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Cerebellar Ataxia

July 21, 2017

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.