Spasmodic Dysphonia in a Patient with Spinocerebellar Ataxia Associated with a Rare AFG3L2 Variant (ATX‐AFG3L2 )

Heterozygous pathogenic variants in ATPase family gene 3‐like 2 (AFG3L2) gene are associated with autosomal dominant cerebellar ataxia (ATX‐AFG3L2), previously known as spinocerebellar ataxia type 28, which typically presents with slowly progressive cerebellar ataxia, dysarthria, oculomotor abnormalities, and pyramidal signs. ¹ , ² Carriers of compound heterozygous AFG3L2 variants may demonstrate other features including ptosis, optic atrophy, external ophthalmoplegia, generalized dystonia, and lingual dyskinesia. ³ , ⁴ , ⁵ Here, we report an individual with a rare compound heterozygous AFG3L2 variant who uniquely presented with spasmodic dysphonia, along with other typical features of ATX‐AFG3L2.

A 47‐year‐old French‐Canadian woman (Fig. 1, IV:5) with no relevant comorbidities presented to our unit with a 14‐year history of slowly progressive dysarthria, unsteady gait, and spasticity. Following these, she developed horizontal diplopia and spasmodic dysphonia that partially responded to botulinum toxin (BoNT‐A) and trihexyphenidyl (6 mg/day). She subsequently manifested with dysphagia, urinary incontinence, depressed mood, and insomnia. She also reported short‐term memory lapses, which improved after discontinuation of trihexyphenidyl. Currently, she is stable on coenzyme Q10 (200 mg/day) and sertraline (50 mg/day) and is slated to resume speech therapy.

FIG. 1.

Partial pedigree of the index case and her kindred. NT, not tested; WT, wild‐type.

Her family history is notable for a mother and an older sister with reported imbalance (Fig. 1, III:6 and IV:1, respectively). One maternal aunt had unsteadiness (III:4), while another aunt had cervical dystonia (III:5). She had a maternal grand aunt with problems in balance, handwriting, and mood (II:3). Her father and son were asymptomatic (III:7 and V:2, respectively). Due to logistical reasons, only her daughter (V:1) was available for clinical evaluation and apart from multiple psychiatric comorbidities and a probable medication‐induced tremor (from lurasidone and aripiprazole use), she did not have signs of gaze and speech abnormalities, spasticity, or ataxia.

On examination, the index patient had bilateral gaze‐evoked nystagmus, slow and hypometric saccades, and horizontal diplopia with a right medial rectus paresis on duction testing. There was no ptosis. Apart from dysarthria, she manifested with an abductor‐type spasmodic dysphonia. She had bilateral lower limb spasticity with reduced hip flexor strength, generalized hyperreflexia with bilateral clonus, positive Hoffman sign, and limb dysmetria (see Video 1). Plantar responses were flexor and sensory examination was unremarkable. She had a spastic gait and could not heel‐toe walk (see Video 1). The Scale for the Assessment and Rating of Ataxia (SARA) score at initial assessment was 6.5.

Video 1.

Abductor‐type spasmodic dysphonia characterized by breathy voice quality and phonatory breaks. Oculomotor examination revealed bilateral horizontal end‐gaze nystagmus, breakdown of smooth pursuit, and slow and hypometric saccades. Version and duction testing disclosed the diplopia that was associated with a right medial rectus paresis. On further motor and coordination examination, the individual was observed to have limb dysmetria as evidenced on finger chase maneuver. Deep tendon reflexes were hyperactive in the lower extremities with associated unsustained clonus bilaterally. Gait was narrow based but unsteady, and the patient was unable to perform tandem gait.

Blood workup revealed normal creatinine kinase, alpha‐fetoprotein, lactate, and vitamin E levels. Baseline and follow‐up brain MRI showed stable mild cerebellar atrophy and nonspecific white matter hyperintensities. Targeted genetic testing revealed a rare, likely pathogenic heterozygous nonsense AGF3L2 variant in exon 2 [c.202C > T, p.(R68*)] (0.00125, gnomAD v2.1.1; PVS1–PM2–BS4), ⁶ and a heterozygous missense variant in exon 16 [c.2167G > A, p.(V723M)] classified as a variant of unknown significance (VUS) (NM_006796.2). The nonsense variant segregated with the patient's mother, while the children harbored only the missense variant. No genetic variants were detected in the maternal aunt with cervical dystonia and the patient's father (Fig. 1).

We report novel observations in an individual with hereditary ataxia arising from a compound heterozygous variant in AFG3L2 gene (ATX‐AFG3L2). The gene codes for a mitochondrial metalloprotease important mainly for respiratory chain complex assembly and proteolytic quality control. ¹ , ⁷ The p.R68* variant has only been documented once in the ClinVar database (VCV000805326.1) and to our knowledge, has never been fully described in the literature. Pathogenic nonsense variants have been associated with an ATX‐AFG3L2 phenotype, ⁴ although further functional analysis is needed to fully demonstrate the downstream effects of the p.R68* variant detected in our case. Additionally, the p.V732M missense variant has been reported in an individual with a compound heterozygous AFG3L2 mutation with a similar clinical presentation, although our case differs with respect to the location of the nonsense variant and the dominant pattern of inheritance. ⁴ Given the absence of AFG3L2 mutations in the father, we speculate that the p.V723M variant in our case arose de novo. Interestingly, neither of her children harboring the p.V723M variant showed features of ATX‐AFG3L2, which may denote that it lacks pathogenicity or is a hypomorphic variant, which would only exert pathogenicity in the presence of other disease‐causing variants. ⁹ Indeed, further work is warranted to delineate the genetic and functional spectrum of AFG3L2 variants.

Our case also manifested with an abductor spasmodic dysphonia, which has not been previously documented in ATX‐AFG3L2. Dystonia is known to occur in several hereditary ataxias (eg, ATX‐ATXN3, ATX‐TBP, ATX‐ATN1), ⁸ and has been documented in ATX‐AFG3L2, although previous cases mainly reported neck, trunk, or limb involvement. ² , ⁵ Spasmodic dysphonia has been described in other forms of hereditary ataxia including ATX‐PPP2R2B and SCA20, ¹⁰ , ¹¹ but its exact genetic and pathophysiological underpinnings remain unknown. Nevertheless, our report raises awareness of this feature as part of the clinical expression of ATX‐AFG3L2. Clinicians should consider testing for AFG3L2 variants in patients presenting with spasmodic dysphonia in combination with spinocerebellar features.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.

N.D.R.: 1A, B, C, 3A

M.C.S.S.: 1A, B, C; 3B

R.P.M: 1A, B, C, 3B.

Disclosures

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Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare no conflict of interest related to this work.

Financial Disclosures for the Previous 12 Months: The authors have no relevant disclosures to report.