Objective: The aim is to describe a Brazilian family with new VUS of PLA2G6 in two brothers with clinical symptoms of PLAN.

Background: PLAN is an autosomal recessive neurodegenerative disease with brain iron accumulation (NBIA). There is a great phenotypic variability, usually presenting clinically with a combination of dystonia, parkinsonism, spasticity and cognitive decline. Several mutations in the PLA2G6 gene have been described being responsible for the disease.

Method: We describe symptoms and genetic findings of a Brazilian family from Porto Alegre.

Results: A family with two sons was evaluated in Hospital Conceição. The parents were asymptomatic and unrelated. The older son (HSP) presented his first symptoms at the age of 18 – gait disturbance and cognitive impairment, impoverished speech, slow thinking. Symptoms progressed with difficulties in reading and understanding simple tasks. Motor symptoms included spasticity and hyperreflexia manly in lower limbs, bilateral Babinski sign, muscle atrophy and bradykinesia. Dystonic closure of the mouth prevented oral feeding. Last time the patient was evaluated, he was bedridden due to severe spasticity, with supranuclear gaze palsy and obeying simple commands. He passed away at the age of 22. The younger brother (TSP) was evaluated once, at the age of 17, one year after onset of mild gait imbalance; he had asymmetric spasticity and hyperreflexia in all four limbs, bradykinesia (including facial) and intention tremor, worse on his left side. There was no cognitive impairment at the time. HSP´s MRI at 20 years old did not show any iron accumulation and TSP´s MRI was not performed because of no family approval. The two patients and their parents underwent genetic testing; HSP and TSP had both a variant of uncertain significance (VUS) for PLA2G6 (c.2032A>G (p.Lys678Glu) and c.1642G>A (p.Val548Met)). The parents were tested for gene segregation – the mother had variant c.1642G>A (p.Val548Met) and the father had variant c.2032A>G (p.Lys678Glu).

Conclusion: HSP and TSP presented early symptoms of a combination of spasticity, parkinsonism, dystonia and cognitive decline. These symptoms are compatible with the diagnosis of PLAN. This NBIA is known for showing no iron accumulation on MRI. Gene segregation corroborates that these variants are responsible for the clinical presentation. Considering symptoms and genetic findings, these two new variants could be considered pathogenic mutations of the gene PLA2G6.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/case-report-of-a-brazilian-family-with-new-vus-for-plan/