SPG6 (NIPA1 variant): A report of a case with early-onset complex hereditary spastic paraplegia and brief literature review

• Published in: Journal of clinical neuroscience 2021-12, Vol.94, p.281-285
• Main Authors: Spagnoli, Carlotta, Schiavoni, Silvia, Rizzi, Susanna, Salerno, Grazia Gabriella, Frattini, Daniele, Koskenvuo, Juha, Fusco, Carlo
• Format: Article
• Language: English
• Subjects: Autosomal dominant; Child; Complex; Epilepsy; Hereditary spastic paraplegia; Humans; Membrane Proteins - genetics; Mutation, Missense; NIPA1; Pure; Spastic Paraplegia, Hereditary - diagnosis; Spastic Paraplegia, Hereditary - genetics; SPG6
• ISSN: 0967-5868; 1532-2653
• DOI: 10.1016/j.jocn.2021.10.026

•SPG6 is regarded as an early adulthood-onset pure hereditary spastic paraplegia.•Complex forms actually represent 22% of published cases.•Generalized drug-responsive epilepsy occurs in 10% of cases.•Drug-resistant eyelid myoclonia with absences can be part of the phenotype.•Early-onset of walking difficulties appears exceptional. SPG6, caused by NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome) gene pathogenic variants, is mainly considered as a pure autosomal dominant hereditary spastic paraplegia (AD-HSP), even if descriptions of complex cases have also been reported. We detected the common c.316G > A, p.(Gly106Arg) pathogenic de novo substitution in a 10-year-old patient with HSP and drug-resistant eyelid myoclonia with absences. In order to assess the significance of this association, we reviewed the literature to find that 25/110 (23%) SPG6 cases are complex, including a heterogeneous spectrum of comorbidities, in which epilepsy is most represented (10%), but also featuring peripheral neuropathy (5.5%), amyotrophic lateral sclerosis (3.6%), memory deficits (3.6%) or cognitive impairment (2.7%), tremor (2.7%) and dystonia (0.9%). From this literature review and our single case experience, two main conclusions can be drawn. First, SPG6 is an AD-HSP with both pure and complex presentation, and frequent occurrence of epilepsy within the spectrum of genetic generalized epilepsies (absences, bilateral tonic-clonic, bilateral tonic-clonic with upper limbs myoclonic seizures and eyelid myoclonia with absences). Second, opposed to previous descriptions, seizures might not always be drug responsive.