Posted - September 2020 in Research Highlights
Challenges in diagnosis experienced
55% of childhood-onset cases were complex forms of HSP and 45% were pure forms in this study of 47 children who had attended the one clinic in Italy between 1990 and 2018. A definite genetic diagnosis was achieved in 36% of cases. SPG3A was found to be the most frequent cause (4 cases) of the pure forms, as has been found in other studies of childhood-onset HSP. A wide range of different genes and HSP types was found across the complex forms.
Aim: To describe the clinical and neurogenetic spectrum of paediatric-onset hereditary spastic paraplegias (HSPs) diagnosed in our unit.
Method: We report on 47 patients (30 males, 17 females; mean [SD] age 12y 7mo [6y 2mo], range 4-34y) clinically diagnosed with an HSP at the Child Neurology Unit, IRCCS-ASMN (Reggio Emilia, Italy) between 1990 and 2018, who were genetically investigated by means of single-gene direct sequencing and/or next-generation sequencing technologies (targeted panels, whole-exome sequencing [WES]).
Results: Complex forms prevailed slightly (n=26), autosomal dominant being the main inheritance pattern (n=11), followed by recessive (n=5) and X-linked (n=1). A definite genetic diagnosis was achieved in 17 patients. Spastic paraplegia 3A (n=4) was the most frequent cause of autosomal dominant HSP in our cohort, while no genetic variant prevailed in autosomal recessive forms and pathogenic/likely pathogenic variants were disclosed in a wide range of different genes.
Interpretation: We found wide phenotypic and genetic heterogeneity. With increasing accessibility to WES, a higher number of patients receive a diagnosis, allowing detection of variants in ultra-rare disease-causing genes and refining genotype-phenotype correlations.
What this paper adds: A genetic diagnosis of paediatric-onset hereditary spastic paraplegia was achieved in one-third of patients. Pathogenic/likely pathogenic variants in rare genes were found. Genotypic and phenotypic heterogeneity favours targeted panel/whole-exome sequencing for diagnosis.
SOURCE: Dev Med Child Neurol. 2020 Sep;62(9):1068-1074. doi: 10.1111/dmcn.14547. Epub 2020 Apr 10. PMID: 32277485 © 2020 Mac Keith Press.
Paediatric-onset hereditary spastic paraplegias: a retrospective cohort study
1 Child Neurology Unit, Department of Paediatrics, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.
2 Child Neuropsychiatry Unit, Neuroscience Division, Medicine & Surgery Department, University of Parma, Parma, Italy.
3 Paediatric Neurophysiology Laboratory, Department of Paediatrics, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.