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. 2024 Jun;23(3):1135-1145.
doi: 10.1007/s12311-023-01620-7. Epub 2023 Oct 31.

The Frequency of Intermediate Alleles in Patients with Cerebellar Phenotypes

Elena Capacci  1 , Silvia Bagnoli  1 , Giulia Giacomucci  1 , Costanza Maria Rapillo  1 , Alessandra Govoni  2 , Valentina Bessi  1 , Cristina Polito  3 , Irene Giotti  4 , Alice Brogi  4 , Elisabetta Pelo  4 , Sandro Sorbi  1   3 , Benedetta Nacmias  1   3 , Camilla Ferrari  5
Affiliations

The Frequency of Intermediate Alleles in Patients with Cerebellar Phenotypes

Elena Capacci et al. Cerebellum. 2024 Jun.

Abstract

Cerebellar syndromes are clinically and etiologically heterogeneous and can be classified as hereditary, neurodegenerative non-hereditary, or acquired. Few data are available on the frequency of each form in the clinical setting. Growing interest is emerging regarding the genetic forms caused by triplet repeat expansions. Alleles with repeat expansion lower than the pathological threshold, termed intermediate alleles (IAs), have been found to be associated with disease manifestation. In order to assess the relevance of IAs as a cause of cerebellar syndromes, we enrolled 66 unrelated Italian ataxic patients and described the distribution of the different etiology of their syndromes and the frequency of IAs. Each patient underwent complete clinical, hematological, and neurophysiological assessments, neuroimaging evaluations, and genetic tests for autosomal dominant cerebellar ataxia (SCA) and fragile X-associated tremor/ataxia syndrome (FXTAS). We identified the following diagnostic categories: 28% sporadic adult-onset ataxia, 18% cerebellar variant of multiple system atrophy, 9% acquired forms, 9% genetic forms with full-range expansion, and 12% cases with intermediate-range expansion. The IAs were six in the FMR1 gene, two in the gene responsible for SCA8, and one in the ATXN2 gene. The clinical phenotype of patients carrying the IAs resembles, in most of the cases, the one associated with full-range expansion. Our study provides an exhaustive description of the causes of cerebellar ataxia, estimating for the first time the frequency of IAs in SCAs- and FXTAS-associated genes. The high percentage of cases with IAs supports further screening among patients with cerebellar syndromes.

Keywords: Cerebellar ataxia; FXTAS; Gray zone; Intermediate allele; SCA2; SCA8.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Distribution of the diagnostic categories in the study population (n = 66)
Fig. 2
Fig. 2
Clinical presentation and disease course in the six FMR1-intermediate allele carriers. Case 1 (yellow line) (45 triplets + ATXN2-IA): total disease duration is 5 years. The disease started 4 years before baseline visit with cognitive and behavioral disorder. Ataxic gait started 1 year before baseline visit. At baseline visit, she scored 4 at SARA. Progression of cerebellar symptoms was mild and the patient got 5 at SARA after 1-year follow-up. Case 2 (light blue line) (48 triplets): total disease duration is 4 years. The disease started 2 years before baseline visit with ataxic gait. SARA score was 5 at baseline visit. During the 2 years of follow-up, the patient also presented dysarthria, dysmetria, and dysdiadochokinesia. The disease worsened rapidly, and the SARA score was 12 at the last follow-up. Case 3 (pink line) (45 triplets): total disease duration is 6 years. The patient presented only diplopia and nystagmus. SARA score was 0 till the last follow-up. Case 4 (blue line) (46 triplets): total disease duration is 21 years. The disease started 20 years before baseline visit with ataxic gait and sensory neuropathy, followed by dysmetria, oculomotor alterations, dysarthria, and dysphagia. SARA score at baseline was 12, and stable in the follow-up period. Case 5 (green line) (52 triplets): total disease duration is 3 years. The disease started 2 years before baseline visit with ataxic gait followed by dysmetria, intention tremor, oculomotor alteration, dysarthria, dysphagia, and cognitive decline. The disease progressed rapidly, and after 2 years from symptoms onset, SARA score was 13. At the last follow-up, 6 months later, SARA score was 14. Case 6 (orange line) (54 triplets): total disease duration is 8 years. The disease started 6 years before baseline visit with diplopia and nystagmus. Four years later, the patient presented also ataxic gait, followed by dysmetria, parkinsonism, and urinary incontinence. SARA score at baseline was 17, and 18 at the last follow-up
Fig. 3
Fig. 3
Neuroimaging abnormalities in patients carrying the intermediate alleles. Case 1 (A–B): axial FLAIR-weighted MRI showing hyperintensity of the subcortical white matter (A) and of the superior cerebellar peduncles with extension to the posterior portion of the midbrain (B). Case 2 (C): axial FLAIR-weighted MRI showing multiple subcortical white matter lesions. Case 3 (D): axial FLAIR-weighted MRI showing no alterations. Case 4 (E): sagittal T1-weighted spin echo MRI showing cerebellar atrophy. Case 6 (F): axial FLAIR-weighted MRI showing subcortical white matter lesions. Case 7 (G): sagittal FLAIR-weighted MRI showing mild cerebellar atrophy. Case 8 (H–I): axial (H) and sagittal (I) FLAIR-weighted MRI showing atrophy of the middle cerebellar peduncle and pons
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