Clinical characteristics.

Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death. Anticipation in this nucleotide repeat disorder may be so dramatic that within a family a child with infantile or early-childhood onset may be diagnosed with what is thought to be an unrelated neurodegenerative disorder years before a parent or grandparent with a CAG repeat expansion becomes symptomatic. In adolescent-onset SCA7, the initial manifestation is typically impaired vision, followed by cerebellar ataxia. In those with adult onset, progressive cerebellar ataxia usually precedes the onset of visual manifestations. While the rate of progression varies in these two age groups, the eventual result for almost all affected individuals is loss of vision, severe dysarthria and dysphagia, and a bedridden state with loss of motor control.

Diagnosis/testing.

The diagnosis of SCA7 is established in a proband by the identification of a heterozygous abnormal CAG trinucleotide repeat expansion in ATXN7 by molecular genetic testing.

Management.

Treatment of manifestations: Multidisciplinary care involves supportive treatment of: neurologic manifestations – physical and occupational therapy to help maintain mobility and function, and pharmacologic treatment to reduce symptoms; dysarthria – speech and language therapy and alternative communication methods; dysphagia – feeding therapy to improve nutrition and reduce the risk of aspiration; and reduced vision – use of low vision aids and consultation with agencies for the visually impaired.

Surveillance: Routine follow up with multidisciplinary care providers.

Agents/circumstances to avoid: Avoid: alcohol intake (especially if excessive) as it can further impair cerebellar function; foods identified by a registered dietitian as possible causes of dizziness or disorientation.

Therapies under investigation: Several ongoing clinical trials for medications used as treatment for ataxia.

Genetic counseling.

SCA7 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting an abnormal CAG repeat expansion in ATXN7. Once an ATXN7 CAG repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for SCA7 are possible.

Suggestive Findings

Spinocerebellar ataxia type 7 (SCA7) should be suspected in individuals with the following clinical findings (by age) and family history.

Establishing the Diagnosis

The diagnosis of SCA7 is established in a proband by the identification of a heterozygous abnormal CAG trinucleotide repeat expansion in ATXN7 by molecular genetic testing (see Table 1).

Note: Pathogenic (CAG)_n repeat expansions in ATXN7 cannot be detected by sequence-based multigene panels, exome sequencing, or genome sequencing.

Repeat sizes

• Normal. 7-27 CAG repeats
• Mutable normal. 28-33 CAG repeats [Lebre et al 2003]. Repeats in this range are meiotically unstable, but not associated with an abnormal phenotype. A mutable normal repeat may expand to the pathogenic range in one generation [Mittal et al 2005].
• Pathogenic. The distinction between reduced-penetrance CAG repeat size and full-penetrance CAG repeat size is likely to remain unclear until more families are reported; nonetheless, regardless of the "descriptor" used for these CAG repeats, they should be considered unstable and pathogenic:
  • Pathogenic reduced penetrance. 34-36 CAG repeats. When manifestations occur, they are more likely to be later onset and milder than average. (See case reports in Genotype-Phenotype Correlations.)
  • Pathogenic full penetrance. 37-460 CAG repeats [Nardacchione et al 1999, van de Warrenburg et al 2001, Michalik et al 2004].

Molecular genetic testing relies on targeted analysis to characterize the number of ATXN7 CAG repeats (see Table 8).

Clinical Description

Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy with progressive central visual loss to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death [Giunti et al 1999].

One important aspect of SCA7 clinical manifestations is their extreme variability with respect to age of onset and rate of progression. Affected individuals may present in infancy, childhood, adolescence, young adulthood, middle age, or old age.

When onset is at or before adolescence, initial manifestations are typically impaired vision, ultimately progressing to blindness from retinal degeneration. Individuals with manifestations in their teens may be blind within a decade or less.

In adults, the progressive cerebellar ataxia (i.e., dysmetria, dysdiadochokinesia, and poor coordination) usually precedes the onset of visual manifestations. The age of onset inversely correlates with rate of progression and extent of symptomatology, as onset in or after the fifth decade of life gives a predominant cerebellar ataxia without progression to significant visual impairment, whereas onset prior to middle age often features progression to vision loss.

Progression to severe disability resulting in death varies based on age of onset, ranging from months in infants to fewer than ten years in older children to two to three decades in adolescents and adults. While the rate of progression varies, the eventual result for almost all affected individuals is severe dysarthria, dysphagia, and a bedridden state with loss of motor control.

To date, more than 1,000 individuals with SCA7 have been identified worldwide. Frequency of select features in adolescent- or adult-onset disease are summarized in Table 2.

Adolescent- or Adult-Onset SCA7

Table 2.

Select Features of Adolescent- or Adult-Onset SCA7

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Feature	% of Persons w/Feature	Comment
Cerebellar ataxia	100%	Unsteady gait; finger-to-nose dysmetria
Dysarthria	100%	Garbled or slurred speech
Dysphagia	40%	Difficulty swallowing
Oculomotor abnormalities	80%	Slowed ocular saccades Ophthalmoplegia
Motor neuron degeneration	100%	Upper motor neuron involvement (hyperreflexia, spasticity); may resemble hereditary spastic paraplegia. Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
Sensory loss	40%	↓ sensation to light touch, pinprick, &/or joint position
Restless leg syndrome	35%	Discomfort in legs resulting in uncontrollable urge to move one’s legs, typically worse in evening or nighttime
Cognitive decline	20%	Impaired executive function
Behavior disorder/ Psychosis	10%	Altered mentation Impaired reality testing
Cone-rod dystrophy	70%	Loss of central vision & color vision Abnormal fundoscopic exam

Neurologic findings. In adult-onset disease (age >30 years), cerebellar ataxia (manifesting as difficulty with walking, manual dexterity, and speech) is the most common clinical feature and is often the first reported manifestation (see Genotype-Phenotype Correlations). Affected individuals often then develop more extensive neurologic deficits, dysarthria, dysphagia, hypoacusis (hearing loss), and eye movement abnormalities (slow ocular saccades, staring). Slowing of ocular saccades may progress to frank ophthalmoplegia.

Involvement of the corticospinal tracts, resulting in brisk tendon reflexes and spasticity, may become evident as the disease progresses.

Cognitive decline and psychosis have been reported [Benton et al 1998]. Neuropsychiatric testing of some individuals has revealed selective deficits in social cognition [Sokolovsky et al 2010].

Retinal degeneration. The retinal degeneration is a progressive cone-rod dystrophy that may result in total blindness [To et al 1993, Aleman et al 2002, Ahn et al 2005, Hugosson et al 2009].

In adolescent- or young adult-onset disease (age <30 years), profound visual loss can be accompanied by minimal ophthalmoscopic findings and minimal ataxia [Thurtell et al 2009] (see Genotype-Phenotype Correlations). The onset of cone-rod dystrophy is often characterized by hemeralopia (inability to see clearly in bright light), photophobia (extreme sensitivity to light), decreased central visual acuity, and abnormalities in the tritan (blue-yellow) axis on detailed color vision testing [Miller et al 2009]. As cone function decreases over time, central visual acuity decreases to 20/200 (legally blind) and central scotomas develop; more prominent macular changes appear (see Figure 1), and all color discrimination is lost. Eventually all vision is lost.

Figure 1.

Funduscopic photo shows extreme macular degeneration of late-stage SCA7.

Early signs of cone-rod dystrophy are subtle granular changes in the macula. Electroretinogram is consistently abnormal early in the disease course, showing a decrease in the photopic (cone) response initially, followed by a decrease in the scotopic (rod) response [Miller et al 2009].

In classic adult-onset disease (age >40 years), vision loss from retinal degeneration typically follows the onset of ataxia (sometimes many years to decades later) and gradually declines, seldom progressing to total blindness [Miller et al 2009].

Genotype-Phenotype Correlations

A correlation between CAG repeat sizes and disease severity exists: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease.

• Infantile onset may be associated with CAG repeat sizes ranging from 200 to 400; however, technical limitations of genetic testing utilizing PCR amplification of the ATXN7CAG repeat region that often underestimate the repeat expansion size may report a CAG repeat size of fewer than 150.
• Childhood onset is usually associated with CAG repeat sizes greater than 100.
• Juvenile onset is often associated with CAG repeat sizes 60-100.

A correlation between CAG repeat size and initial clinical manifestation exists [Johansson et al 1998]:

• CAG repeat sizes greater than 59 are typically associated with adolescent or young-adult onset (age <30 years) and visual impairment as the initial manifestation.
• CAG repeat sizes smaller than 59 are often associated with adult onset (age >30 years) and cerebellar findings as the initial manifestation.

Despite observations correlating CAG repeat length with age of onset, disease severity, and course, CAG repeat size cannot provide sufficient predictive value for clinical prognosis within the classic adult-onset CAG repeat size range of 38 to 50 repeats [Andrew et al 1997].

Reports of pathogenic (age-related reduced-penetrance) repeats include the following:

• A woman with 34 CAG repeats had "very mild symptoms" at age 65 years [Nardacchione et al 1999].
• An individual with 35 CAG repeats was symptomatic [Koob et al 1998], in contrast to asymptomatic adults with 35 CAG repeats described by David et al [1998] and Stevanin et al [1998].
• An individual with 36 CAG repeats developed relatively mild symptoms at age 63 years [Nardacchione et al 1999].

Penetrance

See Genotype-Phenotype Correlations for CAG repeat sizes associated with age-related reduced penetrance.

Anticipation

In families with a pathogenic (full-penetrance) CAG repeat expansion, the repeat size tends to expand with transmission to successive generations, with more marked expansions seen in affected offspring of affected males [Gouw et al 1998]. This explains, at the genetic level, the marked anticipation seen in families with SCA7, now regarded as the most unstable of all CAG repeat disorders.

Anticipation in a family may be so dramatic that a child may be diagnosed with what is thought to be an unrelated neurodegenerative disease years before a parent or grandparent with pathogenic CAG repeat expansion becomes symptomatic [van de Warrenburg et al 2001, Ansorge et al 2004].

Repeat contraction has not been reported.

Nomenclature

Terms used in the past to designate SCA7 include olivopontocerebellar ataxia (OPCA) type III and ADCA type II.

Prevalence

The prevalence is fewer than 1:300,000. In several studies, SCA7 represented 2% of all SCAs [Filla et al 2000, Storey et al 2000].

SCA7 occurs predominantly in two racial population groups: northern Europeans and Africans. Indeed, SCA7 is the only repeat expansion disease, with the exception of Huntington disease-like 2 (HDL2), with a large number of affected individuals of African racial ancestry. For this reason, a substantial fraction of individuals with SCA7 in the United States are of African racial ancestry. Worldwide, SCA7 is seen in North America, Europe, Eurasia, Australia, South Africa, and South America.

Due to a founder effect in Mexico dating back to the colonial era, a very large concentration of individuals with SCA7 have been ascertained in the state of Veracruz in Mexico, with well over 150 documented affected individuals.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 7 (SCA7) of adolescent or adult onset, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management of affected individuals remains supportive, as no known therapy to delay or halt the progression of the disease exists.