Nancy Drew and the Mystery of the Whole Genome
16/06/11 14:50 Filed in: GenomeWeb Daily Scan
Submitted by S. Pelech - Kinexus on Thu, 06/16/2011 - 14:50.
If the Beery twins were already known to have low levels of dopamine, presumably tests should have been performed to assess the levels of other neurotransmitters that may 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 lead to a further reduction in serotonin levels in the twins. It seems that the whole sequencing of the genomes of these twins, their parents and grandparents may have been completely unnecessary if the treating clinicians had a better understanding of basic biochemistry and performed obvious tests of serotonin levels.
While I am sure that it was very satisfying for the treating clinicians to identify the precise genetic defects in these twins and publish their results in Science Translational Medicine, the fact of the matter is that deep genome sequencing was not necessary to produce improvement in the clinical management of these patients.
Link to the original blog post.
If the Beery twins were already known to have low levels of dopamine, presumably tests should have been performed to assess the levels of other neurotransmitters that may 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 lead to a further reduction in serotonin levels in the twins. It seems that the whole sequencing of the genomes of these twins, their parents and grandparents may have been completely unnecessary if the treating clinicians had a better understanding of basic biochemistry and performed obvious tests of serotonin levels.
While I am sure that it was very satisfying for the treating clinicians to identify the precise genetic defects in these twins and publish their results in Science Translational Medicine, the fact of the matter is that deep genome sequencing was not necessary to produce improvement in the clinical management of these patients.
Link to the original blog post.