Phenotype and Genotype Heterogeneity of PLA2G6-associated Neurodegeneration
Ali Reza Tavasoli1, Ali Zare Dehnavi2, Maryam Bemanalizadeh3, Mohammad Kahani4, Mohammad Rohani5, Mehran Beriraghi Toosi6, Mahmoud Reza Ashrafi2, Morteza Heidari2, Man Amanat7, Sareh Hosseinpour2
1Jefferson Molecular Medicine, Thomas Jefferson University, 2Neurology, Tehran University of Medical Sciences, 3Child Growth and Development Research Center, Isfahan University of Medical Sciences, 4Department of Medical Genetic, Tarbiat Modares University, 5Neurology, Iran University of Medical Sciences, 6Neurology, Mashhad University of Medical Sciences, 7Neurology, Kennedy Krieger Institute
Objective:
We reviewed the clinical, imaging, and genetic features of 25 adult and pediatric patients with Phospholipase-associated neurodegeneration (PLAN), and validated a genotype-phenotype correlation in this disorder.
Background:
PLAN is a rare neurodegenerative disorder caused by mutations in PLA2G6 and can present four phenotypes including infantile neuroaxonal dystrophy (INAD), atypical NAD, PLA2G6-related dystonia-parkinsonism, and autosomal recessive early-onset parkinsonism (AREP).
Design/Methods:
An extensive chart review of enrolled patients was carried out. INAD Rating Scale (INAD-RS) was used for evaluating the severity and progression of INAD patients. Whole‑exome sequencing was performed to determine the disease's underlying etiology, and co-segregation analysis was examined using Sanger sequencing. In silico prediction analysis based on the ACMG recommendation was utilized to assess the pathogenicity of detected variants. The HGMD professional database and the chi-square statistical approach were utilized considering all reported disease-causing variants in 17 exons of the PLA2G6 gene in addition to our patient.
Results:
18 cases of INAD and 7 cases of adult-onset NAD with a mean age of disease onset of 22.4 months and 25 years old, respectively, were enrolled. Among 18 INAD patients, gross motor regression was the most common presenting symptom. Considering the INAD-RS total score, 60% percent of the maximum potential loss occurred within 60 months of symptom onset. Among seven adult cases, movement disorders i.e., hypokinesia, tremor, ataxic gait, and cognitive impairment were the most frequent clinical features. Cerebellar atrophy was the most common imaging finding.. We found twenty unique variants in 25 patients including nine novel variants. Based on the retrieved p-value on the chi-Square, no significant phenotype-genotype correlation was obtained in PLAN.
Conclusions:
PLAN presents with a wide spectrum of clinical symptoms spanning from infancy through adulthood. PLAN should be considered in adult patients presenting with parkinsonism or cognitive decline. Genotype of the disease cannot predict the age of disease onset.