# Clinical Features of Families with a Novel Pathogenic Mutation in Sepiapterin Reductase

## TL;DR

A new genetic mutation in SPR causes a rare neurological disorder with symptoms like developmental delays and cognitive issues, which can be managed with specific treatment.

## Contribution

A novel pathogenic SPR mutation is identified and linked to clinical features in two consanguineous families.

## Key findings

- A homozygous SPR c.560A>G mutation was found to segregate with disease in affected individuals.
- Molecular dynamics analysis suggests the mutation affects structural integrity and enzyme function.
- Elevated sepiapterin and biopterin levels in cerebrospinal fluid support the genetic diagnosis of SRD.

## Abstract

Sepiapterin Reductase Deficiency (SRD) is a rare inherited neurometabolic disorder caused by variants in the SPR gene, which may lead to developmental delays, psychomotor retardation, and cognitive impairments. Two consanguineous North African and Middle Eastern families are reported with multiple affected individuals presenting with developmental delay, ataxia, hypotonia, fatigue, and ptosis, or parkinsonism and cognitive impairment. Exome sequencing revealed a novel homozygous SPR c.560A>G (p.Glu187Gly) mutation that segregates with disease. According to molecular dynamics analysis, the substitution is predicted to compromise structural integrity, likely affecting ligand binding and catalytic activity. Elevated cerebrospinal fluid sepiapterin and biopterin levels, along with low neurotransmitter levels, were concordant with a genetic diagnosis of SRD and the reclassification of this variant as pathogenic. SRD patients manifest a broad constellation of symptoms, albeit well-managed using low-dose L-dopa/carbidopa. This study highlights the value of genetic testing in expediting early diagnosis and intervention to mitigate the onset of this disorder.