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Showing posts with label Intellectual Disability. Show all posts
Showing posts with label Intellectual Disability. Show all posts

Thursday, 10 May 2018

Accept Autism or Treat It?


Back in the old days autism was a hidden condition and those affected were usually tucked away in institutions. A trend then slowly developed towards inclusion, with the Individuals with Disabilities Education Act (IDEA) being passed in 1975 in the US.  Other countries have slowly moved in this direction, with France only this year finally following suit.



Having moved on from hiding autism, we then had the new diagnosis of Asperger’s appearing in the 1990s and so autism became a much broader diagnosis. Then followed the idea of awareness and diagnosing adults.
Now we have an ever-growing number of people diagnosed with this “autism” thing, that other people are supposed to be aware of. Is it a disease, a dysfunction, a disability or just a difference?
Most importantly are you supposed to treat it, or just accept it?
I recently watched a BBC documentary where a doctor was the presenter and she was talking about schizophrenia. She said that at medical school she was taught that there are medical problems and there are mental health problems, for some reason she was taught that mental health problems are not just medical problems of the brain. Somehow mental health problems are supposed to be different and not based in biology, where did that idea come from?
The program went on to show that about 8% of schizophrenia appears to be caused by NMDAR antibodies. This is a condition where antibodies attack NMDA receptors in the brain, this causes hallucinations and other symptoms that a psychiatrist would diagnose as schizophrenia.  Rather than treating lifelong with anti-psychotics, the patient needs immunotherapy and can then resume a normal life.
It looks like 30% of modern autism is associated with cognitive impairment leading to a measured IQ of less than 70. This is intellectual disability (ID) to autism parents and mental retardation (MR) to the rest of the world.
The interesting finding in this blog is that some MR/ID is actually treatable. I did suggest to the Bumetanide researchers that they should include measuring IQ in their clinical trials.
I do not see how anyone could object to treating MR/ID, even those parents with Asperger’s who find the idea of treating their child’s severe autism to be repulsive.

Maths, Autism and Hans Asperger
Some people with Asperger’s are brilliant at maths, and I think these are the ones that Hans Asperger was mostly studying in Vienna in the 1940s. Lorna Wing came along in 1981 and then Uta Frith in 1991 and translated into English one of Asperger’s 300 papers, the 1943/4 “Die Autistischen Psychopathen im Kindesalter” and then named autism with no speech delay as Asperger’s Syndrome.
In 1994 the Americans adopted Asperger’s as a diagnosis and then rejected it two decades later in 2013 (DSM5).
In Asperger’s 1943 paper he described Fritz, Harro, Ernst and Hellmuth, who he termed "autistic psychopaths”; all four had high IQs and Asperger called them "little professors" because they could talk about the area of ​​their special interest in detail and often accumulated amazing knowledge.
I think Asperger’s should have been left as the "Little Professor’s Syndrome" (high IQ only).
In 2018 some people have realized that from the mid 1930’s almost all people in high positions in Austria and Germany were implicated in some pretty evil Nazi programs, including killing mentally disabled children. Asperger, being a senior psychiatrist at the University of Vienna, obviously played a role, not wanting to pay a visit to the local Gestapo basement.  He was living in a police state, where people tend to do what they are told.  Unlike most of the University medical faculty he was not a member of the Nazi party.
The particularly evil Austrian psychiatrist was Dr Emil Gelny, who modified an ECT (Electro Convulsive Therapy) device to give his subjects lethal shocks. Having personally killed hundreds of mental patients, after the end of the war he escaped to Baghdad, continued practising as a doctor and lived till he was 71. He was never brought to account and Mossad clearly never paid a visit, so I guess there were no Jewish victims.  His highly publicized use of ECT is one reason why it is little used today, even though it does seem to help certain otherwise untreatable conditions.
What surprised me was that in 1930 (before the rise of Hitler) half of the doctors in Vienna were Jewish and indeed half of the Vienna medical faculty were Jewish. So not so anti-Semitic in 1930.  All these doctors had to leave and so the young Hans Asperger made rapid career progress.
Things were not all rosy elsewhere.
I recently read that in London in the 1950s Jewish doctors struggled to progress within the faculty of medical schools and so some emigrated to the US.
We should also note that the Nazis took their inspiration for eugenics from America, where it backed by well-known names such as the Carnegie Institution and the Rockefeller Foundation. California, which we now might consider very liberal, was the centre for forced sterilization.  Between 1907 and 1963 over 64,000 individuals were forcibly sterilized under eugenic legislation in the United States.
So, I think Asperger deserves a break, he was likely no better or worse than other Austrians, unlike most he did not join the Nazi Party. Wing and Frith (a German) were naïve to name a psychiatric syndrome based on the work of an Austrian written during the Nazi period. I think you would not name a reservation for native Americans after General George Custer. 

Back to Maths
One group of kids with severe autism do have near/distant relatives who have remarkable maths skills but were never diagnosed with anything other than being a bit odd.
Monty, now aged 14 with ASD, had great difficulty with even the most basic maths until the age of 9, so much so that we did not bother to teach it, we focused on literacy.
Five and a half years of drug treatment has produced a boy who is now great at maths, at least in his class of 12 years olds.
Coordinates, no problem; negative numbers, no problem. It still now shocks those who knew him from before.
Today I received a message from Monty’s assistant at school and a photo of his classwork, where he is solving simple equations like
7x - 6 = 15
That is not a complex problem for a typical boy, but at the age of 9, after 5 years of intensive ABA therapy, we were still challenged by the most basic single digit addition.  


Nice neat handwriting


Should you treat autism? 

Pretty obviously I think autism should be treated. I would favour treating all types of genuine disease.
If you can treat it, I’d definitely call it a disease.
I would treat people with Down Syndrome to raise their IQs to improve their quality of life and I would also treat them preventatively to avoid early onset Alzheimer’s, which they are highly likely to develop. By the age of just 40 years old, studies have shown significant levels of amyloid plaques and tau tangles, which will lead to Alzheimer’s type dementia.
If you cannot treat it, then you’re just going to have to accept it.
But how would you know you cannot treat it, if you do not at least try?
Since there are hundreds of types of autism, there is no one-stop treatment shop for autism. For medical advice you should go to see a doctor, but mainstream medicine believes autism is untreatable. Today it is really up to the parents themselves to figure out what, if anything, to do.  Dr Frye might suggest you try Leucovorin, B12 and NAC; some DAN doctor will tell you it is all about candida; another will treat everyone with cod liver oil; another will blame parasites; most will blame vaccines.  One lady will charge you large amounts of money for her genetic tests, baffle you with complicated looking charts and then sell you her supplements by the bucket-load. This blog suggests numerous therapies may be partially effective in specific people, a case for personalized medicine.  My Polypill is what works for my son's autism; it is nice to know it works for some others, but it does not work for all autism, that would never be possible.  
With schizophrenia, you could start by treating that 8% with NMDAR antibodies via a science-based medical therapy; this has got to be a big step forward over psychiatric drugs.
We have gone from aged 9, struggling with: -
5 + 2 =  ?
To aged 14, solving worded maths questions, where you have to create the formula and to neatly solving simple equations like:

7x – 6  =  15                  
In algebra there is no doubt effective treatment wins over acceptance.

There is more to life than algebra, but it looks pretty clear that going through life with an IQ 30+ points less than your potential is a missed opportunity. 

Trivial autism
Many people with mild autism and an IQ much greater than 70 are happy the way they are and do not want treatment. For them autism is not a disability, it is just a difference, so we might call it trivial autism.  Unless years later they commit suicide or hurt other people, then it was not so trivial after all.
Unfortunately, some people with trivial autism will go on to produce children with not so trivial autism.
Then you end up with situation that the adult can block what is in the child’s interest, just like deaf parents who refuse their deaf child to have cochlear implants to gain some sense of hearing. Cochlear implants are only effective when implanted in very young children, so by the time you are old enough to have you own say in the decision, it is too late.  Some deaf parents do not want hearing children – odd but true.
So, I come back to my earlier point better to treat ID/MR, don’t even call it treating autism.
How can the Asperger’s mother then refuse treatment to her son with autism plus MR/ID? She can still be able to celebrate her difference, while he gets a chance to learn to tie his own shoe laces, put his shirt on the right way around and do all kinds of other useful things.


So, focus on the 31% of autism? 





                     
Unfortunately, in the research trials they often exclude severe autism, so they exclude people with epilepsy, people with MR/ID and people will self-injurious behaviour (SIB). The very people who clearly need treatment are excluded from the trials to determine what are effective autism treatments. Rather odd.




Thursday, 7 December 2017

Trajectories of Intellectual Development in Autism




Tracking IQ over a 3-4 year period, in 4 sub-groups of 2-8 year olds

Today’s post is about trajectories of intellectual development in autism, which I have to come to believe is the most important aspect of autism and certainly helps you understand where your type of autism fits in.
As regular readers may recall average IQ = 100 and the IQ scale fits a bell-curve, so most (68%) people have an IQ within the range 85-115.  2.1% of the general population have an IQ less than 70, which is the cut off for a diagnosis of MR/ID (Intellectual Disability).
There are special tests to measure IQ in non-verbal people and IQ testing is matched to your age; so the older a child gets the more there is expected from them in the test.
I do wonder how you can fairly test the IQ of a 2 year old with severe autism. So I think some testing in very young children may substantially underestimate IQ. 
A study was recently published taking data from the Autism Phenome Project run by UC Davies.



Even though the sample size is only a hundred, what makes it interesting is that it is a longitudinal study, meaning they collect data from the same kids over a period of many years.


They fitted data from the hundred kids into four groups and then took the average IQs within each group. The kids had IQ measured twice, not at exactly the same ages, but about 4 years apart. (The youngest at T1 was two years old and the oldest at T2 was eight)
I used their data and apply my interpretation. I do not think they made the most of their own data.
So the first group (black) are the Asperger’s kids who were 22% of the sample group.  This group started out at 2-3 years old with IQ just under 100 but in the next 4 years they raised their cognition at an above average rate, so that average IQ rose to 110. Not bad going.   Average IQ in the general population is 100.
Classic autism is the red group at the bottom and as expected their IQ starts out low and gets worse, because they add skills at a lower rate then NT kids, so even though they learn, their measured IQ falls. This group was 26%.  Even though the sample is very small at 100, this is close to my estimate of classic autism (SDA) being about 30% of all autism. In some countries you have to measure IQ to access services. Our behavioral consultant was not a fan, because the parents get upset when IQ goes down over time, so we never measured IQ. The red line is even lower than I had expected.
The green line I called responsive autism, because even though IQ is low it does not fall during the 4 years period where it was measured. This group account for 18% of the total. These children are acquiring new skills at a fair rate.
The good news is the blue line; in that large sub-group of 35%, the kids had some kind of “dysmaturation” at time 1, allowing them to make rapid cognitive improvement in the 4 years after their diagnosis (Time 1). They have gone from a technical definition of MR/ID to getting close to average IQ.
It would be great to see what happens at Time 3. I suppose if we wait 4 years we may find out.
I think some of the 35% (blue line) likely did not perform to their full ability at the first test (at time 1), for which there are numerous reasons, not liking/being familiar with the tester being an obvious one.  Based on other sources from this blog, I think it is about 15% of autism cases that make such a dramatic improvement to the age of eight.

In the above study the type of intervention chosen by parents (how many hours of ABA, speech therapy etc) had no correlation with IQ improvement from Time 1 to Time 2. It is your biology that matters most and to tweak that you need a little help from chemistry, as some regular readers have discovered. 

Counter Argument 
There is a alternative view that IQ is not important in ensuring favorable outcomes in autism; this does sound rather odd. It is a view put forward not just by the small, but vocal, group with Asperger's promoting their "neurodiversity" ideas, but also some well paid researchers. In my chart above I used Asperger's for the black line representing the people with average IQ. In the actual paper they do not call it Asperger's.


Intelligence scores do not predict success for autistic adults 

This is a very recent, rather light weight, article and would be much better if titled "Intelligence scores do not predict success for Aspies."   
Aspies do indeed share some biological problems with people with severe autism, but their daily life problems are much closer to those faced by people with Schizophrenia or Bipolar. A good example is suicide, where it is extremely common in bipolar, said to be 10% (as cause of death) in schizophrenia and ten times the "normal" level in Asperger's.  In severe autism the suicide rate is zero, they may have accidents but do not try to kill themselves.

In someone with Asperger's and an IQ of 120, boosting their IQ to 140 will likely not help them; it would just make them feel more different. In a ten year old with severe autism and an IQ of 50, a child who cannot figure out which way round to put on his T shirt, cannot tie his shoelaces and does not understand why you need to cut your finger nails, a boost in IQ to 80 would be transformative. 
The education of people with severe autism focuses on adaptive behavior, or life skills. These are key skills for semi-independent living. These are skills that children of average IQ just pick up from observing the people around them. People with impaired cognitive function cannot just pick up these skills, they need to be taught (again and again and again).  I spent three years trying to teach prepositions to my son Monty to the age of eight, using a special computer program created for other people with exactly the same difficulty. Once I started addressing cognitive function, with Bumetanide, from the age of 9, Monty figured out prepositions all by himself, without any teaching. I never even bothered to use the remaining language teaching software that I had paid $1,500 for, as a bundle, when he was four years old.  It is still sitting unopened on the shelf. 







Tuesday, 24 October 2017

Treated ID and CBS/DYRK1A in Autism and Down Syndrome

One of the most interesting concepts I have come across writing this blog is the idea of treating people with mental retardation (MR) / intellectual disability (ID). I do keep using the term MR, because 90% of the world has no idea what ID means. MR is a very precise description, which is increasingly rare these days.
I still recall several years ago going to a French-speaking neighbour’s barbecue. The French are generally very family-oriented, but quite traditional when it comes to parenting, (hence their low rates of ADHD diagnosis). At that time, Monty aged around 8, could act strangely and was rather obsessed with fire, matches and cigarette lighters. Our neighbour introduced us to his French friends and explained Monty with a brief use of the word “retardé”, which did not prompt any comments or requests for clarification. In the English language this might have been regarded as a big faux-pas; it did not bother me.  It seemed to work very well to forewarn people not to over-react to any unexpected behaviours. 
In the English language, autism has become a nice word and seems the new ADHD, with people even wanting to be diagnosed with it.  MR/ID is still something reserved for other people; it is not something most people want to be associated with. I do use the term cognitive dysfunction, which is just as explicit as MR but does not seem to upset people.
Cognitive dysfunction (MR/ID) is an inevitable consequence of more severe autism and it is just a question of degree. It is not a comorbidity, it is all part of the same package.

In Down Syndrome (DS) IQ is usually between 45 and 71 and worsens with age. MR/ID is defined as an IQ less than 70 and accounts for 2.3% of the general population. An IQ of 100 would put you in the middle of the IQ bell curve. People with DS tend to be very happy and contented, without the problematic behaviors that can occur in autism. 
The good news is that cognitive dysfunction (MR/ID) is likely to be treatable, as some readers of this blog have discovered. You just need to figure out how, which in itself is more about your perseverance than your IQ. You do not need to be an Einstein (IQ > 160), rather a marathon runner.
I just had the uncanny experience at school during the parent-teacher meetings, to be told that other class members could learn from my younger son Monty, aged 14 with autism; that he has the neatest handwriting in class, his essay had the best structure and that when his geography teacher told his assistant to skip the final question in the test (using longitude and latitude) because it was hard, the assistant said just let him try it; he was the only one to get it right. 
So from aged 8 to 14 he has gone from “retardé” to being something quite different.  The teachers do love his assistants, who are great; but he has had an assistant from the age of 4 and back then things moved forward extremely slowly. He learnt to read and write the very hard way, with a vast amount of 1:1 instruction and the school was amazed when his then assistant taught him to read; I don’t think they expected it ever to happen. By treating cognitive dysfunction pharmacologically for five years normal learning became possible and remains a big surprise to everyone.  His new English teacher knows him from back in the darker old days and seemed more shocked than surprised, after a month of teaching him. "Is this the same boy?"
For the first time at school I am being told to be proud of my younger son’s academic achievements, rather than how talented my older son is. Big brother certainly did not expect such a day and his response was along the lines of “well the others in his class must be really thick then” (like it or not, this is a typical teenage male comment). Little brother still has autism, but it is much less disabling. Big brother is currently teaching him to fence (sword fighting), which he would not have bothered to try doing until recently, because it would not have ended well. Years ago Monty did learn to ski, play basketball and soccer, but that all took a lot of effort with very patient (mostly female) instruction; he initially had no idea what to do if a ball was rolled towards him.  Last week he happily sat through the new Blade Runner film, which is nearly three hours long with the trailers. 
Perhaps there is no need for further “breakthroughs” with my Polypill therapy.  It may be good enough already.
It just seems a pity that more people with cognitive dysfunctions are not treated. There are some extremely intelligent parents with children who have severe autism, indeed an ironic twist of genetics. Some even write autism research, or indeed fund it. Even these people are not treating it.   Their fear of quackery blinds them. There certainly are quacks and there are also those who straddle the line, some of what they say is nonsense, but other ideas may not be.

Imagine having a conversation with Bill Gates, who is using his billions to use vaccines to save millions of lives in poor countries, about the possibility that in some people vaccines might trigger mitochondrial disease and autism.  Any organization talking about autism in relation to vaccines, chelation, aluminium, heavy metals etc and anyone who associates with them are in effect blacklisted.
Why does the global head of neuroscience at Novartis not attend the Autism One or TACA conferences? He does have a son with severe autism. It would be very difficult for him to apply any therapy promoted by anyone who attends these events.
Why does a Professor of Medicine from the US Ivy League apply ideas from this blog to his son, but never leave a comment? It is very clear to me why.
As our reader Roger has commented, why do some leading autism researchers still go on about vaccines? It does their interests much more harm than good. 
I think Roger could teach Dr Naviaux a thing or two about getting his Suramin research funded.  


Enhancing Cognition
The first area I came across where serious research is underway to treat MR/ID concerns RASopathies, a group of disorders that share disturbed levels of a protein called RAS. It was actually French research.
In Down Syndrome (DS) I highlighted research that aims to increase cognitive function by targeting the alpha 5 subunit of the GABAA receptor. We also saw that the same abnormal level of chloride within in cells that exists in much autism also occurs in Down Syndrome (DS); this is why the Frenchman Ben Ari has patented Bumetanide as a therapy for DS. 
In schizophrenia and bipolar there is also reduced cognitive function, but only in schizophrenia has there been much research and clinical trials to improve it. Histamine receptors were one target of this research. 

Too much or too little CBS (Cystathionine-β-synthase )
One known cause of cognitive dysfunction that has not been mentioned in my posts is CBS and since it was raised in a comment I thought it should be included.
All you need to know if you want to rule out a CBS problem is your level of homocysteine. If it is normal you do not have a problem with CBS. If homocysteine is high you have a case of Hyper-homocystinuria, which may be caused by too little CBS, or for a different reason. If you have very low levels of homocysteine (Hypo-homocystinuria) that may be caused by too much CBS and if you have Down Syndrome elevated CBS is inevitable.
Normalizing CBS is very likely to help cognition.
Cystathionine-β-synthase, also known as CBS, is an enzyme that in humans is encoded by the CBS gene. It catalyzes the first step of the transsulfuration pathway, from homocysteine to cystathionine:

L-serine + L-homocysteine    <------>     L-cystathionine + H2O


Down syndrome is a medical condition characterized by an overexpression of cystathionine beta synthase (CBS) and so a low level of homocysteine in the blood. It has been speculated that cystathionine beta synthase overexpression could be the major culprit in this disease (along with dysfunctioning of GABAA and Dyrk1a). The phenotype of down syndrome is the opposite of Hyperhomocysteinemia (described below). Pharmacological inhibitors of CBS have been patented by the Jerome Lejeune Foundation and trials are planned.


Down's syndrome (DS) or trisomy 21 is the most common genetic cause of mental retardation, and adults with DS develop Alzheimer type of disease (AD). Cystathionine beta-synthase (CBS) is encoded on chromosome 21 and deficiency in its activity causes homocystinuria, the most common inborn error of sulfur amino acid metabolism and characterized by mental retardation and vascular disease. Here, we show that the levels of CBS in DS brains are approximately three times greater than those in the normal individuals. CBS is localized to astrocytes and those surrounding senile plaques in the brains of DS patients with AD. The over-expression of CBS may cause the developmental abnormality in cognition in DS children and that may lead to AD in DS

It is a French foundation that is funding research is develop CBS inhibitors to improve cognition in Down Syndrome.


NovAliX will use its expertise and capabilities in medicinal chemistry and structural biology to develop small molecule lead candidates targeting the cystathionine-beta-synthase (CBS). Indeed inhibition of CBS over-expression has been associated with restoration of cognitive impairment in animal models afflicted with trisomy. 

People with DS have a low incidence of coronary atherosclerotic disease (CAD), which would seem to be linked to their low level of homocysteine (high CBS), but their high level of DYRK1A (see later) may be the cause of their early onset Alzheimer’s. 
Some background on homocystinuria, courtesy of Wikipedia:- 

Classical homocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase.
Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of the amino acid homocysteine in the serum and an increased excretion of homocysteine in the urine.
Signs and symptoms of homocystinuria that may be seen include the following:


The term homocystinuria describes an increased excretion of homocysteine in urine (and incidentally, also an increased concentration in plasma). The source of this increase may be one of many metabolic factors, only one of which is CBS deficiency. Others include the re-methylation defects (cobalamin defects, methionine sythase deficiency, MTHFR) and vitamin deficiencies (cobalamin (vitamin B12) deficiency, folate (vitamin B9) deficiency, riboflavin deficiency (vitamin B2), pyridoxal phosphate deficiency (vitamin B6)). In light of this information, a combined approach to laboratory diagnosis is required to reach a differential diagnosis.  

DYRK1A
You may have noticed that DYRK1A was mentioned as another cause of cognitive loss in Down Syndrome.  DYRK1A is yet another autism gene; it encodes an enzyme that is important in how the brain develops. Too much DYRK1A also leads to reduced levels of homocysteine. 
An OTC DYRK1A inhibitor exists today, epigallocatechin gallate (EGCG).



DYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases

Neurodevelopmental alterations and cognitive disability are constant features of Down syndrome (DS), a genetic condition due to triplication of chromosome 21. DYRK1A is one of the triplicated genes that is thought to be strongly involved in brain alterations. Treatment of Dyrk1A transgenic mice with epigallocatechin gallate (EGCG), an inhibitor of DYRK1A, improves cognitive performance, suggesting that EGCG may represent a suitable treatment of DS. Evidence in the Ts65Dn mouse model of DS shows that EGCG restores hippocampal development, although this effect is ephemeral. Other studies, however, show no effects of treatment on hippocampus-dependent memory. On the other hand, a pilot study in young adults with DS shows that EGCG transiently improves some aspects of memory. Interestingly, EGCG plus cognitive training engenders effects that are more prolonged. Studies in various rodent models show a positive impact of EGCG on brain and behavior, but other studies show no effect. In spite of these discrepancies, possibly due to heterogeneity of protocols/timing/species, EGCG seems to exert some beneficial effects on the brain. It is possible that protocols of periodic EGCG administration to individuals with DS (alone or in conjunction with other treatments) may prevent the disappearance of its effects.


Conclusion

Understanding emerging therapies that treat various types of MR/ID, and also the various types of dementia, should unlock interesting avenues to raise cognitive function in many types of autism.
Homocysteine levels are very easy to measure. 
Because the gene miss-expression in Down Syndrome (DS) is fully understood, it makes sense that treatment is more advanced than in autism, which is so heterogenous. There are a lot of people in the world with DS and so there is a big market for drug makers.
The potential drug therapies to improve cognition in Down Syndrome (DS) appear to be:- 

·        Basmisanil, a negative allosteric modulator of α5 subunit-containing GABAA receptors. It appears that sodium benzoate may have a similar effect.

·        Bumetanide, an NKCC1 inhibitor

·        Potassium bromide, Br- displaces Cl- to lower intracellular Cl-

·        CBS inhibitor

·        DYRK1A inhibitor, like Epigallocatechin gallate (EGCG), but a more potent inhibitor like CX-4945 (Silmitasertib) might be better.

There is mouse model research to show that a single dose just after birth of a drug that stimulates the sonic hedgehog signaling pathway results in a "normal" adult brain.

The risk of Down Syndrome (DS), caused by a third copy of chromosome 21 (trisomy 21), rises rapidly with increasing maternal age, nonetheless the number of births is stable to falling in most developed countries, due to increased prenatal testing and termination of pregnancy for fetal anomaly (TOPFA). TOPFA is not practiced in countries like Poland and Ireland. In Denmark screening has long been free and TOPFA has risen to 98%. In the UK two thirds of mothers opt for their free DS screening and 90% of those who test positive, opt for their free TOPFA. The one third letting nature take its course are probably mainly younger mothers.
In Catholic countries you have both extremes - in Cork, Ireland DS is present 30 times per 10,000 births, but in Zagreb Croatia it is just 6 per 10,000. In the US the CDC say it 14, while in the UK it is 10.  In South Africa 20 cases of DS occur per 10,000 births; mothers are younger than in Ireland.
In developed countries, the natural prevalence of DS looks to be 0.3%, which is the same as the incidence of strictly defined autism (SDA), which I estimated in an earlier post to be 0.3%. It is just that in developed countries most people with DS are never born. 

I would have thought CX-4945 should be trialed by some clever Alzheimer's researcher and indeed for any Tauopathy. In the meantime perhaps Grandad should drink a lot of green tea to get his dose of EGCG.







Thursday, 22 September 2016

More on Treatable ID Masquerading as Autism



I did write a post a while back highlighting an excellent on line resource that gives clinicians data on 81 treatable forms of Intellectual Disability, ID (formerly known as mental retardation, MR).





There is a big overlap between the causes of some ID and causes of some autism.

If you have a case of autism, it is worth reviewing the 81 treatable forms of ID, just in case you have one, even a mild version causing minimal ID.  Partial dysfunctions certainly are possible, as we saw with biotin. 

It is also very interesting to look through the therapies used and see how they overlap with those used by people in their n=1 case of autism.

For example the therapy for SLOS (Smith–Lemli–Opitz syndrome) which is related to very low cholesterol is to give cholesterol and Simvastatin.  Simvastatin is widely used in older people to LOWER cholesterol.  Statins have several other known modes of action. We use Atorvastatin.

Note all the vitamin related syndromes etc.

The data is all on the online resource that is highlighted at the top of every page in this blog, but as one regular reader from Hong Kong pointed out, it is better to actually read it in table form.  

He recommended the two papers below.  I reproduced some of the tables, but I suggest you click the link to read the papers. 

The formatting is not so good, since I have cut and paste from the papers.

You have the syndromes, their therapies and their diagnostic tests.

Complicated questions should be addressed to the authors of the papers or your doctor.







Table 2Overview of all 81 treatable IDs.In this table, the IEMs are grouped according to the biochemical phenotype as presented in standard textbooks, and alphabetically. Of note, primary CoQ deficiency was considered as one single IEM even though more though 6 genes have been described; this is true as well for MELAS and Pyruvate Dehydrogenase Complex deficiency.
Biochemical category
Disease name
OMIM#
Biochemical deficiency
Gene(s)
Amino acids
HHH syndrome (hyperornithinemia, hyperammonemia, homocitrullinemia)
238970
Ornithine translocase
SLC25A15 (AR)
l.o. Non-ketotic hyperglycinemia
605899
Aminomethyltransferase/glycine decarboxylase/glycine cleavage system H protein
AMT/GLDC/GCSH (AR)
Phenylketonuria
261600
Phenylalanine hydroxylase
PAH (AR)
PHGDH deficiency(Serine deficiency)
601815
Phosphoglycerate dehydrogenase
PHGDH (AR)
PSAT deficiency(Serine deficiency)
610992
Phosphoserine aminotransferase
PSAT1 (AR)
PSPH deficiency(Serine deficiency)
614023
Phosphoserine phosphatase
PSPH (AR)
Tyrosinemia type II
276600
Cytosolic tyrosine aminotransferase
TAT (AR)
Cholesterol & bile acids
Cerebrotendinous xanthomatosis
213700
Sterol-27-hydroxylase
CYP27A1 (AR)
Smith–Lemli–Opitz Syndrome
270400
7-Dehydroxycholesterol reductase
DHCR7 (AR)
Creatine
AGAT deficiency
612718
Arginine: glycine amidinotransferase
GATM (AR)
Creatine transporter Defect
300352
Creatine transporter
SLC6A8 (X-linked)
GAMT deficiency
612736
Guanidino-acetate-N-methyltransferase
GAMT (AR)
Fatty aldehydes
Sjögren–Larsson syndrome
270200
Fatty aldehyde dehydrogenase
ALDH3A2 (AR)
Glucose transport & regulation
GLUT1 deficiency syndrome
606777
Glucose transporter blood–brain barrier
SLC2A1 (AR)
Hyperinsulinism hyperammonemia syndrome
606762
Glutamate dehydrogenase superactivity
GLUD1 (AR)
Hyperhomocysteinemia
Cobalamin C deficiency
277400
Methylmalonyl-CoA mutase and homocysteine : methyltetrahydrofolate methyltransferase
MMACHC (AR)
Cobalamin D deficiency
277410
C2ORF25 protein
MMADHC (AR)
Cobalamin E deficiency
236270
Methionine synthase reductase
MTRR (AR)
Cobalamin F deficiency
277380
Lysosomal cobalamin exporter
LMBRD1 (AR)
Cobalamin G deficiency
250940
5-Methyltetrahydrofolate-homocysteine S-methyltransferase
MTR (AR)
Homocystinuria
236200
Cystathatione β-synthase
CBS (AR)
l.o. MTHFR deficiency
236250
Methylenetetrahydrofolate reductase deficiency
MTHFR (AR)
Lysosomes
α-Mannosidosis
248500
α-Mannosidase
MAN2B1 (AR)
Aspartylglucosaminuria
208400
Aspartylglucosaminidase
AGA (AR)
Gaucher disease type III
231000
ß-Glucosidase
GBA (AR)
Hunter syndrome (MPS II)
309900
Iduronate-2-sulfatase
IDS (X-linked)
Hurler syndrome (MPS I)
607014
α-L-iduronidase
IDUA (AR)
l.o. Metachromatic leukodystrophy
250100
Arylsulfatase A
ARSA (AR)
Niemann–Pick disease type C
257220
Intracellular transport cholesterol & sphingosines
NPC1 NPC2 (AR)
Sanfilippo syndrome A (MPS IIIa)
252900
Heparan-N-sulfatase
SGSH (AR)
Sanfilippo syndrome B (MPS IIIb)
252920
N-acetyl-glucosaminidase
NAGLU (AR)
Sanfilippo syndrome C (MPS IIIc)
252930
Acetyl-CoA glucosamine-N-acetyl transferase
HGSNAT (AR)
Sanfilippo syndrome D (MPS IIId)
252940
N-acetyl-glucosamine-6-Sulfatase
GNS (AR)
Sly syndrome (MPS VII)
253220
β-glucuronidase
GUSB (AR)
Metals
Aceruloplasminemia
604290
Ceruloplasmin (iron homeostasis)
CP (AR)
Menkes disease/Occipital horn syndrome
304150
Copper transport protein (efflux from cell)
ATP7A (AR)
Wilson disease
277900
Copper transport protein (liver to bile)
ATP7B (AR)
Mitochondria
Co enzyme Q10 deficiency
607426
Coenzyme Q2 or mitochondrial parahydroxybenzoate-polyprenyltransferase; aprataxin; prenyl diphosphate synthase subunit 1; prenyl diphosphate synthase subunit 2; coenzyme Q8; coenzyme Q9
COQ2, APTX, PDSS1, PDSS2, CABC1, COQ9 (most AR)
MELAS
540000
Mitochondrial energy deficiency
MTTL1MTTQ,MTTHMTTK,MTTCMTTS1,MTND1MTND5,MTND6MTTS2 (Mt)
PDH complex deficiency
OMIM# according to each enzyme subunit deficiency: 312170; 245348; 245349
Pyruvate dehydrogenase complex (E1α, E2, E3)
PDHA1 (X-linked), DLAT (AR), PDHX (AR)
Neurotransmission
DHPR deficiency (biopterin deficiency)
261630
Dihydropteridine reductase
QDPR (AR)
GTPCH1 deficiency (biopterin deficiency)
233910
GTP cyclohydrolase
GCH1 (AR)
PCD deficiency (biopterin deficiency)
264070
Pterin-4α-carbinolamine dehydratase
PCBD1 (AR)
PTPS deficiency (biopterin deficiency)
261640
6-Pyruvoyltetrahydropterin synthase
PTS (AR)
SPR deficiency (biopterin deficiency)
612716
Sepiapterin reductase
SPR (AR)
SSADH deficiency
271980
Succinic semialdehyde dehydrogenase
ALDH5A1 (AR)
Tyrosine Hydroxylase Deficiency
605407
Tyrosine Hydroxylase
TH (AR)
Organic acids
3-Methylcrotonyl glycinuria
GENE OMIM # 210200; 210210
3-Methylcrotonyl CoA carboxylase (3-MCC)
MCC1/MCC2 (AR)
3-Methylglutaconic aciduria type I
250950
3-Methylglutaconyl-CoA hydratase
AUH (AR)
β-Ketothiolase deficiency
203750
Mitochondrial acetoacetyl-CoA thiolase
ACAT1 (AR)
Cobalamin A deficiency
251100
MMAA protein
MMAA (AR)
Cobalamin B deficiency
251110
Cob(I)alamin adenosyltransferase
MMAB (AR)
Ethylmalonic encephalopathy
602473
Mitochondrial sulfur dioxygenase
ETHE1 (AR)
l.o. Glutaric acidemia I
231670
Glutaryl-CoA dehydrogenase
GCDH (AR)
Glutaric acidemia II
231680
Multiple acyl-CoA dehydrogenase
ETFAETFB,ETFDH (AR)
HMG-CoA lyase deficiency
246450
3-Hydroxy-3-methylglutaryl-CoA lyase
HMGCL (AR)
l.o. Isovaleric acidemia
243500
Isovaleryl-CoA dehydrogenase
IVD (AR)
Maple syrup urine disease (variant)
248600
Branched-chain 2-ketoacid complex
BCKDHA/BCKDHB/ DBT (AR)
l.o. Methylmalonic acidemia
251000
Methylmalonyl-CoA mutase
MUT (AR)
MHBD deficiency
300438
2-Methyl-3-hydroxybutyryl-CoA dehydrogenase
HSD17B10 (X-linked recessive)
mHMG-CoA synthase deficiency
605911
Mitochondrial 3-hydroxy-3-Methylglutaryl-CoA synthase
HMGCS2 (AR)
l.o. Propionic acidemia
606054
Propionyl-CoA carboxylase
PCCA/PCCB (AR)
SCOT deficiency
245050
Succinyl-CoA 3-oxoacid CoA transferase
OXCT1 (AR)
Peroxisomes
X-linked adrenoleukodystrophy
300100
Peroxisomal transport membrane protein ALDP
ABCD1 (X-linked)
Pyrimidines
Pyrimidine 5-nucleotidase superactivity
GENE OMIM # 606224
Pyrimidine-5-nucleotidase Superactivity
NT5C3 (AR)
Urea cycle
l.o. Argininemia
207800
Arginase
ARG1 (AR)
l.o. Argininosuccinic aciduria
207900
Argininosuccinate lyase
ASL (AR)
l.o. Citrullinemia
215700
Argininosuccinate Synthetase
ASS1 (AR)
Citrullinemia type II
605814
Citrin (aspartate–glutamate carrier)
SLC25A13
l.o. CPS deficiency
237300
Carbamoyl phosphate synthetase
CPS1 (AR)
l.o. NAGS deficiency
237310
N-acetylglutamate synthetase
NAGS (AR)
l.o. OTC Deficiency
311250
Ornithine transcarbamoylase
OTC (X-linked)
Vitamins/co-factors
Biotinidase deficiency
253260
Biotinidase
BTD (AR)
Biotin responsive basal ganglia disease
607483
Biotin transport
SLC19A3(AR)
Cerebral folate receptor-α deficiency
613068
a.o. Cerebral folate transporter
FOLR1 (AR)
Congenital intrinsic factor deficiency
261000
Intrinsic factor deficiency
GIF (AR)
Holocarboxylase synthetase deficiency
253270
Holocarboxylase synthetase
HLCS (AR)
Imerslund Gräsbeck syndrome
261100
IF-Cbl receptor defects (cubulin/amnionless)
CUBN & AMN (AR)
Molybdenum co-factor deficiency type A
252150
Sulfite oxidase & xanthine dehydrogenase & aldehyde oxidase
MOCS1MOCS2,(AR)
Pyridoxine dependent epilepsy
266100
Pyridoxine phosphate oxidase
ALDH7A1 (AR),
Thiamine responsive encephalopathy
606152
Thiamine transport
SLC19A3 (AR)


Table 5Overview of all causal therapies (n=91).This Table provides an overview of the specific therapy/-ies available for each IEM with relevant level(s) of evidence, therapeutic effect(s) on primary and/or secondary outcomes and use in clinical practice. For 10 IEMs, two therapies are available; these are listed separately (in brackets).
Disease name
Therapeutic modality (−ies)
Level of evidence
Clinical practice
Treatment effect
Literature references
Aceruloplasminemia
Iron chelation
4
Standard of care
D,E
(X-linked)adrenoleukodystrophy
Stemcell transplantation (Gene therapy)
1c (5)
Individual basis (Individual basis)
D,E (D,E)
AGAT deficiency
Creatine supplements
4
Standard of care
A,D
α-Mannosidosis
Haematopoietic stem cell transplantation
4-5
Individual basis
D
[54
l.o. Argininemia
Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation)
2b (4)
Standard of care (Individual basis)
B,C,D,E,F,G (C)
l.o. Argininosuccinic aciduria
Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (liver transplantation)
2b (4)
Standard of care (individual basis)
B,C,D,E,F,G (C)
Aspartylglucosaminuria
Haematopoietic stem cell transplantation
4-5
Individual basis
D
[62
β-Ketothiolase deficiency
Avoid fasting, sickday management, protein restriction
5
Standard of care
C
Biotin responsive basal ganglia disease
Biotin supplement
4
Standard of care
A,E
[66
Biotinidase deficiency
Biotin supplement
2c
Standard of care
A,E,G
[67
Cerebral folate receptor-α deficiency
Folinic acid
4
Standard of care
A,D,E,F
[[68], [69]]
Cerebrotendinous xanthomatosis
Chenodesoxycholic acid, HMG reductase inhibitor
4
Standard of care
B,D,E,G
l.o. Citrullinemia
Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation)
2b (4)
Standard of care (Individual basis)
B,C,D,E,F,G (C)
Citrullinemia type II
Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation)
2b (4)
Standard of care (Individual basis)
B,C,D,E,F,G (C)
Co enzyme Q10 deficiency
CoQ supplements
4
Standard of care
E,F
[[74], [75]]
Cobalamin A deficiency
Hydroxycobalamin, protein restriction
4
Standard of care
C,G
Cobalamin B deficiency
Hydroxycobalamin, protein restriction
4
Standard of care
C,G
Cobalamin C deficiency
Hydroxycobalamin
4
Standard of care
C,D,G
Cobalamin D deficiency
Hydroxy-/cyanocobalamin
4
Standard of care
C,D,G
Cobalamin E deficiency
Hydroxy-/methylcobalamin, betaine
4
Standard of care
C,D,G
Cobalamin F deficiency
Hydroxycobalamin
4
Standard of care
C,D,G
Cobalamin G deficiency
Hydroxy-/methylcobalamin, betaine
4
Standard of care
C,D,G
Congenital intrinsic factor deficiency
Hydroxycobalamin
4
Standard of care
A,E,G
[80
l.o. CPS deficiency
Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation)
2b & 4
Standard of care (Individual basis)
B,C,D,E,F,G (C)
Creatine transporter defect
Creatine, glycine, arginine supplements
4-5
Individual basis
F
[29
DHPR deficiency
BH4,diet, amine replacement, folinic acid
4
Standard of care
A,E
[52
Ethylmalonic encephalopathy
N-acetylcysteine, oral metronidazol
4
Standard of care
E,G
[81
GAMT deficiency
Arginine restriction, creatine & ornithine supplements
4
Standard of care
B,D,E,F
Gaucher disease type III
Haematopoietic stem cell transplantation
4–5
Individual basis
D,G
[[84], [85]]
GLUT1 deficiency syndrome
Ketogenic diet
4
Standard of Care
F
[[19], [86]]
l.o. Glutaric acidemia I
Lysine restriction, carnitine supplements
2c
Standard of care
C,D,E,G
[[87], [88]]
Glutaric acidemia II
Carnitine, riboflavin, β-hydroxybutyrate supplements; sick day management
5
Standard of care
C,G
[[89], [90]]
GTPCH1 deficiency
BH4, amine replacement
4
Standard of care
A,E
[91
HHH syndrome
Dietary protein restriction, ornithine supplement, sodium benzoate, phenylacetate
4
Standard of care
B,C,D,E,F,G
[92
HMG-CoA lyase deficiency
Protein restriction, avoid fasting, sick day management,
5
Standard of care
C
Holocarboxylase synthetase deficiency
Biotin supplement
4
Standard of care
A,E,G
[[94], [95]]
Homocystinuria
Methionine restriction, +/−pyridoxine, +/−betaine
2c
Standard of care
C,D,G
[[96], [76]]
Hunter syndrome (MPS II)
Haematopoietic stem cell transplantation
4–5
Individual basis
D,G
Hurler syndrome (MPS I)
Haematopoietic stem cell transplantation
1c
Standard of care
D,G
Hyperammonemia–Hyperinsulinism syndrome
Diazoxide
4–5
Standard of care
D
[[98], [99]]
Imerslund Gräsbeck syndrome
Hydroxycobalamin
4
Standard of Care
A,E,G
[100
l.o. Isovaleric acidemia
Dietary protein restriction, carnitine supplements, avoid fasting, sick day management
2c
Standard of care
C,G
l.o. NAGS deficiency
Dietary protein restriction, arginine supplement, sodium benzoate, phenylbutyrate (Liver transplantation)
2b & 4
Standard of care (Individual basis)
B,C,D,E,F,G (C)
l.o. Non-ketotic hyperglycinemia
Glycine restriction; +/−sodium benzoate, NMDA receptor antagonists, other neuromodulating agents
4-5
Standard of Care
B,D,E,F
[106
Maple syrup urine disease (variant)
Dietary restriction branched amino-acids, avoid fasting, (Liver transplantation)
4 & 4
Standard of care (Individual basis)
B,C,D (A,C)
MELAS
Arginine supplements
4–5
Standard of Care
C,D,E,F
[26
Menkes disease occipital horn syndrome
Copper histidine
4
Individual basis
D
l.o. Metachromatic leukodystrophy
Haematopoietic stem cell transplantation
4-5
Individual basis
D
[[114], [85]]
3-Methylcrotonyl glycinuria
Dietary protein restriction; carnitine, glycine, biotin supplements; avoid fasting; sick day management
5
Standard of care
C
3-Methylglutaconic aciduria type I
Carnitine Supplements, Avoid Fasting, Sick Day Management
5
Standard of care
C
[117
l.o. Methylmalonic acidemia
Dietary protein restriction, carnitine supplements, avoid fasting, sick day management
2c
Standard of care
C,G
MHBD deficiency
Avoid fasting, sick day management, isoleucine restricted diet
5
Standard of care
C
mHMG-CoA synthase deficiency
Avoid fasting,sick day management, +/−dietary precursor restriction
5
Standard of care
C
Molybdenum co-factor deficiency type A
Precursor Z/cPMP
4
Individual basis
A,F
[25
l.o. MTHFR deficiency
Betaine supplements, +/−folate, carnitine, methionine supplements
4
Standard of care
C,D,G
[[76], [79]]
Niemann–Pick disease type C
Miglustat
1b
Standard of care
D,E
l.o. OTC deficiency
Dietary protein restriction, citrulline supplements, Sodium benzoate/phenylbutyrate (Liver transplantation)
2b & 4
Standard of care (Individual basis)
B,C,D,E,F,G (C)
PCD deficiency
BH4
4
Standard of care
A,E
[91
PDH complex deficiency
Ketogenic diet & thiamine
4
Individual basis
D,E,F
[122
Phenylketonuria
Dietary phenylalanine restriction +/−amino-acid supplements (BH(4) supplement)
2a (4)
Standard of care (Individual basis)
B, D, E (C)
PHGDH deficiency
L-serine & +/−glycine supplements
4
Standard of care
D,F
PSAT deficiency
L-serine & +/−glycine supplements
4
Standard of care
D,F
l.o. Propionic acidemia
Dietary protein restriction, carnitine supplements, avoid fasting, sick day management
2c
Standard of care
C,G
PSPH deficiency
L-serine & +/−glycine supplements
4
Standard of care
D,F
PTPS deficiency
BH4, diet, amine replacement
4
Standard of care
A,E
[91
Pyridoxine dependent epilepsy
Pyridoxine
4
Standard of care
A,F
Pyrimidine 5-nucleotidase superactivity
Uridine supplements
1b
Standard of care
A,B,F,G
[129
Sanfilippo syndrome A (MPS IIIa)
Haematopoietic stem cell transplantation
4–5
Individual basis
D
Sanfilippo syndrome B (MPS IIIb)
Haematopoietic stem cell transplantation
4–5
Individual basis
D
Sanfilippo syndrome C (MPS IIIc)
Haematopoietic Stemcell Transplantation
4–5
Individual Basis
D
Sanfilippo syndrome D (MPS IIId)
Haematopoietic stem cell transplantation
4–5
Individual basis
D
SCOT deficiency
Avoid fasting, protein restriction, sick day management
5
Standard of care
C
[65
Sjögren–Larsson syndrome
Diet: low fat, medium chain & essential fatty acid supplements & Zileuton
5
Individual basis
D,G
Sly syndrome (MPS VII)
Haematopoietic stem cell transplantation
4-5
Individual basis
D
Smith–Lemli–Opitz syndrome
Cholesterol & simvastatin
4–5
Individual basis
B,D
SPR deficiency
Amine replacement
4
Standard of care
A,E
[134
SSADH deficiency
Vigabatrin
4
Individual basis
B,F
[135
Thiamine-responsive encephalopathy
Thiamin supplement
4-5
Standard of care
E
Tyrosine hydroxylase deficiency
L-dopa substitution
4
Standard of care
A,E
[138
Tyrosinemia type II
Dietary phenylalanine & tyrosine restriction
4-5
Standard of care
D,G
Wilson disease
Zinc & tetrathiomolybdate
1b
Standard of care
E,G









Table 2aOverview of the first tier metabolic screening tests denoting all diseases (with OMIM# and gene(s)) potentially identified per individual test.
Diagnostic test
Disease
OMIM#
Gene
Blood tests
Plasma amino acids
l.o. Argininemia
ARG1 (AR)
Plasma amino acids
l.o. Argininosuccinic aciduria
ASL (AR)
Plasma amino acids
l.o. Citrullinemia
ASS1 (AR)
Plasma amino acids
Citrullinemia type II
SLC25A13 (AR)
Plasma amino acids
l.o. CPS deficiency
CPS1 (AR)
Plasma amino acids
HHH syndrome (hyperornithinemia, hyperammonemia, homocitrullinuria)
SLC25A15 (AR)
Plasma amino acids
Maple syrup urine disease (variant)
BCKDHA/BCKDHB/DBT(AR)
Plasma amino acids
l.o. NAGS deficiency
NAGS (AR)
Plasma amino acids (& UOA incl orotic acid)
l.o. OTC deficiency
OTC (X-linked)
Plasma amino acids
Phenylketonuria
PAH (AR)
Plasma amino acids (& UOA)
Tyrosinemia type II
TAT (AR)
Plasma amino acids (tHcy)
l.o. MTHFR deficiency
MTHFR (AR)
Plasma total homocysteine
Cobalamin E deficiency
MTRR (AR)
Plasma total homocysteine
Cobalamin G deficiency
MTR (AR)
Plasma total homocysteine (& UOA)
Cobalamin F deficiency
LMBRD1 (AR)
Plasma total homocysteine (& OUA)
Cobalamin C deficiency
MMACHC (AR)
Plasma total homocysteine (& OUA)
Homocystinuria
CBS (AR)
Plasma total homocysteine (& PAA)
l.o. MTHFR deficiency
MTHFR (AR)
Plasma total homocysteine (& UOA)
Cobalamin D deficiency
MMADHC (AR)
Serum ceruloplasmin & copper (& serum iron & ferritin)
Aceruloplasminemia
CP (AR)
Serum copper & ceruloplasmin (& urine copper)
MEDNIK diseases
AP1S1 (AR)
Serum copper & ceruloplasmin (urine deoxypyridonoline)
Menkes disease/occipital horn syndrome
ATP7A (AR)
Serum copper & ceruloplasmin (& urine copper)
Wilson disease
ATP7B (AR)
Urine tests
Urine creatine metabolites
AGAT deficiency
GATM (AR)
Urine creatine metabolites
Creatine transporter defect
SLC6A8 (X-linked)
Urine creatine metabolites
GAMT deficiency
GAMT (AR)
Urine glycosaminoglycans
Hunter syndrome (MPS II)
IDS (X-linked)
Urine glycosaminoglycans
Hurler syndrome (MPS I)
IDUA (AR)
Urine glycosaminoglycans
Sanfilippo syndrome A (MPS IIIa)
SGSH (AR)
Urine glycosaminoglycans
Sanfilippo syndrome B (MPS IIIb)
NAGLU (AR)
Urine glycosaminoglycans
Sanfilippo syndrome C (MPS IIIc)
HGSNAT (AR)
Urine glycosaminoglycans
Sanfilippo syndrome D (MPS IIId)
GNS (AR)
Urine glycosaminoglycans
Sly syndrome (MPS VII)
GUSB (AR)
Urine oligosaccharides
α-Mannosidosis
MAN2B1 (AR)
Urine oligosaccharides
Aspartylglucosaminuria
AGA (AR)
Urine organic acids
β-Ketothiolase deficiency
ACAT1 (AR)
Urine organic acids
Cobalamin A deficiency
MMAA (AR)
Urine organic acids
Cobalamin B deficiency
MMAB (AR)
Urine organic acids
l.o. Glutaric acidemia I
GCDH (AR)
Urine organic acids
Glutaric acidemia II
ETFA, ETFB, ETFDH(AR)
Urine organic acids
HMG-CoA lyase deficiency
HMGCL (AR)
Urine organic acids
Holocarboxylase synthetase deficiency
HLCS (AR)
Urine organic acids
3-Methylglutaconic aciduria type I
AUH (AR)
Urine organic acids
MHBD deficiency
HSD17B10 (X-linked recessive)
Urine organic acids
mHMG-CoA synthase deficiency
HMGCS2 (AR)
Urine organic acids
SCOT deficiency
OXCT1 (AR)
Urine organic acids
SSADH deficiency
ALDH5A1 (AR)
Urine organic acids (& ACP)
Ethylmalonic encephalopathy
ETHE1 (AR)
Urine organic acids (& ACP)
l.o. Isovaleric acidemia
IVD (AR)
Urine organic acids (& ACP)
3-Methylcrotonylglycinuria
MCC1/MCC2 (AR)
Urine organic acids (& ACP)
l.o. Methylmalonic acidemia
MUT (AR)
Urine organic acids (& tHcy)
Cobalamin C deficiency
MMACHC (AR)
Urine organic acids (& tHcy)
Cobalamin D deficiency
MMADHC (AR)
Urine organic acids (& tHcy)
Homocystinuria
CBS (AR)
Urine organic acids incl orotic acid (& PAA)
l.o. OTC deficiency
OTC (X-linked)
Urine organic acids (& PAA)
Tyrosinemia type II
TAT (AR)
Urine organic acids (& ACP)
l.o. Propionic acidemia
PCCA/PCCB (AR)
Urine organic acids (tHcy)
Cobalamin F deficiency
LMBRD1 (AR)
Urine purines & pyrimidines
Lesch–Nyhan syndrome
HPRT (AR)
Urine purines & pyrimidines
Molybdenum cofactor deficiency type A
MOCS1, MOCS2, (AR)
Urine purines & pyrimidines
Pyrimidine 5-nucleotidase superactivity
NT5C3 (AR)


Table 2bOverview of all diseases (in alphabetical order) requiring second tier biochemical testing, i.e. a specific test per disease approach; for each disease the OMIM# and gene(s) are listed.
Disease
OMIM#
Gene(s)
Diagnostic test
(X-linked) Adrenoleukodystrophy
ABCD1 (X-linked)
Plasma very long chain fatty acids
Biotin responsive basal ganglia disease
SLC19A3 (AR)
Gene analysis
Biotinidase deficiency
BTD (AR)
Biotinidase enzyme activity
Cerebral folate receptor-α deficiency
FOLR1 (AR)
CSF 5′-methyltetrahydrofolate
Cerebrotendinous xanthomatosis
CYP27A1 (AR)
Plasma cholestanol
Co-enzyme Q10 deficiency
COQ2, APTX, PDSS1,PDSS2, CABC1, COQ9(most AR)
Co-enzyme Q (fibroblasts) & gene analysis
Congenital intrinsic factor deficiency
GIF (AR)
Plasma vitamin B12 & folate
Dihydrofolate reductase deficiency
DHFR (AR)
CSF 5′-methyltetrahydrofolate
DHPR deficiency (biopterin deficiency)
QDPR (AR)
CSF neurotransmitters & biopterin loading test
Gaucher disease type III
GBA (AR)
Glucocerebrosidase enzyme activity (lymphocytes)
GLUT1 deficiency syndrome
SLC2A1 (AR)
CSF: plasma glucose ratio
GTPCH1 deficiency
GCH1 (AR)
CSF neurotransmitters & biopterin loading test
Hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC)
SLC30A10
Whole blood manganese
Hyperinsulinism hyperammonemia syndrome
GLUD1 (AR)
Gene analysis (& ammonia, glucose, insulin)
Imerslund Gräsbeck syndrome
CUBN & AMN (AR)
Plasma vitamin B12 & folate
MELAS
MTTL1, MTTQ, MTTH,MTTK, MTTC, MTTS1,MTND1, MTND5, MTND6,MTTS2 (Mt)
Mitochondrial DNA mutation testing
l.o. Metachromatic leukodystrophy
ARSA (AR)
Arylsulfatase-α enzyme activity
Niemann–Pick disease type C
NPC1 NPC2 (AR)
Filipin staining test (fibroblasts) & gene analyses
l.o. Non-ketotic hyperglycinemia
AMT/GLDC/GCSH (AR)
CSF amino acids (& PAA)
PCBD deficiency (biopterin deficiency)
PCBD1 (AR)
CSF neurotransmitters & biopterin loading test
PDH complex deficiency
OMIM# according to each enzyme subunit deficiency: 312170;245348; 245349
PDHA1 (X-linked), DLAT(AR), PDHX (AR)
Serum & CSF lactate:pyruvate ratio enzyme activity, gene analysis
PHGDH deficiency (serine deficiency)
PHGDH (AR)
CSF amino acids (& PAA)
PSAT deficiency (serine deficiency)
PSAT1 (AR)
CSF amino acids (& PAA)
PSPH deficiency (serine deficiency)
PSPH (AR)
CSF amino acids (& PAA)
PTS deficiency (biopterin deficiency)
PTS (AR)
CSF neurotransmitters & biopterin loading test
Pyridoxine dependent epilepsy
ALDH7A1 (AR)
Urine α-aminoadipic semialdehyde & plasma pipecolic acid
Sjögren Larsson syndrome
ALDH3A2 (AR)
Fatty aldehyde dehydrogenase enzyme activity
Smith Lemli Opitz syndrome
DHCR7 (AR)
Plasma 7-dehydrocholesterol:cholesterol ratio
SPR deficiency (biopterin deficiency)
SPR (AR)
CSF neurotransmitters, biopterin & Phe loading test (enzyme activity, gene analysis)
Thiamine responsive encephalopathy
SLC19A3 (AR)
Gene analysis
Tyrosine hydroxylase deficiency
TH (AR)
CSF neurotransmitters, gene analysis
VMAT2 deficiency
SLC18A2 (AR)
Urine mono-amine metabolites