Spinocerebellar Ataxia type 6 (SCA-6)

Timothy C. Hain, MD • Page last modified: October 20, 2019

Rebound nystagmus in SCA-6Supplemental material: Video of rebound nystagmus in SCA-6, (courtesy of Dr. Dario Yacovino).

SCA6 is an autosomal dominant ataxia associated with small expansions of a trinucleotide repeat (CAG) in the gene CACNL1A4, which encodes a voltage-gated calcium channel (Zoghbi, 1997). Another part of this gene also interacts with the cerebellum. SCA6 is one of 4 SCA's (1,2,3,6,7) that make up about 60% of the autosomal dominant ataxias worldwide (Cagnoli et al, 2018).

There are some general problems involved with all of the SCAs. They are rare, so few people have seen a lot of them. There are so many of them that they are hard to remember let alone diagnose. The genetic testing for these disorders is expensive, and sometimes people would rather just not know. So far, treatment is almost non-existent.

Clinical features of SCA-6

Patients with SCA6 can have at least three different syndromes: episodic ataxia, cerebellar ataxia plus brainstem or long tract degeneration, or pure cerebellar ataxia. Calcium channels are identified in Purkinje and granule neurons. Clinically they have a coarse gaze-evoked nystagmus, downbeat nystagmus on lateral gaze (Uueno et al, 2017), and poor visual suppression (Gomez et al, 1997). The movie above shows a variant of their gaze-evoked nystagmus (rebound nystagmus).

Nearly any neurological symptom you can imagine has been reported in SCA-6. SCA-6 is often noted as doing relatively better than the other common dominant ataxia syndromes.

Cerebellar findings (of course).

In patients with sporadic ataxia (i.e. no family history), SCA-6 is the most common gene abnormality found in Japan (Sakakibara et al, 2017).

SCA6 accounts for about 30% of dominant ataxias in Japan, and between 5-15% of dominantly inherited ataxia in the United States (Geshwind et al, 1997; Mosely et al, 1998). Imaging studies reveal cerebellar atrophy with relative sparing of the brainstem. In Japan, ataxia is the most common initial symptom.

Postural tremor is sometimes present (i.e. not all postural tremors are essential). According to Gan et al, "Among 315 SCA patients, postural tremor was most common in SCA2 patients (SCA1, 5.8%; SCA2, 27.5%; SCA3, 12.4%; SCA6, 16.9%; p = 0.007). .. Interestingly, SCA1 and SCA6 patients with postural tremor had a slower rate of ataxia progression (SCA1, beta = -0.91, p < 0.001; SCA6, beta = -1.28, p = 0.025."

Movement disorders:

Patients with prolonged courses exhibit dystonic postures, involuntary movements and abnormalities in tendon reflexes (Ikeuchi et al, 1997). According to Kuo et al (2017), dystonia was found less frequently than in SCA3. They comment "Although relatively rare in SCA6, the presence of dystonia was associated with slower progression of ataxia."

Swallowing disorders:

Dysphagia can occur in SCA6 (Isono et al, 2017), but generally it is milder than in SCA3.

Visual disorders -- eye movements.

Takeichi et al (2000) reported that while ocular smooth pursuit is diminished, vestibular cancellation is normal. This may be a distinctive finding of SCA-6. We think this needs confirmation.

Vestibular disorders

As mentioned above, patients with calcium channelopathies including SCA-6 and EA2 have deficient ocular responses to otolith input. We think this needs confirmation, for example, with oVEMP testing.

While Luis et al, (2016) reported that VHITtesting differentiated SCA1-3 and Friedreich, this has not been studied in SCA6. We would be dubious tht SCA-6 affects VHIT testing.

Cognitive disorders in SCA-6

Patients with SCA-6 are reported to have mild cognitive dysfunction (Rentyia et al, 2018; Tamura et al, 2017). Moriarty et al (2016), stated that SCA-6 patients had the slowest decline compared to SCA1,2,3, and 7. -- "Results suggest possible differences in cognitive decline in SCA subtypes, with the most rapid cognitive decline observed in the SCA1 patients, and the least in the SCA6 patients, congruent with observed patterns of motor deterioration. " Only a small number of patients were studied and these results are certainly not definitive. We would think that having a degenerative disorder of the nervous system might be depressing as well as limit many activities (such as reading for example).

Sleep disorders

Rueda et al (2016) found that 12 SCA 6 patients had more snoring than controls.

Neuropathy.

Linneman et al (2016) studied neuropathy in several SCAs, and stated that "SCA6 patients revealed less axonal damage than patients with other subtypes."

Survival in SCA-6.

According to Diallo et al (2018), " The 10-year survival rate was ... 87% (80-94) for SCA6.

Molecular biology of SCA-6

SCA6 is an autosomal dominant ataxia associated with small expansions of a trinucleotide repeat (CAG) in the gene CACNL1A4, which encodes a voltage-gated calcium channel (Zoghbi, 1997). Another part of this gene also interacts with the cerebellum. There is a mild gene dose effect (Soga et al, 2017).

It is not always obvious that someone has SCA-6

The gold standard diagnosis of SCA-6 is based on genetic testing. (Cagnoli et al, 2018)

We encountered one patient with SCA-6, who was simply dizzy and unsteady, and lacked all signs of central involvement. This example shows that clinical exam may not be sufficient to detect relatively silent clinical diseases like SCA-6.

Treatment

Treatment of SCA-6 is presently symptomatic. There are efforts to develop treatments, so far still experimental. Pastor et al (2018) reported an attempt to use miRNA in mice.

Additional Resources:

In Chicago, at Chicago Dizziness and Hearing, our otoneurologists are well equiped and ready to measure the oculomotor and balance consequences of SCA-6. Additionally, in Chicago, we are fortunate to have Dr. Christopher Gomez in the ataxia clinic at the University of Chicago, who is an expert on SCA6. (e.g. Gomez, 1993; Gomez et al, 1997)

References