heriditary ataxias

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Inherited ataxias : 

Inherited ataxias

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Degenerative ataxias 1.) hereditary 2.) non hereditary Progressive ataxia as prominent symptom AD, AR, X Linked, mitochondrial

ADCA prevalence : 

ADCA prevalence SCA 1,2,3 -50% of ADCAs world wide Asia SCA3 and SCA 6 India SCA 2-17.5% SCA 1-10.5% SCA 3-7% SCA 6-1.8% SCA 12-5 families identified

pathogenesis : 

pathogenesis Trinucleotide ,penta nucleotide repeats CAG – glutamine Polyglutamine disorders-ataxin protein Conformational change to beta pleated TATA binding and CREB binding protein Ubiquitin proteosome system Neuronal apoptosis ‘ANTICIPATION’—eg:SCA 7

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CAG anticipation- more likely if paternal inheritance CTG- if maternal inheritance Trinucleotide repeats may be stable or contract CAG repeat length high specifity,sensitivity CAG repeat allele –full penetrance –disease Mutable normal allele-reduced penetrance

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Genetics of Autosomal Dominant Cerebellar Ataxias Disease Name Gene Symbol Chromosomal Locus Protein Name Type of Mutation SCA1 ATXN1 6p23 Ataxin-1 CAG repeat SCA2 ATXN2 12q24 Ataxin-2 CAG repeat SCA3 ATXN3 14q24.3-q31 Ataxin-3 CAG repeat SCA4 --- 16q22.1 --- --- SCA, 16q22-linked 1 PLEKHG4 16q22 Puratrophin-1 --- SCA5 SPTBN2 11p13 Spectrin beta chain, Nonrepeatmutations SCA6 CACNA1A 19p13 Voltage-dependent P/Q-type calcium CAG channel alpha- 1A subunit SCA7 ATXN7 3p21.1-p12 Ataxin-7 CAG repeat SCA8 ATXN80S 13q21 --- CAG•CTG

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SCA9 --- --- --- --- SCA10 ATXN10 22q13 Ataxin-10 ATTCT repeat SCA11 TTBK2 15q14-q15.3 Tau-tubulin kinase 2 non repeat mutation SCA12 PPP2R2B 5q31-q33 Serine/threonine protein phosphatase 2A 55-kd regulatory subunit B beta isoform Non-repeat mutations SCA13 KCNC3 19q13.3-q13.4 Potassium voltage-gated channel subfamily C member 3 Non-repeat mutations SCA14 PRKCG 19q13.4 Protein kinase C gamma type Non-repeat mutations SCA15 ITPR1 3p26-p25 Inositol 1,4,5-trisphosphate receptor type 1 Deletion of the 5' part of the gene SCA16 SCA16 3p26.2-pter Contactin-4 ---

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SCA17 TBP 6q27 TATAboxbindingprotein CAA/CAG repeat mutation SCA18 SCA18 7q22-q32 --- --- SCA19 SCA19 1p21-q21 --- --- SCA20 SCA20 11p13-q11 --- --- SCA21 SCA21 7p21-p15.1 --- --- SCA22 --- 1p21-q21 --- --- SCA23 --- 20p13-p12.3 --- --- SCA25 SCA25 2p21-p13 --- --- SCA26 --- 19p13.3 --- --- SCA27 FGF14 13q34 Fibroblast growth factor 14 --- SCA28 --- 18p11.22-q11.2 --- ---

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DRPLA ATN 12p13.3 Atrophin-1 CAG repeat EA1 KCNA1 12p13 Potassium voltage-gated channel subfamily A member 1 --- EA2 CACNA1A 19p13,2 Voltage-dependent P/Q-type calcium channel alpha-1A subunit Non-repeat mutations EA3 --- --- --- --- EA4 --- --- --- --- ADSA SAX1 12p13 --- ---

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autosomal dominant cerebellar ataxias not included Ataxia with early sensory/motor neuropathy Cerebellar ataxia, deafness, narcolepsy, and optic atrophy (li A heterozygous mutation in EAAT1, encoding a glutamate transporter (reported in a single individual with episodic ataxia, seizures, and hemiplegic migraine) Ataxia, cerebellar atrophy, mental retardation, and possible attention deficit/hyperactivity disorder (ADHD) (associated with a heterozygous mutation in SCA8, encoding a sodium channel Late-onset (40s-60s) cerebellar ataxia preceded by many years of spasmodic coughing. One individual had calcification of the dentate nuclei on MRI

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All Have Gait Ataxia SCA1 4th decade;15, Pyramidal,extrapyramidalsigns, peripheral neuropathy,opthalmoparesis SCA2 3rd - 4th decade ;10 years,Slow saccadic eye movements, peripheral neuropathy, decreased DTRs, dementia,minimal pyramidal and Ex Pyramidal SCA3 4th decade ; 10 years,Pyramidal and extrapyramidal signs; lid retraction, nystagmus, decreased saccade vel,amyotrophy,opthalmoparesis, fasciculations, sensory loss(machado joseph) SCA4 4th - 7th decade Decades Sensory axonal neuropathy, deafness,normal eye movements

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SCA5 3rd - 4th decade ; >25 years Early onset, slow course,dyarthria 1st reported in descendants of Abraham Lincoln SCA6 5th - 6th decade ;>25 years Sometimes episodic ataxia, very slow progression, mild proprioceptive loss SCA7 3rd - 4th decade ; 20 years ; Visual loss with retinopathy,opthalmoparesis,extensor plantars SCA8 39 yrs Normal lifespan Slowly progressive, sometimes brisk DTRs, decreased vibration sense; rarely, cognitive impairment

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SCA10 36 yrs 9 years Occasional seizures CPS,GTCS,polyneuropathy Most families are of Mexican background SCA11 30 yrs (15-70) Normal lifespan Mild, remain ambulatory SCA12 33 yrs (8-55) Slowly progressive ataxia; action tremor in the 30s; hyperreflexia; subtle Parkinsonism possible; cognitive/psychiatric disorders incl dementia,dysautonomia SCA13 Childhood Unknown Mild mental retardation, short stature

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SCA14 28 yrs (12-42) Decades (1-30) Early axial myoclonus SCA15 Unknown Decades Pure ataxia, very slow progression SCA16 39 yrs (20-66) 1-40 years Head tremor One Japanese family SCA17 6-34 yrs >8 years Mental deterioration; occasional chorea, dystonia, myoclonus, epilepsy parkinsonism, intranuclear inclusions with expanded polyglutamine,MRI shows cerebral and cerebellar atrophy

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SCA19 34 years (20-45) Decades Cognitive impairment, myoclonus, tremor One Dutch family SCA20 46 years (19-64) Decades Early dysarthria, spasmodic dysphonia, hyperreflexia, bradykinesia Calcification of the dentate nucleus SCA21 6-30 yrs Decades Mild cognitive impairment,akinesia,rigidity,tremor SCA22 10-46 yrs Decades Slowly progressive ataxia One Taiwanese family SCA23 5th-6th decade >10 years Dysarthria, abnormal eye movements, reduced vibration and position sense One Dutch family;

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SCA25 ,39 yrs Unknown, Sensory neuropathy One French family SCA26 26-60 yrs Unknown, Dysarthria, irregular visual pursuits One Norwegian-American family; MRI: cerebellar atrophy SCA27 11 yrs Decades Early-onset tremor; dyskinesia, cognitive deficits One Dutch family SCA28 19.5 yrs Decades Nystagmus, ophthalmoparesis, ptosis, increased tendon reflexes One Italian family

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DRPLA 8-20 yrs or 40-60s Chorea, seizures, dementia, myoclonus Often confused with Huntington disease EA1 1st decade (2-15) Attenuates after 20 years Myokymia; attacks lasting seconds to minutes; startle or exercise induced; no vertigo,responds to phenytoin EA2 3-52 yrs Lifelong Nystagmus; attacks lasting minutes to hours; posture change induced; vertigo; later, permanent ataxia,acetozolamide ADSA 10-20 yrs Normal lifespan Initial progressive leg spasticity, distal muscle wasting. MVP, retinal striations Similar to ARSACS

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Disease Name Gene Symbol ChromosomaLocus Protein Friedreich ataxia (FRDA) FXN 9q13 Frataxin Ataxia-telangiectasia (A-T) ATM 11q22.3 Serine-protein kinase ATM Ataxia with vitamin E deficiency (AVED) TTPA 8q13.1-q13.3 Alpha-tocopherol transfer protein Ataxia with oculomotor apraxia type 1 (AOA1)APTX 9p13.3 Aprataxin Ataxia with oculomotor apraxia type 2 (AOA2)SETX 9q34 Probable helicase senataxinIOSCA 1 PEO1 10q24 Twinkle protein Marinesco-Sjögren SIL1 5q31 Nucleotide exchange factor SIL1 Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) SACS 13q12 Sacsin

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Friedreich ataxia (FRDA) 1-2/50,000 1st - 2nd decade (4-40) 10-30 Hyporeflexia, Babinski responses, sensory loss, cardiomyopathyAtaxia-telangiectasia (A-T) 1/40,000 to 1/100,000 1st decade 10-20 Telangiectasia, immune deficiency, cancer, chromosomal instability, increased alpha-fetoprotein Ataxia with vitamin E deficiency (AVED) Rare 2-52 years, usually <20 Decades Similar to FRDA, head titubation (28%)

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Ataxia withoculomotor apraxia type 1 (AOA1) Unknown Childhood Decades Oculomotor apraxia, choreoathetosis, mild mental retardation, hypoalbuminemia Ataxia withoculomotor apraxia type 2 (AOA2) Unknown 10-22 years Decades Cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia IOSCA 1 Rare (Finland) Infancy Decades Peripheral neuropathy, athetosis, optic atrophy, deafness, ophthalmoplegia Marinesco-Sjögren Rare Infancy Decades Mental retardation, cataract, hypotonia, myopathy Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) Decades Childhood Spasticity, peripheral neuropathy, retinal striation

Friedreichs ataxia : 

Friedreichs ataxia Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with onset usually before age 25 years typically associated with depressed tendon reflexes, dysarthria, Babinski responses, and loss of position and vibration senses [. About 25% of affected individuals have an "atypical" presentation with later onset (after age 25 years), retained tendon reflexes, or unusually slow progression of disease. The vast majority of individuals have a GAA triplet-repeat expansion in the FXN gene. Unlike the autosomal dominant cerebellar ataxias caused by CAG trinucleotide repeats, FRDA is not associated with anticipation

criterion : 

criterion QCSFA Harding Filla et al onset,<20 yrs <25yr <20yrs Progressive ataxia ataxia ataxia LL areflexia LLareflexia LL areflexia Dysarthria dysarthria(5) dysarthria Weakness babinski sign babinski Decreased absent/small SAP LVH Vibration sense MCV>40m/s

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Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Testing that supports the diagnosis of individuals with A-T is identification of a 7;14 chromosome translocation on routine karyotype of peripheral blood; the presence of immunodeficiency; and in vitro radiosensitivity assay. Molecular genetic testing of the ATM gene is available for clinical use.

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Ataxia with vitamin E deficiency (AVED) generally manifests in late childhood or early teens with dysarthria, sensory ataxia, and progressive clumsiness resulting from early loss of proprioception. Some individuals experience dystonia, psychotic episodes (paranoia), pigmentary retinopathy and/or intellectual decline. Most individuals become wheelchair bound as a result of ataxia and/or leg weakness between ages 11 and 50 years. phenotypically similar to FRDA, AVED is more likely to be associated with head titubation or dystonia and less likely to be associated with cardiomyopathy. It is important to consider the diagnosis of AVED (which can be made by measuring serum concentration of vitamin E) because it is treatable with vitamin E supplementation

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Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia , followed in a few years by oculomotor apraxia that progresses to external ophthalmoplegia. All affected individuals have a severe primary motor peripheral neuropathy leading to quadriplegia with loss of ambulation about seven to ten years after onset. Intellect remains normal in affected individuals of Portuguese ancestry but mental deterioration has been seen in affected individuals of Japanese ancestry.

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Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between ages ten and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum concentration of alpha-fetoprotein (AFP) The diagnosis of AOA2 is based on clinical and biochemical findings, family history, and exclusion of the diagnosis of ataxia-telangiectasia and AOA1. Infantile-onset SCA (IOSCA) is a rare disorder reported from Finland with degeneration of the cerebellum, spinal cord, and brain stem and sensory axonal neuropathy [. Marinesco-Sjögren syndrome is a rare disorder in which ataxia is associated with mental retardation, cataract, short stature, and hypotonia

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is characterized by early-onset (age 12-18 months) difficulty in walking and gait unsteadiness. Ataxia, dysarthria, spasticity, extensor plantar reflexes, distal muscle wasting, a distal sensorimotor neuropathy predominantly in the legs, and horizontal gaze nystagmus constitute the major neurologic signs, which are most often progressive. Yellow streaks of hypermyelinated fibers radiate from the edges of the optic fundi in the retina .. Individuals with ARSACS become wheelchair bound at the average age of 41 years; cognitive skills are preserved long term and individuals are able to accomplish activities of daily living late into adulthood. Death commonly occurs in the sixth decade

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X-Linked Hereditary Ataxias X-linked sideroblastic anemia and ataxia (XLSA/A) is characterized by early-onset ataxia, dysmetria, and dysdiadochokinesis. The ataxia is either non-progressive or slowly progressive. Upper motor neuron (UMN) signs (are present in some males. Mild learning disability is seen. Anemia is mild without symptoms. Carrier females have a normal neurologic examination. Causative mutations are present in ABC7, encoding a protein involved with mitochondrial iron transport, suggesting a common pathogenesis with Friedreich ataxia Adult-onset ataxia, especially in men, may be part of the fragile X-associated tremor/ataxia syndrome (FXTAS)

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Ataxias with Mitochondrial Disorders A progressive ataxia is sometimes associated with mitochondrial diseases such as MERRF (myoclonic epilepsy with ragged red fibers), NARP (neuropathy, ataxia, and retinitis pigmentosa) and Kearns-Sayre syndrome . Mitochondrial disorders are often associated with additional clinical manifestations, such as seizures, deafness, diabetes mellitus, cardiomyopathy, retinopathy, and short stature. A deficiency of coenzyme Q10 has been described in individuals with cerebellar ataxia, usually with childhood onset and often associated with seizures. The symptoms may respond to coenzyme Q10 treatment.

Evaluation strategy : 

Evaluation strategy Medical history Physical examinaton Family history Excluding non heriditary causes Neuro imaging molecular studies-DNA based non DNA based

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Family history s/o AD inheritance stepwise SCA1,2,3,6,7 then 10,12,14,17,DRPLA Individualise for less common:ethnic background SCA10,tremor SCA 12,cognitive defects,chorea SCA 17,uncomplicated,long duration SCA8,14,retinopathy SCA7,positive family history for a known type

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Family history s/o affected siblings only consider AR diseases clinical findings help in differentiating Simplex case :single occurrence in family(sporadic),13% have SCA1,2,3,6,8,17 or can be due to de novo mutation, decreased penetrance, alternate paternity

Genetic counselling : 

Genetic counselling Interpretation of results is complex Experienced people Testing for asymptomatic kin-is only predictive and not diagnostic Not appropriate in children <18 Prenatal testing –if parents ask, family member is definitely identified

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