Purpose

To report the variability and progression of clinical presentation in three family members with spinocerebellar ataxia Type 7 including early recognizable features on retinal imaging and magnetic resonance imaging.

Methods

Retrospective case series.

Results

The proband, Patient 1 (mother) presented at age 26 with light perception vision. Initial examination was significant for optic disc pallor, vascular attenuation, and central macular atrophy. Two years later, her vision declined to no light perception, and fundus examination demonstrated marked progression of macular atrophy and peripheral bone spicule formation. Seven years after the onset of vision loss, neurologic examination demonstrated ataxia, dysarthria, and slowed saccades. Genetic testing of ATXN7 identified heterozygous 61-CAG trinucleotide repeat expansion confirming the diagnosis of spinocerebellar ataxia Type 7. Patient 2 (son) presented at age 11 with visual acuity of 20/300 bilaterally and decreased color vision. Funduscopic examination was notable for disc pallor, vascular attenuation, and peripheral pigmentary changes. Electroretinography demonstrated diminished rod and cone function, and Goldmann visual field testing revealed paracentral scotoma. Patient 3 (daughter) presented at age 14 with visual acuity of 20/50 bilaterally and minimal funduscopic changes. The only significant ophthalmic finding was retinal thinning with atrophy of the outer nuclear layer and subfoveal ellipsoid zone on optical coherence tomography. Early cerebellar volume loss was also noted on magnetic resonance imaging.

Conclusion

The clinical presentation of spinocerebellar ataxia Type 7 can vary widely even within the same family. In individuals with vision loss and normal fundus examination, careful evaluation of optical coherence tomography and brain magnetic resonance imaging facilitates early diagnosis and genetic testing.

Achromatopsia (ACHM) is an autosomal recessive disease that results in severe visual loss. Symptoms of ACHM include impaired visual acuity, nystagmus, and photoaversion starting from infancy; furthermore, ACHM is associated with bilateral foveal hypoplasia and absent or severely reduced cone photoreceptor function on electroretinography. Here, we performed genetic sequencing in 3 patients from 2 families with ACHM, identifying and functionally characterizing 2 mutations in the activating transcription factor 6 (ATF6) gene. We identified a homozygous deletion covering exons 8-14 of the ATF6 gene from 2 siblings from the same family. In another patient from a different family, we identified a heterozygous deletion covering exons 2 and 3 of the ATF6 gene found in trans with a previously identified ATF6 c.970C>T (p.Arg324Cys) ACHM disease allele. Recombinant ATF6 proteins bearing these exon deletions showed markedly impaired transcriptional activity by qPCR and RNA-Seq analysis compared with WT-ATF6. Finally, RNAscope revealed that ATF6 and the related ATF6B transcripts were expressed in cones as well as in all retinal layers in normal human retina. Overall, our data identify loss-of-function ATF6 disease alleles that cause human foveal disease.