomena" of axons resulting in the loss of large myelinated axons as well as secondary gliosis. These are mainly observed in the spinal cord and spinal roots. Specifically, the depletion of myelinated axons is occurring in the posterior columns, and the corticospinal and spinocerebellar tracts. Overall, the spinal cord becomes thin and the dorsal spinal ganglia shrink.

Different neuronal types are prone to pathologic changes and each contributes to clinical manifestations [6]. For example, the atrophy of dorsal root ganglia causes peripheral neuropathy while the depletion of large axons in the posterior columns explains the deficits of the position and vibration senses. Since the lateral and ventral spinocerebellar tracts, dentate nucleus, and other close pathways are affected, cerebellar ataxia and abnormalities in proprioception manifest.

Furthermore, corticospinal tracts beyond the cervicomedullay junction are markedly degenerated, and this reflects the typical bilateral extensor plantar responses as well as the weakness experienced in advanced states. Additionally, the loss of large neurons in the sensory ganglia accounts for the absence of tendon reflexes.

The atrophied nuclei of cranial nerves VII, X, and XII result in facial weakness and difficulties in swallowing and speaking. Cardiac muscle fibers demonstrate degeneration as well. The sequelae, chronic interstitial myocarditis, develops as the fibers undergo fibrosis.

Prevention

Since this an inherited disease, it is not preventable. However, genetic counseling for those with FA provides information on the probability of passing the mutation to future children as well as other relevant details. Also, individuals with an affected family member may be offered genetic testing.

Summary

Friedreich ataxia (FA) is a hereditary disease caused by a trinucleotide GAA repeat in the mutated FXN gene, which codes for the mitochondrial protein known as frataxin. This autosomal recessive disorder is characterized by progressive degeneration of the nervous system and the heart [1], resulting in severe morbidity and mortality. Cardiac complications such as congestive heart failure and arrhythmias account for the latter. 

The age of onset is typically around puberty but ranges from 8 to 15 years. This disease is most prevalent in Europeans and individuals of European descent. Due to the neuronal loss of the spinal cord and important sensory pathways, the patients present with a myriad of features. Specifically, individuals with FA display gait instability, progressive ataxia, paresis, dysarthria, and dysphagia. Additionally, these patients exhibit a loss of reflexes and vibratory and position senses. Many will also develop foot deformities, scoliosis, and cardiomyopathy

Diagnosis is confirmed through genetic testing in addition to a detailed history and physical exam. Imaging modalities and nerve conduction tests are also beneficial. Therapy consists of a multidisciplinary approach towards cardiac manifestations and diabetes as well as correction and improvement of the disabilities. Patients should also undergo close surveillance for heart complications. 

Patient Information

Freidrich ataxia (FA) is named after the doctor that first wrote about the disease in 1863. It results from a specific mutation or change in the DNA.  Also, FA is inherited in an autosomal recessive pattern. This means that an affected individual inherited a bad copy of the gene from each parent. It is more commonly found in Europeans and North Americans with European ancestry. This disease develops between the ages of 5 and 15 although it can occur at younger and older ages as well. It is typically milder in older ages. 

This disorder causes loss and deterioration of the nerve cells in the brainstem and spinal cord. Therefore, patients will experience difficulty with coordination, balance, walking, standing, and running. They also lose the sense of position and reflexes. Additionally, they experience difficulty with speaking and swallowing. Some of the other features include heart diseases and diabetes. These patients can develop heart failure and abnormal heart rhythms resulting in death. Due to the progressive weakness, trouble with walking, deformities of the foot (clubfoot), and scoliosis, patients usually become confined to a wheelchair by the age of 25. 

Diagnosis occurs with the doctor obtaining a detailed history, physical exam, and genetic testing. Also, an MRI of the brain and spinal cord may be helpful. Since the heart is often affected, an ultrasound of this organ called echocardiogram can show heart failure and thickening of the left ventricle. Since these patients can have abnormal heart rhythms, they should have EKG testing. Other studies will evaluate the nerve conduction. 

The treatment focuses on the heart symptoms, diabetes, and the physical handicaps. For example, antiarrhythmics are important for those with dangerous heart rhythm patterns while patients with heart failure require specific therapy as well. Diabetes is treated with diet modification and medications if needed. As for the physical troubles, wheelchairs, walking aids, physical therapy, and other resources may be necessary. Since this disease takes an emotional toll on patients and their family members, counseling is usually helpful. Genetic counseling can offer patients and their family members very important information about the disease and how it is inherited. A family member can opt for testing as well. 

References

Article

  1. Harding AE, Zilkha KJ. Pseudo-dominant' inheritance in Friedreich's ataxia. Journal of Medical Genetics. 1981; 18(4):285-7.
  2. Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, et al Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Human Molecular Genetics. 1997; 6(11): 1771-80.
  3. Campuzano V, Montermini L, Moltò MD, Pianese L, Cossée M, Cavalcanti F, et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science. 1996; 271(5254): 1423-7.
  4. De Michele GFilla ACavalcanti F et al. Late onset Friedreich's disease: clinical features and mapping of mutation to the FRDA locus. Journal of Neurology, Neurosurgery, and Psychiatry.1994;57(8): 977- 979.
  5. Moschner CPerlman SBaloh RW Comparison of oculomotor findings in the progressive ataxia syndromes. Brain. 1994;117 (pt 1): 15- 25.
  6. Weidemann F, Rummey C, Bijnens B, Störk S, Jasaityte R, Dhooge J, et al. The Heart in Friedreich Ataxia: Definition of Cardiomyopathy, Disease Severity, and Correlation with Neurological Symptoms. Circulation. 2012; 125(13):1626-34.
  7. Koeppen A The neuropathology of inherited ataxias. Manto MPandolfo MThe Cerebellum and its Disorders. New York, NY. Cambridge University Press. 2002; 387- 405.
  8. Parkinson MH, Boesch S, Nachbauer W, Mariotti C, Giunti P. Clinical features of Friedreich's ataxia: classical and atypical phenotypes. Journal of Neurochemistry. 2013; 126 Suppl 1:103-17.
  9. Harding AE. Friedreich's ataxia: a clinical and genetic study of 90 families with an analysis of early diagnosis criteria and intrafamilial clustering of clinical features. Brain. 1981;104 (3) 589- 620.
  10. Synofzik M, Godau J, Lindig T, Schöls L, Berg D. Transcranial sonography reveals cerebellar, nigral, and forebrain abnormalities in Friedreich's ataxia. Neurodegenerative Diseases. 2011. 8(6):470-5.

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Last updated: 2018-06-22 07:07