Profiling a rare genetic disorder

A deep dive into data about a rare amino acid deficiency points the way towards early diagnosis and drug discovery



Researchers from across Saudi Arabia have analysed clinical data from patients with  the often fatal metabolic disorder asparagine synthetase deficiency (ASNSD), revealing new criteria for diagnosis and potential treatment. ASNSD can be treated if detected early, but clinicians struggle to promptly diagnose the condition.

Our bodies naturally manufacture the amino acid asparagine, and asparagine synthetase is a critical enzyme in this process. 

ASNSD diagnosis is challenging because tests based on biochemical analysis of asparagine levels in plasma or cerebrospinal fluid (CSF) have proven unreliable. Naif Almontashiri at Taibah University in Saudi Arabia sought to get a deeper understanding of this disorder, and approached Majid Alfadhel at KAIMRC, an established expert on ASNSD. “We collaborated with him and submitted our unpublished cases, collecting the largest cohort in the world for this disorder,” says Alfadhel.

The researchers examined clinical reports about 31 ASNSD patients from 13 Saudi families and identified some consistent patterns. Seizures and spasticity were particularly common neurological manifestations, and all affected children also presented with malformation of the brain, skull and facial features. They also identified a range of other symptoms that only occurred in a subset of families, including manifestations affecting the bones, lungs, skin, or hearing.

Their analysis also confirmed that many patients retained modest levels of asparagine in their plasma and CSF, and the team showed that this diagnostic test has a false-negative rate of 17%. But the authors also identified potentially useful alternative indicators. “We delineated clinical phenotypes and radiological findings which could help diagnosis before molecular genetic testing,” says Alfadhel. This is important, because the progression of the disease can be halted in some patients by prompt supplementation of asparagine.

This study uncovered a range of different mutations in the asparagine synthetase gene, and Alfadhel is now looking to understand how these contribute to the severity and manifestation of the disease. “Understanding the molecular genetic mechanisms will help us with treatment discovery,” he says.

These insights could also assist in efforts to develop a robust test for this condition as part of the national premarital screening program (Healthy Marriage Program) in Saudi Arabia for rare genetic disorders.


  1. Alharby, E., Faqeih, E.A., Saleh, M., Alameer, S., Almuntashri, M.  et al. Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort. Genet. Med. Published online 3 August 2020. | article

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