# PNPT1 Spectrum Disorders: An Underrecognized and Complex Group of Neurometabolic Disorders

## TL;DR

This paper describes a rare neurometabolic disorder caused by a mutation in the PNPT1 gene, presenting with spastic ataxia, optic atrophy, and cognitive decline.

## Contribution

The paper highlights the underrecognized complexity of PNPT1-related disorders and their distinct clinical features.

## Key findings

- A heterozygous pathogenic variant in the PNPT1 gene was identified in a patient with spastic ataxia and optic atrophy.
- PNPT1 mutations can present with a wide range of neurological symptoms, including cognitive decline and visual loss.
- Clinicians should consider PNPT1-related disorders in cases with spastic paraplegia and optic atrophy.

## Abstract

An 18-year-old man presented with slowly progressive infancy-onset spasticity of the lower limbs and cerebellar ataxia, associated with painless strabismus, intellectual disability, urinary incontinence, bilateral progressive visual loss, and cognitive decline since early adolescence. A neurological examination disclosed spastic dysarthria, left eye divergent strabismus, bilateral ophthalmoparesis, impaired smooth pursuit, severe spastic paraparesis of the lower limbs with global brisk tendon reflexes, bilateral extensor plantar responses, and bilateral ankle clonus reflex. Bilateral dysdiadochokinesia of the upper limbs, Stewart-Holmes rebound phenomenon, bilateral dysmetria, and a bilateral abnormal finger-to-nose test were observed. Markedly reduced bilateral visual acuity (right side 20/150, left side 20/400) and moderate to severe optic atrophy were detected. Neuroimaging studies showed cerebellar atrophy and bilateral optic nerves and optic tract atrophy as the main findings. As a complicated Hereditary Spastic Paraplegia, autosomal dominant Spinocerebellar Ataxia, or inherited neurometabolic disorders were suspected, a large next-generation sequencing-based gene panel testing disclosed the heterozygous pathogenic variant c.162-1G>A in intron 1 of the PNPT1 gene. A diagnosis of PNPT1-related spastic ataxia was established. Clinicians must be aware of the possibility of PNPT1 pathogenic variants in cases of spastic ataxia and spastic paraplegias that are associated with optic atrophy and marked cognitive decline, regardless of the established family history of neurological compromise.