An atypical case of FA2H-related HSP35 with subtle neuroimaging findings and a novel variant in a young adult with spastic paraparesis

Subhajit Roy ¹, Pooja Mailankody ², Gautham Arunachal ³

⁰Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, Karnataka, India.

Acta Neurologica Belgica +

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September 27, 2025

View abstract on PubMed

Summary

A rare genetic mutation in the FA2H gene caused spastic paraparesis in a young woman, expanding the known symptoms of this condition. This case highlights the need for genetic testing in atypical spastic paraparesis cases.

Area Of Science

Genetics
Neurology
Rare Diseases

Background

Hereditary spastic paraparesis (HSP) encompasses a group of neurological disorders.
FA2H gene mutations are a known cause of autosomal recessive spastic paraparesis, but phenotypic variability exists.

Purpose Of The Study

To report a novel presentation of FA2H-related HSP.
To broaden the understanding of the phenotypic spectrum associated with FA2H mutations.
To emphasize the diagnostic utility of genetic testing in complex neurological cases.

Main Methods

Clinical case report of a young Indian woman.
Neuroimaging (MRI) to assess spinal cord and brain structures.
Whole exome sequencing (WES) with mitochondrial DNA analysis to identify genetic variants.

Main Results

A homozygous deletion (c.32_34delTCT, p.Phe11del) in the FA2H gene was identified, classified as a likely pathogenic variant.
The patient presented with progressive spastic paraparesis, skeletal deformities, and subtle oculomotor signs, expanding the known phenotype.
MRI showed diffuse spinal cord atrophy, but other investigations were non-contributory.

Conclusions

This case expands the known clinical spectrum of FA2H-related HSP, including atypical and late-onset presentations.
Genetic testing is essential for diagnosing FA2H-related HSP, especially in consanguineous populations and when imaging is non-specific.
Early diagnosis through genetic analysis aids in prognostication and genetic counseling for affected families.

Keywords:

FA2H HSP 35 Hereditary spastic paraplegia Novel Whole exome sequencing