Recessive ITPA mutations cause an early infantile encephalopathy

Area of Science:

• Neurogenetics
• Molecular Metabolism
• Medical Imaging

Background:

• A novel heritable encephalopathy presents with severe neurological deficits and early mortality.
• Previous research linked ITPA gene variants solely to drug adverse reactions, not primary genetic disorders.
• The precise etiology of this rare encephalopathy remained unidentified.

Purpose of the Study:

• To identify the genetic cause of a newly observed heritable encephalopathy.
• To characterize the clinical and neuroimaging features of affected patients.
• To investigate the role of the ITPA gene in this neurological disorder.

Main Methods:

• Utilized Magnetic Resonance Imaging (MRI) pattern analysis to identify patients with similar brain abnormalities.
• Performed homozygosity mapping and whole exome sequencing (WES) to detect causative gene mutations.
• Assessed inosine triphosphate pyrophosphatase (ITPase) enzyme activity in patient samples.

Main Results:

• Identified seven patients from four families with a consistent MRI pattern including T2 signal abnormalities and diffusion restriction in specific brain tracts, alongside delayed myelination and atrophy.
• Patients exhibited early infantile onset encephalopathy with microcephaly, seizures, cardiac defects, and premature death.
• Whole exome sequencing revealed recessive loss-of-function mutations in the ITPA gene, with severely reduced ITPase activity observed in patients.

Conclusions:

• This study is the first to associate mutations in the ITPA gene with a human disorder, a novel heritable encephalopathy.
• ITPA mutations disrupt purine metabolism, leading to toxic accumulation of noncanonical nucleotides, neuronal apoptosis, and severe neurological impairment.
• Combining MRI pattern recognition with WES is an effective strategy for rapid diagnosis of unclassified genetic encephalopathies.