PMID- 37403138 OWN - NLM STAT- MEDLINE DCOM- 20230707 LR - 20230718 IS - 1750-1172 (Electronic) IS - 1750-1172 (Linking) VI - 18 IP - 1 DP - 2023 Jul 5 TI - Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients. PG - 177 LID - 10.1186/s13023-023-02780-9 [doi] LID - 177 AB - BACKGROUND: Phospholipase-associated neurodegeneration (PLAN) caused by mutations in the PLA2G6 gene is a rare neurodegenerative disorder that presents with four sub-groups. Infantile neuroaxonal dystrophy (INAD) and PLA2G6-related dystonia-parkinsonism are the main two subtypes. In this cohort, we reviewed clinical, imaging, and genetic features of 25 adult and pediatric patients harboring variants in the PLA2G6. METHODS: An extensive review of the patients' data was carried out. Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS) was used for evaluating the severity and progression of INAD patients. Whole-exome sequencing was used to determine the disease's underlying etiology followed by co-segregation analysis using Sanger sequencing. In silico prediction analysis based on the ACMG recommendation was used to assess the pathogenicity of genetic variants. We aimed to survey a genotype-genotype correlation in PLA2G6 considering all reported disease-causing variants in addition to our patients using the HGMD database and the chi-square statistical approach. RESULTS: Eighteen cases of INAD and 7 cases of late-onset PLAN were enrolled. Among 18 patients with INAD, gross motor regression was the most common presenting symptom. Considering the INAD-RS total score, the mean rate of progression was 0.58 points per month of symptoms (Standard error 0.22, lower 95% - 1.10, and upper 95% - 0.15). Sixty percent of the maximum potential loss in the INAD-RS had occurred within 60 months of symptom onset in INAD patients. Among seven adult cases of PLAN, hypokinesia, tremor, ataxic gate, and cognitive impairment were the most frequent clinical features. Various brain imaging abnormalities were also observed in 26 imaging series of these patients with cerebellar atrophy being the most common finding in more than 50%. Twenty unique variants in 25 patients with PLAN were detected including nine novel variants. Altogether, 107 distinct disease-causing variants from 87 patient were analyzed to establish a genotype-phenotype correlation. The P value of the chi-square test did not indicate a significant relationship between age of disease onset and the distribution of reported variants on PLA2G6. CONCLUSION: PLAN presents with a wide spectrum of clinical symptoms from infancy to adulthood. PLAN should be considered in adult patients with parkinsonism or cognition decline. Based on the current knowledge, it is not possible to foresee the age of disease onset based on the identified genotype. CI - (c) 2023. The Author(s). FAU - Dehnavi, Ali Zare AU - Dehnavi AZ AD - Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. FAU - Bemanalizadeh, Maryam AU - Bemanalizadeh M AD - Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. AD - Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran. FAU - Kahani, Seyyed Mohammad AU - Kahani SM AD - Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran, Iran. FAU - Ashrafi, Mahmoud Reza AU - Ashrafi MR AD - Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. FAU - Rohani, Mohammad AU - Rohani M AD - Skull Base Research Center, The Five Senses Health Institute, Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran. AD - Department of Neurology, Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, Iran. FAU - Toosi, Mehran Beiraghi AU - Toosi MB AD - Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. AD - Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. FAU - Heidari, Morteza AU - Heidari M AD - Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. FAU - Hosseinpour, Sareh AU - Hosseinpour S AD - Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. FAU - Amini, Behnam AU - Amini B AD - Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. FAU - Zokaei, Shaghayegh AU - Zokaei S AD - Dr. Farhud's Genetic Clinic, Tehran, Iran. AD - School of Advanced Medical Science, Islamic Azad University, Tehran, Iran. FAU - Rezaei, Zahra AU - Rezaei Z AD - Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. FAU - Aryan, Hajar AU - Aryan H AD - Dr. Farhud's Genetic Clinic, Tehran, Iran. AD - National Institute of Genetic Engineering and Biotechnology, Tehran, Iran. FAU - Amanat, Man AU - Amanat M AD - Department of Neurology, Johns Hopkins Medicine, Baltimore, MD, USA. FAU - Vahidnezhad, Hassan AU - Vahidnezhad H AD - Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA. AD - Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA. FAU - Mohammadi, Pouria AU - Mohammadi P AD - Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran, Iran. AD - Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran. FAU - Garshasbi, Masoud AU - Garshasbi M AD - Faculty of Medical Sciences, Department of Medical Genetics, Tarbiat Modares University, Tehran, Iran. Masoud.garshasbi@modares.ac.ir. FAU - Tavasoli, Ali Reza AU - Tavasoli AR AUID- ORCID: 0000-0003-0440-5809 AD - Department of Pediatrics, Division of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. alirezatavasoli236@gmail.com. AD - Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA. alirezatavasoli236@gmail.com. AD - Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran. alirezatavasoli236@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230705 PL - England TA - Orphanet J Rare Dis JT - Orphanet journal of rare diseases JID - 101266602 RN - EC 3.1.1.4 (Group VI Phospholipases A2) RN - EC 3.1.1.4 (PLA2G6 protein, human) SB - IM EIN - Orphanet J Rare Dis. 2023 Jul 17;18(1):190. PMID: 37461050 MH - Adult MH - Child MH - Humans MH - Genotype MH - Group VI Phospholipases A2/genetics MH - Mutation/genetics MH - *Neuroaxonal Dystrophies/genetics MH - *Parkinsonian Disorders/genetics MH - Phenotype PMC - PMC10320940 OTO - NOTNLM OT - INAD OT - Mutation OT - Neuroaxonal dystrophy OT - PLA2G6 OT - PLA2G6-associated dystonia-parkinsonism OT - PLAN COIS- All authors declare no conflict of interest. EDAT- 2023/07/05 01:06 MHDA- 2023/07/06 06:42 PMCR- 2023/07/05 CRDT- 2023/07/04 23:42 PHST- 2022/11/15 00:00 [received] PHST- 2023/06/18 00:00 [accepted] PHST- 2023/07/06 06:42 [medline] PHST- 2023/07/05 01:06 [pubmed] PHST- 2023/07/04 23:42 [entrez] PHST- 2023/07/05 00:00 [pmc-release] AID - 10.1186/s13023-023-02780-9 [pii] AID - 2780 [pii] AID - 10.1186/s13023-023-02780-9 [doi] PST - epublish SO - Orphanet J Rare Dis. 2023 Jul 5;18(1):177. doi: 10.1186/s13023-023-02780-9.