C9orf72 Repeat Expansions as Genetic Modifiers for Depression in Spinocerebellar Ataxias

The genetic interactions between pathological repeat expansions have been of major interests in neurodegenerative disorders. Recently, pathogenic C9orf72 repeat expansions, a main genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia and pathogenic ATXN2 repeat expansions, the causative gene for spinocerebellar ataxia (SCA) type 2, are reported to coexist in a single family with ataxia.¹ Therefore, this observation raises an interesting possibility that C9orf72 repeat expansions could be genetic modifiers in CAG-repeat SCAs and might influence the disease progression.

Therefore, we studied 277 patients with SCA1, 2, 3 and 6 from the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA) cohort,² and we determined the C9orf72 repeat length as previously described.³ The Scale for Assessment and Rating of Ataxia (SARA) and the 9-item Patient Health Questionnaire (PHQ-9) were used to measure the severity of ataxia and depression, respectively. We studied the rate of ataxia and depression progression using generalized estimating equation to test whether the intermediate repeats of C9orf72 were associated with ataxia or depression progression in SCAs. As described previously, full repeat expansions of C9orf72 were defined as ≥ 31 hexanucleotide repeats whereas intermediate repeat expansions were 8–30.^3–5

We identified seven patients (3 out of 51 SCA1; 2 out of 58 SCA2; 1 out 109 SCA3; 1 out of 59 SCA6) with pathogenic C9orf72 repeat expansions. None of the 7 cases had motor neuron disease, but they had various degrees of motor neuron signs (Table 1). Compared to cognitively normal control (The original paper cites 1039 Europeans and 620 African American) population,⁵ the frequencies of expanded C9orf72 repeats in our cohort were significantly higher in SCA1, 2, and 6 but not in SCA3 (Supplemental table 1). Forty percent of SCA patients carry intermediate C9orf72 repeat expansions, and the demographic and clinical features of SCA subjects with normal and intermediate alleles of C9orf72 are shown in Supplemental table 2. Intermediate C9orf72 repeat expansions did not influence the rate of ataxia progression but were associated with different rates of depressive symptom progression in SCA1, 3, and 6 (SCA1: β = −1.90, p < 0.005; SCA3: β = 3.48, p < 0.001; SCA6: β = −1.72, p < 0.05; Supplemental table 3).

Table 1.

Demographic and clinical features of 7 SCA patients with full C9orf72 repeat expansions

Patient Number	SCA Type	CAG Repeats Number (Small/Large)	C9orf72 Repeats	Gender	Age of Onset	SARA	Mental Status	Motor neuron deficits
								Fasciculation	Weakness	Reflexes of Extremities	Plantar Reflex	Spasticity
1	1	30/44	5/>30	Woman	38	10.5	MoCA 25/30	Present	None	Hyperreflexia in biceps, patellar and Achilles	Extensor	Mild in lower and upper limbs
2	1	30/42	10/>30	Woman	45	0.5	MoCA 30/30	Present	None	Hyperreflexia in biceps, patellar and Achilles	Flexor	Not evaluated
3	1	30/42	10/>30	Woman	52	8.5	MoCA 25/30	Present	None	Hyperreflexia in biceps, patellar and Achilles	Flexor	Mild in lower limbs
4	2	22/39	6/>30	Man	35	24	Not evaluated	None	None	Areflexia in biceps, patellar and Achilles	Extensor	Moderate in lower limbs, mild in upper limbs
5	2	22/39	2/>30	Woman	40	24.5	Poor in serial 7s	Mild in tongue/ face and four limbs	Mild in four limbs	Areflexia in biceps, patellar and Achilles	Flexor	None
6	3	28/70	2/>30	Woman	48	30.5	Not evaluated	Moderate in tongue and face	Mild in four limbs	Areflexia in biceps, hyperreflexia in patellar and Achilles	Extensor	Moderate in four limbs
7	6	11/23	8/>30	Man	59	12.5	Not evaluated	None	None	None	None	None

Abbreviations: SCA: spinocerebellar ataxias, SARA: scale for ataxia rating and assessment, MoCA: Montreal Cognitive Assessment, Serial 7s: serial sevens subtraction test,

In the present study, we identified patients of SCA1, 2, 3, and 6 who also carry pathogenic C9orf72 repeat expansions. Intermediate C9orf72 repeat expansions might influence the non-motor symptom (i.e. depression) progression in SCAs. Our study highlights the genetic interactions between repeat expansions.

The presence of CAG repeat expansions could interfere with the DNA repair process,⁶ which may destabilize C9orf72 repeat expansions and explain the co-existence of C9orf72 repeat expansions and expanded CAG repeats. Since cerebellar pathology could be found in C9orf72-linked ALS, the presence of C9orf72 repeat expansions might affect polyglutamine aggregates preferentially in the cerebellum or brainstem structures implicated in depression.

In conclusion, our study provides supporting evidence that repeat expansions of C9orf72 may be genetic modifiers in SCAs, and perhaps ataxia patients in general.⁷ Therefore, the interplay of repeat expansions in two different loci may lead to diverse clinical phenotypes in degenerative cerebellar ataxia.