A Happy Sequencing Ending
27/08/12 13:02 Filed in: GenomeWeb Daily Scan
Submitted by S. Pelech - Kinexus on Mon, 08/27/2012 - 13:52
This is one of the rare examples of where whole genome-wide DNA sequencing is reported to provide vital clues as to the underlying nature of an illness that afflicted children. It's actually old news and was previously covered by Richard Knox at the NPR Shots (http://www.npr.org/blogs/health/2011/06/18/137204964/genome-maps-solve-m...) and The Daily Scan (http://www.genomeweb.com/blog/nancy-drew-and-mystery-whole-genome). It appears that Dr. Topol's NBC interview is aimed to drum up support for a research project called IDIOM at Scripps Health, which seeks to use genome sequencing to help determine the causes of idiopathic disease, or rare conditions that are unresponsive to regular treatment.
The problem with this example, which I previously commented upon in the first Daily Scan report, is that it is unclear that genome-wide DNA sequencing of these twins, their parents and grandparents was even necessary in this case if the treating clinicians had a better understanding of basic biochemistry. The Beery twins were already known to have low levels of dopamine, and tests should have been performed to assess the levels of other neurotransmitters that share overlapping metabolic pathways. In many cases of dystonia that are DOPA-responsive, it is well known that these can arise from sepiapterin reductase (SPR) deficiency (DRDSPRD) [MIM:612716]. The disease has been well described to be due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in the synthesis of 5,6,7,8-tetrahydrobiopterin (BH4) catalyzed by SPR.
Noradrenaline is produced from dopamine so the inclusion of L-dopa would have resulted in normalization of the noradrenaline levels in these patients. However, serotonin is produced from 5-hydroxytryptophan by aromatic amino acid decarboxylase, which is the same enzyme that produces dopamine from L-dopa. BH4 is a cofactor required for the enzymatic activity of aromatic amino acid decarboxylase. Supplementation with higher levels of L-dopa may have been able to overcome deficiencies in the enzymatic activity of aromatic amino acid decarboxylase. However, substrate competition may have well led to a further reduction in serotonin levels in the twins. The attending physicians should have performed obvious tests for serotonin levels in the Beery twins in the first place.
Link to the original blog post
This is one of the rare examples of where whole genome-wide DNA sequencing is reported to provide vital clues as to the underlying nature of an illness that afflicted children. It's actually old news and was previously covered by Richard Knox at the NPR Shots (http://www.npr.org/blogs/health/2011/06/18/137204964/genome-maps-solve-m...) and The Daily Scan (http://www.genomeweb.com/blog/nancy-drew-and-mystery-whole-genome). It appears that Dr. Topol's NBC interview is aimed to drum up support for a research project called IDIOM at Scripps Health, which seeks to use genome sequencing to help determine the causes of idiopathic disease, or rare conditions that are unresponsive to regular treatment.
The problem with this example, which I previously commented upon in the first Daily Scan report, is that it is unclear that genome-wide DNA sequencing of these twins, their parents and grandparents was even necessary in this case if the treating clinicians had a better understanding of basic biochemistry. The Beery twins were already known to have low levels of dopamine, and tests should have been performed to assess the levels of other neurotransmitters that share overlapping metabolic pathways. In many cases of dystonia that are DOPA-responsive, it is well known that these can arise from sepiapterin reductase (SPR) deficiency (DRDSPRD) [MIM:612716]. The disease has been well described to be due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in the synthesis of 5,6,7,8-tetrahydrobiopterin (BH4) catalyzed by SPR.
Noradrenaline is produced from dopamine so the inclusion of L-dopa would have resulted in normalization of the noradrenaline levels in these patients. However, serotonin is produced from 5-hydroxytryptophan by aromatic amino acid decarboxylase, which is the same enzyme that produces dopamine from L-dopa. BH4 is a cofactor required for the enzymatic activity of aromatic amino acid decarboxylase. Supplementation with higher levels of L-dopa may have been able to overcome deficiencies in the enzymatic activity of aromatic amino acid decarboxylase. However, substrate competition may have well led to a further reduction in serotonin levels in the twins. The attending physicians should have performed obvious tests for serotonin levels in the Beery twins in the first place.
Link to the original blog post