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.

Spinocerebellar Ataxia Type 36

Spinocerebellar ataxia type 36 (SCA36; Asidan – MIM 614153) is a cerebellar/motor neuron combination disease in which affected individuals present with ataxia, dysarthria, tongue fasciculations, and nystagmus in the fifth to sixth decade and subsequently develop muscle weakness, atrophy, and fasciculations. Hyperreflexia is also common, and the disease can be associated with progressive sensorineural hearing loss and oromandibular dystonia. Neuroimaging shows cerebellar atrophy. SCA36 maps to chromosome 20p13 and is caused by GGCCTG hexanucleotide repeats in intron 1 of the NOP56 gene, which encodes an important component of the transcription and RNA splicing machinery. Normal repeat number is 5–14, while pathogenic repeats can number 650–2500. Levels of the NOP56 protein do not appear to be altered in affected individuals, but RNA foci are present, suggesting a toxic gain-of-function as the pathogenic mechanism.

Spinocerebellar Ataxia Type 5

Spinocerebellar ataxia type 5 (SCA5 – MIM 600224) patients suffer from mild disturbance of gait and limb coordination that worsens with age. Some patients manifest increased reflexes, gazed-evoked nystagmus, facial myokymia, and decreased vibration sense. Juvenile-onset SCA5 patients present with bulbar and pyramidal dysfunction as well as cerebellar dysfunction; this may shorten life. All four reported juvenile-onset cases resulted from maternal inheritance.

SCA5 is caused by mutations in the SPTBN2 gene that encodes β-III spectrin, a protein expressed throughout the brain and in high levels in Purkinje cells. Pathogenesis is believed to occur secondary to decreased trafficking of proteins from the Golgi complex to the membrane, which affects stabilization of the excitatory amino acid transporter EAAT4 at the plasma membrane and disrupts other intracellular transport pathways. The mutation may also exhibit dominant negative effects secondary to loss of native protein association with ARP1, a component of the dynactin/dynein complex. β-III spectrin has also been implicated in normal neuronal development and in the recessive disorder spectrin-associated autosomal cerebellar ataxia type 1 (SPARCA1). Unlike SCA5, which is typically an adult disease, SPARCA1 presents with childhood ataxia and cognitive impairment and is typically associated with truncating β-III spectrin mutations.

Spinocerebellar Ataxia Type 11

Spinocerebellar ataxia type 11 (SCA11 – MIM 604432) is a rare, relatively benign, late-onset, slowly progressive pure cerebellar syndrome occasionally associated with mild hyperreflexia and vertical nystagmus. Truncating mutations in the tau tubulin kinase 2 ( TTBK2 ) gene cause SCA11. TTBK2 is involved in ciliogenesis ; how this relates to SCA11 pathology is unclear.

Spinocerebellar Ataxia Type 13

Spinocerebellar ataxia type 13 (SCA13 – MIM605259) is unusual in that it can start in early childhood and includes moderate mental retardation (IQ=62–76) as a prominent feature. Patients exhibit slowly progressive gait ataxia, dysarthria, moderate mental retardation, mild developmental motor delay, and, in some cases, epilepsy. Nystagmus and pyramidal signs are sometimes observed. Patients older than 50 years of age show additional neurological signs such as dysphagia, urinary urgency, and bradykinesia. MRI shows moderate cerebellar and pontine atrophy.

SCA13 is caused by missense mutations in the voltage gated potassium channel Kv3.3 (KCNC3). The mutations are dominant-negative in nature, with those affecting channel gating properties and neuronal excitability associated with early-onset phenotypes, whereas those affecting current amplitude are associated with late-onset phenotypes. Mutations associated with infantile onset are also associated with axonal pathfinding errors in a zebrafish model, suggesting that this may play a role in early pathogenesis.

Spinocerebellar Ataxia Type 14

Spinocerebellar ataxia type 14 (SCA14 – MIM605361) presents with slowly progressive gait ataxia, dysarthria, horizontal gaze nystagmus, and abnormal smooth pursuit movements with or without hyper- and hyporeflexia, myoclonus, dystonia, and/or peripheral neuropathy. There is large variation in age of onset, with earlier onset tending to produce a broader range of symptoms. Imaging reveals atrophy of the cerebellar vermis and/or hemispheres. Limited pathologic specimens suggest a primary Purkinje cell defect.

Molecular studies reveal that missense mutations in exon 4 of the protein kinase Cγ (PKCγ) gene are responsible. Mutations alter kinase activity and membrane targeting of PKCγ in response to calcium. Mutant PKCγ forms intracellular aggregates that appear to impair the ubiquitin proteasome system and lead to endoplasmic reticulum stress. Overexpression of mutant protein in Purkinje cells causes abnormalities of dendritic branching and decreased synaptic pruning. There also appears to be crosstalk between PKCγ and proteins involved in other human ataxias, as mutant PKCγ preferentially phosphorylates aprataxin, the mutated protein in ataxia with oculomotor apraxia type I (AOA1).

Spinocerebellar Ataxia Type 15

Spinocerebellar ataxia type 15 (SCA15 – MIM 606658) is an autosomal dominant, slowly progressive ataxia associated with nystagmus and dysarthria. Action and postural tremor, buccolingual dyskinesias, chorea, facial myokymia, pyramidal signs, and cognitive decline can also be part of the clinical spectrum. Neuroimaging demonstrates cerebellar atrophy. Identification of the causative gene came not from positional cloning efforts but rather serendipitously through analysis of a spontaneous mutation that arose in a transgenic mouse colony. SCA15 is caused by mutations in ITPR1 , which encodes the inositol 1,4,5-triphosphate receptor type I, a calcium channel found predominantly in the endoplasmic reticulum. This locus had initially been excluded from the original family but was subsequently shown to be involved in that and other kindreds. Further studies showed that SCA16 and SCA29, both originally thought to be distinct entities, were also caused by ITPR1 mutations. The SCA16 and SCA29 designations are therefore left blank.

Spinocerebellar Ataxia Type 19

Spinocerebellar ataxia type 19 (SCA19 – MIM 607346) can present with a pure cerebellar syndrome or ataxia accompanied by cognitive impairment, irregular postural tremor, and myoclonus. Neuroimaging shows atrophy of the cerebellar hemispheres or vermis. SCA19 is caused by mutations in KCND3 , which encodes the Kv4.3 voltage-gated potassium channel. The mutations appear to prevent channel targeting to the plasma membrane and are accompanied by a complete lack of channel conductance. This molecular cloning also revealed that SCA19 and SCA22 are caused by the same mutations; the SCA22 nomenclature has subsequently been vacated.

Spinocerebellar Ataxia Type 23

Spinocerebellar ataxia type 23 (SCA23 – MIM 610245) is an infrequent (<0.5% of all cases) cause of ataxia. Disease appears in midlife (>40), is slowly progressive, and includes gait and limb ataxia, disturbance of oculomotor control, dysarthria, hyperreflexia, and sometimes peripheral neuropathy. Neuroimaging demonstrates severe cerebellar atrophy. Pathology in a single individual who died at 80 years of age showed loss of Purkinje cells, neurons in the dentate nuclei, and inferior olives; thinning of the cerebellopontine tracts; demyelination of the posterior and lateral columns in the spinal cord; and ubiquitin-positive, polyglutamine-negative intranuclear inclusions in nigral neurons that resembled Marinesco bodies. The pathogenic significance of this last finding is uncertain. SCA23 is caused by point mutations in PDYN , which encodes prodynorphin, the precursor protein for the opioid neuropeptides, α-neoendorphin, and dynorphins A and B. Some of these mutations increase dynorphin A levels, which has been associated with increased glutamate-mediated neurotoxicity.

Spinocerebellar Ataxia Type 26

Spinocerebellar ataxia type 26 (SCA26 – MIM 609306) was described in a single six-generation family of Norwegian descent with slowly progressive gait and upper limb ataxia accompanied by dysarthria. Age of onset ranged from 26 to 60 years. Brain pathology showed significant loss of Purkinje cells with minimal effects in other brain regions. Mutations in the gene encoding eukaryotic elongation factor 2 (eEF2) co-segregate with the disease phenotype. These mutations interfere with translocation during protein translation, suggesting a novel pathogenic mechanism.

Spinocerebellar Ataxia Type 27

Spinocerebellar ataxia type 27 (SCA27 – MIM 609307), formerly fibroblast growth factor 14-SCA (MIM 601515), presents with trembling of the hands during childhood followed by slowly progressive limb ataxia, dysmetric saccades and smooth pursuit movements, nystagmus, psychiatric symptoms, and decreased cognitive performance. Brain imaging is normal or shows cerebellar atrophy.

SCA27 is caused by mutations in the FGF14 gene, and has also been associated with chromosomal translocation involving the FGF14 locus. Interestingly, a patient with a reciprocal chromosomal translocation involving the FGF14 locus presented with a paroxysmal nonkinesigenic dystonia phenotype. Mice lacking FGF14 are ataxic and have paroxysmal dystonia, demonstrating the linkage between the two phenotypes. FGF14 is transported into neuronal processes, and introduction of mutant protein into an in vitro cerebellar culture system impairs Ca ²⁺ channels and synaptic transmission, suggesting a possible pathogenic mechanism.

Spinocerebellar Ataxia Type 28

Spinocerebellar ataxia type 28 (SCA28 – MIM 610246) is a rare infantile-, childhood- or juvenile-onset, slowly progressive SCA that typically presents with mild gait incoordination and includes nystagmus, dysarthria, ophthalmoparesis, ptosis and hyperreflexia. Neuroimaging shows cerebellar atrophy. SCA28 is caused by mutations in AFG3L2 , which encodes a mitochondrial protein that is a component of the m -AAA metalloprotease complex involved in the maintenance of the mitochondrial proteome. AFG3L2 forms this complex with paraplegin, a protein that is mutated in a type of recessive spastic paraplegia (SPG7) ; homozygous AFG3L2 mutations cause a syndrome that combines features of SCA28 and SPG7. In yeast, mutations in AFG3L2 impair mitochondrial respiration, cytochrome oxidase-c activity, and the proteolytic activity of the m -AAA metalloprotease complex. These impairments likely lead to respiratory chain compromise and increased generation of reactive oxygen species, which could lead to Purkinje cell degeneration and cerebellar dysfunction.

Spinocerebellar Ataxia Type 35

Spinocerebellar ataxia type 35 (SCA35 – MIM 613908) has been described in three Chinese families. The age of onset ranged from 40 to 48 years; presenting features were a slowly progressive gait ataxia and dysarthria (patients needed a walking aid or wheelchair after about 10 years); upper limb incoordination appeared later. With disease progression patients also developed pyramidal signs with hyperreflexia and extensor plantar responses, torticollis, tremor, dysmetria, position sense defects, and pseudobulbar palsy in the absence of nystagmus. Neuroimaging shows cerebellar and brainstem atrophy, and pathology studies show loss of Purkinje cells, deep cerebellar nuclear neurons, and lower motor neurons. A combination of linkage analysis and exome sequencing demonstrated that SCA35 is caused by mutations in TGM6 , which encodes a transglutaminase gene. Pathogenesis could be linked to alterations in transglutaminase activity that lead to apoptosis and/or through interactions with polyglutamine proteins.

Spinocerebellar Ataxia Type 4

The clinical phenotype of spinocerebellar ataxia type 4 (SCA4 – MIM 600223) consists of ataxia coupled with prominent axonal sensory neuropathy and extensor plantar reflexes. Analysis of 34 candidate genes failed to reveal the causative locus.

A phenotypically distinct disorder (16q-ADCA) consisting of late-onset, pure cerebellar ataxia (ataxia, dysarthria, and nystagmus) with or without sensorineural hearing impairment has been described in Japan. 16q-ADCA maps to the same general chromosomal location as SCA4 and appears to be caused by single nucleotide substitutions in the 5′-untranslated region of puratrophin-1, a protein found in multiple tissues and predicted to be involved in intracellular signaling and Golgi apparatus targeting. Puratrophin-1 functions as a guanine nucleotide exchange factor important for GTPase signaling. Cytoplasmic aggregates containing puratrophin-1 are found exclusively in Purkinje cells of affected individuals. Screening of 537 unrelated European ataxia patients excluded for SCA1, 2, 3, 6, and 17 failed to reveal the described substitution. However, as the puratrophin-1 gene is large and complex, it remains undetermined whether mutations are causative in Europeans.

Spinocerebellar Ataxia Type 18

Spinocerebellar ataxia type 18 (SCA18 – MIM 607458), or sensory motor neuropathy with ataxia (SMNA), was described in a single five-generation American family of Irish descent. The clinical presentation consists first of gait instability in the dark, followed by limb ataxia, nystagmus, decreased vibratory and position sense, decreased deep tendon reflexes, and proximal or distal muscle weakness and atrophy occasionally associated with upgoing plantar responses and/or pes cavus. Neuroimaging was normal or demonstrated mild cerebellar atrophy. EMG/NCV showed evidence of denervation and axonal sensory neuropathy. The disorder was mapped to chromosome 7q22-32; interferon-related developmental regulator gene 1 ( IFDR1 ) has been suggested as a candidate gene.

Spinocerebellar Ataxia Type 20

Spinocerebellar ataxia type 20 (SCA20 – MIM 608687) was described in a single kindred of Anglo-Celtic origin. Dysarthria is often the initial symptom; palatal tremor and a characteristic dysphonia are other distinguishing symptoms. Imaging shows mild to moderate cerebellar atrophy and the unique finding of dentate calcification in the absence of basal ganglia calcification. SCA20 is associated with duplications of chromosome 11q12.2-q12.3.

Spinocerebellar Ataxia Type 21

Spinocerebellar ataxia type 21 (SCA21 – MIM 607454) was described in a single French kindred with moderate gait and limb ataxia, extrapyramidal signs such as tremor, akinesia and cogwheeling, hyporeflexia, and mild mental impairment. Eye movements are normal, and disease progression is slow. SCA21 maps to chromosome 7p21.3-p15.1. The phenotypes of several parent-child pairs suggest anticipation. Brain imaging shows marked atrophy of the cerebellum.

Spinocerebellar Ataxia Type 25

Spinocerebellar ataxia type 25 (spinocerebellar ataxia with sensory neuropathy; SCA25 – MIM 608703) was described in a single French kindred with variable clinical presentations ranging from pure sensory neuropathy with little cerebellar involvement to a Friedreich’s ataxia-like phenotype. Cerebellar ataxia, peripheral sensory neuropathy manifest as loss of vibratory, light touch and pain sensation, pes cavus, and scoliosis were present in different family members. The index case of the family started walking at age 17 months with frequent falls, and suffered repeated vomiting from the age of 2 years; gastrointestinal symptoms were initial features in two other patients. There is no evidence of anticipation for age of onset, but the two most incapacitated individuals were from the most recent generation. Brain imaging showed global cerebellar atrophy. SCA25 maps to chromosome 2p15-p21.

Spinocerebellar Ataxia Type 30

Spinocerebellar ataxia type 30 (SCA30 – MIM 613371), a relatively pure, midlife onset cerebellar ataxia, has been described in a single Australian family of Anglo-Celtic ethnicity. SCA30 appears to have a particularly insidious onset, with slowly evolving gait ataxia and mild to moderate dysarthria. Four of the six affected individuals had lower-limb hyperreflexia; all had hypermetric saccades; one had slight gaze-evoked nystagmus. Neuroimaging of two patients showed cerebellar atrophy. The locus was mapped to chromosome 4q34.3-q35.1.

Spinocerebellar Ataxia Type 32

Spinocerebellar ataxia type 32 (SCA32 – MIM 613909) was described in a single Chinese kindred. The presentation was of cerebellar ataxia, azoospermia with complete absence of testicular germ cells and progenitors in men, and intellectual impairment if the onset of symptoms was prior to age 40. Neuroimaging showed cerebellar atrophy. The locus maps to chromosome 7q32-q33.

Spinocerebellar Ataxia Type 34

Spinocerebellar ataxia type 34 (SCA34 – MIM 633190) is a neurocutaneous syndrome that was first reported in a five-generation French Canadian kindred. Shortly after birth the affected individuals developed distinct papulosquamous erythematous ichthyosiform plaques on their skin, predominantly on the dorsal aspects of the hands, feet, and ears or at the joints (elbows, knees, ankles, wrists). These lesions tended to subside during the summer and were greatly attenuated after age 25; curiously, they would sometimes reappear after age 40. In their 20s, patients might display extremely subtle deficits such as slight gait hesitation after a long walk or diminished tendon reflexes. In their 40s, however, patients developed a slowly progressive neurological syndrome characterized by severely diminished tendon reflexes (without loss of position or vibration sense), limb paresthesias and muscle spasms, and, by advanced age, nystagmus, dysarthria, and a severe gait ataxia. A subsequent genetic study identified other affected families in Europe and mapped the locus to chromosome 6p12.3-p16.2.

Case Discussions

These cases were chosen because they emphasize the difficulties associated with clinical diagnosis of the dominantly inherited ataxias. Patient #1 came from an Azorean family in which both parents showed signs of SCA3 by the age of 27, though this case was described in 1982 when the disease was known only as Machado-Joseph disease and anticipation was not yet understood (and sometimes, therefore, dismissed). This patient and his younger brother were the only two of the large number of children known to be affected. The infantile death of five other children, however, is suspicious, even though the report indicated that there had been no sign of neurologic disease. Because both parents had SCA3, it is virtually impossible to believe that they had only two affected children out of 11. It is possible that neurologic disease simply wasn’t recognized in these children, either because neonatal SCA3 looks drastically different from early-onset disease, or because the children were never seen by a neurologist before their deaths. Without an understanding of anticipation, it would have been difficult to attribute the deaths to the same disease that was causing no or only mild symptoms in the young parents. Notice that the pathology is considerably broader than it would be in an adult-onset case—involvement of the sensory ganglia and the gracile and cuneate nuclei is not associated with adult SCA3—and that there may be anatomic lesions that produce little clinical correlate. Dysautonomia besides the tachycardia was absent, for example, despite degeneration of the dorsal nuclei of the vagus and the intermediolateral columns.

Patient #2, despite the retinal degeneration associated almost exclusively with SCA7, actually had infantile SCA2. DNA testing revealed 220 CAG repeats. A correct diagnosis in this case was facilitated by an obvious family history: the father had an expanded SCA2 allele of 43 repeats. This was the first case reported of an SCA2 patient with pigmentary retinopathy, which had been considered pathognomonic for SCA7. As mentioned earlier, juvenile cases often show pathology in neural tissues quite distinct from those affected by the adult-onset disorders; the retina is neural tissue, but it may simply have a higher threshold for damage from CAG repeats than other brain tissues. As the authors of this report point out, visual impairment is the most common initial symptom in SCA2 patients with more than 59 repeats, whereas ataxia is the presenting symptom in those individuals with pathologic repeats of less than 59.

Patient #3 was diagnosed early on as having Kearns-Sayre syndrome (KSS). The presentation made this a reasonable diagnosis: ptosis, ophthalmoplegia, pigmentary degeneration of the retina, cerebellar ataxia, and short stature. However, the lab results were normal, and an MRI when LW was 11 years old revealed cerebellar atrophy and other findings that the neuroradiologist noted were consistent with a dominant ataxia. The apparent lack of family history of inherited ataxia probably caused the physicians to overlook an SCA diagnosis despite the absence of common KSS symptoms such as comcardiomyopathy, hearing loss, or hypoparathyroidism. It is not possible to tell from the case report whether the parents themselves were short, or whether the child’s stature was unusual for the family (LW was cared for by his aunt because of “psychosocial problems”). It is common, however, for juvenile-onset SCA patients to be small in comparison with healthy children. When the autopsy showed dramatic loss of Purkinje cells and internal granule cells in the cerebellar cortex and anterior horn cells within the spinal cord, along with atrophy of the basis pontis, inferior olive, and cerebellum ( Figure 50.1A through 1C ), postmortem DNA analysis was performed. Molecular testing revealed that LW had juvenile-onset SCA7 with 70 to 87 CAG repeats. Family history can, of course, appear to be negative in cases of alternate paternity, adoption, or the death of an affected parent before symptom onset. It is important to remember, however, that individual members of even large families with multiple affected generations have often received numerous incorrect diagnoses. Thanks to the advent of DNA-based molecular genetic testing, this diagnostic confusion should become a rarer event.

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