Spinocerebellar Ataxia Type 3

Clinical characteristics.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is characterized by progressive cerebellar ataxia and variable findings including pyramidal signs, a dystonic-rigid extrapyramidal syndrome, significant peripheral amyotrophy and generalized areflexia, progressive external ophthalmoplegia, action-induced facial and lingual fasciculations, and bulging eyes. Neurologic findings tend to evolve as the disorder progresses.

Diagnosis/testing.

The diagnosis of SCA3 is established in a proband with suggestive findings and a heterozygous abnormal CAG trinucleotide repeat expansion in ATXN3 identified by molecular genetic testing.

Management.

Treatment of manifestations: Management is supportive as no medication slows the course of disease. The goals of treatment are to maximize function and reduce complications. It is recommended that each individual be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech therapists, social workers, and psychologists. Various manifestations may respond to pharmacologic agents. Regular physical activity is recommended, including combined physical and occupational therapy focused on gait and coordination. Canes and walkers help prevent falling; motorized scooters, weighted eating utensils, and dressing hooks help to maintain independence. Speech therapy and communication devices may benefit those with dysarthria, and dietary modification those with dysphagia. Other recommendations include home adaptations to prevent falls and improve mobility, dietary supplements if caloric intake is reduced, weight control to facilitate ambulation and mobility, and caution with general anesthesia.

Surveillance: Annual assessments (or more frequently as needed) of neurologic findings (e.g., dysarthria, dysphagia, bladder dysfunction, neuropathic pain, cognitive and psychiatric manifestations), weight and nutritional status, and social support.

Genetic counseling.

SCA3 is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the ATXN3 CAG repeat expansion.

Once the CAG repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Note: The prenatal finding of an ATXN3 CAG repeat expansion cannot be used to accurately predict onset, severity, type of symptoms, or rate of progression of SCA3.

Suggestive Findings

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), should be suspected in individuals with the following clinical findings and family history [Lima & Coutinho 1980, D'Abreu et al 2010].

Clinical findings. Progressive cerebellar ataxia often and variably associated with:

• Pyramidal signs
• A dystonic-rigid extrapyramidal syndrome
• Significant peripheral amyotrophy and generalized areflexia
• Progressive external ophthalmoplegia
• Action-induced facial and lingual fasciculations; bulging eyes

Family history. Consistent with autosomal dominant inheritance (i.e., multiple affected family members in successive generations or a single occurrence in a family). Absence of a family history of SCA3 does not preclude this diagnosis.

Establishing the Diagnosis

The diagnosis of SCA3 is established in a proband with suggestive findings and a heterozygous abnormal CAG trinucleotide repeat expansion in ATXN3 identified by molecular genetic testing (see Table 1).

Note: Pathogenic (CAG)_n repeat expansions in ATXN3 cannot be detected by sequence-based multigene panels, exome sequencing, or genome sequencing.

Repeat sizes [Costa Mdo & Paulson 2012 and references therein]:

• Normal. 12 to 44 CAG repeats. Overall, 93.5% of normal alleles have fewer than 31 CAG repeats.
• Intermediate. CAG repeat size ranges between clearly normal and full penetrance. The smallest unstable repeat size is 45 CAG repeats [Padiath et al 2005]. Some intermediate alleles are not associated with classic clinical features of SCA3 [Costa Mdo & Paulson 2012 and references therein].
• Pathogenic (full penetrance). ~60 to 87 [Kawaguchi et al 1994, Costa Mdo & Paulson 2012 and references therein]. The smallest full-penetrance allele is not well defined.

Molecular genetic testing relies on targeted analysis to characterize the number of ATXN3 CAG repeats (see Table 7).

Clinical Description

Spinocerebellar ataxia type 3 (SCA3) is characterized by progressive cerebellar ataxia and variable findings including pyramidal signs, a dystonic-rigid extrapyramidal syndrome, significant peripheral amyotrophy and generalized areflexia, progressive external ophthalmoplegia, action-induced facial and lingual fasciculations, and bulging eyes. Neurologic findings tend to evolve as the disorder progresses.

Age of onset of SCA3 is highly variable but most commonly in the second to fifth decade. In a large cohort of affected individuals from the Azores, the mean onset was age 37 years. The range of age of onset largely reflects differences in CAG repeat size (see Genotype-Phenotype Correlations) and the specific clinical features can vary greatly, depending largely on CAG repeat length and age of onset [Cancel et al 1995, Maciel et al 1995, Matilla et al 1995, Dürr et al 1996, Matsumura et al 1996, Schöls et al 1996, Vale et al 2010].

Presenting features include gait problems, speech difficulties, clumsiness, and vestibular and oculomotor findings (for review see Mendonça et al [2018], Klockgether et al [2019], and references therein; see also Yoshizawa et al [2004], Rana et al [2016], Wolf et al [2017], and Wu et al [2017]).

Progressive ataxia, nystagmus, diplopia, dysarthria, and hyperreflexia may occur early in the disease. An early sign can be a feeling of unsteadiness on head turning, indicating vestibular dysfunction. Subtle balance issues usually predate hand incoordination.

Upper motor neuron signs often become prominent, and in some families may resemble hereditary spastic paraplegia [Gan et al 2009, Wang et al 2009, Lin et al 2018].

Earlier-onset disease (before age ~25 years) often manifests dystonia [Nunes et al 2015], whereas later-onset disease (after age ~50 years) often manifests peripheral neuropathy and amyotrophy.

SCA3 should also be considered in cases of familial Parkinsonism, especially in individuals with African ancestry [Subramony et al 2002, Lu et al 2004].

Other findings may include the following:

• Autonomic problems, including bladder and thermoregulation disturbances; both cardiovascular and sudomotor dysfunction may be present [Yeh et al 2005, França et al 2010, Takazaki et al 2013].
• Disabling sleep disturbances [Pedroso et al 2016], including rapid eye movement sleep behavior disorder [Friedman 2002, Friedman et al 2003] and restless legs syndrome [Schöls et al 1998, van Alfen et al 2001, D'Abreu et al 2009, Pedroso et al 2011].
• Fatigue that is often associated with depression and daytime somnolence [Martinez et al 2017]. Given the frequency of sleep disturbance in SCA3, evaluation for disruptive sleep disturbance such as obstructive sleep apnea as the cause of fatigue is recommended.
• Impaired executive and emotional functioning, referred to as cerebellar cognitive affective syndrome [Braga-Neto et al 2012, Roeske et al 2013, Tamura et al 2018], as well as depression [Lo et al 2016], that are unrelated to ataxia severity. However, such individuals do not develop dementia [Zawacki et al 2002]. Verbal fluency and visual memory deficits have also been noted [Kawai et al 2004].
• Chronic pain, often in the lumbosacral region [França et al 2007]. The basis for pain can range from dystonia to peripheral neuropathy. Cramps associated with neuropathy can be bothersome.
• Vocal cord paralysis, though uncommon, has been described [Isozaki et al 2002] but is not viewed as a distinctive disease feature.

Disease progression

• Ambulation becomes increasingly difficult, leading to the need for assistive devices (including wheelchair) ten to 15 years following onset.
• Profound ataxia of limbs and gait becomes prominent. Individuals with later adult onset and shorter CAG repeats can manifest a disorder that combines ataxia, generalized areflexia, peripheral neuropathy, and muscle wasting.
• Saccadic eye movements become slow and ophthalmoparesis develops, resulting initially in up-gaze restriction. Dysconjugate eye movements result in diplopia.
• At the same time, a number of other "brain stem" signs develop, including temporal and facial atrophy, characteristic action-induced perioral twitches, vestibular symptoms, tongue atrophy and fasciculations, dysphagia, and poor ability to cough and clear secretions.
• Often a staring appearance to the eyes is observed, but neither this nor the perioral fasciculations are specific for SCA3.
• Evidence of a peripheral polyneuropathy [França et al 2009] may appear later, with loss of distal sensation, ankle reflexes, and sometimes other reflexes as well, and with some degree of muscle wasting.
• Parkinsonism that can respond to dopaminergic agents (e.g., levodopa) occurs in a subset of patients.
• Sitting posture is compromised later in disease, with affected individuals assuming various tilted positions.
• Autonomic dysfunction can sometimes be disabling, but is not always related to severity of motor dysfunction or disease duration.

Late in the disease course, individuals are usually wheelchair bound and have severe dysarthria, dysphagia, facial and temporal atrophy, poor cough, often dystonic posturing and ophthalmoparesis, and occasionally blepharospasm.

Life span. The disease progresses relentlessly; death from pulmonary complications and cachexia occurs from six to 29 years after onset [Sudarsky et al 1992, Sequeiros & Coutinho 1993]. In a study from Brazil, the mean age of onset was 36 years with a 21-year mean survival after onset [Kieling et al 2007].

Subtypes of SCA3. Clinical features can vary greatly, due largely to varying CAG repeat size. Based on this phenotypic variability, Portuguese researchers classified SCA3 into several subtypes in addition to ataxia, including a dystonic-rigid syndrome, a parkinsonian syndrome, and a neuronal amyotrophy syndrome with muscle wasting and peripheral neuropathy [Riess et al 2008]. However, striving to place affected individuals into a specific SCA3 subtype has little clinical value because of the considerable overlap across subtypes, and because one type can evolve into another during the course of disease [Fowler 1984].

Brain MRI most often reveals pontocerebellar atrophy [Bürk et al 1996]. The most commonly observed abnormality is enlargement of the fourth ventricle [Onodera et al 1998], which reflects atrophy of the cerebellum and brain stem. The degree of brain atrophy detectable by MRI varies greatly, consistent with the wide clinical variability observed. In a large European natural history study, clinical dysfunction in SCA3 correlated with the degree of total brain stem atrophy [Schulz et al 2010].

Brain magnetic resonance spectroscopy (MRS) can detect early neurochemical abnormalities in brain regions of SCA3 and similar SCAs [Joers et al 2018]. Efforts are underway to determine whether MRS in select brain regions can be used in clinical trials as an early biomarker of disease state or progression [Ashizawa et al 2018].

Nerve conduction velocity studies often reveal involvement of sensory nerves as well as motor neurons [Lin & Soong 2002, França et al 2009].

Neuropathologic studies have established that degeneration is widespread and not confined to the cerebellum, brain stem, and basal ganglia [Rüb et al 2008]. In general, however, the cerebral cortex is largely spared despite evidence of cognitive dysfunction. While the cerebellum typically shows atrophy (particularly of the deep cerebellar nuclei) in some individuals, Purkinje cells and inferior olivary neurons are relatively spared [Sequeiros & Coutinho 1993].

Genotype-Phenotype Correlations

Age of onset inversely correlates with the size of the CAG repeat expansion. Some individuals with the largest reported expansions (86 and 83 repeats) had disease onset at age five years and 11 years, respectively [Zhou et al 1997]. Despite such observations, there is evidence that other nonspecified genetic or non-genetic factors also contribute [van de Warrenburg et al 2005, Globas et al 2008].

Phenotype. A loose correlation exists between the size of the CAG repeat expansion and the clinical phenotype [Cancel et al 1995, Maciel et al 1995, Matilla et al 1995, Sasaki et al 1995, Dürr et al 1996, Lerer et al 1996, Matsumura et al 1996, Schöls et al 1996, Vale et al 2010].

In general, the longest disease-causing CAG repeats cause earlier-onset disease that is more likely to have dystonia as part of the presentation.

In contrast, the shortest disease-causing CAG repeats cause later-onset disease that is more likely to have peripheral manifestations such as neuropathy and weakness. Parkinsonism, which occurs in a subset of affected persons, is not associated with any particular CAG repeat size. Rare intermediate alleles of 45 to about 60 CAG repeats may show variable expressivity; in particular, these rare intermediate alleles can manifest with isolated restless legs syndrome with no other features of disease.

Intrafamilial variation in severity has been reported [Lerer et al 1996, Carvalho et al 2008]. Variation in severity is largely attributed to differences in CAG repeat size.

Homozygosity for the CAG repeat has been associated with more severe disease in a few families [Lerer et al 1996, Carvalho et al 2008]. However, many homozygotes in a Yemeni family were no more severely affected than heterozygotes in other families.

Penetrance

In SCA3, penetrance approaches 100% and is age related.

CAG repeat sizes associated with reduced penetrance of SCA3 are not firmly defined. Of note, an asymptomatic individual age 66 years with 68 CAGs has been reported [van Alfen et al 2001].

Anticipation

Instability of the CAG repeat expansion has been documented in transmission of the repeat from parent to child. Overall, expansion of the repeat is more common than contraction; thus, anticipation (earlier age of onset and more severe disease manifestations in offspring) occurs in SCA3.

Although the probability of CAG repeat expansion may be greater with paternal than with maternal transmission, the paternal bias is not pronounced (as, for example, in Huntington disease) [Souza et al 2016].

Nomenclature

SCA3 is also known as Machado-Joseph disease (MJD) and Azorean ataxia. In fact, this autosomal dominant form of ataxia, which was first described among immigrants from the Portuguese Azorean islands, was initially known as MJD. In the early 1990s the locus for MJD was identified on chromosome 14 and revealed to be a CAG repeat expansion in MJD1 (now renamed ATXN3). During this same time, scientists mapped what was initially thought to be an unrelated ataxia, SCA3, to the same chromosomal region. Once the ATXN3 CAG repeat expansion underlying MJD was discovered, it soon became clear that SCA3 and MJD were caused by CAG repeat expansions in the same gene.

Prevalence

No accurate data are available regarding the prevalence of SCA3 in the general population, though in many populations SCA3 is the most common of the autosomal dominant ataxias, which overall are rare.

Worldwide, SCA3 is thought to be the most common spinocerebellar ataxia (SCA), comprising 20%-50% of families (reviewed in Klockgether et al [2019]).

Countries in which SCA3 is the most common SCA include Portugal (58%-74%), Brazil (69%-92%), China (48%-49%), the Netherlands (44%), Germany (42%), and Japan (28%-63%).

In contrast, countries in which SCA3 is quite rare include Italy (1%) and South Africa (4%) [Klockgether et al 2019 and references therein].

In the US and Canada, SCA3 is one of several SCAs comprising the most common autosomal dominant ataxias, with SCA3 accounting for 21%-25% of families [Klockgether et al 2019 and references therein].

Origin of the CAG repeat expansion. Haplotype analyses suggest that the CAG repeat expansion arose independently from at least two distinct events, the first occurring in Asia and the second in the Portuguese population [Gaspar et al 1996, Martins et al 2007, Klockgether et al 2019 and references therein]. Most disease worldwide likely resulted from Portuguese emigration.

A large international genetic study showed that a single intragenic haplotype is shared by a majority of the families studied (including those from the Azorean island of Flores), suggesting a single founder variant. However, at least two other haplotypes have been identified in the Portuguese population [Gaspar et al 2001, Verbeek et al 2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 3 (SCA3), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.