Glutaric acidemia type 1

Gandalf, I had no idea, I just caught up with this thread! I'm so sorry to read this! :(
I can only give you my support, unfortunately.
I will keep little Liam, your family and you in my thoughts and prayers.
If there is anything we can do to help, let us know, OK?
:hug2:
 
I've found a bunch of things in my digging that may or may not help fwiw

_http://www.jbc.org/content/280/23/21830.full
Bioenergetics in Glutaryl-Coenzyme A Dehydrogenase Deficiency

A ROLE FOR GLUTARYL-COENZYME A

[..]

Reduced glutathione concentrations in Gcdh–/– mice support a role for increased oxidative stress in GCDH deficiency. Inhibition of KG-DHc by glutaryl-CoA might be amplified by increased oxidative stress, resulting in a synergistic reduction of flux through the TCA cycle. If reduced KGDHc activity contributes to the neuropathogenesis of GCDH deficiency, treatment with thiamine and α-lipoic acid in concert with other antioxidants, such as α-tocopherol and N-acetylcysteine, might be helpful to (partially) restore KGDHc function and glutathione levels.

_http://run.unl.pt/bitstream/10362/6759/1/Lucas_2011.pdf (English version near the bottom of the doc)

Cofactors and metabolites as potential stabilizers of mitochondrial acyl-CoA dehydrogenases

Abstract

Protein misfolding is a hallmark of a number of metabolic diseases, in which fatty acid oxidation defects are included. The latter result from genetic deficiencies in transport proteins and enzymes of the mitochondrial β-oxidation, and milder disease conditions frequently result from conformational destabilization and decreased enzymatic function of the affected proteins. Small molecules which have the ability to raise the functional levels of the affected protein above a certain disease threshold are thus valuable tools for effective drug design. In this work we have investigated the effect of mitochondrial cofactors and metabolites as potential stabilizers in twoβ-oxidation acyl-CoA dehydrogenases: short chain acyl-CoA dehydrogenase and the medium chain acyl-CoA dehydrogenase as well as glutaryl-CoA dehydrogenase, which is involved in lysine and tryptophan metabolism. We found that near physiological concentrations (low micromolar) of FAD resulted in a spectacular enhancement of the thermal stabilities of these enzymes and prevented enzymatic activity loss during a 1 h incubation at 40 °C. A clear effect of the respective substrate, which was additive to that of the FAD effect, was also observed for short- and medium-chain acyl-CoA dehydrogenase but not for glutaryl-CoA dehydrogenase. In conclusion, riboflavin may be beneficial during feverish crises in patients with short- and medium-chain acyl-CoA dehydrogenase as well as in glutaryl-CoA dehydrogenase deficiencies, and treatment with substrate analogs to butyryl- and octanoyl-CoAs could theoretically enhance enzyme activity for some enzyme proteins with inherited folding difficultes.

Upregulation of FAD (although it may not work if the signalling sites are mutated - see next quote after this one)
_http://en.wikipedia.org/wiki/Fatty_acid_synthesis
Regulation

In B. subtilis, this pathway is regulated by a two-component system: DesK and DesR. DesK is a membrane-associated kinase and DesR is a transcriptional regulator of the des gene.[5][9] The regulation responds to temperature; when there is a drop in temperature, this gene is upregulated. Unsaturated fatty acids increase the fluidity of the membrane and stabilize it under lower temperatures. DesK is the sensor protein that, when there is a decrease in temperature, will autophosphorylate. DesK-P will transfer its phosphoryl group to DesR. Two DesR-P proteins will dimerize and bind to the DNA promoters of the des gene and recruit RNA polymerase to begin transcription.[5][9]

_http://www.ncbi.nlm.nih.gov/pubmed/16377226
Riboflavin-responsive glutaryl CoA dehydrogenase deficiency.

Chalmers RA, Bain MD, Zschocke J.


Source

CIMOA, London NW1 0NH, UK. rachalmers@cimoa.org.uk


Abstract


We report here riboflavin responsiveness in a patient with glutaryl CoA dehydrogenase (GCDH) deficiency, compound heterozygous for the S139L and P248L mutations and with 20% residual GCDH enzyme activity in vitro. Our results suggest the mitochondrial GCDH homotetramer remains intact with one of these mutations associated with the binding site of the single FAD cofactor and that pharmacological doses of the cofactor precursor may be sufficient to induce an increase in activity in the mutant GCDH enzyme, although not sufficient to normalise urinary organic acid excretion. Serine139 is one of nine conserved amino acid residues that line the binding site of the protein and is in close proximity to both substrate and FAD cofactor. It is possible that steric alterations caused by substitution of serine with leucine at this position may be overcome with high cofactor concentrations. P248L is also associated with some residual GCDH activity in other patients and the unique combination of S139L with P248L may also explain the results in our patient. Responsiveness to riboflavin in our patient has been compared with two other patients with glutaric aciduria type 1 and minimal residual GCDH activity, one with homozygosity for the R257Q mutation and one with heterozygosity for the G354S mutation and a novel G156V mutation. A low lysine diet reduced glutaric acid excretion in our riboflavin-responsive GCDH-deficient patient almost to control values. She is now 21 years of age and clinically and neurologically normal.

I'm not sure how much use the above will be - but to provide context:

_http://www.ncbi.nlm.nih.gov/pubmed/4220222
Inborn errors of metabolism. Vitamin-responsive genetic disease.

Mudd SH.


Abstract


The several ways in which vitamin administration may bring about a biochemical response in genetic abnormalities have been discussed. Two major interrelated lessons emerge from what we now know about vitamin-responsive genetic disease. First, it is possible to enhance metabolite flow through partially deficient reactions by suitable manipulation of the environment in which a fixed amount of enzyme functions or by changing the concentration of the enzyme itself. The latter approach may be the most versatile in the long run since there may be agents other than vitamins which increase enzyme concentrations. A striking example of such an effect in mammals is furnished by the work of Pitot and his collaborators, who by administration of casein hydrolysate to rats, increased threonine dehydratase activity several hundred-fold (Peraino and Pitot, 1964) by increasing the rate of enzyme synthesis (Jost, Khairallah, and Pitot, 1968). Other means of enhancing enzyme activities, ranging from tissue transplantation to transfer of genetic material, have been discussed elsewhere (for example, see Brady, 1973). These procedures will not be discussed here, other than to mention a recent report (Mukherjee and Krasner, 1973) who transferred several small plugs of liver tissue (approximately 5% of the liver) from normal rats to the livers of rats genetically deficient in bilirubin uridine diphosphate glucuronyltransferase activity. Twelve weeks later the specific activity of glucuronyltransferase had risen in the livers of the recipient rats to 6-23% of normal, and the serum bilirubin of these rats, which had initially been elevated, had fallen to close to, or within, the normal range. Thus liver grafts between suitably matched individuals, may in the near future, become a means of increasing hepatic activities of deficient enzymes to extents which are therapeutically meaningful. The second lesson to be learned from the review presented here is that enhancement of enzyme activity may be therapeutically beneficial even though the increase is small and the activity attained is still reduced relative to normal. It will be well to bear this in mind in any attempts to treat inborn errors of metabolism.
 
Thanks so much RedFox.

I have just send the links of the articles to the mother.
 
Thanks very much for your support. I'm Liam's grandmother.

I begin to read and reply on the Forum's threads in English.

Liam was / is force feeding and take his special milk like. His body doesn't feel good but he has a smile and in his eyes, he loves his parents.

We (my daughter and me) took some courses to help him. Miss Pandovan open a centre to help the autistic persons and TDH, TDDH... and her method names "Padovan". Since his mother tries that with Liam, he began to digest. I took Brain Gym and tactile touch courses to help him too. His tonus member are well. Little step by little step with him. For the parents, it's a all day reality, so the mourning isn't done yet.

And last week, I had a SRT (Patrick Rodriguez) about Liam and his lifes' story. Very interesting!
I learnt about his past lifes, I can release more. I do what I can to help the parents but It's not all my responsibility. I'm learning gradually my lesson. I was very disappointed and upset but I can't give my health for him.

The suffering, it's always when a patterns blocks the energy to flow freely inside. As Dr Gabor Mate said: "the suffering it's the resistance to the reality".

One year later, I feel better and I'm very happy to participate the Forum's group. I can have time to read books and some threads.
Thanks a lot,
 
France said:
Thanks very much for your support. I'm Liam's grandmother.

I begin to read and reply on the Forum's threads in English.

Liam was / is force feeding and take his special milk like. His body doesn't feel good but he has a smile and in his eyes, he loves his parents.

We (my daughter and me) took some courses to help him. Miss Pandovan open a centre to help the autistic persons and TDH, TDDH... and her method names "Padovan". Since his mother tries that with Liam, he began to digest. I took Brain Gym and tactile touch courses to help him too. His tonus member are well. Little step by little step with him. For the parents, it's a all day reality, so the mourning isn't done yet.

And last week, I had a SRT (Patrick Rodriguez) about Liam and his lifes' story. Very interesting!
I learnt about his past lifes, I can release more. I do what I can to help the parents but It's not all my responsibility. I'm learning gradually my lesson. I was very disappointed and upset but I can't give my health for him.

The suffering, it's always when a patterns blocks the energy to flow freely inside. As Dr Gabor Mate said: "the suffering it's the resistance to the reality".

One year later, I feel better and I'm very happy to participate the Forum's group. I can have time to read books and some threads.
Thanks a lot,

I am very happy to read your post, France. I've been thinking about Liam and wondering how he is doing. Like you say, a little step after another. I was also curious about the Padovan method you mention, and I found some more info here, it sounds like another useful tool to know about:

_http://www.ergoenergie.com/en/padovan-method

Neurofunctional reorganisation (NFR) was developed by Mrs Beatriz Padovan, speech pathologist. This method is based on the work of Temple Fay, neurosurgeon, himself influenced by the work of Gesell. It is based on neurodevelopmental principles.

The NFR - Padovan Method® advocates the link among the neurological organisation and the developmental stage of the child. It draws its inspiration from the studies of Rudolf Steiner on the interrelationship among the three types of human activities (walking-talking-thinking) and from Piaget's observation on sensorimotor intelligence. In rehabilitation, it is common to use the developmental sequence to teach people how to use their bodies (walking, manipulate objects, swallowing, talking…) and their brains (affective, perceptual and cognitive) again.

Who can benefit from NFR?

There are more therapists using NFR with children suffering from neurological deficits. It is however also used to treat adults with neurological conditions and other types of pathologies:

Stroke
Multiple Sclerosis and other degenerative neurological diseases,
Neurovegetative Dystonia,
Fibromyalgia
Myalgic encephalomyelitis (chronic fatigue syndrome)
Parkinson's disease,
Schizophrenia,
Head trauma
Perceptual and cognitive difficulties (dyslexia, agnosia, impaired attention, impaired memory)
Dysphagia (swollowing disorders),
Autism and pervasive developmental disorders.
Dyspraxia,
Aphasia,
Stuttering,
Obstructive Slepp Apnea,
Bruxism (teeth grinding or clenching during sleep)
Malocclusion
Temporo-mandibular Joint Dysfunction (TMJD)

People looking for personal development can also benefit from the NFR to improve their body awareness, their posture, their athletic or vocal performance, their public speaking abilities, their concentration and focus in a high stress and high performance work environment...

"Neurons that fire together wire together" Hebbian learning


Neuronal plasticity

Many researchers previously spoke of neuronal plasticity -Mark Rosenzweig working with rats, Michael Merzenich with monkeys, Edward Taub and Paul Bach-y-Rita with humans – but it is only with the technology of the end of the 20th century that scientific facts on neuronal plasticity slowly break the scientific dogma of cerebral "localizationism". Many pioneer therapists in rehabilitation such are Bertha Bobath, Jean Ayres, Svetlana Masgutova and Beatriz Padovan, had already observed this organisational potential with their patients using their respective methods of treatment. Recent studies on neuronal plasticity and the capacity of the nervous system to recuperate from the function support the NFR method.

Research shows over and over again that principle of brain function: If you don't use it, you lose it. However, it can be relearned. Such as, when learning to play a musical instrument, the ingredients to succeed are repetition, intensity, rhythm, the personal interest of the person learning a new skill and the gradation of the proposed exercise and activity. Mrs. Padovan adds the recapitulation of the neurosensorimotor developmental sequence in her approach.

Enough scientific data can presently allow us to say that a rehabilitation period is not fixed to a few months following an accident for brain plasticity to occur. It is now accepted to say that even many years after a stroke, a head trauma or a degenerative neurological disease, there is potential for rehabilitation.

Exercise sequence

A series of body exercises following the neurodevelopmental pattern is performed in each treatment session. It includes legs, arms, hands, fingers and eyes as well as global coordination movements. Emphasis is put on certain exercises more than other by the therapist according the specific needs of each client.

Another series of exercises for the oral and peri-oral functions is also included in the same treatment session. Rhythm is used during the exercises to reinforce the work of the NFR at the neuronal activation level as well as to facilitate motor initiation and coordination activity. Adding specific exercises or tasks is done gradually according to the client's difficulties and his/her personal needs.
 
France said:
Thanks very much for your support. I'm Liam's grandmother.

I begin to read and reply on the Forum's threads in English.

Liam was / is force feeding and take his special milk like. His body doesn't feel good but he has a smile and in his eyes, he loves his parents.

We (my daughter and me) took some courses to help him. Miss Pandovan open a centre to help the autistic persons and TDH, TDDH... and her method names "Padovan". Since his mother tries that with Liam, he began to digest. I took Brain Gym and tactile touch courses to help him too. His tonus member are well. Little step by little step with him. For the parents, it's a all day reality, so the mourning isn't done yet.

And last week, I had a SRT (Patrick Rodriguez) about Liam and his lifes' story. Very interesting!
I learnt about his past lifes, I can release more. I do what I can to help the parents but It's not all my responsibility. I'm learning gradually my lesson. I was very disappointed and upset but I can't give my health for him.

The suffering, it's always when a patterns blocks the energy to flow freely inside. As Dr Gabor Mate said: "the suffering it's the resistance to the reality".

One year later, I feel better and I'm very happy to participate the Forum's group. I can have time to read books and some threads.
Thanks a lot,

I'm so happy to see you here and yet so very sorry it is under these circumstances. My heart goes out to you and your daughter (and your husband and son in law) and Little Liam. I'm so thankful that you can all be there to support each other. My family and I will be thinking of you. If I come across any alternative therapies, I will be sure to post the links.
BIG HUGS
 
Alana said:
Many pioneer therapists in rehabilitation such are Bertha Bobath, Jean Ayres, Svetlana Masgutova and Beatriz Padovan, had already observed this organisational potential with their patients using their respective methods of treatment. Recent studies on neuronal plasticity and the capacity of the nervous system to recuperate from the function support the NFR method.

Research shows over and over again that principle of brain function: If you don't use it, you lose it. However, it can be relearned. Such as, when learning to play a musical instrument, the ingredients to succeed are repetition, intensity, rhythm, the personal interest of the person learning a new skill and the gradation of the proposed exercise and activity. Mrs. Padovan adds the recapitulation of the neurosensorimotor developmental sequence in her approach.
We have their centre in Montreal. They help so much families. They talk about all the reflex in pregnancy and before two years old. How the brain works after those reflexs.

Magpie said:
If I come across any alternative therapies, I will be sure to post the links.

Thanks Maggie.
 
France and Gandalf, I just saw this thread today and I had no idea of it! This is so sad and depressing...
I am very sorry to hear what you are going through and I will keep you all in my thoughts and prayers.
I really hope there will be a way for Liam and his family to get out this nightmare. :hug2:
 
Hello France, thank you for updating on how Liam and family are doing. I can't offer anything to you or Gandalf other than to say that Liam is fortunate to have such caring grandparents to help him and his parents. :hug2:
 
voyageur said:
Hello France, thank you for updating on how Liam and family are doing. I can't offer anything to you or Gandalf other than to say that Liam is fortunate to have such caring grandparents to help him and his parents. :hug2:

Same goes for me. Thanks for the update. Hoping for the best for all involved. :hug2:
 
Thanks to all,

This situation helped all members of my family.

When a dramatic and unknown situation arrives at us, how do we react?

Someone frozen, others were searched of knowledge and others got up again sleeves to survive and establish markers news to pass across event.
It is a job of team, otherwise physical and psychological reactions attain the parents or main persons who help to hold the cape and to have intuition to find resolutions with court or a long term when emergency or first reactions facing unknown situation recovered.

I see it as it in several situations of our life. If they do not work in team or group, they miss a party of experience because it is longer to go through and sometimes they arrive there in no way because the force of an individual and talents is not worth those of a group which searches the same thing or goal.
 
Thank you for the update France, I'm glad things have improoved :flowers:

France said:
When a dramatic and unknown situation arrives at us, how do we react?

I think that is one thing I appreciate about this forum the most. The willingness of the members to help people navigate such events.
 
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