Cerebellar Ataxia
Disease synonyms
Cerebellar ataxia
Inheritance pattern
Autosomal recessive, X-linked, autosomal dominant
Clinical features
Cerebellar ataxias are a highly heterogeneous group of genetic disorders distinguished by abnormal wide-based gait, irregular eye and hand movements, speech difficulties, and morphologically characterized by cerebellar atrophy. Ataxia is a neurological feature of abnormal gait due to the lack of appropriate muscle coordination and it is a common clinical symptom in hundreds of different diseases. Hereditary ataxias are caused by changes in more than 50 genes1, 2 and can be inherited in autosomal dominant, recessive, X-linked or mitochondrial fashion.
The prevalence of hereditary ataxias is estimated at 1–9/100,000 people 1, 2, 3. Prevalence of autosomal dominant cerebellar ataxias is estimated at 1-5/100,000 1, 2, while autosomal recessive types of hereditary ataxia account for approximately 3/100,000 1, 2. The prevalence of genetic early-onset/childhood ataxia is estimated at 0.1-10/100,000 1, 3.
Clinical features of hereditary cerebellar ataxia are poor coordination of movement and abnormal, dysfunctional, wide-based uncoordinated and unsteady gait. In a vast majority of cases cerebellar ataxia may result from one or any of the following:
- Cerebellar dysfunction and/or abnormalities in associated brain areas
- Spinal cord lesions
- Peripheral sensory loss Hereditary ataxias exhibit a wide variety of clinical phenotypes.
Commonly ataxias are presented as “pure cerebellar” phenotypes, characterized by ataxic gait and movements, nystagmus, dysarthria and hypotonia. Magnetic resonance imaging demonstrates cerebellar atrophy, as a pathological sign of the disease. Other forms of ataxias can present with additional neurological symptoms, including tremor, epilepsy, spasticity, dementia, and/or neuropathy, and some patients demonstrate deafness and intellectual disability. The age of onset in affected individuals is also variable, with symptoms presenting from birth through late decades of life. Congenital ataxias display symptoms within the first year of life and are often non-progressive, while the late onset ataxias are more commonly progressive and result in patients rapidly becoming wheelchair bound.
The classification and nomenclature of the hereditary ataxias is an ongoing process; however to date more than 40 different forms of hereditary cerebellar ataxias have been identified, including spinocerebellar ataxia type 1 (SCA1)-SCA42 1, 4. Spinocerebellar ataxia (SCA) is a historical term, first used for autosomal dominant hereditary ataxias. The numbers of SCA subtypes are assigned in the order of disease discovery.
Hereditary cerebellar ataxias are classified mainly according to the inheritance pattern as follows:
- Autosomal dominant cerebellar ataxias are classified as “ADCA”
- Autosomal recessive SCAS are referred as “SCAR”
- X-linked ataxias are labeled as “SCAX
- Episodic ataxias are labeled as “EA”
- SPAX refers to ataxia subtypes that have a prominent component of spasticity 1, 5.
Typical clinical signs and symptoms of autosomal dominant ataxias (ADCA) include the following:
- Limb and truncal ataxia
- Hyperreflexia and spasticity (pyramidal signs) are commonly found in patients with SCA1 and SCA3
- Cognitive impairment has been reported in association with SCA2, SCA12, SCA13, and SCA17
- Chorea may manifest in patients with dentatorubral-pallidoluysian atrophy (DRPLA) or SCA17
- Common findings include dysarthria, dysphagia, and neuropathy
- SCA2 shows Parkinsonian signs.
ADCAs are usually slowly progressive and have an age of onset from childhood to adulthood. They cannot be differentiated by clinical or neuroimaging studies, however, they are associated with cerebellar atrophy.
The most common forms of autosomal dominant ataxias are caused by an expansion of trinucleotide repeats in one of the ataxin-related genes (ATXN1, ATXN2 etc.). The most common repeat expansions are CAG expansions, polyglutamine or polyQ repeats (CAG encodes glutamine, amino acid “Q”). There are currently seven known autosomal dominant ataxias caused by CAG polyglutamine expansions: SCA1, SCA2, SCA3 (Machado Joseph disease/MJD), SCA6, SCA7, SCA17, and DRPLA. Repeat expansions could be localized outside the coding region, in untranslated regions of the gene or introns, where they interfere with the gene regulation. Examples of these mutations are the following: CTG repeats in SCA8, ATTCT in SCA10, CAG in SCA12, TGGAA in SCA31 and GGCCTG in SCA36. Other subtypes of autosomal dominant ataxia are caused by conventional mutations including insertions, SNVs and deletions, such as SCA28 (AFG3L2), SCA29/SCA16 (ITPR1) or SCA14 (PRKCG).
Autosomal recessive cerebellar ataxias may present with additional extra–central nervous system signs and symptoms, including the following:
- Slowly progressive early onset ataxia
- Oculomotor apraxia
- Telangiectasias
- Dysarthria
- Common findings include deafness, seizures, optic atrophy, myopathy, nystagmus etc.
Common forms of autosomal recessive ataxias (reported in more than 5 families1, 5) include the following:
- Friedrich ataxia, caused by CAG trinucleotide expansion in FXN
- Ataxia with oculomotor apraxia, caused by mutations in APTX or SETX
- Ataxia-telangiectasia caused by mutations in ATM
- Ataxia with vitamin E deficiency (AVED), caused by mutations in TTPA
- Ataxia with oculomotor apraxia type 1 (AOA1) caused by mutations in APTX
- Ataxia with oculomotor apraxia type 2 (AOA2) caused by mutations in SETX
- POLG (polymerase γ1)-associated hereditary ataxias, mitochondrial recessive ataxic syndrome and SANDO (sensory ataxia, neuropathy, dysarthria, and ophthalmoplegia).
- Autosomal recessive spastic ataxia of Charlevoix-Saguenay, caused by mutations in SACS.
- Refsum disease, associated with mutations in PHYH and PEX7.
- Coenzyme Q10 (CoQ10) deficiency, associated with mutations in COQ2, COQ8A, COQ9, PDSS1 or PDSS2.
Numerous conditions with autosomal recessive inheritance are accompanied by ataxia and/or cerebellar atrophy, such as Joubert syndrome, congenital disorders of glycosylation, peroxisomal biogenesis disorders, Zellweger spectrum disorders, and others.
X-linked inheritance of cerebellar ataxia is uncommon except for the Fragile X tremor ataxia syndrome (FXTAS), caused by mutations in FMR1. Also, some rare ataxia forms are associated with mutations in mitochondrial DNA, including MERRF (myoclonic epilepsy with ragged red fibers), NARP (neuropathy, ataxia, and retinitis pigmentosa), and Kearns-Sayre syndrome5.
Table 1. Overview of genes included in the ataxia comprehensive panel
Gene | OMIM (Gene) | Associated diseases (OMIM) | Inheritance |
---|---|---|---|
ABCB7 | 300135 | Anemia, Sideroblastic, and Spinocerebellar Ataxia | XLR |
ABHD12 | 613599 | Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract | AR |
ABHD5 | 604780 | Chanarin-Dorfman syndrome | AR |
ACADVL | 609575 | very long chain acyl-CoA dehydrogenase deficiency | AR |
ACO2 | 100850 | Infantile cerebellar-retinal degeneration | AR |
AFG3L2 | 604581 | spinocerebellar ataxia 28; spastic ataxia 5 | AD, AR |
AHI1 | 608894 | Joubert syndrome 3 | AR |
ALDH5A1 | 610045 | Succinic semialdehyde dehydrogenase deficiency | AR |
AMACR | 604489 | Alpha-methylacyl-CoA racemase deficiency | AR |
ANO10 | 613726 | autosomal recessive spinocerebellar ataxia 10 | AR |
AP1S2 | 300629 | Pettigrew syndrome | XLR |
APTX | 606350 | Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia | AR |
ARL13B | 608922 | Joubert syndrome 8 | AR |
ARL6 | 608845 | Bardet-Biedl syndrome type 1; Bardet-Biedl syndrome 3; Retinitis pigmentosa 55 | AR, DiR |
ARSA | 607574 | metachromatic leukodystrophy | AR |
ATCAY | 608179 | Ataxia, cerebellar, Cayman type | AR |
ATM | 607585 | familial breast-ovarian cancer type 2; ataxia-telangiectasia | AD, AR |
ATN1 | 607462 | Dentatorubro-pallidoluysian atrophy; congenital hypotonia, epilepsy, developmental delay, and digital anomalies | AD |
ATP13A2 | 610513 | Kufor-Rakeb syndrome; spastic paraplegia type 78 | AR |
ATP1A3 | 182350 | Dystonia 12; Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss; Alternating hemiplegia of childhood 2 | AD |
ATP2B3 | 300014 | spinocerebellar ataxia, X-linked 1 | XLR |
ATP8A2 | 605870 | Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 4 | AR |
ATXN1 | 601556 | spinocerebellar ataxia 1 | AD |
ATXN10 | 611150 | spinocerebellar ataxia 10 | AD |
ATXN2 | 601517 | Susceptibility to late-onset Parkinson disease; spinocerebellar ataxia 2 | AD |
ATXN3 | 607047 | spinocerebellar ataxia 3 | AD |
ATXN7 | 607640 | spinocerebellar ataxia 7 | AD |
ATXN8OS | 603680 | Susceptibility to late-onset Parkinson disease; spinocerebellar ataxia 8 | AD |
B9D1 | 614144 | Meckel Syndrome, Type 9 | AR |
BBS1 | 209901 | Bardet-Biedl syndrome type 1 | AR, DiR |
BBS12 | 610683 | Bardet-Biedl syndrome type 12 | AR |
BEAN1 | 612051 | spinocerebellar ataxia 31 | AD |
BSCL2 | 606158 | Lipodystrophy, congenital generalized, type 2; spastic paraplegia 17; Neuropathy, distal hereditary motor, type V; Encephalopathy, progressive, with or without lipodystrophy | AD, AR |
BTD | 609019 | biotinidase deficiency | AR |
C12orf65 | 613541 | Combined oxidative phosphorylation deficiency 7 | AR |
C19orf12 | 614297 | neurodegeneration with brain iron accumulation 4; spastic paraplegia 43 | AD, AR |
CA8 | 114815 | Cerebellar ataxia and mental retardation with or without quadrupedal locomotion 3 | AR |
CACNA1A | 601011 | episodic ataxia type 2; familial hemiplegic migraine 1; spinocerebellar ataxia 6; early infantile epileptic encephalopathy, 42 | AD |
CACNB4 | 601949 | Epilepsy, Idiopathic Generalized, Susceptibility To, 9; Episodic ataxia, type 5 | AD |
CAMTA1 | 611501 | Cerebellar ataxia, nonprogressive, with mental retardation | AD |
CASK | 300172 | Fg Syndrome 4; Mental retardation and microcephaly with pontine and cerebellar hypoplasia | XLD |
CC2D2A | 612013 | COACH syndrome; Meckel syndrome 6; Joubert syndrome 9 | AR |
CCDC88C | 611204 | Hydrocephalus, nonsyndromic, autosomal recessive 1; spinocerebellar ataxia type 40 | AD, AR |
CEP290 | 610142 | Joubert syndrome type 5; Senior-Loken syndrome type 6; Meckel syndrome type 4; Leber congenital amaurosis type 10; Bardet-Biedl syndrome type 14 | AR |
CEP41 | 610523 | Joubert syndrome 15 | AR |
CHMP1A | 164010 | pontocerebellar hypoplasia 8 | AR |
CLCN2 | 600570 | Epilepsy, Idiopathic Generalized, Susceptibility To, 11; Leukoencephalopathy with ataxia | AD, AR |
CLN5 | 608102 | neuronal ceroid lipofuscinosis type 5 | AR |
CLN6 | 606725 | adulte onset neuronal ceroid lipofuscinosis, Kufs type; neuronal ceroid lipofuscinosis type 6 | AR |
CLPP | 601119 | Perrault syndrome 3 | AR |
COASY | 609855 | Neurodegeneration with brain iron accumulation 6; Pontocerebellar hypoplasia type 12 | AR |
COQ2 | 609825 | Multiple system atrophy, susceptibility to; Coenzyme Q10 deficiency, primary, 1 | AD, AR |
COQ8A | 606980 | primary Coenzyme Q10 deficiency type 4 - COQ10D4 | AR |
COQ9 | 612837 | Coenzyme Q10 deficiency, primary, 5 | AR |
COX20 | 614698 | Mitochondrial complex IV deficiency | AR, M |
CP | 117700 | aceruloplasminemia | AR |
CPLANE1 | 614571 | oral-facial-digital syndrome 6; Joubert syndrome 17 | AR |
CSPP1 | 611654 | Joubert syndrome 21 | AR |
CWF19L1 | 616120 | autosomal recessive spinocerebellar ataxia 17 | AR |
CYP27A1 | 606530 | cerebrotendinous xanthomatosis | AR |
DARS2 | 610956 | leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation | AR |
DLAT | 608770 | Pyruvate dehydrogenase E2 deficiency | AR |
DNAJC19 | 608977 | 3-methylglutaconic aciduria, type 5 | AR |
DNAJC5 | 611203 | neuronal ceroid lipofuscinosis type 4, Parry type | AD |
DNMT1 | 126375 | cerebellar ataxia, deafness and narcolepsy; Neuropathy, hereditary sensory, type IE | AD |
EIF2B1 | 606686 | leukoencephaly with vanishing white matter | AR |
EIF2B2 | 606454 | leukoencephaly with vanishing white matter | AR |
EIF2B3 | 606273 | leukoencephaly with vanishing white matter | AR |
EIF2B4 | 606687 | leukoencephaly with vanishing white matter | AR |
EIF2B5 | 603945 | leukoencephaly with vanishing white matter | AR |
ELOVL4 | 605512 | Spinocerebellar ataxia 34; Stargardt disease 3; Ichthyosis, spastic quadriplegia, and mental retardation | AD, AR |
ELOVL5 | 611805 | spinocerebellar ataxia 38 | AD |
EXOSC3 | 606489 | pontocerebellar hypoplasia type 1B | AR |
FA2H | 611026 | spastic paraplegia 35 | AR |
FBXL4 | 605654 | mitochondrial DNA depletion syndrome 13 | AR |
FGF14 | 601515 | spinocerebellar ataxia 27 | AD |
FLVCR1 | 609144 | Ataxia, posterior column, with retinitis pigmentosa | AR |
FTL | 134790 | Hyperferritinemia With Or Without Cataract; neurodegeneration with brain iron accumulation 3 | AD, AR |
FXN | 606829 | Friedreich ataxia | AR |
GALC | 606890 | Krabbe disease | AR |
GBA | 606463 | Lewy body dementia; Susceptibility to late-onset Parkinson disease; Gaucher disease type 1; Gaucher disease type 2 (acute); Gaucher disease type 3 (subacute/ chronic); Gaucher disease, cardiovascular form; Gaucher disease, perinatal-lethal form | AD, AR |
GBA2 | 609471 | spastic paraplegia 46 | AR |
GFAP | 137780 | Alexander disease | AD |
GJB1 | 304040 | Charcot-Marie-Tooth disease type 1 | XLD |
GJC2 | 608803 | Leukodystrophy, hypomyelinating, 2; spastic paraplegia 44 | AD, AR |
GOSR2 | 604027 | Epilepsy, progressive myoclonic 6 | AR |
GRID2 | 602368 | autosomal recessive spinocerebellar ataxia 18 | AR |
GRM1 | 604473 | autosomal recessive spinocerebellar ataxia 13; Spinocerebellar ataxia type 44 | AD, AR |
GSS | 601002 | Glutathione synthetase deficiency | AR |
HEPACAM | 611642 | megalencephalic leukoencephalopathy with subcortical cysts type 2A; megalencephalic leukoencephalopathy with subcortical cysts type 2B, remitting, with or without mental retardation | AD, AR |
HEXB | 606873 | Sandhoff disease | AR |
HIBCH | 610690 | 3-hydroxyisobutryl-CoA hydrolase deficiency | AR |
INPP5E | 613037 | Joubert syndrome 1; Mental retardation, truncal obesity, retinal dystrophy, and micropenis | AR |
ITM2B | 603904 | Cerebral amyloid angiopathy, itm2b-related, 2; Cerebral amyloid angiopathy, itm2b-related, 1 | AD |
ITPR1 | 147265 | spinocerebellar ataxia 29; Gillespie syndrome; spinocerebellar ataxia 15 | AD, AR |
KCNA1 | 176260 | Episodic ataxia/myokymia syndrome | AD |
KCNC3 | 176264 | spinocerebellar ataxia 13 | AD |
KCND3 | 605411 | spinocerebellar ataxia 19 | AD |
KCNJ10 | 602208 | autosomal recessive deafness type 4 with enlarged vestibular aqueduct; Seizures, Sensorineural Deafness, Ataxia, Mental Retardation, And Electrolyte Imbalance | AR |
KIF1A | 601255 | spastic paraplegia 30; Neuropathy, hereditary sensory, type IIC; MENTAL RETARDATION, AUTOSOMAL DOMINANT 9 | AD, AR |
KIF1C | 603060 | Spastic ataxia 2, autosomal recessive | AR |
KIF5A | 602821 | spastic paraplegia 10; Neonatal intractable myoclonus | AD |
KIF7 | 611254 | Acrocallosal syndrome; Joubert syndrome 12; Hydrolethalus syndrome 2 | AR |
LAMA1 | 150320 | Poretti-Boltshauser syndrome | AR |
LMNB1 | 150340 | Leukodystrophy, adult-onset, autosomal dominant | AD |
LRPPRC | 607544 | Leigh syndrome, French-Canadian type | AR |
MARS2 | 609728 | AR | |
MKS1 | 609883 | Meckel syndrome type 1; Bardet-Biedl syndrome type 13; Joubert syndrome type 28 | AR |
MLC1 | 605908 | megalencephalic leukoencephalopathy with subcortical cysts type 1 | AR |
MRE11 | 600814 | Ataxia-telangiectasia-like disorder type 1 | AR |
MTFMT | 611766 | Combined oxidative phosphorylation deficiency 15 | AR |
MTPAP | 613669 | AR | |
MTTP | 157147 | Abetalipoproteinemia; protection against metabolic syndrome | AD, AR |
NDUFAF6 | 612392 | AR | |
NDUFS1 | 157655 | AR | |
NDUFS2 | 602985 | AR | |
NDUFS4 | 602694 | mitochondrial complex I deficiency | AR |
NDUFS7 | 601825 | Mitochondrial complex I deficiency, nuclear type 3 | AR |
NDUFV1 | 161015 | AR | |
NOP56 | 614154 | spinocerebellar ataxia 36 | AD |
NPC1 | 607623 | Niemann-Pick disease type C/D | AR |
NPC2 | 601015 | Niemann-Pick disease type C2 | AR |
NPHP1 | 607100 | nephronophthisis 1; Joubert syndrome 4 | AR |
NUBPL | 613621 | AR | |
OFD1 | 300170 | Simpson-Golabi-Behmel syndrome type 2; Retinitis pigmentosa 23; Joubert syndrome 10; oral-facial-digital syndrome 1 | XLD, XLR |
OPA1 | 605290 | Optic atrophy plus syndrome; optic atrophy type 1; Behr syndrome; Glaucoma, normal tension, susceptibility to; Mitochondrial DNA depletion syndrome 14 | AD, AR |
OPA3 | 606580 | Optic atrophy type 3 with cataract; 3-methylglutaconic aciduria type III | AD, AR |
OPHN1 | 300127 | X-linked mental retardation with cerebellar hypoplasia and distinctive facial appearance | XLR |
PANK2 | 606157 | neurodegeneration with brain iron accumulation type 1; HARP syndrome | AR |
PAX6 | 607108 | Aniridia 1; foveal hypoplasia type 1 | AD |
PDHX | 608769 | Lacticacidemia due to PDX1 deficiency | AR |
PDSS1 | 607429 | Coenzyme Q10 deficiency, primary, 2 | AR |
PDSS2 | 610564 | Coenzyme Q10 deficiency, primary, 3 | AR |
PDYN | 131340 | spinocerebellar ataxia 23 | AD |
PEX10 | 602859 | peroxisome biogenesis disorder 6A (Zellweger); peroxisome biogenesis disorder 6B | AR |
PEX2 | 170993 | peroxisome biogenesis disorder type 5A (Zellweger); peroxisome biogenesis disorder type 5B | AR |
PEX7 | 601757 | Rhizomelic chondrodysplasia punctata type 1; peroxisome biogenesis disorder type 9B (Zellweger) | AR |
PHYH | 602026 | Refsum disease | AR |
PLA2G6 | 603604 | infantile neuroaxonal dystrophy; neurodegeneration with brain iron accumulation 2B; Parkinson disease 14 | AR |
PLP1 | 300401 | Pelizaeus-Merzbacher disease; spastic paraplegia 2 | XLR |
PNKD | 609023 | dystonia 8 | AD |
PNKP | 605610 | type 2B2 Charcot-Marie-Tooth disease; early infantile epileptic encephalopathy 10 | AR |
PNPLA6 | 603197 | Boucher-Neuhauser syndrome; spastic paraplegia 39 | AR |
POLG | 174763 | progressive external ophthalmoplegia; mitochondrial DNA depletion syndrome type 4A; autosomal recessive progressive external ophthalmoplegia; sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome; mitochondrial DNA depletion syndrome type 4B | AD, AR |
POLR3A | 614258 | hypomyelinating leukodystrophy-7 | AR |
POLR3B | 614366 | hypomyelinating leukodystrophy-8 | AR |
PPP2R2B | 604325 | spinocerebellar ataxia 12 | AD |
PRICKLE1 | 608500 | Epilepsy, progressive myoclonic 1B | AR |
PRKCG | 176980 | spinocerebellar ataxia 14 | AD |
PRRT2 | 614386 | Episodic kinesigenic dyskinesia 1; Convulsions, familial infantile, with paroxysmal choreoathetosis; Seizures, benign familial infantile, 2 | AD |
RARS2 | 611524 | pontocerebellar hypoplasia type 6 | AR |
RPGRIP1L | 610937 | COACH syndrome; Joubert syndrome 7; Meckel syndrome type 5 | AR |
RRM2B | 604712 | mitochondrial DNA depletion syndrome 8A; progressive external ophthalmoplegia with mitochondrial DNA deletions 5 | AD, AR |
RUBCN | 613516 | autosomal recessive spinocerebellar ataxia 15 | AR |
SACS | 604490 | spastic ataxia of Charlevoix-Saguenay | AR |
SCN2A | 182390 | benign familial neonatal-infantile seizures type 3; early infantile epileptic encephalopathy 11 | AD |
SETX | 608465 | amyotrophic lateral sclerosis 4; autosomal recessive spinocerebellar ataxia 1 | AD, AR |
SIL1 | 608005 | Marinesco-Sjogren syndrome | AR |
SLC16A2 | 300095 | Allan-Herndon-Dudley syndrome | XL |
SLC17A5 | 604322 | infantile sialic acid storage disorder; Salla disease | AR |
SLC1A3 | 600111 | episodic ataxia type 6 | AD |
SLC20A2 | 158378 | Basal ganglia calcification, idiopathic, 1 | AD |
SLC25A46 | 610826 | Neuropathy, hereditary motor and sensory, type VIB | AR |
SLC2A1 | 138140 | Dystonia-9; GLUT1 deficiency syndrome; dystonia 18; Epilepsy, idiopathic generalized, suscpetibility to, 12 | AD, AR |
SLC52A3 | 613350 | Fazio-Londe disease; Brown-Vialetto-Van Laere syndrome 1 | AR |
SLC9A6 | 300231 | Christianson type of X-linked syndromic mental retardation | XLD |
SPG11 | 610844 | Amyotrophic lateral sclerosis 5, juvenile; spastic paraplegia type 11; Charcot-Marie-Tooth disease, axonal, type 2X | AR |
SPG7 | 602783 | spastic paraplegia 7 | AD, AR |
SPR | 182125 | Dystonia, dopa-responsive, due to sepiapterin reductase deficiency | ?AD, AR |
SPTBN2 | 604985 | spinocerebellar ataxia 5; autosomal recessive spinocerebellar ataxia 14 | AD, AR |
STUB1 | 607207 | autosomal recessive spinocerebellar ataxia 16; ?Spinocerebellar ataxia 48 | AD, AR |
SYNE1 | 608441 | autosomal recessive spinocerebellar ataxia 8; Emery-Dreifuss muscular dystrophy 4 | AD, AR |
TBP | 600075 | Susceptibility to late-onset Parkinson disease; spinocerebellar ataxia 17 | AD |
TCTN2 | 613846 | Meckel syndrome 8; Joubert syndrome type 24 | AR |
TGM6 | 613900 | spinocerebellar ataxia 35 | AD |
TMEM216 | 613277 | Meckel Syndrome type 2; Joubert syndrome type 2 | AR |
TMEM237 | 614423 | Joubert syndrome 14 | AR |
TMEM240 | 616101 | spinocerebellar ataxia 21 | AD |
TMEM67 | 609884 | COACH syndrome; Meckel Syndrome, Type 3; Joubert syndrome 6; nephronophthisis 11; Bardet-Biedl syndrome type 14 | AR |
TPP1 | 607998 | neuronal ceroid lipofuscinosis type 2; autosomal recessive spinocerebellar ataxia type 7 | AR |
TSEN2 | 608753 | pontocerebellar hypoplasia type 2B | AR |
TSEN34 | 608754 | pontocerebellar hypoplasia type 2C | AR |
TSEN54 | 608755 | pontocerebellar hypoplasia type 4; pontocerebellar hypoplasia type 2A; pontocerebellar hypoplasia type 5 | AR |
TTBK2 | 611695 | spinocerebellar ataxia 11 | AD |
TTC19 | 613814 | nuclear mitochondrial complex III deficiency type 2 | AR |
TTPA | 600415 | ataxia with vitamin E deficiency | AR |
TUBB4A | 602662 | dystonia 4; hypomyelinating leukodystrophy-6 | AD |
TWNK | 606075 | Mitochondrial DNA depletion syndrome 7 (hepatocerebral type); Progressive external ophthalmoplegia, autosomal dominant, 3 | AD, AR |
UBA5 | 610552 | early infantile epileptic encephalopathy, 44 | AR |
VAMP1 | 185880 | Spastic ataxia 1, autosomal dominant; Myasthenic syndrome, congenital, 25 | AD, AR |
VLDLR | 192977 | Cerebellar ataxia, mental retardation, and dysequilibrium syndrome | AR |
VRK1 | 602168 | pontocerebellar hypoplasia type 1A | AR |
WDR81 | 614218 | Cerebellar ataxia, mental retardation, and dysequilibrium syndrome 2 | AR |
WFS1 | 606201 | congenital nuclear cataract type 41; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Wolfram syndrome; Deafness, autosomal dominant 6/14/38; Wolfram-like syndrome | AD, AR |
WWOX | 605131 | Esophageal cancer, somatic; autosomal recessive spinocerebellar ataxia 12; early infantile epileptic encephalopathy 28 | AR |
ZFYVE26 | 612012 | spastic paraplegia type 15 | AR |
Differential diagnosis
The differential diagnosis of cerebellar ataxia-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Acquired, non-genetic causes of ataxia:
- Alcoholism
- Vitamin deficiencies
- Multiple sclerosis
- Vascular disease
- Primary or metastatic tumors or paraneoplastic diseases associated with occult carcinoma of the ovary, breast, or lung
- Disorders of mitochondrial oxidative metabolism
- Hyperammonemias caused by deficiencies of urea cycle enzymes
- Aminoacidurias, including Hartnup disease.
Testing strategy
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for episodic ataxia using NGS Panel Genomic targeted towards this specific cerebellar ataxia phenotype:
Step 1: Repeat expansions analysis is offered for FXN.
Step 2: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Cerebellar ataxia panel. Copy Number Variants analysis derived from NGS data is also included.
Step 3: If no mutation is identified after analysis of the Cerebellar ataxia panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
Referral reasons
The following individuals are candidates for cerebellar ataxia panel testing:
- Individuals with a family history of cerebellar ataxia and presentation of the most common symptoms
- Individuals without a positive family history of cerebellar ataxia, but with resembling symptoms
- Individuals with a negative but suspected family history of cerebellar ataxia, in order to perform proper genetic counseling.
Test utility
Sequencing, deletion/duplication of the panel genes should be performed in all individuals suspected of having episodic ataxia and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the cerebellar ataxia and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.