Showing posts with label 3HIA. Show all posts
Showing posts with label 3HIA. Show all posts

Wednesday 10 December 2014

Biotin/Biotinidase Deficiency in Autism and perhaps Autistic Partial Biotin Deficiency (APBD)?

Crete, as seen from the International Space Station
By ISS Expedition 28 crew (NASA Earth Observatory) [Public domain], via Wikimedia Commons

In this blog there is a tab at the top called “Disorders leading to Autism”.  This includes a long list of, supposedly rare, known conditions that lead to the development of autism.

In that list is Biotin deficiency and I even put the name of the gene that is thought to be dysfunctional.  The BTD gene encodes an enzyme called Biotinidase, that in turn allows the body to use and recycle biotin.

Biotin deficiency is a known cause of autism, but it seems that the assumption is made that the cause is Biotinidase deficiency.  The usual test done is for Biotinidase deficiency.

In good hospitals they routinely test for many of these dysfunctions when a child is originally diagnosed with autism.  When I say good hospitals, I mean big US hospitals attached to a university.  In other countries such testing rarely takes place, nor is it even mentioned.

We will see later that even these good hospitals may be getting the result wrong.  They are likely testing for the wrong defect, and so getting a "false negative" in some cases.

The take home message is that Biotin Deficiency may not be rare in autism, only Biotinidase Deficiency is rare.  Both are treatable.

How rare is Biotin Deficiency?

Biotin deficiency is supposed to be extremely rare.

One of this blog’s readers made reference to a recent Greek study.  They checked 187 children in Crete, diagnosed with autism, for various metabolic dysfunctions.

Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD)

As the reader pointed out, the results are very odd.

The researchers identified 13 children whose results suggested something strange was going on with biotin.  When they did the further tests for biotin deficiency, which is usually caused by deficiency in  biotinidase, they could find nothing unusual.

Nonetheless, they implemented the standard therapy for biotin/biotinidase deficiency.  This involved large doses of oral biotin, which is very cheap and seemingly harmless.

The researchers found that 7 of the 13 made clear advances.  This indicates that they suffered from a biotin deficiency, but not a biotinidase deficiency. Biotinidase is used by the body to recycle its biotin.

Biochemical abnormalities suggestive of IEM

For 12/187 (7%) of patients, urinary 3-hydroxyisovaleric acid (3-OH-IVA) was elevated and sera methylcitrate and lactate levels were also elevated in two of these patients. Despite these biochemical abnormalities, defects in biotinidase, or holocarboxylase synthetase could not be demonstrated in either sera or fibroblasts. Of interest, none of these 12 patients was undergoing valproate intervention, the latter a potential source of 3-OH-IVA elevation in urine. Despite an absence of confirmatory enzyme deficiencies in these 12 patients, we nonetheless opted to treat empirically with biotin for 3 weeks, 2 × 10 mg and then for 6 months at 2 × 5 mg, which led to a clear therapeutic benefit in 7/13 consisting of improvement in the Childhood Autism Rating Scale (CARS; Table Table2).2). For those benefiting from biotin intervention, the most impressive outcome centered on a 42 month-old boy whose severe ASD was completely ameliorated following biotin intervention. This patient was subsequently followed for 5 years, and cessation of biotin intervention (or placebo replacement) resulted in the rapid return of ASD-like symptomatology. This patient currently attends public school without any clinical sequelae and remains on biotin at 20 mg/d.

In the following table are the results showing the effect on the CARS rating scale, before and after treatment with biotin.

Patient #1

Just look at what happened to the first patient in the above table.

For those benefiting from biotin intervention, the most impressive outcome centered on a 42 month-old boy whose severe ASD was completely ameliorated following biotin intervention. This patient was subsequently followed for 5 years, and cessation of biotin intervention (or placebo replacement) resulted in the rapid return of ASD-like symptomatology. This patient currently attends public school without any clinical sequelae and remains on biotin at 20 mg/d.

He went from severe autism to no autism.  (and back, when he stops the biotin)

Yet, if he was tested for the standard biotin(idase) disorder, even at the best center for autism in the world, nothing would show up

Biotin Deficiency

Genetic disorders such as Biotinidase deficiency, Multiple carboxylase deficiency, and Holocarboxylase synthetase deficiency can also lead to inborn or late-onset forms of biotin deficiency. In all cases – dietary, genetic, or otherwise – supplementation with biotin is the primary method of treatment.


Of 187 children, 13 were identified for biotin treatment and 7 responded .  None of these children would have been noticed by the normal diagnostic procedures of even the best laboratory, which look for biotinidase deficiency.

Also of interest is the effect of partial biotin deficiency.

·        profound biotinidase deficiency (<10% of mean normal serum activity)
·        partial biotinidase deficiency (10%–30% of mean normal serum activity).

Children with partial biotinidase deficiency and who are not treated with biotin do not usually exhibit symptoms unless they are stressed (i.e., prolonged infection)

Partial biotinidase deficiency isusually due to the D444H mutation in the biotinidase gene

Profound biotin deficiency would hopefully be noticed

Mild symptoms linked to biotin deficiency:-

  •        Loss of hair colour
  •         Loss of hair
  •         Fine and brittle hair


The results of clinical studies have provided evidence that marginal biotin deficiency is more common than was previously thought. A previous study of 10 subjects showed that the urinary excretion of biotin and 3-hydroxyisovaleric acid (3HIA) are early and sensitive indicators of marginal biotin deficiency.

It does seem that biotin deficiency is usually caused by things that lead to biotinidase deficiency, so let’s look at the data on frequency (Epidemiology)

Biotin Deficiency – Epidemiology
Based on the results of worldwide screening of biotinidase deficiency in 1991, the incidence of the disorder is: 5 in 137,401 for profound biotinidase deficiency

·         One in 109,921 for partial biotinidase deficiency
·         One in 61,067 for the combined incidence of profound and partial biotinidase deficiency
·         Carrier frequency in the general population is approximately one in 120.

Both parents need to carry the genetic defect, for a child to inherit it.

So something odd is going on (in Greece).

In 61,067 people we would expect 600 people with autism.

It seems that in 600 Greek children with autism there may be 22 with a biotin dysfunction.  This is vastly higher than we would expect.

Not everyone with biotin dysfunction has autism and even if they did, in Greece there would be 22x greater incidence than elsewhere.


I think we (and the Greeks) have likely discovered some new phenomenon “autistic partial biotin deficiency”, APBD, which is not caused by the usual lack of biotinidase.  Somehow the dietary biotin is insufficient in these people, even though biotinidase is present.

APBD does not seem to cause all the severe symptoms of biotin deficiency, just the neurological ones and so remains undiagnosed.

Perhaps one of the other odd metabolic disorders in autism is affecting the biotin metabolism?  Remember that Harvard study suggesting the oxidative stress in the autistic brain reduces the activity of a key enzyme D2, that is needed to convert the thyroid pro-hormone T4 into the active hormone T3.  This would mean that despite a “normal” set of thyroid lab results from your doctor, you might well be hypothyroid inside the brain (low on T3).

Those with access to a good laboratory might consider sending a urine sample to measure 3-hydroxyisovaleric acid (3HIA).

Those without these options might have to settle with the option of trying 10-20 mg of Biotin for a short period and see if it has any effect.

Biotin appears to be one of those vitamins, like B12, where even huge doses may have no ill effect; they are just excreted.  The supplement companies are selling 10 mg pills of biotin;  the RDA for a 10 year old is 0.03 mg which is 333 times less.

Based on the Greek study, you would expect about 4% of autistic people to show a clear benefit, without first doing the 3HIA urine test.

A small chance of success per child, but a chance nonetheless.

Note on the study
I have referred to this Greek study once before. On that occasion I was talking about the ketogenic diet and modified Atkins diet.

It is widely accepted that the ketogenic diet can greatly reduce epileptic seizures, so it is not really surprising that it can also help some people with autism (but which ones?).

In the Greek study, via laboratory tests, they identified 9 % children who might benefit from this diet.  Just over a third of these identified children did indeed improve on the diet.

16/30 patients manifested increased sera beta hydroxybutyrate (b-OH-b) production and 18/30 had a paradoxical increase of sera lactate. Six patients with elevated b-OH-b in sera showed improved autistic features following implementation of a ketogenic diet (KD).

This remarkable study was published one year ago.

It has been cited just one time in subsequent literature (although twice now in this blog); this really tells us a lot. (nobody is interested)

Changing diet can require a great deal of effort and, if a fussy eater is involved, it can be even more difficult.  If biomarkers exist to narrow down who would benefit from a modified diet, this is really very significant.

You can easily try biotin pills for a couple of weeks, trying a ketogenic diet just on the "off chance", requires much more bother.