Friedreich's ataxia: Difference between revisions
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=== Neck === | === Neck === | ||
* Neck examination of patients with Friedreich ataxia is usually normal. | * Neck examination of patients with Friedreich's ataxia is usually normal. | ||
=== Lungs === | === Lungs === | ||
* | * Most patients with advanced Friedreich's ataxia suffer from a [[Restrictive lung disease|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]]. | |||
* Asymmetric | |||
* Lungs | * Findings in lung examination of patients with Friedreich's ataxia may include: | ||
* Fine | ** Asymmetric and decreased chest expansion | ||
** Lungs may be hyporesonant | |||
** Fine [[crackles]] upon auscultation of the lung bases bilaterally due to [[heart failure]] | |||
** [[Wheezing]] also may be present | |||
* | |||
* [[ | |||
=== Heart === | === Heart === | ||
Revision as of 19:58, 19 March 2019
| Friedreich's ataxia | |
| ICD-10 | G11.1 |
|---|---|
| ICD-9 | 334.0 |
| OMIM | 229300 |
| DiseasesDB | 4980 |
| MeSH | D005621 |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]
Historical Perspective
Discovery
- 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.
Famous Cases
- Geraint Williams: He 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
Pathogenesis and genetics
- 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. These functions include:
- Biogenesis of iron-sulfur clusters
- Iron chaperoning
- Iron storage
- Control of iron-mediated oxidative tissue damage
Associated Conditions
Conditions associated with friedreich’s ataxia include:
- Hypertrophic cardiomyopathy
- Diabetes mellitus
- Scoliosis
- Distal wasting
- Optic atrophy
- Sensorineural deafness
- Sleep apnea
- Pes cavus in 55% to 75% of cases
Gross Pathology
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
- The thinning is especially evident in the thoracic region
- Thin and gray dorsal spinal roots
- Smallness and gray discoloration of the dorsal column
- Thin and gray gracile and cuneate fasciculi
- 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
- “Marble”-like discoloration of the myocardium
Microscopic Pathology
On microscopic histopathological analysis, involvement of spinal cord, cerebellum, heart and pancreas are characteristic findings of Friedreich's ataxia.
Spinal cord
- 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
- Increased ferritin immunoreactivity in satellite cells
Cerebellum
- 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
- Frataxin-deficient mitochondria
Heart
- 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
- Myocardial fiber necrosis and an inflammatory reaction in the severe cases of cardiomyopathy
Pancreas
- Cell stains in samples of pancreas reveal:
- Lose of the sharp demarcation of the synaptophysin-positive islets of pancreas
- The “fade” appearance of the β-cells into the surrounding exocrine pancreas
Causes
Genetic 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: Other family members of these patients may have frontotemporal dementia or motor neuron disease
- Progressive cerebellar atrophy with epileptic encephalopathy: Infantile seizures, intellectual deficits, microcephaly
- Rapid-onset ataxia: Cerebellar atrophy
- CAPOS mutation: (Cerebellar ataxia, areflexia, Pes cavus, optic atrophy, sensorineural hearing loss, and alternating hemiplegia)
Epidemiology and Demographics
Incidence
- The incidence of Friedreich’s ataxia is approximately 2-4 per 100,000 individuals worldwide.
Prevalence
- The prevalence of Friedreich’s ataxia is approximately 2-4 per 100,000 individuals worldwide.
Age
- 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.
Race and Region
- 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.
Gender
- 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
- Age of diagnosis
Screening
There is insufficient evidence to recommend routine screening for Friedreich’s Ataxia.
Natural History, Complications, and Prognosis
Natural History
- The symptoms of Friedreich’s Ataxia usually develop in the second decade of life but onset of disease may be as early as age 2 years and as late as the 8th decade, and start with progressive ataxiae.
Complications
- Common complications of Friedreich’s Ataxia include:
- The presence of diabetes and dilated cardiomyopathy has a negative impact on survival of patients with Friedreich’s Ataxia.
Prognosis
- 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.
Diagnostic Study of Choice
Study of choice
Triplet Repeat Primed PCR (TP PCR) is the gold standard test for the diagnosis of Friedreich’s Ataxia.
Diagnostic results
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.
Sequence of Diagnostic Studies
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
Common Symptoms
The hallmark of Friedreich’s Ataxia 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
- Weakening of the heart
- Swallowing problems
Physical Examination
Physical examination of patients with Friedreich’s Ataxia is usually remarkable for balance difficulty (ataxia), loss of joint sensation (proprioception), absence of deep tendon reflexes.
Appearance of the Patient
- Patients with Friedreich’s Ataxia usually appear normal.
Vital Signs
- Vital signs of patients with Friedreich’s Ataxia are usually normal.
Skin
- Skin examination of patients with Friedreich’s Ataxia is usually normal.
HEENT
HEENT examination of patients with Friedreich’s Ataxia may be remarkable for:
- Nystagmus
- Dysarthria
- Compromised chewing
- Extra-ocular movements of the eyes may be abnormal
- Decreased visual acuity
- Diffuse optic nerve pallor in the ophthalmoscopic exam
- Hearing acuity may be reduced:
- Children with Friedreich ataxia has a higher degree of everyday listening and communication difficulty than the controls.
- Weber test may be abnormal
Neck
- Neck examination of patients with Friedreich's ataxia is usually normal.
Lungs
- 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.
- Findings in lung examination of patients with Friedreich's ataxia may include:
- Asymmetric and decreased chest expansion
- Lungs may be hyporesonant
- Fine crackles upon auscultation of the lung bases bilaterally due to heart failure
- Wheezing also may be present
Heart
- Cardiovascular examination of patients with [disease name] is usually normal.
OR
- Chest tenderness upon palpation
- PMI within 2 cm of the sternum (PMI) / Displaced point of maximal impulse (PMI) suggestive of ____
- Heave / thrill
- Friction rub
- S1
- S2
- S3
- S4
- Gallops
- A high/low grade early/late systolic murmur / diastolic murmur best heard at the base/apex/(specific valve region) may be heard using the bell/diaphgram of the stethoscope
Abdomen
- Abdominal examination of patients with [disease name] is usually normal.
OR
- Abdominal distension
- Abdominal tenderness in the right/left upper/lower abdominal quadrant
- Rebound tenderness (positive Blumberg sign)
- A palpable abdominal mass in the right/left upper/lower abdominal quadrant
- Guarding may be present
- Hepatomegaly / splenomegaly / hepatosplenomegaly
- Additional findings, such as obturator test, psoas test, McBurney point test, Murphy test
Back
- Back examination of patients with [disease name] is usually normal.
OR
- Point tenderness over __ vertebrae (e.g. L3-L4)
- Sacral edema
- Costovertebral angle tenderness bilaterally/unilaterally
- Buffalo hump
Genitourinary
- Genitourinary examination of patients with [disease name] is usually normal.
OR
- A pelvic/adnexal mass may be palpated
- Inflamed mucosa
- Clear/(color), foul-smelling/odorless penile/vaginal discharge
Neuromuscular
- Neuromuscular examination of patients with [disease name] is usually normal.
OR
- Patient is usually oriented to persons, place, and time
- Altered mental status
- Glasgow coma scale is ___ / 15
- Clonus may be present
- Hyperreflexia / hyporeflexia / areflexia
- Positive (abnormal) Babinski / plantar reflex unilaterally/bilaterally
- Muscle rigidity
- Proximal/distal muscle weakness unilaterally/bilaterally
- ____ (finding) suggestive of cranial nerve ___ (roman numerical) deficit (e.g. Dilated pupils suggestive of CN III deficit)
- Unilateral/bilateral upper/lower extremity weakness
- Unilateral/bilateral sensory loss in the upper/lower extremity
- Positive straight leg raise test
- Abnormal gait (describe gait: e.g. ataxic (cerebellar) gait / steppage gait / waddling gait / choeiform gait / Parkinsonian gait / sensory gait)
- Positive/negative Trendelenburg sign
- Unilateral/bilateral tremor (describe tremor, e.g. at rest, pill-rolling)
- Normal finger-to-nose test / Dysmetria
- Absent/present dysdiadochokinesia (palm tapping test)
Extremities
- Extremities examination of patients with [disease name] is usually normal.
OR
- Clubbing
- Cyanosis
- Pitting/non-pitting edema of the upper/lower extremities
- Muscle atrophy
- Fasciculations in the upper/lower extremity
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It is named after the German physician Nicholaus Friedreich, who first described the condition in the 1860s.
Prevalence
Friedreich's ataxia, although rare, is the most prevalent inherited ataxia, affecting about 1 in 50,000 people in the United States. Males and females are affected equally.
Due to the relatively heterogenous population of Quebec, a 1984 Canadian study was able to trace 40 cases of classical Friedreich's disease from 14 previously unrelated French-Canadian kindreds to one common ancestral couple arriving in New France in 1634: Jean Guyon and Mathurine Robin.
Delatycki et al. (2000) provided an overview of the clinical features, pathology, molecular genetics, and possible therapeutic options in Friedreich’s Ataxia.
Genetics
Friedreich's ataxia is an autosomal recessive congenital ataxia and is caused by a mutation in Gene X25 that codes for frataxin, located on chromosome 9. This protein is essential in neuronal and muscle cells for proper functioning mitochondria (it has been shown to be connected with the removal of iron from the cytoplasm surrounding the mitochondria, and in the absence of frataxin, the iron builds up and causes free radical damage).
The classic form has been mapped to 9q13-q21; the mutant gene contains expanded GAA triplet repeats in the first intron of "frataxin gene". Because the defect is located on an intron (which is removed from the mRNA transcript between transcription and translation), this mutation does not result in the production of abnormal frataxin proteins. Instead, the mutation causes gene silencing (the mutation decreases the transcription of the gene) through induction of a heterochromatin structure in a manner similar to position-effect variegation.
Relationship to muscular dystrophy
Friedreich's ataxia and muscular dystrophy, though often compared, are completely different diseases. Muscular dystrophy is the result of muscle tissue degeneration whereas Friedreich's ataxia is the result of nerve tissue degeneration caused by a trinucleotide repeat expansion mutation. Both are researched by the Muscular Dystrophy Association.
Types of Friedreich's ataxia
There are two types, the classic form and one in association with a genetic vitamin E deficiency. They cannot be distinguished clinically in lab.
Symptoms
Symptoms typically begin sometime between the ages of 5 to 15 years, but in Late Onset FA may occur in the 20's or 30's. Symptoms include any combination, but not necessarily all of the following:
- Muscle weakness in the arms and legs
- Loss of coordination
- Vision impairment
- Hearing loss
- Slurred speech
- Curvature of the spine (scoliosis)
- High plantar arches
- Diabetes
- Extreme heart conditions (e.g., atrial fibrillation, and resultant tachycardia (fast heart rate) and cardiomyopathy (enlargement of the heart))
It presents before 25 years of age with progressive staggering gait, frequent falling and titubation. Lower extremities are more severely involved.
These symptoms are slow and progressive. Long-term observation shows that many patients reach a plateau in symptoms in the patient's early adulthood. Because of many of these symptoms, a person suffering from Friedrich's Ataxia may require some surgical interventions (mainly for the spine and heart). Often a metal rod is inserted in the spine to help prevent or slow the progression of scoliosis. As progression occurs, assistive devices such as a cane or walker or a wheelchair are required for mobility (independence).
Signs
- Cerebellar: Nystagmus, fast saccadic eye movements, truncal titubation, dysarthria, dysmetria.
- Pyramidal: absent deep tendon reflexes, extensor plantar responses, and distal weakness are commonly found.
- Dorsal column: Loss of vibratory and proprioceptive sensation occurs.
- Cardiac involvement occurs in 91% of patients, including cardiomegaly (up to dilated cardiomyopathy), symmetrical hypertrophy, murmurs, and conduction defects. Median age of death is 35 years, while females have better prognosis with a 20-year survival of 100% as compared to 63% in men.
20% cases are found in association with diabetes mellitus type 1 or 2 or pancreatic β cell dysfunction.
Diagnosis
- Cardiac MRI is indicated in patients suspected of this disease.
AHA Scientific Statement: Management of Cardiac Involvement Associated With Neuromuscular Diseases
Cardiac Evaluation in Friedrich Ataxia (FA)
| Class I |
| "1. Cardiology evaluation with examination, ECG, echocardiogram, and ambulatory electrocardiographic monitoring should occur at the time of FA diagnosis. (Level of Evidence: C) " |
| "2. Asymptomatic FA patients should be followed up at least annually with examination, ECG, and echocardiogram. (Level of Evidence: C) " |
| "3. Symptomatic FA patients should be followed up more frequently than annually. (Level of Evidence: C) " |
| Class IIa |
| "1. Ambulatory electrocardiographic monitor- ing or monitoring with an event recorder is reasonable in FA patients with symptoms of palpitations and in those without symptoms every 1 to 4 years, increasing in frequency with increasing age. (Level of Evidence: C) " |
ACC/AHA Guidelines- ACCF/ACR/AHA/NASCI/SCMR 2010 Expert Consensus Document on Cardiovascular Magnetic Resonance (DO NOT EDIT)
| “ |
CMR may be used for assessment of patients with LV dysfunction or hypertrophy or suspected forms of cardiac injury not related to ischemic heart disease. When the diagnosis is unclear, CMR may be considered to identify the etiology of cardiac dysfunction in patients presenting with heart failure, including
|
” |
Pathogenesis
The primary site of pathology is spinal cord and peripheral nerves. Sclerosis and degeneration of spinocerebellar tracts, lateral corticospinal tracts, and posterior columns. In peripheral nerves there is a loss of large myelinated fibres.
Treatment
The symptoms can be treated but there is no treatment for Friedrich's Ataxia at this time. There are several clinical trials taking place, including one for idebenone, in the United States. Assistive Technology, such as a standing frame, can help reduce the secondary complications of prolonged use of a wheelchair. In many cases, patients experience significant heart conditions as well. These conditions, fortunately, are much more treatable, and are often countered with ACE inhibitors such as Lisinopril and other heart medications such as Digoxin.
Current Research
Recent research led by Joel Gottesfeld of The Scripps Research Institute has indicated that Histone Deacetylase Inhibitors are able to reverse the silencing of the frataxin gene in human primary lymphocytes. This class of chemicals is thought to enable DNA transcription of the frataxin gene because the inhibition of histone deacetylation, makes the terminal tails of histones H3 and H4 more likely to remain fully acetylated. Acetylation removes the positive charge from the lysine (an amino acid that is a part of the n-terminal tail of the histone proteins), and thus makes the histones less able to neutralize the charges of the DNA (specifically the negatively charged phosphate backbone). This causes the DNA and the histone proteins to be less condensed (back to the form of euchromatin). This increases the ability of regulatory proteins and RNA polymerases to access the frataxin gene, and therefore returns the transcription (and the overall expression) of the frataxin gene to normal levels.
Because the genetic defect occurs in the intron, the excess nucleotides repeats are removed from the mRNA transcript, and the resulting frataxin proteins are not defective. The HDACi chemicals effect the histone proteins throughout the cell, but gene expression microarray experiments reveal that the effects are limited, and do not appear to be clustered into any family of genes that might cause deleterious side effects. The compounds are not cytotoxic to lymphocytes or to mice when administered at therapeutic doses.
On April 11th, 2007, Repligen Corporation, a biopharmaceutical company, entered into an exclusive commercial license with The Scripps Research Institute for the development of HDACi compounds that could have clinical uses in the treatment of Friedreich's Ataxia.
See also
References
External links
Friedreich's Ataxia Research Alliance (FARA) http://www.cureFA.org
Patient Recruitment for Friedreich's Ataxia Upcoming Clinical Research Trials: to sign up http://www.cureFA.org/registry/
FARA Electronic News Bulletin for latest research and news relevant to Friedreich's ataxia: To sign up http://visitor.constantcontact.com/email.jsp?m=1101190303489
- FARA What is Friedreich's Ataxia? at www.cureFA.org
- Babel FAmily Multilingual mailing-list about Friedreich's ataxia. Includes latest news about research and fundraising to help defeat this neurodegenerative disease. at Yahoo! Groups
- Template:NINDS
- Asks the Experts - Responses: Friedreich's Ataxia at Muscular Dystrophy Association
- Friedreich's Ataxia Enters 'the Treatment Era' at Muscular Dystrophy Association
- NCBI Genes and Disease: Friedreich's ataxia at National Center for Biotechnology Information
- friedreich at NIH/UW GeneTests
- Ataxia Forums at ataxiaforums.co.uk
- Muscular Dystrophy Association's website in Greece at mdahellas.gr
- http://www.curefa.org/news/pr_2007-04-11.asp
- http://www.lacaf.org/en/ Canadian Association for Familial Ataxias - Claude St-Jean Foundation
Template:Diseases of the nervous system Template:Mitochondrial diseases
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