HSPs studied in children

20 new genetic variants discovered

64% of 106 children with childhood-onset HSP had a confirmed genetic diagnosis, 31% were unsolved and 5% had a candidate genetic variant identified in this Brazilian study of children with HSP.

The most common childhood-onset type was SPG4 (22%) followed by SPG3A (16%). Over half of the SPG4 cases had missense variants. 20 new genetic variants were discovered in the study.

Abstract

The present study aimed to characterize clinical and molecular data of a large cohort of subjects with childhood-onset hereditary spastic paraplegias (HSPs). A multicenter historical cohort was performed at five centers in Brazil, in which probands and affected relatives’ data from consecutive families with childhood-onset HSP (onset < 12 years-old) were reviewed from 2011 to 2020.

106 individuals (83 families) with suspicion of childhood-onset HSP were evaluated, being 68 (50 families) with solved genetic diagnosis, 6 (5 families) with candidate variants in HSP-related genes and 32 (28 families) with unsolved genetic diagnosis. The most common childhood-onset subtype was SPG4, 11/50 (22%) families with solved genetic diagnosis; followed by SPG3A, 8/50 (16%). Missense pathogenic variants in SPAST were found in 54.5% of probands, favoring the association of this type of variant to childhood-onset SPG4.

Survival curves to major handicap and cross-sectional Spastic Paraplegia Rating Scale progressions confirmed the slow neurological deterioration in SPG4 and SPG3A. Most common complicating features and twenty variants not previously described in HSP-related genes were reported. These results are fundamental to understand the molecular and clinical epidemiology of childhood-onset HSP, which might help on differential diagnosis, patient care and guiding future collaborative trials for these rare diseases.

SOURCE:  Sci Rep. 2021 Nov 15;11(1):22248. doi: 10.1038/s41598-021-01635-2. PMID: 34782662 © 2021. The Author(s).

Clinical and molecular characterization of a large cohort of childhood onset hereditary spastic paraplegias

Gabriela Marchisio Giordani  1   2 Fabrício Diniz  3 Helena Fussiger  1   2 Carelis Gonzalez-Salazar  3 Karina Carvalho Donis  2   4 Fernando Freua  5 Roberta Paiva Magalhães Ortega  6 Julian Letícia de Freitas  7 Orlando Graziani Povoas Barsottini  7 Sergio Rosemberg  6   8 Fernando Kok  5 José Luiz Pedroso  7 Marcondes Cavalcante França Jr  3   9 Jonas Alex Morales Saute  10   11   12   13   14

1. Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

2. Neurogenetics, Clinical Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil.

3. Graduate Program in Medical Physiopathology, Universidade Estadual de Campinas (UNICAMP), Campinas, Brazil.

4. Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Ramiro Barcelos, 2350, Porto Alegre, 90035-903, Brazil.

5. Departamento de Neurologia, Hospital das Clínicas, Universidade de São Paulo, São Paulo, SP, Brazil.

6. Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, SP, Brazil.

7. Department of Neurology, Ataxia Unit Universidade Federal de São Paulo, São Paulo, Brazil.

8. Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, SP, Brazil.

9. Department of Neurology, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Campinas, Brazil.

10. Graduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. [email protected]

11. Neurogenetics, Clinical Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil. [email protected]

12. Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Ramiro Barcelos, 2350, Porto Alegre, 90035-903, Brazil. [email protected]

13. Neurology Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil. [email protected]

14. Internal Medicine Department, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. [email protected]

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