Autism
By Andrius Baskys, MD, PhD
Autism, the prototypic pervasive developmental disorder, usually evident by the age of three to four years, is defined by the following core symptoms:
- limited or absent verbal communication
- lack of reciprocal social interaction/responsiveness
- restricted, stereotypic, often ritualized patterns of behavior and/or interest.
Autism spectrum disorder (ASD) covers a broader range of symptom combinations, which also includes the less severe Asperger’s syndrome and pervasive developmental disorder not otherwise specified (PDD NOS). Intellectual disabilities coexist with ASD, but are absent in Asperger’s syndrome.
Approximately 1 in 68 children have been diagnosed with ASD according to the latest data from Centers for Disease Control (CDC). ASD exists in all socioeconomic, ethnic and racial groups, and is nearly 5 times more likely to affect boys than girls. It is highly heritable: among identical twins the concordance rate is 40-95% and in non-identical twins the concordance rate is 30% or more.
Treatment of core symptoms of ASD
Autism is not a medical diagnosis. It is a “container” of several hundred or more diseases or developmental errors arising from genetic variations, inherited or appearing anew (de novo).
Knowing precisely what these variations are opens an opportunity to employ highly specific, individualized treatment and follow-up strategies. In our clinic we use Next Generation DNA sequencing (NGS) to identify pathogenic variants responsible for core symptoms and comorbidities. A decade of Genomic Medicine has already demonstrated its superior effectiveness and increased patient satisfaction compared to conventional approaches.
Treatment of comorbidities
The ASD core symptoms vary in severity, rarely occur in isolation and are often associated with a number of comorbidities. The most common among them are intellectual disability (ID) and seizures. The former is seen in about 60% of ASD cases and the latter occurs in about 20-30% of ASD cases. Other common conditions associated with ASD are:
- Behavioral/psychiatric (ADHD, disruptive behavior, aggression)
- Sleep disturbances
- Gastrointestinal.
Pharmacotherapy with psychotropic and anti-epileptic medications is a mainstay treatment for ASD comorbidities. For example, antipsychotics aripiprazole (Abilify®) and risperidone (Risperdal®) have been approved by the US Food and Drug Administration (FDA) for treatment of irritability in ASD.
However, use of these drugs in children with ASD could be problematic due to their adverse effects. Muscle rigidity, restlessness or weight gain could significantly reduce medication adherence and clinical utility.
The solution to this problem is genetic data guided medication selection or Pharmacogenomics (PGx for short). In our clinic we implemented PGx-guided prescribing that significantly reduces medication side effects while improving their effectiveness and patient adherence. You can find more on PGx by clicking a link to Personalized Prescribing.
Genetics of ASD
Genetic abnormalities associated with ASD include chromosomal aberrations, copy number variations and pathogenic variants in genes associated with nervous system development and functions. To date, deleterious variants in over 700 genes, both [simple_tooltip content=’Variants that were not present in both parents’]de novo[/simple_tooltip] and inherited, have been discovered using molecular techniques. Molecularly defined ASD is responsible for about 20% of all ASD cases.
Examples of several important genes harboring deleterious mutations responsible for ASD symptoms are shown below. These examples illustrate how genetic data can be used to guide treatment and medical follow up (surveillance) of patients with ASD.
Pathogenic variants in CHD8, Chromodomain Helicase DNA Binding Protein 8 gene have been associated with ASD.
SYMPTOMS may include gastrointestinal problems such as constipation, reduced bowel motility. Seizures may be present as well. There is a risk of malignancy.
APPEARANCE. Mutation carriers may have prominent supraorbital ridges, widely spaced eyes, small head or pointed chin.
TREATMENT goals should include seizure control and maintaining bowel motility. Examples of pharmaceuticals and nutraceuticals interacting with the CHD8 gene are beta-methylcholine, copper sulfate, decitabine, dexamethasone, finasteride, indomethacin, sulindac, testosterone and troglitazone (withdrawn in 2000).
SURVEILLANCE for malignancy should be part of a routine medical follow up.
ADNP, Activity Dependent Neuroprotector Homeobox gene has been associated with ASD.
SYMPTOMS include mood disorders, anxiety, temper tantrums, attention deficit-hyperactivity disorder (ADHD), obsessive-compulsive disorder and sleep problems.
APPEARANCE. Mutation carriers may have prominent forehead, high hairline, outside corners of the eyes that point upward or downward, droopy eyelids, broad nasal bridge, thin upper lip, unusually shaped ears, hand and finger abnormalities, eye and vision abnormalities (eyes that do not point in the same direction), farsightedness and early appearance of primary (baby) teeth.
TREATMENT should target mood and anxiety symptoms, temper tantrums, as well as attention deficit (ADD/ADHD), obsessive-compulsive behavior and sleep problems.
Pharmacogenetics should be used for medication selection to minimize side effects and improve adherence.
Nutraceuticals known to interact with ADNP are quercetin (from oak bark) and Jin Fu Kang (traditional Chinese medicine).
SCN2A, Sodium Voltage-gated Channel Alpha Subunit 2 gene.
SYMPTOMS include seizure disorder (epilepsy) and reduction in size of a brain structure called cerebellum, which is involved in movement and balance coordination.
TREATMENT should be directed to seizure control. Examples of medications (approved and investigational) are lamotrigine, valproic acid, zonisamide, phenytoin, propofol, fospropofol, brivaracetam, carbamazepine, oxcarbazepine, phenobarbital, topiramate, safinamide and metergoline.
Examples of nutraceuticals known to interact with the SCN2A gene are genistein (found in soy products) and grape seed proanthocyanidins (found in grape seeds).
Medication effectiveness vary greatly depending on the variants present in the SCN2A gene. Therefore, to be effective, medication selection should be guided by pharmacogenetics (PGx).
ARID1B, AT-Rich Interaction Domain 1B gene. At least 13 ARID1B gene mutations have been identified in individuals with ASD.
SYMPTOMS. Mutation carriers often have intellectual disability (ID), significant speech problems and brain malformations that can be seen on imaging studies.
APPEARANCE. Excessive hair growth, coarse face, malformed ears, short stature, small, undeveloped 5th finger. Cryptorchidism, also known as undescended testicles, may be present in males. Boys who have had cryptorchidism that was not corrected in early childhood are at increased risk for developing cancer of the testicles. Abnormalities of the roof of the mouth, also known as Coffin-Siris syndrome 1, may be present.
TREATMENT is symptomatic. Examples of medications and nutraceuticals known to interact with the ARID1B gene are antirheumatic agents, copper, ethinyl estradiol, finasteride, phenobarbital, troglitazone (withdrawn in 2000) and dietary fats.
TBR1, T-Box, Brain 1 gene.
SYMPTOMS. Intellectual disability (ID) and growth retardation.
APPEARANCE. Small head size and underdeveloped brain structures known as pons and cerebellum seen on brain imaging.
TREATMENT is symptomatic. Examples of medications known to interact with the TBR1 gene are valproate, acetaminophen and tretinoin. Examples of nutraceuticals are epigallocatechin gallate (found in tea), genistein (found in soy products) and zinc sulfate.
DYRK1A, Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A gene.
SYMPTOMS are intellectual disability (ID), speech problems and anxiety. Weak muscle tone, foot abnormalities, and walking problems may also be present. Seizures may be present.
APPEARANCE. Small head, bitemporal narrowing (size of the head above the eyebrows is narrow), deep-set eyes, large simple ears and a pointed nasal tip.
TREATMENT is symptomatic and should include seizure control (if present). Examples of pharmaceuticals known to interact with the DYRK1A gene are valproic acid, acetaminophen and antirheumatic agents. Examples of nutraceuticals known to interact with this gene are harmine, choline, epigallocatechin gallate, folic acid, Jin Fu Kang, methionine and resveratrol.
The above examples are not meant to be exhaustive. However, they illustrate a diversity of medical conditions that could be seen as “autism” or “ASD” based on the clinical information alone. Whole Exome or Whole Genome (WES or WGS) DNA sequencing can uncover pathogenic variants allowing to individualize treatment and medical follow up with potentially much improved outcomes.
Inborn errors of metabolism – a treatable cause of ASD?
ASD is not infrequently seen in association with genetic disorders known as Inborn Errors of Metabolism (IEM). An IEM means that a genetic mutation causes a block in a metabolic pathway resulting either in accumulation of toxic substances or deficiency of substances needed for normal organ function.
Most IEMs affect the nervous system causing behavioral and neuropsychiatric abnormalities that include ASD, learning disorders, social deficits, hyperactivity, aggression, catatonia, psychosis and depression.
Symptoms of an IEM may be acute, appearing in the first 2-3 years of life, or chronic. Symptoms of a chronic IEM may come to medical attention at any time in life. A well known example of an IEM is phenylketonuria or PKU. The frequency of IEMs is approximately 1 in 500-800 births.
The following are examples of IEM symptoms affecting each of the major organ systems.
- Growth failure, failure to thrive, weight loss
- Ambiguous genitalia, delayed puberty, precocious puberty
- Developmental delay, seizures, dementia, encephalopathy, stroke
- Deafness, blindness, pain agnosia
- Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps
- Dental abnormalities
- Immunodeficiency, low platelet count, low red blood cell count, enlarged spleen, enlarged lymph nodes
- Many forms of cancer
- Recurrent vomiting, diarrhea, abdominal pain
- Excessive urination, kidney failure, dehydration, edema
- Low blood pressure, heart failure, enlarged heart, hypertension, myocardial infarction
- Liver enlargement, jaundice, liver failure
- Unusual facial features, congenital malformations
- Excessive breathing (hyperventilation), respiratory failure
- Abnormal behavior, depression, psychosis, ASD
- Joint pain, muscle weakness, cramps
- Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus.
(From Wikipedia, with modifications)
Many IEMs are treatable by nutrient or vitamin supplementation, or withdrawal of certain nutrients. However, deciding on which nutrients should be withheld and which should be added to the diet is only possible if the exact nature of the IEM is known. Because of a large number (thousands) of genetic errors that could result in IEMs and, consequently, symptoms, it is not possible to diagnose IEMs from a clinical examination alone. At this time, Whole Exome and Whole Genome DNA sequencing are the only tools that can accurately identify the majority of IEMs.
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