Due to Repeat Expansions
The majority of the dominantly inherited ataxias are caused by repeat expansions in either coding or noncoding parts of the relevant genes [Dueñas et al., 2006]. Polyglutamine (CAGn) expansions are the most common of these and comprise SCAs 1, 2, 3, 6, 7, and 17 and DRPLA. Genotype–phenotype correlations of these disorders are well described [Schöls et al., 2004] with the disease manifesting above a threshold of CAG repeats. The noncoding expansion SCAs comprise SCA8 (CTGn), SCA10 (ATTCTn), SCA12 (CAGn), SCA31 (TGGAAn), and SCA36 (GGCCTGn). Larger repeat numbers generally result in an earlier age of onset and more severe phenotype (genetic anticipation). Anticipation has been demonstrated to a varying degree by all of the repeat expansion SCAs. A summary of the dominant ataxia genes is provided in Table 1.
Table 1. Autosomal Dominant Ataxias
|Repeat Expansions: coding|
|SCA1||164400||6p22.3||ATXN1||Ataxin 1||CAG repeat||6–27%||Common: South Africa, Japan, India, Italy, Australia||Hyperreflexia, sensory neuropathy, mild cognitive impairment|
|SCA2||183090||12q24.12||ATXN2||Ataxin 2||CAG repeat||13–18%||Common: United States, Spain, India, Mexico, Italy||Polyneuropathy, parkinsonism, dysphagia|
|SCA3||109150||14q32.12||ATXN3||Ataxin 3||CAG repeat||20–50%||Most common worldwide||Spasticity, polyneuropathy, dystonia, parkinsonism|
|SCA6||183086||19p13.2||CACNA1A||Calcium channel, voltage dependent, P/Q type, α1A subunit||CAG repeat||13–15%||Common: United States, Germany, Australia, Taiwan||Late onset, pure ataxia|
|SCA7||164500||3p14.1||ATXN7||Ataxin 7||CAG repeat||3–5%||Finland, Mexico, South Africa||Retinal degeneration|
|SCA17||607136||6q27||TBP||TATA box-binding protein||CAG repeat||Rare||United Kingdom, Belgium, France, Germany, Japan||Dementia|
|DRPLA||125370||12p13.31||ATN1||Atrophin 1||CAG repeat||0.8:100,000 (Japan) Rare worldwide||Japan, Portugal, United States||Dementia, epilepsy|
|HD||143100||4p16.3||HTT||Huntingtin||CAG repeat||3–7:100,000||Worldwide||Chorea, dementia|
|Repeat Expansions: noncoding|
|SCA8||608768||13q21.33||ATXN8OS||Ataxin 8 opposite strand||CTG repeat||3%||Common: Finland||Pure ataxia|
|SCA10||603516||22q13.31||ATXN10||Ataxin 10||ATTCT repeat||Unknown||Mexico, Brazil||Seizures|
|SCA12||604326||5q32||PPP2R2B||Protein phosphatase 2, regulatory subunit B, β||CAG repeat||Rare worldwide 7% in India||Common: India||Tremor, polyneuropathy|
|SCA31||117210||16q21||BEAN||Brain expressed associated with NEDD4||TGGAA repeat||8–40% in Japan Rare worldwide||Japan esp. Nagano prefecture||Spasmodic torticollis|
|SCA36||614153||20p13||NOP56||Nuclear protein 56||GGCCTG repeat||6.3% Galicia, Spain 9 Japanese families||Spain, Japan||Motor neurone involvement|
|SCA5||600224||11q13||SPTBN2||Beta 3 Spectrin||Deletions, missense mutations||Rare||United States, Germany, France||Pure ataxia, facial myokymia, gaze palsy|
|SCA11||611695||15q15.2||TTBK2||Tau tubulin kinase 2||Nonsense, frameshift deletions/insertions||Rare||United Kingdom, France, Germany||Pure ataxia|
|SCA13||605259||19q13.3-q13.4||KCNC3||Potassium channel, voltage-gated, shaw-related subfamily, member 3||Missense||1% (France)||France, Philippines||Early onset, mental retardation|
|SCA14||176980||19q13.4||PRKCG||Protein kinase C gamma||Missense, deletion||2% (France)||United Kingdom, France, Netherlands, United States, Japan, Australia||Myoclonus, dystonia|
|SCA15||606658||3p26-p25||ITPR1||Inositol 1, 4, 5-triphosphate receptor type 1||Muliti-exon or whole gene deletion, missense||1.8% (France) 0.3% (Japan)||United Kingdom, France||Pure ataxia|
|SCA20||608687||11q12||–||–||260kb duplication||Rare||Australia||Dentate calcification, bulbar symptoms|
|SCA27||609307||13q33.1||FGF14||Fibroblast growth factor 14||Missense||Rare||Netherlands||Onset with tremor, psychiatric episodes|
|SCA28||610246||18p11.21||AFG3L2||ATPase FAMILY GENE 3-LIKE 2||Missense, deletion||3%||Italy, France, United Kingdom||Ophthalmoplegia, spasticity|
|SCA35||613908||20p13||TGM6||Transglutaminase 6||Missense||Rare||China||Pure ataxia|
Due to Conventional Mutations
A minority of the dominant ataxia syndromes (SCAs 5, 11, 13, 14, 15, 20, 23, 27, 28, and 35) is caused by conventional mutations. In a French ataxia series, conventional mutations accounted for 6% of all dominant ataxia, repeat expansions accounted for 45% with the remaining 48% being genetically undiagnosed [Durr et al., 2009]. Genotype–phenotype correlations are much harder to determine in this group, owing to the limited number of families affected by these mutations. Functional analysis of potassium channels (EA1, SCA13) and calcium channels (SCA6, EA2) has demonstrated a correlation between the degree of functional impairment and the severity of the phenotype. In contrast to the repeat expansion SCAs, these disorders often have a “purer” cerebellar phenotype (ADCAIII), with a slower rate of progression.
SCA5 is caused by a mutation in the SPTBN2 gene, which encodes B3 spectrin [Ikeda et al., 2006]. Missense and in-frame deletions have been described resulting in a pure cerebellar syndrome with onset between 15 and 50 years. The first SCA5 kindred was reported in 1994 with 56 affected individuals over 10 generations who were descendants of the paternal grandparents of Abraham Lincoln. SCA5 has also been reported in French and German pedigrees [Zühlke et al., 2007].
SCA11, initially reported in two British families, is caused by stop mutations, frameshift insertions or deletions in the TTBK2 gene, resulting in a pure cerebellar syndrome with normal life expectancy [Houlden et al., 2007]. Pathogenic variants in TTBK2 have also been reported in French and German families [Bauer et al., 2010].
SCA13 was initially reported in French and Filipino families and is caused by missense mutations in KCNC3, which encodes a voltage-gated potassium channel [Figueroa et al., 2010]. There is a wide phenotypic spectrum that correlates with different missense mutations. The childhood-onset form, in which motor and mental developmental delay is a common feature, has been associated with two variants: (g.10693G>A p.Arg423His) and (g. 10767T>C p.Phe448Leu) described in European and Filipino families, respectively [Figueroa et al., 2011]. Females are more frequently affected and of the two missense mutations reported, the p.Phe448Leu variant results in the more severe phenotype. The p.Arg423His variant has also been reported in a Caucasian family in the United States.
SCA14 is caused by mutations in PRKCG [Yabe et al., 2003], resulting in a variable ataxic phenotype, which may include myoclonus, dystonia, or peripheral neuropathy. The onset is usually in adulthood. The majority of mutations (missense) have been reported in exons 4, 5, 10, and 18. It has been reported in more than 20 families from Europe, Japan, and Australia [Klebe et al., 2005].
SCA15/16 is caused by heterozygous deletions of the 5′ part of the ITPR1 gene [van de Leemput et al., 2007] although a missense mutation (c.1480G>A p.V494I) has been reported. The ITPR1 protein is highly expressed in cerebellar Purkinje cells and is an important modulator of intracellular calcium signaling. SCA15/16 is characterized by a mild cerebellar ataxia with slow disease progression. In a French ataxia series, SCA15 was identified in 1.8% of patients [Marelli et al., 2011]. SCA15/16 shares a locus with SCA29, raising the possibility that they are allelic disorders.
SCA20 has been described in a single Australian family of Anglo-Celtic descent and is the result of a 260 kb duplicated region comprising >12 genes at 11q12 [Knight et al., 2004]. Bulbar symptoms including dysphonia and spasmodic cough in addition to dentate nucleus calcification are characteristic of this condition.
SCA23 is due to missense mutations of PDYN [Bakalkin et al., 2010], which encodes prodynorphin protein, an opioid neuropeptide precursor. This causes a relatively pure cerebellar syndrome with a late onset (43–73 years) and slow progression. The disease has been reported in only a single large Dutch ataxia family and was not identified on screening a large German ataxia series [Schicks et al., 2011].
SCA27 causes an early-onset ataxia [Brusse et al., 2006], associated cognitive deficits, and head or limb tremor and dyskinesia that can be exacerbated by stress or exercise. The causal gene was identified, in a large Dutch kindred, fibroblast growth factor 14 (FGF14) with missense and nonsense mutations having been reported. There is normal life expectancy; however, most affected patients are unable to walk by the seventh to eighth decade. The disease has also been reported in a German ataxia patient.
SCA28 is caused by a mutation in AFG3L2, which encodes a mitochondrially located metalloprotease [Di Bella et al., 2010]. Missense mutations have been reported which are commonly located in the proteolytic domain of the protein with a mutation hotspot in exons 15–16. SCA28 has a typically early onset between 12 and 36 years and is characterized by a slowly progressive cerebellar ataxia with ophthalmoparesis and lower limb hyperreflexia. The disease is estimated to account for 1.5% of European ADCA cases [Cagnoli et al., 2010].
SCA35 is caused by mutations in the cerebral transglutaminase TGM6 and was the first dominant ataxia gene to be identified through exome sequencing [Wang et al., 2010]. Missense mutations were reported in two Chinese families in which a late-onset cerebellar syndrome with associate upper motor neuron involvement was reported. There was moderate progression with patients commonly using a wheelchair 20 years after disease onset.
The episodic ataxias are a group of heterogeneous channel disorders characterized by attacks of ataxia, which may be associated with a range of other neurological manifestations including myokymia, migraine, seizures, or chorea. Eight episodic ataxia syndromes have been described: EA 1–7 and episodic ataxia with paroxysmal choreoathetosis and spasticity (CSE). EA 1 and 2 are the most common and best characterized of these. The genes for EA 1, 2, 5, and 6 (Table 2) have been identified with linkage loci mapped in EA 3, 7, and CSE. Episodic ataxia is rare with a combined incidence of <1:100,000.
Table 2. Episodic Ataxias
|EA1||160120||12p13.32||KCNA1||Potassium channel, voltage gated, shaker-related subfamily, member 1||Missense||Worldwide||Attacks last seconds–minutes; myokymia|
|EA2||108500||19p13.2||CACNA1A||Calcium channel, voltage dependent, P/Q type, α1a Subunit||Missense, nonsense, large deletions||Worldwide||Attacks last hours; allelic with SCA6, familial hemplegic migraine|
|EA5||613855||2q23.3||CACNB4||Calcium channel, voltage dependent, β-4 Subunit||Missense||French-Canadian family||Attacks last hours–days; late onset, seizures|
|EA6||612656||5p13.2||SLC1A3||Solute carrier family 1 (glial high affinity glutamate transporter), member 3||Missense||United States, Netherlands||Alternating hemiplegia, seizures|
EA1 is primarily due to missense mutations in KCNA1 [Browne et al., 1994] although truncation mutations have been reported. The disease is characterized by brief periods of ataxia (seconds to minutes) and interictal myokymia. The degree of channel impairment correlates with the severity of the phenotype… Mutations associated with severe phenotypes that may be poorly treatment responsive or associated with seizures or neuromyotonia show the most significant impairment of potassium channel function.
EA2 is due to a range of mutations in CACNA1A [Ophoff et al., 1996], which include missense, nonsense, aberrant splicing, and nucleotide insertions and deletions. EA2 typified by longer periods of ataxia lasting several hours with baseline nystagmus and progressive ataxia. There is a wide spectrum of phenotypes associated with mutations in CACNA1A. EA2 is allelic with SCA6 and familial hemiplegic migraine (FHM). Most of the mutations that cause EA2 disrupt the open reading frame, whereas FHM is caused primarily by missense mutations.
EA5 has been described in a single French-Canadian family that was heterozygous for a missense mutation in the CACNB4 gene, resulting in a phenotype similar to EA2 [Escayg et al., 2000]. The precise functional effects of this mutation are not clear as the same mutation was identified in a German family with generalized epilepsy but no ataxia.
EA6 was initially reported in a patient from the United States presenting with characteristic episodes of hemiplegia, seizures, and ataxia. A de novo mutation was identified in the SLC1A3 gene, which results in complete loss of function of the protein EAAT1—a glutamate transporter localized to astrocytes. Other cases have been reported in the Netherlands with the p.C186S variant that resulted in a milder phenotype without the manifestations of seizures or alternating hemiplegia [de Vries et al., 2009].
The recessive ataxias are a particular diverse group of disorders that are generally early onset with significant variation in clinical phenotype, which is variably associated with neuropathy, ophthalmological disturbance, seizures, and a range of other neurological and non-neurological manifestations. These disorders are discussed in detail in other reviews; a nonexhaustive summary of recessive ataxia genes are listed in Table 3. FRDA is the most common recessive ataxia worldwide [Palau and Espinós, 2006] and is mainly due to homozygous GAA expansions in the FXN gene, but few patients show compound heterozygosity for a point mutation and the GAA-repeat expansion. Some common pathological pathways have been described in the recessive ataxias including DNA repair dysfunction, mitochondrial dysfunction, defects in lipoprotein metabolism, and protein chaperone dysfunction. There is significant overlap of clinical phenotype with a range of metabolic ataxias (Table 4), which are invariably complex multisystem disorders that can result in severe disability despite dietary modification where possible.
Table 3. Autosomal Recessive Ataxias
|Friedrich ataxia||606829||FXN||Frataxin||GAA repeat expansions; point mutations in compound heterozygotes||Incidence: 1:30–50,000Carrier frequency: 0.9–1.6%||Worldwide except natives to: Far East, sub-Saharan Africa, Australia, America||Spasticity, neuropathy, cardiac involvement|
|Ataxia-telangiectasia||607585||ATM||Ataxia telangiectasia mutated||Deletions: splice-site related; nonsense; missense||Incidence: 1:400,000–450,000 live birthsCarrier frequency: 0.35–1%||Reported in many worldwide populations||Oculomotor apraxia; extrapyramidal features; increased cancer risk/ radiosensitivity|
|Ataxia-telangiectasia like disorder (ATLD)||604391||MRE11A||Meiotic recombination 11, S. cerevisiae, homolog of||Missense||25 reported cases worldwide||Saudi Arabia (15 cases), Japan (4 cases), UK (4 cases), Italy (2 cases)||Similar to ATM but milder phenotype|
|Ataxia-oculomotor apraxia type 1||208920||APTX||Aprataxin||Insertion, deletion, missense||Rare worldwide—More common in Portuguese and Japanese populations||Portugal, Japan, France, Tunisia||Oculomotor apraxia, peripheral neuropathy|
|Cerebellar ataxia with muscle coenzyme Q10 deficiency||607426||APTX||Aprataxin||Missense||Rare||Single Italian family||Low coenzyme Q10 levels; late-onset hypergonadotrophic hypogonadism|
|Ataxia-oculomotor apraxia type 2||606002||SETX||Senataxin||Nonsense, missense||Carrier frequency: 2.1–3.5%Incidence: 1:400,000 (Alsace)||Commoner in French-Canadian populations||Oculomotor apraxia (variable); extrapyramidal features; peripheral neuropathy|
|Spastic ataxia of charlevoix-saguenay (ARSACS)||270550||SACS||Sacsin||Stop-gain deletions and point mutations most common||Carrier frequency (Quebec): 4.5%Incidence: 1/1930||Most common in Quebec. Tunisian, Turkish, Italian, Japanese families reported||Myelinated retinal fibers; prominent lower limb spasticity|
|Cerebellar ataxia, seizures and ubiquinone deficiency||612016||ADCK3||aarF domain containing kinase 3||Missense, splice site, frame shift, deletion||Rare||French, Dutch, British families reported||Mental retardation, seizures, low coenzyme q10 levels|
|Spinocerebellar ataxia with axonal neuropathy (SCAN1)||607250||TDP1||Tyrosyl DNA phosphodiesterase 1||Missense||Rare||Saudi Arabian family||Axonal neuropathy|
|Autosomal recessive spinocerebellar ataxia type 8||610743||SYNE1||Synaptic nuclear envelope protein 1||Splice site, intronic||Rare worldwide 3rd most common ARCA in Quebec||Canada||Hyperreflexia|
|Autosomal recessive spinocerebellar ataxia type 10||613728||ANO10||Anoctamin 10||Missense, splice site, deletion||Rare||French, Dutch, Serbian families||Tortuous conjunctival vessels|
Table 4. Metabolic Ataxias
|Ataxia with selective vitamin E deficiency||277460||TTPA||Tocopherol transfer protein alpha||Frameshift, missense||Prevalence: 0.55–3.5:1000,000||United Kingdom, French, Italian, Moroccan, Japanese families reported.||Low vitamin E; resembles FRDA|
|Abetalipoproteinemia||200100||MTTP||Microsomal triglyceride transfer protein||Missense, nonsense||Prevalence: <1:1000,000||Global||Acanthocytosis; pigmentary retinal degeneration; polyneuropathy|
|Refsum disease||266500||PHYH||Phytanoyl-CoA hydroxylase||Missense, nonsense, deletions, splice site mutations||Prevalence: 1:1000,000||Global||Deafness, retinitis pigmentosa, icthyosis, demyelinating polyneuropathy|
|Cerebrotendinous xanthomatosis||213700||CYP27A1||Cytochrome p450 subfamily XXVIIA, polypeptide 1||Missense, deletions, splice site mutations||Prevalence (Moroccan Jews): 1:108 United States: 1:50,000||More common in Moroccan Jews||Widespread cholesterol deposits: tendons, brain, lungs; cataracts; dementia|
|Niemann Pick Type C||607623||NPC1||NPC1 protein||Deletions, point mutations||Prevalence: 1:100,000–150,000||Global||Extrapyramidal features, seizures, dementia,|
|Wilson's disease||277900||ATP7B||ATPase, Cu(2+)-Transporting, beta polypeptide||Point mutations, nonsense mutations||Prevalence: 1:10,000–30,000||Global—higher incidence in China, Japan, Sardinia||Extrapyramidal features; liver disease|