I believe I have a novel dominantly inherited familial disorder that inter alia appears to present with conditions associated with P5CR disorders, diarrhea and with neurodegenerative and neuropsychiatric problems that include symptoms of psychosis. The disorder is identifiable by repeating low serum amino acids ornithine and serine.
However, despite considerable efforts and a world-wide search, until recently I was not able to identify a doctor or researcher prepared to investigate my disorder. In other words, the progress I feel I have made has been made on my own.
I identified the tests that showed the most significant abnormalities and I established what these results likely meant in terms of the mechanism of my disorder. I am making progress in identifying effective treatments. I feel I am a small part of the patient revolution.
I believe my repeating low ornithine very likely reflects over-activation of a cortisol up-regulated pathway from proline to proline dehydrogenase to pyrroline-5-carboxylic acid to ornithine to ornithine decarboxylase to polyamines. Over-activation of this pathway would explain my repeating low ornithine and would also directly explain my high maltase and lactase on the low side of normal. In support of this conclusion, I refer to Enhanced intestinal synthesis of polyamines from proline in cortisol-treated piglets - Wu et al - 2000.
In the case of the repeating low serine, I am investigating whether there is a connection between my low serine and nitric oxide, sGC, cGMP and/or serine proteases.
Clinically speaking, over-activation of the proline to polyamine pathway would account for the cortisol triggers the disorder presents with, and the prevalence of P5CR conditions in me and my family. This being because P5CR reverses the proline to pyrroline-5-carboxylic acid pathway. RU486, which is reported to abolish cortisol stimulation of the proline to polyamine pathway in pigs, is mifepristone. Mifepristone is a drug which is in late-stage trials for psychotic depression. So over-activity of this polyamine pathway may also account for the symptoms of psychosis that the disorder presents with. A connection between serine and nitric oxide/sGC/cGMP would account for the diarrhea and the symptoms of neuro-degeneration.
I suspect that there may be connections between nitric oxide and sGC/cGMP and the urea cycle, and there may be signalling from the vicinity of sGC/cGMP that results in over-expression of ornithine decarboxylase.
Whilst I recognize that as an ‘amateur’ I may have made mistakes in researching my own condition, I do think the broader conclusions I have drawn that are outlined below have merit and should be addressed by the medical profession.
Some cancers, neurodegenerative and neuropsychiatric diseases are reported to present with recurring abnormal patterns of amino acid abnormalities. Abnormal amino acid profiles are diagnostic of some metabolic disorders, for example, P5CS disorders and some urea cycle disorders. This strongly suggests that under-pinning at least some of these disease states are as yet unidentified metabolic/enzymatic disorders (‘metabolic disorders’). I would class my own disorder as a metabolic disorder.
Whilst identifying the numerous metabolic disorders that may be causative of the disease states may take some time, this information could and should be put to immediate use.
In drug trials for those diseases that are already known to present with abnormal amino acid profiles, it surely makes sense to test the amino acid profiles of the trial participants to assess which underlying disorders/abnormal amino acid profiles respond to the drug being trialled.
Further, given the variety and complexity of metabolic pathways, it is probable that there are a multitude of different metabolic/enzymatic defects responsible for various disease states. If a disease state caused by an underlying metabolic disorder is treated and the underlying disorder is left untreated, the disorder will, in all likelihood, find an alternative expression in another disease state.
There should therefore be a greater focus on identifying and treating the individual patient’s underlying disorder.
In large part, this lack of focus on identifying and targeting the expected plethora of underlying disorders is because resources are mainly focused on finding universal biomarkers and one-size-fits-all treatments for disease states. Identifying and treating the underlying disorders causing each individual’s disease should receive a greater share of research resources.
What surprised me most in reading research was the lack of any systematic or organized approach to by far the majority of the research into the causes of diseases. This lack of co-ordination and structure is obviously not an effective problem solving method.
Rapid Response:
Re: Towards the patient revolution
I believe I have a novel dominantly inherited familial disorder that inter alia appears to present with conditions associated with P5CR disorders, diarrhea and with neurodegenerative and neuropsychiatric problems that include symptoms of psychosis. The disorder is identifiable by repeating low serum amino acids ornithine and serine.
However, despite considerable efforts and a world-wide search, until recently I was not able to identify a doctor or researcher prepared to investigate my disorder. In other words, the progress I feel I have made has been made on my own.
I identified the tests that showed the most significant abnormalities and I established what these results likely meant in terms of the mechanism of my disorder. I am making progress in identifying effective treatments. I feel I am a small part of the patient revolution.
I believe my repeating low ornithine very likely reflects over-activation of a cortisol up-regulated pathway from proline to proline dehydrogenase to pyrroline-5-carboxylic acid to ornithine to ornithine decarboxylase to polyamines. Over-activation of this pathway would explain my repeating low ornithine and would also directly explain my high maltase and lactase on the low side of normal. In support of this conclusion, I refer to Enhanced intestinal synthesis of polyamines from proline in cortisol-treated piglets - Wu et al - 2000.
In the case of the repeating low serine, I am investigating whether there is a connection between my low serine and nitric oxide, sGC, cGMP and/or serine proteases.
Clinically speaking, over-activation of the proline to polyamine pathway would account for the cortisol triggers the disorder presents with, and the prevalence of P5CR conditions in me and my family. This being because P5CR reverses the proline to pyrroline-5-carboxylic acid pathway. RU486, which is reported to abolish cortisol stimulation of the proline to polyamine pathway in pigs, is mifepristone. Mifepristone is a drug which is in late-stage trials for psychotic depression. So over-activity of this polyamine pathway may also account for the symptoms of psychosis that the disorder presents with. A connection between serine and nitric oxide/sGC/cGMP would account for the diarrhea and the symptoms of neuro-degeneration.
I suspect that there may be connections between nitric oxide and sGC/cGMP and the urea cycle, and there may be signalling from the vicinity of sGC/cGMP that results in over-expression of ornithine decarboxylase.
Whilst I recognize that as an ‘amateur’ I may have made mistakes in researching my own condition, I do think the broader conclusions I have drawn that are outlined below have merit and should be addressed by the medical profession.
Some cancers, neurodegenerative and neuropsychiatric diseases are reported to present with recurring abnormal patterns of amino acid abnormalities. Abnormal amino acid profiles are diagnostic of some metabolic disorders, for example, P5CS disorders and some urea cycle disorders. This strongly suggests that under-pinning at least some of these disease states are as yet unidentified metabolic/enzymatic disorders (‘metabolic disorders’). I would class my own disorder as a metabolic disorder.
Whilst identifying the numerous metabolic disorders that may be causative of the disease states may take some time, this information could and should be put to immediate use.
In drug trials for those diseases that are already known to present with abnormal amino acid profiles, it surely makes sense to test the amino acid profiles of the trial participants to assess which underlying disorders/abnormal amino acid profiles respond to the drug being trialled.
Further, given the variety and complexity of metabolic pathways, it is probable that there are a multitude of different metabolic/enzymatic defects responsible for various disease states. If a disease state caused by an underlying metabolic disorder is treated and the underlying disorder is left untreated, the disorder will, in all likelihood, find an alternative expression in another disease state.
There should therefore be a greater focus on identifying and treating the individual patient’s underlying disorder.
In large part, this lack of focus on identifying and targeting the expected plethora of underlying disorders is because resources are mainly focused on finding universal biomarkers and one-size-fits-all treatments for disease states. Identifying and treating the underlying disorders causing each individual’s disease should receive a greater share of research resources.
What surprised me most in reading research was the lack of any systematic or organized approach to by far the majority of the research into the causes of diseases. This lack of co-ordination and structure is obviously not an effective problem solving method.
Competing interests: No competing interests