Autism and Salt Wasting

I am new to the IAN Project. I have recently filled out the questionnaires and reviewed some of the research findings to date. I was wondering if anyone had ever heard of any research findings linking salt wasting (or other metabolic disorders) to autism. Let me briefly give you my family background and the reason I am asking this question:

I am the father of a boy diagnosed with autism:
Age - 56 months
Diagnosed with autism - 47 months
Non-verbal with several stereotypical behavior patterns

At an age of 1 month my son spent a week in the children's hospital for low sodium levels in his blood serum. A few months later he received a diagnosis of pseudohypoaldosteronism (PHA) which is a rare genetic disease with symptoms of salt wasting. The only treatment is to give him extra salt in his diet which we continue to do to this day.

PHA is a very rare genetic disease. Only approximately 70 cases have been reported since 1958 according to emedicine.com. That is why I am skeptical that his autism is unrelated. The probability that two unrelated diseases will occur in the same individual equals the product of the separate probabilities. Thus, if PHA is a 1 out of 100 million event and autism is a 1 out of 150 event, then for both of them to occur indepedently in the same person is a 1 out of 15 billion event. Since the world's population is only 6.5 billion people then we wouldn't expect any human being to have both of these diseases at the same time.

So my gut instinct tells me there must be some connection, particularly when I realize that the brain is essentially a bio-electrical computer. Changing basic parameters in the system like the electrolyte content of the fluid (which influences the electrical conductivity of the brain) should radically alter the behavior of the system. All of the medical professionals that I have talked to are telling me that there is absolutely no connection between autism and salt wasting. I guess I am in denial about that one.

Sincerely,
Tom Marking

BTW, at an age of 1 year blood samples from our son, myself, and my wife were sent to the Lifton Lab at Yale University run by Dr. Richard Lifton who is the world's foremost expert on blood electrolyte disorders. They screened my son's blood for genetic anomalies in the genes known to cause PHA. Nothing was found.

More recently we had some genetic screening done looking for Fragile X and other disorders related to autism. A chromosome microarray analysis was done of my son's blood. Again, there were no genetic anomalies found.

Welcome, Tom, and thank you for taking part in the IAN Project.

I will try to find an answer for you regarding any association between metabolic disorders and autism. I do not know the answer to that offhand!

One thing to keep in mind is that even children with autism can have other, unrelated conditions just as a person with MS can also have Diabetes. It's natural for parents to wonder, however, when a child with autism also has something else. For example, my son with Asperger's also has dreadful psoriasis. Autism has been linked to autoimmune and inflammatory processes gone wrong, but is there a link in his case? He did not get the psoriasis until he was on a certain medication, so is it a side-effect and not to do with autism itself? In truth, no one can answer these questions yet. We just don't know.

It can be terribly frustrating, as a parent, to not know, and to be unable to find out because science isn't there yet. In fact, IAN was born out of precisely that kind of parental frustration. Drs. Paul and Kiely Law felt so unsatisfied with the state of autism research when they were trying to help their own young son, they came up with IAN to try to make more research happen faster.

I will let you know if I find out more about metabolic disorders and autism.

Tom, I asked Dr. Andrew Zimmerman, a pediatric neurologist and researcher investigating autoimmune issues and autism, your question.

Dr. Zimmerman said that quite a few metabolic disorders have been seen in association with autism, including glutaric aciduria and phenylketonuria (PKU). He has seen nothing so far in the literature suggesting an association between PHA and autism. (This does not mean it cannot exist, just that it has not been investigated or observed in a way that made it into a scientific publication.)

Because of PHA's rarity, it may be that experts in that disorder would be aware of any association that has been observed. In fact, your son's case has just become an observation of the two at least co-existing (whether or not they are connected) in one person.

I would not say that you're in denial about "no connection" because we just don't know. I was asking my son's psychiatrist the other day a question much like yours --"Is such and such connected? Could it be? Do you think?" He gave me a sad little smile and said: "You know we don't know."

And that, I fear, is the truth of the matter.

Thanks Connie for the information. If you come across anything else concerning salt wasting and autism please post it. It's really the rareness of PHA that has me suspicious of a linkage. And if there is such a linkage then what subtype of autism would my son have? Would the appropriate therapies change in that case? So it opens up a big can of worms with questions like these.

Thanks for the information.

I believe I have found something interesting in regards to a connection between PHA (pseudohypoaldosteronism) and autism. I went to the OMIM (Online Mendelian Inheritance of Man) web site which is http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM.

PHA Type I Autosomal Dominant is linked to chromosome locus 4q31.1.

PHA Type 1 Autosomal Recessive is caused by mutations in 3 subunits: alpha, beta, and gamma which are linked to the loci 12p13, 16p13-p12, and 16p13-p12, respectively.

So far so good. I went back over the e-mails that we received from the Lifton Lab at Yale University and they screened my son's DNA for both of these types of PHA, and found nothing.

But then I looked at PHA Type II (also called Gordon syndrome) whose symptoms are hyperkalemia (high potassium) and mild hyperchloremia (high chloride). It also says the a researcher found that it is sometimes accompanied by intellectual impairment. This was the first thing I've ever read that linked any kind of cognitive difficulty with salt wasting. I went back and looked at my son's test data and sure enough, his chloride was a little above the normal range - this was unexplained at the time. And he had hyperkalemia too.

PHA Type II has several loci but one of them is 17q21-q22 (WNK4 gene).

So far so good. Now when I search for autism susceptibility genes there are several of them, but one of them is 17q21 thought to be associated with the ITGB3 gene. This is just too close to be a coincidence, the same chromosome, the same long arm of the chromosome, and the same band (21) is associated both with PHA and autism.

There's a journal abstract on it:

Replication of autism linkage: fine-mapping peak at 17q21
Cantor RM, Kono N, Duvall JA, Alvarez-Retuerto A, Stone JL, Alarcón M, Nelson SF,
Geschwind DH
American Journal of Human Genetics, 2005 June, 76(6), 1050-1056

Autism is a heritable but genetically complex disorder characterized by deficits in
language and in reciprocal social interactions, combined with repetitive and
stereotypic behaviors. As with many genetically complex disorders, numerous genome
scans reveal inconsistent results. A genome scan of 345 families from the Autism
Genetic Resource Exchange (AGRE) (AGRE_1), gave the strongest evidence of linkage at
17q11-17q21 in families with no affected females. Here, we report a full-genome scan
of an independent sample of 91 AGRE families with 109 affected sibling pairs (AGRE_2)
that also shows the strongest evidence of linkage to 17q11-17q21 in families with no
affected females. Taken together, these samples provide a replication of linkage to
this chromosome region that is, to our knowledge, the first such replication in autism.
Fine mapping at 2-centimorgan (cM) intervals in the combined sample of families with
no affected females reveals a linkage peak at 66.85 cM, which places this locus at
17q21.

So what do you think? This is a very strange coincidence if they are unrelated.

Tom, that is definitely an intriguing circumstance. I fear I don't have the expertise in genetics to know how significant the fact that both conditions have been associated with the same chromosomal locus may be. Let me see what I can find out.

One thing I wanted to note for all our readers, and especially for those who are reading the scientific literature and thinking intently about how various topics may be related:

Most scientific articles provide information on how to contact the authors. There may be an e-mail, or simply an address. If you have questions or comments for the authors, or want to share an idea, there is usually a way to reach them!