The phospholipase A2 group VI (PLA2G6) gene is associated with several neurodegenerative diseases with diverse clinical presentations. 1 Nearly 200 variants of PLA2G6 have been reported in 3 gene variant databases (ClinVar, Human Gene Mutation Database (HMGD), and Leiden Open Variation Database (LOVD)). This significant genetic heterogeneity is considered a contributing factor to this clinical spectrum and diversity. 2
These neurodegenerative diseases are classified according to age of onset and clinical progression. One such condition is the rare, neurodegeneration with brain iron accumulation (NBIA)/hereditary dystonia (DYT)/designated genes involved in familial Parkinson's disease (PARK)‐PLA2G6 or autosomal recessive parkinsonism type 14 (Online Mendelian Inheritance in Man #612953), characterized by parkinsonism and early‐onset dystonia. 1 , 3 , 4 , 5 , 6 The clinical spectrum of NBIA/DYT/PARK‐PLA2G6 comprises severe cognitive decline, psychiatric disorders such as depression and hallucinations, dysarthria, dysphonia, dysphagia, rigid‐akinetic syndrome, ataxia, and epilepsy. 4 , 7
Herein we describe a Brazilian patient with early‐onset neurodegeneration, iron brain accumulation on imaging, and heterozygous PLA2G6 variants, compatible with the early‐onset dystonia–parkinsonism phenotype.
A 42‐year‐old woman experienced an onset of clinical manifestations with psychiatric symptoms, including mood changes, fear, and aggressiveness at the age of 24 years. There had been no problems at birth, and her neurodevelopmental milestones were normal.
The patient developed stiffness probably caused by neuroleptic use (haloperidol and aripiprazole) attributed to psychiatric symptoms. This side effect was improved by the short‐term use of biperiden. During the following years, she had no new psychiatric features, and these medications were withdrawn. Posteriorly, it was necessary the use of sertraline for mood disorder symptoms.
At 31 years of age, she developed atypical symmetrical rigid‐akinetic parkinsonism. Levodopa/benserazida, 100/25 mg twice a day, induced dyskinesias, but with no functional improvement. The patient developed gait impairment and became wheelchair bound at the age of 35 years. This was followed by generalized tonic–clonic seizures 1 year later. Administration of valproic acid and lamotrigine controlled the seizures.
Currently she is bedridden with tracheostomy with continuous positive airway pressure and gastrostomy. She is on akinetic mutism, with generalized and severe rigidity and spasticity, bradykinesia and tremor in both hands, dystonia in the upper limbs, bilateral Babinski sign, and generalized hyperreflexia (Video 1). There is also autonomic dysfunction with urinary incontinence and constipation.
Video 1.
Video shows the progression of clinical manifestation. In 2009, at 32 years of age, the patient was independent and able to walk alone. In 2014, at the age of 37, she presented with significant stiffness, bradykinesia, and freezing of gait and could only walk with assistance. In 2021, at the age of 43, she was bedridden and experienced akinetic mutism.
At 32 years of age, magnetic resonance imaging (MRI) of the brain showed signs of brain volume reduction, which was more evident in the cerebellum, and iron deposition in the caudate nuclei and putamen. Another MRI scan 10 years later demonstrated generalized cerebral and cerebellar atrophy with severe caudate nuclei atrophy. Susceptibility‐weighted images revealed more extensive iron accumulation in the globus pallidus and putamen, including the posterior portion (Fig. 1).
FIG. 1.
Brain magnetic resonance imaging abnormalities. (A) Coronal T2: parietal and occipitotemporal atrophy with cerebellar atrophy involving the vermis and cerebellar hemispheres. (B) Axial fluid‐attenuated inversion recovery: atrophy of the temporal poles with hypersignaling of the uncus and hippocampus. (C) Axial T2: marked frontal and parietal atrophy with increased dimensions of the lateral ventricles and thickening of the skull cap. (D) Sagittal T1: thinning of the corpus callosum and cerebellar vermis and relative preservation of the brain stem. (E) Axial susceptibility (susceptibility‐weighted image): hyposignal related to iron deposition in the globus pallidum, putamen, and caudate nuclei. (F) Axial T2 (previous exam performed 10 years ago): comparison showing mild cerebral atrophy.
Repeated electroencephalograms did not show any abnormalities. An electroneuromyography failed to show abnormalities. Serum copper, ceruloplasmine, and creatine phosphokinase levels were normal. Acanthocytes were not detected in the blood smear. Genetic tests for spinocerebellar ataxia types 1, 2, 3, and 7 were normal.
Examination of the family revealed no consanguinity, and the patient's 2 siblings are healthy. Next‐generation sequencing of a panel of 56 genes related to dystonia was performed using the MiSeq instrument (Illumina). Using the software Variant Interpreter (version 2.13), 2 PLA2G6 missense variants were detected in the proband (NM_003560.2; NP_003551.2): c.386T>C (p.Leu129Pro), classified as variant of uncertain significance, and c.1627C>T (p.Arg543Cys), classified as probably pathogenic.
Sanger sequencing of healthy family members confirmed that her mother was heterozygous for the variant in exon 3 (c.386T>C) and the father was heterozygous for the variant in exon 12 (c.1627C>T) of PLA2G6. Her sister was heterozygous, similar to the mother, whereas her brother did not carry either of the PLA2G6 variants. The Supplementary Material contains more details of the genetic analysis.
Pathogenic PLA2G6 variants are among the causes of early‐onset parkinsonism. 8 They have been described in homozygosity or in compound heterozygosity. 9 , 10 NBIA/DYT/PARK‐PLA2G6 is a rare autosomal recessive disease with a wide variety of clinical manifestations. It has been reported in populations, including Chinese, Indian, and Pakistanis. 3 , 10 Here we describe the first report of the NBIA/DYT/PARK‐PLA2G6 phenotype in a Brazilian patient, without consanguinity or a family history of similar cases.
The clinical picture of our patient is similar to that of other NBIA/DYT/PARK‐PLA2G6 cases reported in the literature. Lack of functional improvement despite the presence of dyskinesias after brief exposure to levodopa has also been described in other patients with the same condition. 4
Brain MRI findings in patients with NBIA/DYT/PARK‐PLA2G6 are nonspecific. They may include diffuse cerebral atrophy, gliosis, and accumulation of iron. 1 In our case, brain MRI revealed cerebral and cerebellar atrophy and iron brain accumulation in the putamen and caudate nuclei. These findings were more evident on the second MRI scan. This demonstrates the importance of dedicated MRI protocols for the assessment of neurodegenerative disorders.
In conclusion, our case report illustrates the clinical and radiological features of the wide phenotype of NBIA/DYT/PARK‐PLA2G6, suggesting that this condition should be investigated even in patients without consanguinity.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
P.O.: 1A, 1B, 1C, 2A
V.M.: 1B, 2A, 2B
D.C.: 1B, 1C, 2A, 2B
B.M.: 1C
A.F.: 1A
F.C.: 2B
Disclosures
Ethical Compliance Statement: This study was approved by the Research Ethics Committee of the Association of Social Pioneers of the Sarah Network of Rehabilitation Hospitals. A written informed consent form was signed by the person responsible for the patient. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest: No specific funding was received for this study. The authors declare that there are no conflicts of interest relevant to this study.
Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.
Supporting information
Supplementary File S1. Genetic data analysis.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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Supplementary Materials
Supplementary File S1. Genetic data analysis.