Mutation screening of PLA2G6 in Japanese patients with early onset dystonia-parkinsonism

Abstract

A recessive mutation in PLA2G6, which is known to cause infantile neuroaxonal dystrophy (INAD) and neurodegeneration associated with brain iron accumulation (NBIA), has recently been shown to be responsible for PARK14-linked dystonia-parkinsonism. To study the frequency of PLA2G6 mutations, including those caused by gene rearrangement in patients with parkinsonism, we performed direct sequencing and investigated copy number variations (CNVs) of this gene in 109 Japanese patients with parkinsonism. Direct sequencing revealed a homozygous mutation (c.1495G>A; p.A499T), which is likely to be pathogenic and is already registered as rs141045127, and two compound-heterozygous mutations we have previously reported. No CNVs in PLA2G6 were detected in our subjects. Our results suggest that CNV in PLA2G6 is rare in parkinsonism, at least in the Japanese population, in contrast to the reports of its frequency in INAD. Further large studies in various populations are warranted to elucidate what causes the difference in frequencies of PLA2G6 rearrangement mutations between INAD and dystonia-parkinsonism.

Neuropathology of PARK14 is identical to idiopathic Parkinson's disease

“…Cardiac uptake of meta‐iodobenzylguanidine, a physiological analog of norepinephrine, was reduced. Genetic analysis of these siblings revealed a homozygous mutation of p.A499T (c. 1495G>A), as reported previously . The patient died of sepsis at the age of 48.…”

Dissecting the Phenotype and Genotype of PLA2G6‐Related Parkinsonism

“…Eyelid-opening apraxia was reported in six cases. 8,24,25,55 Dysarthria was described in 29/30 (96.7%; Fig. 1E) cases.…”

Non-Motor Symptoms in PLA2G6-Associated Dystonia-Parkinsonism: A Case Report and Literature Review

“…Taking into account the information on all the PLAN-DP patients published to date, we found that NMS are very frequent in this condition, evident in more than 80% of patients. NMS preceded the diagnosis of parkinsonism in 46% of patients [ 4 , 16 , 18 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 38 ], sometimes even 20 years earlier. Unlike idiopathic Parkinson´s disease (iPD) in which hyposmia, REM sleep behavior disorder, depression and constipation are the most frequent premotor symptoms [ 39 ], neuropsychiatric symptoms dominate the clinical landscape in pre-motor PLAN-DP.…”

“…In this review, impaired cognition was the most frequent NMS, evident in 64% of patients [ 4 , 7 , 16 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 28 , 29 , 32 , 33 , 37 , 38 ]. This phenomenon was detected before PD diagnosis usually manifested as school failure [ 4 , 18 , 24 , 25 , 29 ] and after the diagnosis of parkinsonism. Memory complaints are frequent in early iPD [ 39 ], although cognitive changes are usually subtle [ 41 ].…”

“…We also searched the national Dialnet and IBECS databases using the same terms in Spanish. We found 67 articles, 25 of which described one or more patients [ 4 , 6 , 7 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. We also included another article published after November 2019 [ 38 ].…”