A series of Greek children with pure hereditary spastic paraplegia: clinical features and genetic findings.
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.
First Department of Pediatrics, Aghia Sophia Children's Hospital, University of Athens, Thivon and Micras Asias, 11527, Athens, Greece.
Alexandros A
AA
Polymeris
Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy.
Alessandra
A
Tessa
Molecular Genetics Department, Genomedica S.A., Piraeus, Greece.
Katherine
K
Anagnostopoulou
Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy.
Anna
A
Rubegni
Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy.
Daniele
D
Galatolo
Third Department of Pediatrics, Attikon Hospital, University of Athens, Athens, Greece.
Argirios
A
Dinopoulos
First Department of Pediatrics, Aghia Sophia Children's Hospital, University of Athens, Thivon and Micras Asias, 11527, Athens, Greece.
Artemis D
AD
Gika
First Department of Pediatrics, Aghia Sophia Children's Hospital, University of Athens, Thivon and Micras Asias, 11527, Athens, Greece.
Sotiris
S
Youroukos
Neonatal Intensive Care Unit, IASO, MITERA and REA Hospitals, Athens, Greece.
Eleni
E
Skouteli
Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy.
Filippo M
FM
Santorelli
First Department of Pediatrics, Aghia Sophia Children's Hospital, University of Athens, Thivon and Micras Asias, 11527, Athens, Greece. roserpons@med.uoa.gr.
Roser
R
Pons
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004185:Disability Evaluation; D018450:Disease Progression; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006115:Greece; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D012720:Severity of Illness Index; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D000074181:Spastin
D008565:Membrane Proteins; C440006:ATL1 protein, human; D000251:Adenosine Triphosphatases; D019204:GTP-Binding Proteins; D000074181:Spastin; C400283:SPAST protein, human
Children; Early onset; Hereditary spastic paraplegia; Mutation screening; Pure