Objective: To better characterize spastic paraplegia type 7 (SPG7) phenotype in a Portuguese cohort of patients.

Background: Hereditary spastic paraplegias(HSP) and cerebellar ataxias(CA) are heterogeneous groups of progressive neurodegenerative conditions with considerable overlap, leading to difficulties in disease classification and approach to genetic diagnosis. Pathogenic variants in the SPG7 gene cause disease when transmitted in an autosomal recessive fashion, although autosomal dominant cases have been reported. Recent studies report that SPG7 mutations can be clinically predicted by a hybrid spastic-ataxic phenotype and might constitute a major genetic cause of ataxia presenting in mid-adult life.

Method: We present a cross-sectional study of the clinical and genetic characteristics of a cohort of patients with SPG7 mutations followed at a tertiary centre in Portugal. Genetic data derived from single gene testing and next-generation sequencing panels. We analyzed clinical, emphasizing the oculomotor evaluation, and MRI features.

Results: A total of 5 patients, belonging to 4 unrelated families, were identified with SPG7 mutations. Two patients from the same family, with a complex family history (consanguinity and presence of the disease in two consecutive generations), presented at a mean age of disease onset of 38 years.Their phenotype was predominant a HSP with cerebellar features. In both, an homozygous variant in exon 11(c1454_1462) was identified.
The other 3 unrelated cases have no family history and were older at disease onset (mean age 51,67 years). The presenting symptom differed between them: pure HSP, complicated HSP (waddling gait), and cerebellar ataxia with dysarthria. On follow-up, ataxia was the predominant feature with progressive external ophtalmoplegia. Patients were clinically diagnosed and investigated for ataxic disorders and, in all, brain MRI showed a marked cerebellar atrophy. We identified a compound heterozygous SPG7 mutations in one case and 2 heterozygous mutations (c.-9C>T-5’UTR and c.397C>T-exon 4) in the other two cases.

Conclusion: In our SPG7 patients, the phenotypic spectrum of SPG7 includes a predominantly ataxic presentation. We highlight that SPG7 mutations need to be considered in the differential diagnosis of spastic-ataxic syndromes, even in sporadic cases. In the future it will be interesting to see whether specific mutations predispose to an ataxic or spastic presentation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-and-imagiological-features-in-portuguese-patients-with-spg7-mutations/