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Neurodegeneration with brain iron accumulation: a case series highlighting phenotypic and genotypic diversity in 20 Indian families

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Abstract

Neurodegeneration with brain iron accumulation (NBIA) is an umbrella term encompassing various inherited neurological disorders characterised by abnormal iron accumulation in basal ganglia. We aimed to study the clinical, radiological and molecular spectrum of disorders with NBIA. All molecular-proven cases of NBIA presented in the last 5 years at 2 tertiary care genetic centres were compiled. Demographic details and clinical and neuroimaging findings were collated. We describe 27 individuals from 20 unrelated Indian families with causative variants in 5 NBIA-associated genes. PLA2G6-associated neurodegeneration (PLAN) was the most common, observed in 13 individuals from 9 families. They mainly presented in infancy with neuroregression and hypotonia. A recurrent pathogenic variant in COASY was observed in two neonates with prenatal-onset severe neurodegeneration. Pathogenic bi-allelic variants in PANK2, FA2H and C19ORF12 genes were observed in the rest, and these individuals presented in late childhood and adolescence with gait abnormalities and extrapyramidal symptoms. No intrafamilial and interfamilial variability were observed. Iron deposition on neuroimaging was seen in only 6/17 (35.3%) patients. A total of 22 causative variants across 5 genes were detected including a multiexonic duplication in PLA2G6. The variants c.1799G > A and c.2370 T > G in PLA2G6 were observed in three unrelated families. In silico assessments of 8 amongst 9 novel variants were also performed. We present a comprehensive compilation of the phenotypic and genotypic spectrum of various subtypes of NBIA from the Indian subcontinent. Clinical presentation of NBIAs is varied and not restricted to extrapyramidal symptoms or iron accumulation on neuroimaging.

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Data Availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Funding

We received support from the following: “The Department of Biotechnology, New Delhi, India” (Grant number: BT/PR26428/MED/12/783/2017), “Indian Council of Medical Research, New Delhi, India” (Grant Number: 33/9/2019-TF/Rare/BMS, 33/2/2019-TF/Rare/BMS) and “National Institutes of Health,NIH, USA” (Grant Number: 1R01HD093570-01A1).

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Authors and Affiliations

  1. Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, India

    Haseena Sait, Somya Srivastava, Manmohan Pandey, Kausik Mandal, Deepti Saxena, Arya Shambhavi, Shubha R. Phadke & Amita Moirangthem

  2. Department of Radiodiagnosis, Medanta Hospital, Lucknow, India

    Deepak Ravichandran

  3. Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India

    Anju Shukla, Purvi Majethia & Lakshmi Priya Rao

  4. Neurology Division, Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children’s Hospital, New Delhi, India

    Suvasini Sharma

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  1. Haseena Sait
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Contributions

• AM: 1A,1B,1C,3B,2C.

• HS: Writing -2A,2B,3B.

• SS,AS,PM,LP: 2C

• MP: 2A,2B

• DR: 2A

• AS: 2C,3B

• KM,DS,SS: 1C,2C,3B

• SP: 1A,1B,1C,3B

Corresponding author

Correspondence to Amita Moirangthem.

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Ethical approval

The study was approved by the institutional ethics committees of Sanjay Gandhi Postgraduate Institute of Medical Sciences and Kasturba Medical College. Informed written consent was obtained from the parents of study participants. 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.

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Sait, H., Srivastava, S., Pandey, M. et al. Neurodegeneration with brain iron accumulation: a case series highlighting phenotypic and genotypic diversity in 20 Indian families. Neurogenetics 24, 113–127 (2023). https://doi.org/10.1007/s10048-023-00712-0

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