Milestones in ataxia

Abstract

The past 25 years have seen enormous progress in the deciphering of the genetic and molecular basis of ataxias resulting in an improved understanding of their pathogenesis. The most significant milestones during this period were the cloning of the genes associated with the common spinocerebellar ataxias (SCAs), ataxia telangiectasia (AT) and Friedreich ataxia (FRDA). To date, the causative mutations of more than 30 SCAs and 20 recessive ataxias have been identified. In addition, there are numerous acquired ataxias with defined molecular causes so that the entire number of distinct ataxia disorders exceeds 50 and possibly approaches 100. Despite this enormous heterogeneity, a few recurrent pathopyhsiological themes stand out. These include protein aggregation, failure of protein homoestasis, perturbations in ion channel function, defects in DNA repair and mitochondrial dysfunction. The clinical phenotypes of the most common ataxia disorders have been firmly established, and their natural history is being studied in ongoing large observational trials. Effective therapies for ataxias are still lacking. However, novel drug targets are under investigation, and it is expected that there will be an increasing number of therapeutic trials in ataxia.

a. Introduction – summary of the state of the field 25 years ago

Ataxia literally means absence of order and denotes a clinical syndrome of incoordination caused by lesions of the cerebellum and its afferent or efferent connections. The term ataxia is also used to designate specific diseases of the nervous system in which progressive ataxia is the prominent clinical manifestation. The practice to use ataxia to designate a disease goes back to the mid of the 19^th century, when Duchenne coined the term locomotor ataxia for tabes dorsalis. In the 20^th century, a neuropathological approach to the ataxias inspired by the seminal work of Holmes and Greenfield, prevailed, and classifications based on neuropathological categories, such as olivopontocerebellar atrophy, cerebellar cortical atrophy, or spinocerebellar degeneration, were in common use.^1,2 However, a consensus on the proper classification of cerebellar degenerations was never reached. The situation changed with the work of Harding in the early eigthies of the 20^th century. Harding clearly recognized the inconsistencies of the neuropathological classifications, in particular that hereditary diseases manifesting in a single family often had to be assigned to different neuropathological categories, whereas on the other hand disorders that were clinically and genetically distinct were put into the same category. Consequently, Harding proposed a new classification that was mainly based on clinical and genetic criteria.³ The new classification was not only widely accepted, but paved the way for a renewed interest of clinical neurologists in ataxias. Intensive clinical research at that time coincided with the advent of novel molecular genetic methods that allowed to successfully link chromosomal loci to ataxia disorders in large multi-generation families, an approach that finally led to the identification of the first ataxia genes in the nineties (table 1).

Table 1.

Classification of ataxias

1 Hereditary ataxias 1.1 Autosomal recessive ataxias 1.1.1 Friedreich ataxia (FRDA) 1.1.2 Ataxia telangiectasia (AT) 1.1.3 Autosomal recessive ataxia with oculomotor apraxia type 1 (AOA1) 1.1.4 Autosomal recessive ataxia with oculomotor apraxia type 2 (AOA2) 1.1.5 Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) 1.1.6 Ataxia with isolated vitamin E deficiency (AVED) 1.1.7 Marinesco-Sjögren syndrome (MSS) 1.1.8 Autosomal recessive ataxias due to POLG mutations (MIRAS, SANDO) 1.1.9 Cerebrotendinous xanthomatosis (CTX) 1.1.10 Refsum disease 1.1.11 Abetalipoproteinemia 1.1.12 Other autosomal recessive ataxias 1.2 Autosomal dominant ataxias 1.2.1 Spinocerebellar ataxias (SCA) 1.2.2 Episodic ataxias (EA) 1.3 X-linked ataxias 1.3.1 Fragile X–associated tremor/ataxia syndrome (FXTAS) 1.3.2 Other X-linked ataxias 1.4 Ataxias due to mitochondrial mutations 2 Non-hereditary degenerative ataxias 2.1 Multiple system atrophy, cerebellar type (MSA-C) 2.2 Sporadic adult-onset ataxia of unknown origin (SAOA) 3 Acquired ataxias 3.1 Alcoholic cerebellar degeneration (ACD) 3.2 Ataxia due to other toxic reasons 3.3 Ataxia due to acquired vitamin deficiency 3.4 Paraneoplastic cerebellar degeneration 3.5 Other immune-mediated ataxias 3.6 Ataxia in chronic CNS infection 3.7 Superficial siderosis

b. Advances in past 25 years

i. Genetic

Among all disciplines, genetics had the strongest impact on the development of the ataxia field in the past 25 years. During this period, linkage of numerous ataxia disorders to chromosomal loci was demonstrated, and in most cases, the mutations causing these disorders were subsequently found. The identification of mutations causing dominantly inherited SCAs started in 1993 with the discovery that an unstable expansion of a translated CAG repeat underlies SCA1.⁴ This finding placed SCA1 in the group of polyglutamine disorders which at that time included spinobulbar muscular atrophy (SBMA) and Huntington’s disease (HD). Subsequently, translated CAG repeat mutation were also found to cause SCA2, MJD/SCA3, SCA6, SCA7, and SCA17. A common feature of all CAG repeat disorders is the inverse relation between age of onset and age at disease onset. In SCA8, SCA10, SCA12 and SCA31, untranslated repeat expansions in non-coding regions of the respective genes were identified. More recently, non-repeat mutations were increasingly found to cause dominantly inherited ataxias. The affected genes include beta-III spectrin (SPTBN2) in SCA5, tau tubulin kinase 2 (TTBK2) in SCA11, a potassium channel in SCA13, protein kinase Cγ, PKCγ in SCA14, nositol 1,4,5-triphosphate receptor type 1 (ITPR1) in SCA15/16, fibroblast growth factor 14 (FGF14) in SCA27, and ATPase family gene 3-like 2 (AFG3L2) in SCA28 (table 2).^5,6

Table 2.

Spinocerebellar ataxias (SCAs): Molecular genetics and clinical phenotype

Disorder	Mutation	Gene product	Clinical phenotype
SCA1	translated CAG repeat expansion	ataxin-1	ataxia, pyramidal signs, neuropathy, dysphagia, restless legs syndrome
SCA2	translated CAG repeat expansion	ataxin-2	ataxia, slow saccades, neuropathy, restless legs syndrome
SCA3/ Machado- Joseph disease (MJD)	translated CAG repeat expansion	ataxin-3	ataxia, pyramidal signs, ophthalmoplegia, neuropathy, dystonia, restless legs syndrome
SCA4	unknown	unknown	ataxia, sensory neuropathy
SCA5	point mutation	beta-III spectrin (SPTBN2)	almost purely cerebellar ataxia
SCA6	translated CAG repeat expansion	calcium channel subunit (CACNA1A)	almost purely cerebellar ataxia
SCA7	translated CAG repeat expansion	ataxin-7	ataxia, ophthalmoplegia, visual loss
SCA8	3′ untranslated CTG repeat expansion	ataxin-8	ataxia, sensory neuropathy, spasticity
SCA10	intronic ATTCT repeat expansion	ataxin-10	ataxia, epilepsy
SCA11	Insertion, deletion	tau tubulin kinase 2 (TTBK2)	almost purely cerebellar ataxia
SCA12	5′ untranslated CAG repeat expansion	phosphatase subunit (PP2A- PR55ß)	ataxia, tremor
SCA13	point mutation	potassium channel (KCNC3)	ataxia, mental retardation
SCA14	point mutation	protein kinase C γ (PKCγ)	ataxia, myoclonus, dystonia, sensory loss
SCA15/16	deletion	inositol 1,4,5- triphosphate receptor, type 1 (ITPR1)	almost purely cerebellar ataxia
SCA17	translated CAG repeat expansion	TATA binding protein (TBP)	ataxia, dystonia, chorea, dementia, psychiatric abnormalities
SCA18	unknown	unknown	ataxia, sensory neuropathy, neurogenic muscle atrophy
SCA19/22	unknown	unknown	ataxia, myoclonus, cognitive impairment
SCA20	unknown	unknown	ataxia, dysphonia
SCA21	unknown	unknown	ataxia, parkinsonism
SCA23	unknown	unknown	ataxia, sensory neuropathy, pyramidal signs
SCA25	unknown	unknown	ataxia, sensory neuropathy
SCA26	unknown	unknown	almost purely cerebellar ataxia
SCA27	point mutation	fibroblast growth factor 14 (FGF14)	ataxia, tremor, mental retardation
SCA28	missense	ATPase family gene 3-like 2 (AFG3L2)	ataxia, opthalmoparesis, pyramidal signs
SCA30	unknown	unknown	almost purely cerebellar ataxia
SCA31	pentanucleotide (TGGAA) repeat insertion	unknown	almost purely cerebellar ataxia

A similar degree of heterogeneity is present in recessive ataxia. In a number of recessive ataxias, such as Refsum’s disease, abetalipoproteinemia, cerebrotendinous xanthomatosis (CTX) and ataxia with vitamin E deficiency (AVED), the biochemical defects were known before the new positional cloning techniques in the nineties allowed a breakthrough in the genetic elucidation of ataxias. The most important discoveries in the genetics of recessive ataxia were the cloning of the ataxia-telangiectasia mutated (ATM) gene in 1995⁷ and the discovery of an intronic GAA repeat mutation causing FRDA in 1996.⁸ Subsequently, more than twenty genes for recessive ataxias were identified, many of them by the use of homozygosity mapping. Among the recessive ataxias, two larger groups of disorder can be delineated, one including FRDA and AVED that is associated with mitochondrial dysfunction and oxidative stress, and another group including ataxia telangiectasia (AT) associated with defective DNA repair mechanisms. In addition, there are numerous disorders that cannot be categorized under these two groups (table 3).⁹

Table 3.

Autosomal recessive ataxias: Molecular genetics and clinical phenotype

Disorder	Gene product	Function
Mitochondrial/Oxidative stress
Friedreich ataxia (FRDA)	frataxin	synthesis of rion sulphur clusters
Mitochondrial recessive ataxia syndrome (MIRAS)	polymerase gamma (POLG)	mitochondrial DNA proofreading
Infantile onset spinocerebellar ataxia (IOSCA)	twinkle	mitochondrial DNA proofreading
Autosomal recessive cerebellar ataxia type 2 (ARCA2, SCAR9)	ADCK3	coenzyme Q10 synthesis
Ataxia with isolated vitamin E deficiency (AVED)	α-tocopherol transport protein	vitamine E
Abetalipoproteinemia	microsomal triglyceride transfer protein	vitamine E
DNA repair
Ataxia telangiectasia (AT)	ATM protein	phosphoinositol-3 kinase activity: cell cycle checkpoint control and DNA repair
Ataxia telangiectasia-like disorder (ATLD)	MRE11	double strand DNA repair
Ataxia with oculomotor apraxia type 1 (AOA1)	aprataxin	single strand DNA repair
Ataxia with oculomotor apraxia type 2 (AOA2, SCAR2)	senataxin	single strand DNA repair
Spinocerebellar ataxia with axonal neuropathy 1 (SCAN1)	tyrosyl-DNA phosphodi-esterase- 1 (TDP1)	DNA replication
Other mechanisms
Refsum disease	phytanoyl-CoA hydroxylase	oxidation of phytanic acid
Cerebrotendinous xanthomatosis (CTX)	sterol-27 hydroxylase	sterol hydroxylation
ARSACS	sacsin	proteasomal system
Marinesco-Sjögren syndrome (MSS)	SIL1	ER glycoprotein
Autosomal recessive cerebellar ataxia type 1 (ARCA1, SCAR8)	SYNE1	Member of spectrin family
Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC)	ABHD12	endocannabinoid metabolism: hydrolysis 2-arachidonoyl glycerol (2-AG)

Fragile X-associated tremor/ataxia syndrome (FXTAS) was established as a novel disorder that occurs in male and less frequently female FMR1 premutation carriers. CGG expansions of the 5′ untranslated region of the FMR1 gene beyond a critical threshold of 200 are the cause of the fragile X syndrome (FXS), the most common inherited form of mental retardation in boys. FXTAS arises from FMR1 premutations with a repeat length ranging from 55 to 200. The clinical spectrum of FXTAS includes progressive cerebellar ataxia with prominent tremor, often accompanied by cognitive decline, parkinsonism, neuropathy, and autonomic failure.¹⁰

ii. Clinical

The new genetic discoveries yielded numerous clinical reports that led to a firm understanding of the genotype-phenotype relationship in the common hereditary ataxias. One of the great surprizes was the finding that Machado-Joseph disease (MJD), a dominantly inherited movement disorder with a variable phenotype that had been first described in families of Azorean origin,¹¹ was genetically identical with SCA3, an autosomal dominantly inherited ataxia with a worlwide distribution.¹²

Clinical research in the ninethies of the 20^th century established that SCA1, SCA2 and SCA3 patients typically present with ataxia in combination with various additional symptoms, whereas SCA6 is an almost purely cerebellar disorder. SCA6 is also different in that it begins between the age of 50 to 60 years, whereas SCA1, SCA2 and SCA3 have an onset between 30 and 40 years.¹³ More detailed clinical work revealed that the phenotypic variability of these disorders could be partly attributed to differences in repeat length of the expanded allele. Thus, in SCA3 large expanded alleles were found in patients with early disease onset and marked pyramidal and extrapyramidal features, whereas those with prominent ataxia and ophthalmoplegia and patients with late disease onset and marked peripheral involvement had smaller expansions.¹⁴ Whereas these “common” SCAs are caused by translated CAG repeat mutations, many of the rarer SCAs that were subsequently found, were caused by untranslated repeat mutations and by conventional non-repeat mutations. In general, these SCAs were found to take a more benign course, in some instances rather resembling developmental than degenerative disorders.

The clinical studies following the discovery of the FRDA mutation demonstrated that the clinical spectrum of FRDA was broader than previously thought. Up to 30% of FRDA patients have a “late” disease onset after the age of 20 years and/or retained tendon reflexes.¹⁵ Following FRDA, ataxia with oculomotor apraxia type 2 (AOA2) is the second most common recessive ataxia. Interestingly, only half of AOA2 patients have oculomotor apraxia, whereas the prevalence of polyneuropathy in AOA2 is almost 100%.¹⁶

One of the greatest breakthroughs in the understanding of the sporadic ataxias was the clinical delineation of multiple system atrophy (MSA) defined as a sporadic, adult-onset disease presenting with either sporadic ataxia or levodopa-unresponsive parkinsonism in combination with severe autonomic failure.¹⁷ In a large case series of sporadic ataxia patients with adult onset, MSA accounted for about 30% of all cases.¹⁸

iii. Pathological

After the delineation of the first ataxia disorder by Friedreich in 1863, the field was dominated by neuropathology for more than a century. In the past 25 years, however, clinicians and geneticists rather than neuropathologists left their marks on ataxia research. Nevertheless, numerous new insights came from neuropathological studies, the most important one being the recognition of intracellular proteinaceous inclusions as pathological hallmarks of a number of ataxia disorders. In brains of patients with the polyglutamine ataxias, SCA1, SCA3, SCA7 and SCA17, neuronal intranuclear inclusions (NIIs) containing the expanded disease protein were observed.¹⁹ On the other hand, NIIs are less frequent or absent in SCA2 and SCA6, disorders which also belong to the group of polyglutamine diseases. While most scientists agree that the large inclusions seen inside neurons in disease brain are not the primary culprit causing neurons to die, they do represent a pathological hallmark reflecting a chronic problem with protein homeostasis.

Following the clinical delineation of MSA as a disease entity, glial cytoplasmic inclusions (GCIs) were discovered in oligodendroglial cells of MSA brains.²⁰ A major component of GCIs is α-synuclein, an observation that placed MSA in the group of synucleipathies together with Parkinson disease and Lewy body dementia.²¹

iv. Epidemiologic

The past 25 years have seen a number of epidemiologcal studies that attempted to determine the prevalence of certain ataxias in defined regions. Nevertheless, a reliable estimation of the prevalence of all ataxias is still not possible. In Europe, FRDA is the most frequent recessive ataxia with a prevalence ranging between 1.7 and 3.7 : 100,000.²², whereas it is almost absent in the East Asian population. A Dutch and a Norwegian survey found a prevalence of dominantly inherited SCAs of 3.0 and 4.2 : 100,000, respectively.^23,24 Studies of sporadic ataxia performed in the Aosta valley (Italy) and in south east Wales (U.K.) reported a prevalence of 6.9 : 100,000 and 8.4 : 100,000.^25,26 In the Japanese population, the prevalence of sporadic ataxias including MSA was determined to be 18.5 : 100,000.²⁷ Epidemiological studies of acquired ataxias are widely lacking.

On the basis of the available figures one can estimate that the overall prevalence of ataxias is at least 15: 100,000 and may rather approach 20 : 100,000. Thus, ataxia appears to be more frequent than generally assumed. Nevertheless, ataxia remains an orphan disease according to current definitions of the National Institutes of Health and European Commission.

v. Therapeutic

Although the genetic defects of many hereditary ataxias were discovered in the past 25 years, this has not yet led to new therapies. Etiological treatment approaches are available only for some rare forms of ataxia with known biochemical defects, such as Refsum’s disease, CTX and AVED. In most other types of hereditary and non-hereditary degenerative ataxia only supportive treatment is possible. Repeated claims that centrally acting drugs, such as 5-hydroxytryptophan, buspirone, physostigmine, thyrotropin-releasing hormone and D-cycloserine have an antiataxic action and temporarily improve cerebellar ataxia, often based on uncontrolled observations in small patients samples, did not stand up to subsequent larger trials.^28,29

c. Where we are now

i. Classification

Following the discovery of the genes and mutations causing hereditary ataxias and elucidation of the molecular causes of many non-hereditary ataxias, a wide consensus with respect to the proper classification of ataxias has been reached. According to current aetiology-based classifications, the ataxias can be subdivided into three major groups: the hereditary ataxias, the non-hereditary degenerative ataxias, and the acquired ataxias which are due to exogeneous or endogeneous non-genetic causes (table 1).^6,9,30

ii. Cohort Studies and Clinical Scales

In clinical research, the focus has shifted from cross-sectional studies that aimed to define the phenotype of a specific ataxia disorder to prospective studies of large cohorts of ataxia patients. Worldwide, consortia have been formed that are conducting large prospective studies.^31,32 An important precondition for these studies was the development of validated clinical assessment methods. The Scale for the Assessment and Rating of Ataxia (SARA) is is based on a semi-quantitative assessment of cerebellar ataxia on an impairment level. SARA underwent a rigorous validation procedure involving four clinical trials in large groups of SCA and non-SCA ataxia patients, and controls. Compared to the previously used International Cooperative Ataxia Rating Scale (ICARS), SARA has favourable biometric properties and is easier to handle.³³

Studies in various neurodegenerative disorders have shown that quality of life is only partly related to disease-related factors that are assessed by clinical instruments, such as SARA or ICARS. Other factors, such as emotional wellbeing, coping strategies, and comorbidity may play a role for health perception. Therefore, patient-based measures are increasingly considered to be important for outcome assessment in interventional trials. There is intense ongoing research aiming to assess quality of life in ataxias and to identify the factors that determine it.³⁴

iii. Understanding molecular pathogenesis

The wide range of genes implicated in degenerative ataxias implies that multiple pathways can induce cerebellar dysfunction and atrophy.⁶ Fortunately, however, certain pathogenic themes keep surfacing. In particular, five recurrent themes stand out: (1) dynamic repeat expansions cause many dominant ataxias, as well as at least one key recessive ataxia and one X-linked ataxia; (2) polyglutamine expansion is a shared mutational mechanism for the most common dominant ataxias; (3) perturbations in ion channel function, either directly through mutations or indirectly through involvement of electrophysiological pathways, underlie some ataxias; (4) defects in DNA repair are the cause of some recessive ataxias, and the nucleus plays a key role in many other ataxias beyond DNA repair; and (5) mitochondrial perturbation due to mutations in mitochondrial or nuclear-encoded genes, or due to specific nutritional deficiencies (vitamin E), is increasingly appreciated as the basis of ataxia.

As outlined above, one group of ataxia disorders is caused by dynamic repeat expansions.³⁵ Some repeat expansion diseases result in expansions in the encoded proteins, while others occur in non-protein coding regions of the gene. Although it is not yet certain how noncoding repeat expansions cause neurodegeneration, the prevailing theory is that at least some of them act through a dominant toxic mechanism occurring at the RNA level, much like myotonic dystrophy.³⁶ Fragile X-associated tremor ataxia syndrome (FXTAS) belongs to this class of diseases. Another noncoding repeat disease is SCA8, which is associated with a large CAG/CTG repeat expansion. The mechanism of pathogenesis in SCA8 is debated, with recent studies suggesting bidirectional expression that could lead both to RNA-mediated and protein-mediated toxicity.

SCA1, SCA2, MJD/SCA3, SCA6, SCA, and SCA17 are caused by polyglutamine-encoding CAG repeat expansions. Most studies, from the test tube to animal models, suggest that the toxic action of polyglutamine expansion occurs primarily at the protein level.^35,37 The idea that abnormal protein aggregation reflects a failure in protein quality control in the brain may apply beyond the ataxias to Parkinson and Alzheimer disease. A failure in protein homeostasis could precipitate numerous deleterious consequences ranging from aberrant gene expression to dysfunction of organelles to defects in axonal transport or synaptic activity.

Many research groups now study the biochemical process of polyglutamine protein aggregation, with increasing focus on the earliest steps in the aggregation pathway because oligomers or misfolded monomers may drive toxicity rather than the larger downstream amyloid fibrils. Efforts are also underway in many labs to harness the quality control machinery in cells (molecular chaperones, ubiquitin-proteasome, lysosome-autophagy pathway) to enhance the clearance of mutant polyglutamine proteins. Drug screens are beginning to identify compounds that reduce steady state levels of the mutant proteins and/or facilitate their degradation; some of these compounds likely act through chaperone pathways while others may facilitate autophagy.

Despite their shared mutations, the various polyglutamine SCAs do not have precisely the same clinical features. The marked clinical differences among these disorders illustrates the importance of disease protein context to pathogenesis. The mutant proteins must affect the brain somewhat differently in each disease. For example, the set of interacting proteins with which a given disease protein interacts is bound to differ: while ataxin-1, ataxin-2 and ataxin-3 may bind some of the same proteins, the differences in their protein interactions will far outweigh their commonalities. This difference may help explain the disease-specific consequences of each disease protein. SCA1 provides a compelling example of this phenomenon. The first identified polyglutamine ataxia, SCA1 remains better understood than other SCAs. When the disease protein, ataxin-1, contains an expansion its ability to form the correct ratios of specific protein complexes inside the nucleus is disrupted, contributing to neurotoxicity.³⁸

Channel dysfunction in ataxia can occur directly or indirectly.³⁹ The two most common forms of dominantly inherited episodic ataxia, EA1 and EA2, are caused by mutations in a voltage-gated potassium channel (KCNA1) and voltage-gated calcium channel (CACNA1A4), respectively. EA-2 is due to mutations in the same gene that is mutated in both SCA6 and familial hemiplegic migraine, demonstrating the phenomenon of allelic heterogeneity, in which different mutations in the same gene can cause distinct clinical syndromes. SCA13 is caused by mutations in the KCNC3 gene, which encodes a voltage-gated potassium channel (Kv3.3) that is highly enriched in cerebellum. Mutations in this gene have a dominant effect on electrophysiological properties of this multi subunit channel. A particularly exciting area of investigation now is the likelihood that channel function is indirectly perturbed in various ataxias caused by mutations with no direct link to ion channels.

Interest is growing in the nucleus as a central site of toxicity in many ataxias, and not simply the well-defined DNA repair ataxias. Several recessive ataxias in cluding AT are due to mutations in genes linked to DNA repair. Their existence suggests that single strand DNA damage, and perhaps even double strand DNA damage, harms the postmitotic neuron over time.⁴⁰ The nucleus is implicated in many other ataxias as well, including the polyglutamine ataxias. While the disease genes in these disorders may not directly affect DNA, they alter the precise, regulated expression of specific genes. Most polyglutamine proteins normally reside in the nucleus or become concentrated in the nucleus during disease, thus the hypothesis that they trigger disease in part by perturbing nuclear gene expression is attractive. Expanded polyglutamine proteins can engage in aberrant protein interactions in the nucleus, including with transcription factor complexes and chromatin proteins. Several polyglutamine disease proteins are even directly involved in transcription: the SCA1 protein ataxin-1 is a transcriptional corepressor, the SCA7 protein ataxin-7 is part of a transcriptional complex and the SCA17 protein is the basal transcription factor, TATA-binding protein (TBP). Because transcriptional dysregulation caused by mutant polyglutamine proteins partly reflects changes in histone acetylation, this suggests a potential route to therapy: histone deacetylase inhibitors that reverse some of the gene repression occurring in disease.

Mutations in the mitochondrial genome certainly cause important forms of ataxia, and mutations in the nuclear gene encoding polymerase gamma (POLG) are now recognized to be an important cause of progressive ataxia due to mitochondrial dysfunction. Perhaps the most important mitochondrial disease, however, is FRDA. The nuclear encoded disease protein, frataxin acts inside the mitochondria, and the consensus is that the causative mutation impairs mitochondrial function.⁴¹ GAA repeat expansions lead to trasncriptional silencing resulting in reduced levels of the frataxin mRNA and protein. Frataxin deficiency causes accumulation of iron within mitochondria and signs of oxidative stress. The protein is critically important for the biosynthesis of iron-sulfur cluster enzymes in mitochondria, leading to the compelling hypothesis that disease pathogenesis reflects oxidative stress from impaired mitochondrial energetics.

FRDA is probably the leading success story in the burgeoning ataxia field: in little over a decade, scientists have proceeded from discovering the mutation to understanding the basic problem to testing rational therapies in humans. The coenzyme Q10 analogue, idebenone, has already been tested in a phase III trial.⁴² This success notwithstanding, it is still uncertain how reduced levels of this key mitochondrial protein cause selective neurodegeneration of certain regions of the nervous system.

d. Future directions

The greatest challenge for ataxia research is the development of effective therapies. So far, only idebenone in FRDA made its way to a phase III trial which then unfortunately failed.⁴² In the future, it will be of vital importance for academic research and pharmaceutical industry to join forces in order to establish an effective research pipeline including development of standardized criteria for the rigorous evaluation of molecular targets, of pathogenic mechanisms, and of therapeutic approaches which will finally result in successful clinical trials. The possible therapeutic strategies are diverse and range from conventional pharmaceutical approaches to gene therapy.

Silencing of disease genes using RNA interference (RNAi) is a novel experimental therapeutic approach which appears to specifically suitable for polyglutamine SCAs. The therapeutic value of this approach in SCAs has already been shown in transgenic disease models.⁴³ However, numerous problems related to safety, delivery and dosage remain to be solved before RNAi will become a viable alternative to conventional pharmacological approaches. In FRDA, boosting levels of the deficient protein, frataxin, is a promising strategy. This may be achieved by enhancing transcription using histone deacetylases inhibitors.⁴⁴

A promising strategy for the development of therapies is the selection of an appropriate drug target based on an understanding of the molecular mechanisms leading to ataxia or a specific ataxia disorder. This approach is greatly facilitated by knowledge of the gene mutations causing the common hereditary ataxia disorders and the availability of transgenic animal models. Examples of drug candidates that emerged from this approach are lithium,⁴⁵ the rapamycin ester temsirolimus,⁴⁶ and dantrolene⁴⁷ for SCAs as weel as antioxidants for FRDA. Given the central role of protein aggregation in pathogenesis, the search for anti-aggregation compounds may yield a compound that acts on all polyglutamine diseases.

An alternative approach are treatments that aim to to normalize disturbed neuronal activity in the cerebellum and thereby exert a “symptomatic” antiataxic effect. Such a treatment approach has the advantage that it is not limited to one particular ataxia disorder, but may be beneficial in a larger group of ataxias that share common effector mechanisms such as Purkinje neuron dysfunction. In the current scientific discussion on treatment strategies in neurodegenerative diseases, these “symptomatic” approaches play an increasingly important role because it is recognized that the early phases of neurodegeneration are characterized by neuronal dysfunction, while impaired neuronal cell metabolism and cell death are events that occur later in the disease course. It is also conceivable that early interference with neuronal dysfunction may not only temporarily improve symptoms, but also have a disease modifying effect. One possible approach is interference with small-conductance calcium-activated potassium (SK) channels which play a critical role in the regulation of neuronal activity in the cerebellar cortex and deep cerebellar nuclei.³⁹ In the future, detailed functional analysis of cerebellar circuits in transgenic models of ataxia will therefore play an increasingly important role to identify novel drug targets.

Genetic research of the past 25 years has identified an impressingly large number of ataxia genes. Nevertheless, a significant proportion of ataxia patients still cannot be assigned to a proper diagnosis.^18,48 For the early onset ataxias, most of which are autosomal recessively inherited, it is expected, that novel genes will be found with refined mapping and sequencing technology. However, most of these new genes will be responsible for only a very small number of families. New dominant genes will similarly account for only a limited number of families. For clinical practice, it will be more important to offer comprehensive genetic testing in a cost-effective way. A promising strategy towards this aim is the use of microarray technology. The situation is different in sporadic ataxia with adult disease onset, where monogenic mutations probably account only for few cases. In these patients, the search for novel acquired causes has to be continued. On the other hand, it is conceivable that these disorders nevertheless have a genetic background that can be elucidated by genome-wide association studies. This underlines the need to recruit, characterise and follow large patient cohorts.