2022.11.21 | Questions 9-10
An adult with trouble walking and vision loss
This week’s questions highlight an important class of adult-onset movement disorders with a unique mechanism of disease.
As always, please feel free to reach out with any comments, questions or ideas (studyraregenetics@gmail.com)
Happy Thanksgiving! 🦃
-Daniel
Questions
Question 9
A 45-year-old man presents with progressive difficulty walking and speaking over the last 3 years. He recently started using a walker to maintain his balance. He has poor visual acuity of 20/150 that has progressively worsened over the past 12 months. Physical exam is notable for a broad-based gait, scanning speech, and difficulty with finger-to-nose testing. A dilated fundus exam reveals hypopigmentation and atrophy of the macula. Which of the following is the most likely diagnosis?
Question 10
Genetic testing is sent for the individual described in Question 9 and reveals a variant in the gene ATXN7. Which of the following is the most likely type of variant to be found in this gene?
Explanation
This patient has spinocerebellar ataxia type 7 (SCA7). The spinocerebellar ataxias (SCA) are a group of several dozen autosomal dominant, progressive neurologic disorders that typically present in adulthood. The unstable gait, scanning speech, and difficulty with finger-to-nose testing seen in this patient are all signs of cerebellar ataxia, a clinical hallmark of the spinocerebellar ataxias. Of note, SCA7 is the only type of SCA to have both cerebellar ataxia and retinal degeneration (i.e. “hypopigmentation and atrophy of the macula” in Question 9).
💡In a patient with ataxia and vision problems, think about SCA7. Think "VisioN is affected in SCA seVeN."
Like most other SCAs, SCA7 is inherited in an AD manner and is caused by a trinucleotide repeat expansion (Question 10). More specifically, SCA7 is caused by a CAG trinucleotide repeat expansion in exon 3 of the gene ataxin-7 (ATXN7). Diseases caused by CAG repeat expansions (which encode the amino acid glutamine) are known as polyglutamine diseases and include Huntington disease, spinobulbar muscular atrophy, and SCAs 1-3, 6, and 7.
💡Clinical pearl: Because most SCAs are repeat-mediated disorders, short-read exome or genome sequencing often are not validated to make this diagnosis. In most cases, separate trinucleotide repeat studies (e.g. using PCR / Southern Blot) must be sent to make the diagnosis.
Disorders caused by trinucleotide repeat expansions exhibit genetic anticipation, whereby the trinucleotide repeats become longer in each successive generation. For most SCAs, including SCA7, genetic anticipation is more likely to occur when inherited from the paternal lineage (vs Fragile X, a trinucleotide disorder where genetic anticipation is seen when inherited from the maternal lineage). For many trinucleotide repeat disorders, including SCA7, longer repeats are associated with more severe and earlier-onset symptoms.
On a molecular level, most trinucleotide repeat expansions occur in exons (and maintain the transcriptional reading frame), while most tetra and pentanucleotide repeat expansions that cause disease (e.g. the AATCT pentanucleotide repeat in SCA10) occur in introns (see Fig. 1 below).
Regarding the other answer choices in Question 9, Alström syndrome presents with retinal degeneration and vision loss but not ataxia. Vision problems may cause vestibular and balance issues but would not present with clinical signs of ataxia. Spinocerebellar ataxia type 1 (SCA1) can present with adult-onset ataxia but does not typically present with retinal degeneration. Stargardt disease, similar to Alström syndrome, is characterized by vision loss but not ataxia (think "Stargazer" to remember the vision loss in Stargardt).
Learning objective
Spinocerebellar ataxia type 7 (SCA7) is a trinucleotide repeat mediated disorder that is classically associated with the onset of ataxia followed by retinal degeneration in a young or middle-aged adult. Other SCAs present with adult-onset ataxia but not retinal degeneration.
References
Spinocerebellar ataxia type 7. GeneReviews.
2023 ABMGG General Exam Blueprint | V. Single Gene Inheritance → d. Single Gene Disorders → v) Neurogenetic disorders (page 3)