LAUSR

The phospholipase A2 group VI (PLA2G6) gene is associated with several neurodegenerative diseases with diverse clinical presentations. 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. 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. 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. 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 During the following years, she had no new psychiatric features, and these medications were withdrawn.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 rigidakinetic 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. 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). 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