Posted - September 2016 in Research Highlights
Clinical and genetic findings
The study of 15 children in Greece revealed:
four with SPAST (SPG4) mutations, two of which were new
three with SPG3A mutations
and one each in SPG5A, SPG7 and SPG31
five mutations (33%) remained unidentified
three mutations were apparently de novo or sporadic meaning that no family history existed and the mutations occurred by chance.
Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. Adult case series dominate the literature, and there have been only a few studies in children.
The purpose of this study is to describe our experience with pediatric HSP in Greece. We report the clinical and genetic findings in our patients and aim to offer insights into the diagnostic difficulties of childhood-onset disease. A series of 15 Greek children affected by pure HSP underwent extensive diagnostic investigations. Molecular analysis included whole exome sequencing (WES) or consecutive screening of candidate genes ATL1, SPAST, REEP1, and CYP7B1.
WES performed in three cases yielded previously reported mutations in ATL1 and CYP7B1, and a variant c.397C>T of unknown significance in SPG7. Candidate gene screening performed in the remaining patients identified previously reported mutations in ATL1 (2), SPAST (2), and REEP1 (1), and two novel mutations, c.1636G>A and c.1413+3_6delAAGT, in SPAST. In six cases, the mutations were inherited from their parents, while in three cases, the mutations were apparently de novo.
Our data confirm the genetic heterogeneity of childhood-onset pure HSP, with SPG4/SPAST and SPG3A/ATL1 being the most frequent forms. De novo occurrence of HSP does not seem to be uncommon. Candidate gene studies guided by diagnostic algorithms and WES seem both to be reasonable genetic testing strategies.
SOURCE: J Neurol. 2016 Aug;263(8):1604-11. doi: 10.1007/s00415-016-8179-z. Epub 2016 Jun 3. PMID: 27260292 [PubMed – in process]
A series of Greek children with pure hereditary spastic paraplegia: clinical features and genetic findings.
Polymeris AA1, Tessa A2, Anagnostopoulou K3, Rubegni A2, Galatolo D2, Dinopoulos A4, Gika AD1, Youroukos S1, Skouteli E5, Santorelli FM2, Pons R6.
1First Department of Pediatrics, Aghia Sophia Children’s Hospital, University of Athens, Thivon and Micras Asias, 11527, Athens, Greece.
2Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy.
3Molecular Genetics Department, Genomedica S.A., Piraeus, Greece.
4Third Department of Pediatrics, Attikon Hospital, University of Athens, Athens, Greece.
5Neonatal Intensive Care Unit, IASO, MITERA and REA Hospitals, Athens, Greece.
6First Department of Pediatrics, Aghia Sophia Children’s Hospital, University of Athens, Thivon and Micras Asias, 11527, Athens, Greece. [email protected]