Expanding SPG18 clinical spectrum: autosomal dominant mutation causes complicated hereditary spastic paraplegia in a large family.

Autor: Trinchillo A; Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, Italy., Valente V; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy., Esposito M; Clinical Neurophysiology Unit, Cardarelli Hospital, Naples, Italy., Migliaccio M; IRCCS SDN SYNLAB, Naples, Italy., Iovino A; Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, Italy., Picciocchi M; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy., Cuomo N; Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, Italy., Caccavale C; Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, Italy., Nocerino C; Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, Italy., De Rosa L; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy., Salvatore E; CDCD Neurology, 'Federico II' University Hospital, Naples, Italy., Pierantoni GM; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy., Menchise V; Institute of Biostructure and Bioimaging, National Research Council (CNR) and Molecular Biotechnology Center, Turin, Italy., Paladino S; Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy., Criscuolo C; Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, Italy. sky569@hotmail.com.; CDCD Neurology, 'Federico II' University Hospital, Naples, Italy. sky569@hotmail.com.
Jazyk: angličtina
Zdroj: Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology [Neurol Sci] 2024 Sep; Vol. 45 (9), pp. 4373-4381. Date of Electronic Publication: 2024 Apr 12.
DOI: 10.1007/s10072-024-07500-0
Abstrakt: Background: SPG18 is caused by mutations in the endoplasmic reticulum lipid raft associated 2 (ERLIN2) gene. Autosomal recessive (AR) mutations are usually associated with complicated hereditary spastic paraplegia (HSP), while autosomal dominant (AD) mutations use to cause pure SPG18.
Aim: To define the variegate clinical spectrum of the SPG18 and to evaluate a dominant negative effect of erlin2 (encoded by ERLIN2) on oligomerization as causing differences between AR and AD phenotypes.
Methods: In a four-generation pedigree with an AD pattern, a spastic paraplegia multigene panel test was performed. Oligomerization of erlin2 was analyzed with velocity gradient assay in fibroblasts of the proband and healthy subjects.
Results: Despite the common p.V168M mutation identified in ERLIN2, a phenoconversion to amyotrophic lateral sclerosis (ALS) was observed in the second generation, pure HSP in the third generation, and a complicated form with psychomotor delay and epilepsy in the fourth generation. Erlin2 oligomerization was found to be normal.
Discussion: We report the first AD SPG18 family with a complicated phenotype, and we ruled out a dominant negative effect of V168M on erlin2 oligomerization. Therefore, our data do not support the hypothesis of a relationship between the mode of inheritance and the phenotype, but confirm the multifaceted nature of SPG18 on both genetic and clinical point of view. Clinicians should be aware of the importance of conducting an in-depth clinical evaluation to unmask all the possible manifestations associated to an only apparently pure SPG18 phenotype. We confirm the genotype-phenotype correlation between V168M and ALS emphasizing the value of close follow-up.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: