Dominantly Inherited Spinocerebellar Syndromes

Spinocerebellar Ataxia Type 1

Spinocerebellar ataxia type 1 (SCA1 – MIM 164400) typically causes a slowly progressive ataxia and dysarthria; over time, the disease evolves to include optic nerve atrophy, maculopathy, retinal nerve fiber degeneration, pyramidal and extrapyramidal symptoms, cognitive impairment, and peripheral nerve involvement. Bulbar dysfunction ensues, starting as dysphagia and progressing to choking spells and aspiration; eventual respiratory failure and pneumonia are common causes of death. The typical age of onset is in the third or fourth decade of life, but symptoms can start in childhood or as late as 60 years of age. Childhood onset is associated with more rapid disease progression and broader symptomatology including mild mental retardation. SCA1 has been described in multiple ethnic groups.

SCA1 is caused by CAG repeat expansion in the SCA1 gene. Normal SCA1 alleles have 6 to 44 CAG repeats, and those with 20 or more repeats are interrupted by 1 to 4 CAT trinucleotide units. In contrast, disease-causing alleles have 39 to 82 repeats and lack intervening CAT sequences. More than 70 repeats tends to cause juvenile onset. The SCA1 gene encodes ataxin-1, a protein that is expressed in several tissues and that shuttles between the cytoplasm and nucleus in neurons. Although its exact functions are unknown, native ataxin-1 interacts with multiple proteins involved in cell signaling, chromatin modulation, regulation of gene expression and RNA splicing. CAG repeat expansions alter ataxin-1’s interactions with its native protein partners, making some complexes more persistent and leading to wide-reaching changes in gene expression. Both gain and loss of normal ataxin-1 function contribute to SCA1 pathogenesis. Phosphorylation of ataxin-1 governs protein-protein interactions and is important for normal function and pathogenesis.

Native ataxin-1 appears to play a role in controlling maturation of climbing fiber input to Purkinje cells. Loss of ataxin-1 function impairs spatial and motor learning in mice, and human patients with chromosomal deletions spanning SCA1 develop mental retardation and seizures ; neither develops ataxia or neuronal degeneration. An intriguing recent report suggests that the SCA1 locus also encodes an out-of-frame transcript that interacts with ataxin-1 ; what (if any) bearing this has on pathogenesis is still unclear. Intermediate expansions (>31 repeats) are associated with sporadic amyotrophic lateral sclerosis (ALS).

SCA1 mouse models have revealed a great deal about the molecular pathogenesis of the disease and allowed the testing of several potential therapeutic avenues. For example, chaperone protein overexpression, which presumably aids in the folding and/or elimination of expanded ataxin-1, resulted in improved motor coordination and suppressed Purkinje cell degeneration in transgenic mice. Genetic and pharmacological inhibition of ataxin-1 phosphorylation improved pathology and neurological function. Lithium therapy, which is thought to induce beneficial changes in gene expression, improved motor function in transgenic mice. Genetic overexpression and pharmacological administration of vascular endothelial growth factor (VEGF) mitigated pathogenesis. It is particularly noteworthy that exercise extended the lifespan of transgenic mice. Aminopyridine treatment also mitigates cerebellar dysfunction and pathology.

Spinocerebellar Ataxia Type 2

Spinocerebellar ataxia type 2 (SCA2 – MIM 183090) is the most common SCA in Cuba and Mexico, though it also occurs in patients from other ethnic backgrounds. The clinical findings are ataxia, dysarthria, tremor, nystagmus, and extremely slow saccades. There is also evidence for autonomic cardiovascular involvement in presymptomatic individuals. Hyporeflexia and ophthalmoparesis occur in more than half of the patients. Pyramidal signs are present; deep tendon reflexes are brisk early on and are absent later in the course. Dystonia, chorea, and fasciculations have been reported; cognitive impairment and dementia occur in a significant minority of patients. Periodic leg movements (PLMs) and REM sleep pathology are common and correlate with disease severity. Dysphagia and bulbar failure occur in the last stages of the disease. About 40% of patients develop symptoms before their 25 ^th birthday. Childhood onset can present as a developmental regression syndrome ; infantile onset, which occurs with extreme CAG repeat expansion (>130 copies), presents with hypotonia, dysphagia, ocular signs, visual impairment, retinitis pigmentosa, autonomic dysfunction, global developmental delay, infantile spasms, and infant-onset epilepsy.

SCA2 is caused by expansion of a CAG repeat tract in the coding region of the SCA2 gene. The normal and disease ranges of CAG repeats are 14 to 31 and 34 to 750 repeats, respectively. All but the shortest repeat tracts in normal alleles are interrupted by 1–3 CAA. Mutant alleles are typically uninterrupted, although cases with a single CAA have been reported; these cases tend to be associated with sporadic or familial parkinsonism. Mild SCA2 expansions can produce parkinsonism and multiple system atrophy (MSA) phenotypes. Interestingly, intermediate-length (27–33) expansions are an independent risk factor for the development of amyotrophic lateral sclerosis.

SCA2 encodes ataxin-2, a cytoplasmic protein whose mRNA is alternatively spliced and found in multiple tissues and all regions of the CNS, where it is present predominantly in neurons and is highly expressed in Purkinje cells. Ataxin-2 is a cytoplasmic protein that is subcellularly localized to the Golgi apparatus and rough endoplasmic reticulum. Nuclear localization of mutant ataxin-2 protein is not necessary for SCA2 pathogenesis, but expanded ataxin-2 does accumulate in the cytoplasm of affected neurons.

At the molecular level, ataxin-2 associates with RNA-binding proteins, polyribosomes and stress granules, suggesting that it functions in RNA processing and translational regulation of protein production. The Drosophila homolog of ataxin-2 has recently been shown to regulate translation of proteins involved in the circadian rhythm, an intriguing finding that could help explain sleep disturbances in SCA2 patients. Ataxin-2 may also be involved in endocytosis of and trophic signaling mediated by receptor tyrosine kinases, and polyglutamine expansion changes the levels of associated proteins. The morphological changes seen in diseased Purkinje cells may result from abnormal cytoskeletal architecture secondary to disruption of microtubule assembly ; whether these effects are mediated through RNA interactions is unknown. There is some evidence that ataxin-2 functions as a mediator of oxidative damage. Parkin, a gene associated with Parkinson disease, interacts with ataxin-2 and can increase clearance of normal and expanded ataxin-2. Mutant ataxin-2 has also been linked to Ca ²⁺ -mediated cytotoxicity through association with the inositol 1,4,5-trisphosphate receptor; inhibition of signaling through this receptor decreased Ca ²⁺ levels in a mouse model of SCA2, concomitantly mitigating incoordination and Purkinje cell death. ALS-associated polyglutamine expansions in ataxin-2 enhance stress-induced caspase activation and could provide a mechanism for motor neuron death. There is also evidence of interaction between ataxin-1 and ataxin-2. Interestingly, the gene mutated in SCA6 ( CACNA1A ) is, when not mutated, a disease modifier for SCA2: longer repeat lengths in normal alleles are associated with earlier age of SCA2 onset.

Spinocerebellar Ataxia Type 3

Spinocerebellar ataxia type 3 (SCA3 – MIM 109150), also called Machado-Joseph disease (MJD) after two affected families of Portuguese-Azorean origin, accounts for 30–50% of dominantly inherited ataxias and is the most common hereditary spinocerebellar ataxia worldwide. Originally regarded as separate entities, genetic mapping and subsequent molecular cloning revealed that SCA3 and MJD are caused by triplet repeat mutations in the same gene. Typical clinical features of SCA3 include progressive ataxia, areflexia, peripheral amyotrophy, external ophthalmoplegia, bulging eyes, faciolingual myokymia, muscle atrophy, parkinsonian features, dystonia, spasticity, dementia, and dysautonomia. SCA3 expansions have also been associated with pure parkinsonism in the absence of ataxia. Disease onset is usually in the second to fourth decades of life.

The MJD1 gene encodes ataxin-3, the smallest polyglutamine protein. Predominantly a cytoplasmic protein, expanded ataxin-3 accumulates in ubiquitinated nuclear inclusions that colocalize with the proteasome. Ataxin-3 functions in the ubiquitin proteasome pathway to regulate protein degradation. Interestingly, one of the E3-ubiquitin ligases that interacts with ataxin-3 is parkin, providing a potential link to parkinsonian features of the disease. Ataxin-3 also functions as a transcriptional repressor via chromatin binding activity and association with histone deacetylases, an interaction that is disrupted in expanded alleles. Overexpression of expanded ataxin-3 in cultured cells induces apoptosis, suggesting that the mutant protein is either directly or indirectly involved with a cellular suicide pathway. Other studies suggest that protein misfolding, presumably initiated by the expanded polyglutamine tract, leads to ubiquitination and subsequent formation of intranuclear inclusions. Cleavage of ataxin-3 by cellular proteases releases the polyglutamine region and is important in pathogenesis ; phosphorylation of ataxin-3 plays a role in nuclear localization, nuclear inclusion formation, and protein stability. Similar to ataxin-2, mutant ataxin-3 associates with the inositol 1,4,5-trisphosphate receptor; inhibition of Ca ²⁺ release in a mouse model of SCA3 using dantrolene improved coordination. Ataxin-3 interacts with a huntingtin-associated protein, and ataxin-2 is a modifier of the ataxin-3 neurodegeneration phenotype in Drosophila .

Recent work suggests that treatment of adult patients with the α4β2 neuronal nicotinic acetylcholine receptor partial agonist varenicline improves some aspects of the ataxia. The HDAC inhibitor sodium butyrate delayed the onset of neurological phenotypes and Purkinje cell degeneration in a mouse model of SCA3. Evidence from a mouse model suggests that reducing levels of expanded ataxin-3 yields lasting improvements in neurological status.

Spinocerebellar Ataxia Type 6

Spinocerebellar ataxia type 6 (SCA6 – MIM 183086) is among the most common SCAs, particularly in individuals of Asian descent. Clinically, SCA6 typically presents as a slowly progressive ataxia and dysarthria with associated intention tremor and dysphagia. Patients can develop diplopia, hyperreflexia, extensor plantar responses, and nystagmus. As in SCA2 and SCA3, SCA6 can be associated with parkinsonian symptoms and dopaminergic dysfunction. A significant minority of patients also develop dementia.

SCA6 is caused by CAG repeat expansions in the C-terminal coding region of the CACNA1A gene. These polyglutamine tracts are the shortest to be found among the triplet repeat diseases, with a mere 21 repeats being pathogenic. Homozygosity for expanded repeats does not alter phenotypic presentation or age of onset, suggesting that loss of function is not a primary pathogenic mechanism. CACNA1A encodes the brain-specific, voltage-sensitive αα _1A (Ca _v 2.1) subunit of the P/Q-type calcium channel, which is highly expressed in Purkinje cells. The expanded proteins aggregate in the cytoplasm of Purkinje cells, but these inclusions are not ubiquitinated and lack several other components found in the inclusions of other CAG repeat disorders. Abnormalities of the endolysosomal protein degradation pathway, not changes in Ca ²⁺ -channel function, appear to mediate disease pathogenesis. Recent work has added a new level of complexity by showing that CACNA1A actually encodes a bicistronic message, where the C-terminus of the α1A subunit (α1ACT) can be translated independently of the channel and functions as a transcription factor. Expression of α1ACT containing a triplet repeat expansion is cytotoxic and inhibits neurite outgrowth, while overexpression of α1ACT in mouse models of SCA6 actually rescues some pathologic features.

While triplet repeat expansions cause SCA6, point mutations and deletions in the CACNA1A coding sequence cause episodic ataxia type 2 and familial hemiplegic migraine type 1 (see below, under Episodic Ataxias ). These mutations can present as early as infancy with isolated symptoms, such as nystagmus, and then progress to ataxia. Some affected families display significant phenotypic overlap between the three entities.

Spinocerebellar Ataxia Type 7

Spinocerebellar ataxia type 7 (SCA7 – MIM 164500) is the only SCA that commonly occurs with retinal degeneration. Decreased visual acuity secondary to progressive pigmentary macular degeneration begins as a cone dystrophy and progresses to involve the entire retina, often leading to complete blindness. As in other SCAs, progressive cerebellar ataxia, dysarthria, dysphagia, dysmetria, dysdiadochokinesia, external ophthalmoplegia, hyperreflexia, ptosis, auditory hallucinations, and delusions are also common. Patients may present first with ataxia, visual loss, or both; those with cerebellar ataxia may have normal vision for decades, whereas those with primary visual symptoms usually develop ataxia within a few years. An aggressive infantile-onset form of SCA7 presents with hypotonia, dysphagia, myoclonic seizures, and visual disturbances that typically lead to rapid mental deterioration and severe physical disability, culminating in death by age 3 or earlier. This occurs only with paternal transmission of the disease allele and is associated with cardiac abnormalities, particularly patent ductus arteriosus. Childhood-onset SCA7, which may be associated with myoclonic seizures, is less aggressive than the infantile-onset form but more progressive than the adult-onset form.

The CAG expansions that cause SCA7 are the most unstable of the polyglutamine diseases, and can be upwards of 300 repeats. As with other triplet repeat diseases, expansion length is inversely correlated with age of onset. The SCA7 locus encodes ataxin-7, a protein required for normal neuronal and photoreceptor development that participates in epigenetic regulation of gene expression through its interactions with histone acetyltransferase complexes. Expansion of the polyglutamine region in mutant ataxin-7 proteins disrupts these interactions and alters gene expression, findings that have been linked to retinal dystrophy and neuronal dysfunction. In addition, protein interactome studies have identified genes associated with macular degeneration in the interactome of ataxin-7. Pathology studies demonstrate morphological evidence for mitochondrial pathology, and expanded alleles might activate a mitochondrial-mediated apoptotic cascade that results in neuronal death. Ubiquitin-positive nuclear inclusions are found in patients’ brains and SCA7 transgenic mouse models. However, cellular dysfunction predates the appearance of neuronal inclusions and dysfunction of the ubiquitin proteasome pathway does not occur, suggesting that inclusions in and of themselves are not the primary cause of dysfunction and that they may in fact be neuroprotective. Interestingly, mutant protein malfunction in multiple cell types, and excitotoxicity mediated by glial abnormalities, appear to play roles in pathogenesis.

A very recent report suggests that administration of interferon-β can improve motor function in a transgenic mouse model of SCA7. Another promising finding is that abolishing expression of mutant ataxin-7 protein halts and/or reverses disease progression in a transgenic mouse model, suggesting that there is hope for an eventual treatment that could slow or halt disease progression.

Spinocerebellar Ataxia Type 17

Phenotypic variability in spinocerebellar ataxia type 17 (SCA17 – MIM 607136) is striking, even for a triplet repeat disease: the disease can present as cerebellar ataxia associated with dysarthria and extrapyramidal symptoms (e.g. parkinsonism and dystonia), or as a Huntington disease phenocopy with chorea as the major manifestation, or it can appear first in the form of cognitive decline with any of a variety of psychiatric symptoms from depression to hallucinations. Individuals within the same family can present with dramatically different clinical features, and the same individual over time can manifest each of the various subtypes. Epilepsy can develop late in the disease course. Neuroimaging shows diffuse cortical and cerebellar atrophy that is most pronounced in the vermis. Pathologic specimens reveal loss of Purkinje cells, anterior horn cells, and neurons of the inferior olivary nucleus, and overall brain atrophy.

SCA17 is caused by CAG repeat expansions in the TATA-binding protein ( TBP ) gene. Short CAA tracts interrupt the CAG repeats in both healthy and disease alleles, which distinguishes TBP from other SCA-associated genes. Repeat sizes of 42–49 repeats show variable penetrance. Interestingly, small expansions of the SCA17 allele have also been associated with isolated parkinsonism in the absence of ataxia.

TBP is the DNA binding subunit required for transcription initiation by all three eukaryotic RNA polymerases. Mutant TBP interacts aberrantly with transcription factors, altering transcription of chaperone proteins important for protein folding and degradation. Intranuclear inclusions containing expanded TBP and ubiquitin are found in several neuronal cell types including Purkinje cells.

Dentatorubral-Pallidoluysian Atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA; Haw River Syndrome – MIM 125370) is very rare except in Japan, where it accounts for a significant proportion of autosomal dominant SCAs. It is characterized by progressive ataxia, myoclonus, epilepsy, choreoathetosis, dystonia, dementia, and psychiatric symptoms. Haw River Syndrome, once thought to be a separate entity described in several generations of an African-American family without myoclonic epilepsy but with basal ganglia calcifications and neuroaxonal dystrophy, is caused by the same mutation. Clinical onset prior to 20 years of age tends to present as progressive epilepsy, myoclonus, cerebellar ataxia, and intellectual disability; onset after age 20 tends to present as cerebellar ataxia, choreoatheotosis, tremors, and dementia. Anticipation is prominent, and the phenotypic diversity within and among families is striking, as is the overlap with the clinical presentation of Huntington’s chorea. Neuroimaging shows cerebellar, tegmental, and cerebral atrophy accompanied by white matter signal changes; late onset cases can also have signal changes in the pons, midbrain, thalamus, and globus pallidus. Neuronal loss occurs in the dentate nucleus, red nucleus, globus pallidus, and subthalamic nucleus, and leukoencephalopathy occurs in the cerebral white matter.

DRPLA is caused by CAG repeat expansions in the atrophin-1 gene. Anticipation occurs with both paternal and maternal transmission of the disease allele, and extreme expansions (>90 repeats) can lead to infantile disease. Phenotypic severity is affected by gene dosage, with homozygosity for a pathogenic allele causing more severe clinical manifestations than would otherwise be predicted based on repeat length. Atrophin-1 mRNA and protein are expressed ubiquitously in human tissue ; the number of CAG repeats varies in different tissues and tends to be larger in brain, suggesting somatic instability of the repeat. However, the degree of expansion does not seem to parallel neuropathologic involvement. Intranuclear inclusions containing the polyglutamine-expanded protein are found in both neurons and glia; their presence in oligodendrocytes may cause the observed white matter lesions.

The first protein found to interact with atrophin-1 was glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which also interacts with the SCA1, Huntington, and SBMA proteins and thus seems likely to interact with the polyglutamine domain itself. Atrophin-1 participates in transcriptional regulation, which may occur at the epigenetic level through alterations in histone acetylation ; administration of a histone deacetylase inhibitor improved symptoms and survival in a transgenic mouse model. Atrophin-1 may also normally function in a pathway with insulin/IGF-1. Proteolytic processing of the expanded protein appears to play a role in pathogenesis and the formation of nuclear inclusions. Toxicity might also result from the sequestration of atrophin-1 interacting proteins from their normal sites of action. Expanded atrophin-1 alleles do not appear to function in a dominant-negative way.

Spinocerebellar Ataxia Type 8

Spinocerebellar ataxia type 8 (SCA8 – MIM 608768) presents with ataxic dysarthria, nystagmus, limb and gait ataxia, limb spasticity, and diminished vibratory sense. Cases can present in childhood. MRI of the brain demonstrates cerebellar atrophy that may be accompanied by white matter hyperintensities in other brain areas. The vast majority of SCA8 disease alleles in individuals of European descent share a common haplotype. Neuropathology reveals intranuclear inclusions in both mouse models and human tissue.

SCA8 has several characteristics that make it unusual among dynamic repeat diseases. The SCA8 locus harbors a noncoding gene with a CTG repeat region that is transcribed into mRNA but not translated into protein and, in the opposite direction, a CAG repeat in a polyglutamine expansion protein designated ataxin-8. Repeat length is highly variable in wild-type alleles and can be as large as 174, by far the largest number of wild-type repeats of any SCA; SCA8 is also unique in that there is also substantial overlap between pathogenic and nonpathogenic repeat lengths. Homozygosity for an expanded allele does not exacerbate the disease phenotype as it does in typical polyglutamine expansion SCAs and DRPLA. Penetrance is variable, and repeat lengths contract with paternal transmission but expand with maternal transmission, two more unusual aspects of this disease. SCA8 expansions have been found in some SCA1 and SCA6 kindreds and in patients with Alzheimer’s disease, Parkinson’s disease, and vitamin E deficiency heterozygous for the TTPA mutation; the significance of this is unclear.

Expanded CTG and CAG alleles may cause disease through both RNA- and protein-mediated mechanisms. It has therefore been suggested that the noncoding SCA8 mRNA functions as an endogenous inhibitory RNA for KLHL1 , a gene whose locus it partially overlaps, or as a regulator of RNA-binding proteins and splice factors. KLHL1 appears to be necessary for proper Purkinje cell dendritic branching and has been implicated in modulating P/Q-type calcium channel function; what role, if any, this plays in SCA8 pathogenesis is unclear.

Spinocerebellar Ataxia Type 10

The mutation that causes spinocerebellar ataxia type 10 (SCA10 – MIM 603516) appears to have arisen in New World Amerindians, with cases described in people of Brazilian, Mexican, and Portuguese descent. The association of ataxia, dysarthria, and nystagmus with epilepsy distinguishes this SCA clinically. Mood disorders and evidence of polyneuropathy on nerve conduction studies can also be seen. Brain imaging shows cerebellar atrophy.

SCA10 is one of two human diseases (the other being SCA31) known to be caused by a pentanucleotide repeat. The ATTCT repeat sequence occurs in intron 9 of the ataxin-10 gene and is highly unstable: normal individuals have 10 to 29 repeats, while affected individuals typically have 750 to 4500 repeats. As with other repeat disorders, there is an inverse correlation between expansion size and age of onset. Genetic anticipation is present, with paternally inherited repeats being highly unstable while maternal transmission results in more stable repeats.

Ataxin-10 is widely expressed in the brain and other tissues, and is localized to the neuronal cytosol and perinuclear region. Ataxin-10 transcripts may participate in nucleosome formation, which is altered in repeat expansions, and the native protein may be involved in neuritogenesis through interactions with G-proteins and also in cytokinesis. Data from cell culture and transgenic mouse models indicate that decreased ataxin-10 RNA levels and expression of expanded RNAs both result in increased apoptosis, possibly through a ribonucleoprotein-related mechanism. This suggests that SCA10 pathogenesis cannot be accounted for by a simple gain- or loss-of-function model.

Spinocerebellar Ataxia Type 12

The initial symptom of spinocerebellar ataxia type 12 (SCA12 – MIM 604326) is typically action tremor, a feature that distinguishes the disease from other SCAs. SCA12 is slowly progressive, with symptoms including head tremor, gait ataxia, dysmetria, dysarthria, hyperreflexia, parkinsonian signs, abnormal eye movements, and occasionally dementia. Childhood-onset nystagmus and lower extremity dystonia have been reported. Brain imaging reveals both cortical and cerebellar atrophy. Pathology is available only on a single brain, and revealed diffuse atrophy of cerebral and cerebellar cortices and loss of Purkinje cells. SCA12 is the third most common SCA in India but otherwise has been described in only a few families of German-American pedigree.

SCA12 is caused by a noncoding triplet CAG expansion found 133 nucleotides upstream of the transcription start site for PPP2R2B, a brain-specific regulatory subunit of protein phosphatase 2A (PP2A). The expanded allele does not lead to a polyglutamine tract, and how it affects PPP2R2B function is unknown. The minimum repeat length necessary to cause disease has not yet been established, and no relationship between repeat size and age of onset has yet been discerned. PPP2RB subunits are thought to modulate PP2A function by regulating substrate specificity and intracellular targeting, and recent evidence suggests that mitochondrial impairment leading to oxidative stress might play a role in pathogenesis.

Spinocerebellar Ataxia Type 31

Spinocerebellar ataxia type 31 (SCA31 – MIM 117210) is one of the most common SCAs in Japan but is rare elsewhere. Symptoms include late-onset pure cerebellar ataxia consisting of gait and limb ataxia, nystagmus and hypotonia, typically accompanied by sensorineural hearing impairment. Neuroimaging shows isolated cerebellar atrophy.

SCA31 is caused by TGGAA pentanucleotide repeat insertions in the introns of the TK2 and BEAN genes, which are on opposite strands and transcribed in opposite directions. The length of the insertion is inversely correlated with age of disease onset but not with rate of disease progression. Mild anticipation is manifest, suggesting that the insertion might have a propensity towards expansion. Notably, expression of TK2 and BEAN is not altered by the expansions, but expanded RNAs form nuclear RNA foci and bind splicing factors; how this might lead to pathogenesis is unknown.