New Insights of Phospholipase A2 Associated Neurodegeneration Phenotype Based on the Long-Term Follow-Up of a Large Hungarian Family

Abstract

IntroductionPhospholipase A2-associated Neurodegeneration (PLAN) is a group of neurodegenerative diseases associated with the alterations of PLA2G6. Some phenotype-genotype association are well known but there is no clear explanation why some cases can be classified into distinct subgroups, while others follow a continuous clinical spectrum.MethodsLong-term neurological, and psychiatric follow-up, neuropathological, radiological, and genetic examinations, were performed in three affected girls and their family.ResultsTwo 24-years old twins and their 22-years old sister harbored the p.P622S, and p.R600W mutation in PLA2G6. The age of onset and the most prominent presenting symptoms (gaze palsy, ataxia, dystonia, psychomotor regression indicated atypical neuroaxonal dystrophy (ANAD), however, optic atrophy, severe tetraparesis would fit into infantile neuroaxonal dystrophy (INAD). All siblings had hyperintensity in the globi pallidi and substantiae nigrae which is reported in ANAD, whereas it is considered a later neuroradiological marker in INAD. The slow progression, rigidity, bradykinesis, and the prominent psychiatric symptoms indicate PLA2G6-related dystonia-parkinsonism. Abnormal mitochondria, lipid accumulation and axonal spheroids were observed in the muscle and nerve tissue. Brain deposition appeared 6 years following the initial cerebellar atrophy. Mild MRI alterations were detected in the asymptomatic carrier parents.ConclusionThe colorful clinical symptoms, the slightly discordant phenotype, and the neuroimaging data in the family supports the view that despite the distinct definition of age-related phenotypes in PLAN, these are not strict disease categories, but rather a continuous phenotypic spectrum. The mild MRI alterations of the parents and the family history suggest that even heterozygous pathogenic variants might be associated with clinical symptoms, although systematic study is needed to prove this.

Novel PLA2G6 Pathogenic Variants in Chinese Patients With PLA2G6-Associated Neurodegeneration

“…We found 7 references, and predefined data were extracted. The summary of the demographic, clinical, genetic, and radiological data of the reported 21 patients in literature ( Table 2 ) ( 4 , 5 , 14 – 18 ) was shown in Table 1 , where among the 21 ANAD patients, 86% (18/21) have iron deposition, 62% (13/21) parkinsonism, 71% (15/21) cerebellar atrophy, 67% (14/21) pyramidal signs, 52% (11/21) cognitive impairment, and 29% (6/21) nystagmus or Strabismus. Genetic analysis had been conducted on eleven of the reported ANAD patients, and c.238G>A was found to be the most popular mutation, which was detected in two unrelated pedigrees.…”

PLA2G6-Associated Neurodegeneration: A Rare Case Report of Neurodegeneration with Brain Iron Accumulation in Children

“… 6 Another study in 2021 presented a girl with bilateral optic nerve atrophy (without retinal hyperpigmentation). 7 An abnormal iron deposition follows a specific pattern of almost symmetrical involvement of the deep grey matter nuclei of the brain in NBIA. 8 Neurodegeneration with brain iron accumulation (NBIA) encompasses a group of inherited disorders that share the clinical features of an extrapyramidal movement disorder accompanied by varying degrees of intellectual disability and abnormal iron deposition in the basal ganglia (e.g., globuspallidus mainly).…”

“… 2 A case study from Hungary showed the development of severe spastic paraparesis with moderate ataxia in two girls diagnosed with PLAN. 7 …”

“…2 A case study from Hungary showed the development of severe spastic paraparesis with moderate ataxia in two girls diagnosed with PLAN. 7 Mutations in the calcium-independent phospholipase A2 gene PLA2G6, which plays a critical role in cell membrane phospholipid homeostasis, are responsible for PLAN. To date, all defective proteins in the NBIA disorders are known or suspected to be essential for mitochondrial function, but only two have a known role in iron homeostasis: ferritin light chain and ceruloplasmin.…”