Objective: To delineate clinical, molecular, and radiological landscape of patients with Neurodegeneration with Brain Iron Accumulation (NBIA) in a nationwide Indian cohort.

Background: NBIAs are a complex group of genetic disorders with heterogeneous clinical features. Data from geographically diverse populations remains limited and is crucial in enhanced understanding of key characteristics.

Method: Patients with clinical and/or radiological features consistent with NBIA and genetic confirmation were recruited from 12 centers across India with movement disorders expertise and through Parkinson Research Alliance of India. Participating clinicians completed a predesigned proforma to capture clinical, genetic, and radiological data.

Results: Fifty patients (male: female= 28: 22) with pathogenic variants in six different genes (PLA2G6, PANK2, c9orf12, WDR45, VAC14 and FA2H) were identified. PLA2G6-associated neurodegeneration (PLAN) was the major NBIA subtype (n=25, 52.1%), followed by pantothenate kinase associated neurodegeneration (PKAN) (n=13; 27%), MPAN (n=8; 16.6%) and one each of Wodehouse-Sakati syndrome, FAHN and VAC14-associated neurodegeneration. The outstanding features were dystonia (90%) and parkinsonism (85%) across all NBIAs, with noticeable oromandibular dystonia, retrocollis and opisthotonos. Striking spasticity was seen in MPAN. Patients with PLAN had prominent cognitive impairment (50%), psychiatric abnormalities (25%), pyramidal signs (33.3%), postural instability (40%) cerebellar ataxia (35%), and bowel/bladder disturbances (60%). Iron deposition in basal ganglia/substantia nigra was seen in 85% of PLAN patients. The most common PLA2G6 variant, seen in 45%, was the c.2222G>A variant. All such patients exhibited severe cognitive/psychiatric comorbidities. Two patients with PLAN with levodopa-responsive parkinsonism and early levodopa-induced dyskinesias underwent STN-DBS with good improvement. One patient with atypical PKAN underwent Gpi-DBS and one had pallidotomy with partial benefit.

Conclusion: This study highlights the complex phenotypes observed in patients with NBIA. PLAN was the most common NBIA in Indian patients. Genotype-phenotype correlation was noted for the c.2222G>A variant, which correlated with prominent cognitive and/or psychiatric dysfunction. MRI iron deposition was not seen in 15% patients with PLAN.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-landscape-of-neurodegeneration-with-brain-iron-accumulation-in-indian-patients-lessons-from-a-multicentric-cross-sectional-study/