PUS3 – Related Syndrome

PUS3-Related neurodevelopmental disorder is an ultra-rare, severe neurodevelopmental and multi-system disorder caused by pathogenic variants in the PUS3 gene. The clinical picture is heterogeneous but characterized by a combination of severe intellectual disability (ID), epilepsy, microcephaly, and systemic issues such as nephropathy (kidney abnormalities). The condition is considered extremely rare, with only a small number of affected individuals described in medical literature (PubMed, OMIM).

PUS3-Related Disorder is caused by pathogenic changes affecting the PUS3 (Pseudouridylate Synthase 3) gene, located on chromosome 11q24.2 – OMIM ID: 616283

https://www.omim.org/entry/616283?search=PUS3&highlight=pus3

The PUS3 gene encodes the enzyme Pseudouridylate Synthase 3. This enzyme is responsible for a critical post-transcriptional RNA modification, specifically converting uridine to pseudouridine ($\Psi$) on transfer RNA (tRNA) molecules (typically at positions 38 and 39). Biallelic pathogenic variants in PUS3 lead to a loss-of-function of this enzyme, causing a severe reduction in pseudouridylation of tRNA. Since these pseudouridine modifications are vital for the stability, structure, and translational fidelity of tRNA, their absence impairs overall protein synthesis in the cell, driving the severe neurodevelopmental and systemic pathology.

The clinical presentation of PUS3-Related Disorder is complex and typically severe, with onset in early childhood.

• Neurodevelopmental: Global developmental delay is universal, leading to moderate-to-severe intellectual disability. Most affected individuals are nonverbal, and attainment of independent walking is significantly delayed or not achieved.
• Neurological: Epilepsy is a common feature, with varied seizure types and age of onset. Hypotonia (low muscle tone) is frequently reported. Microcephaly (small head circumference) is a characteristic finding.
• Neuroimaging: Brain MRI frequently identifies leukoencephalopathy (white matter abnormalities), which can be widespread, involving both the cerebral and cerebellar white matter. Signs of brain volume loss or cerebellar hypoplasia have also been reported.
• Systemic and Other: A critical non-neurological feature is nephropathy (kidney disease), which can manifest as proteinuria or nephrotic syndrome, sometimes with a later onset in older children or adults. Growth failure and short stature are common. Other findings include certain dysmorphic facial features (though no specific gestalt is recognizable), retinal dystrophy, and, occasionally, congenital heart defects.

Although presentations vary, clinicians typically suspect PUS3-related disease when the following features appear together:

• Global developmental delay / intellectual disability
• Microcephaly (often congenital or early-onset)
• Hypotonia
• Growth delay
• Variable congenital anomalies (may include kidney, cardiac, or skeletal findings)
• Speech impairment
• Sometimes seizures (not always reported but possible)

Clinical features alone are not diagnostic, but they guide the decision to pursue genetic testing. The only definitive way to diagnose PUS3-associated syndrome is by detecting biallelic pathogenic variants in PUS3.

Recommended genetic tests include:

1.      Whole-exome sequencing (WES)

• Most common method to diagnose PUS3-associated syndrome.
• Identifies both known and novel pathogenic variants.

2. Whole-genome sequencing (WGS)
   • Useful if WES is negative but clinical suspicion remains.
   • Detects non-coding variants or structural variants affecting PUS3.
3. Targeted gene panels for neurodevelopmental disorders
   • Some panels include PUS3, but not all.
   • Useful if rapid diagnosis is needed and the gene is included.

There is currently no disease-modifying or curative treatment for PUS3-Related Disorder. Management is supportive and symptomatic, requiring coordinated care from a multidisciplinary team.

• Neurological Care: Anti-seizure medications are used to control epilepsy. Comprehensive physical, occupational, and speech therapy are essential to manage global developmental delay, hypotonia, and motor deficits.
• Systemic Care: Regular monitoring and management of kidney function by a nephrologist is necessary for individuals with nephropathy. Other medical manifestations are managed by appropriate specialists.