CHAPTER11

Childhood Disorders

AUTISM SPECTRUM DISORDERS

Autism is often considered a childhood condition, although many of its symptoms persist lifelong. Some people with autism also have mood and anxiety disorders, seizures, intellectual disability, attention deficit hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD). However, more than 40 percent of people with autism have normal or above-average intelligence. With symptoms that range from mildly to severely disabling, autism is considered a spectrum. Autism spectrum disorders (ASD) are diagnosed based on two main criteria: impaired social communication and interaction, and repetitive behaviors or narrow, obsessive interests. For example, some people on the autism spectrum are unable to speak, while others are socially awkward but highly articulate. Many adults with an autism diagnosis think of their autism as a strength — enabling or motivating them to develop deep expertise in an area or a different perspective on the world — rather than a disorder that needs to be cured.

Currently, 1 of every 68 American 8-year-olds is estimated to meet the diagnostic criteria for an autism spectrum disorder. The prevalence of ASD has risen dramatically since the 1970s, but it is unclear whether changes to diagnostic criteria and wider recognition of ASD have contributed to the increase in diagnoses.

Four to five times more boys than girls are diagnosed with autism, although it is not clear whether some of that pattern is because of underdiagnosis of girls. Environmental factors such as parents having children later in life, fever and infection during pregnancy, and premature birth have been linked to an increased risk of autism in children. A huge number of studies have found no connection between childhood vaccination and the increase in autism diagnoses.

Autism is believed to be at least partially driven by genetics, but how do scientists know that for sure? One low-tech approach uses twin studies: If one of a pair of identical twins receives an autism diagnosis, the other twin has greater than a 50 percent chance of also being diagnosed with ASD. Children who have an older sibling on the spectrum also have a higher likelihood of being diagnosed with autism — nearly one in five also receives a diagnosis of ASD.

The genetics of autism is very complicated in most cases, involving dozens (or more) of genes, leading to a unique condition in nearly every person. Recently, however, high-throughput genomic analyses have broadened the pool of potential genes, revealed their roles in the body, and suggested possible new therapies.

It appears that many genes, each with a small effect, contribute to the inheritance of most ASDs. But such small effects make these genes hard to identify in genome-wide association studies. Scientists are now looking at the rare variants associated with ASD. These afflict fewer people with ASD, but their effects are larger and easier to detect. Some of these rare mutations are in single genes whose impairment is already known to cause intellectual disability and social dysfunction. These genes include FMR1 (codes for fragile X mental retardation protein, but its non-mutant form is needed for normal cognitive development); PTEN (codes for a tumor suppressor enzyme that regulates cell division, so cells don’t divide or grow too fast); and TSC1 or TSC2 (tuberous sclerosis complex 1 and 2), which also code for proteins that help control cell growth and size. Between 50 to 60 percent of people with fragile X syndrome and approximately 40 percent of people with tuberous sclerosis complex have ASD. Children with a variant of the gene NF-1 develop tumors in childhood (neurofibromatosis) and a 2011 study found that nearly 10 percent met the criteria for autism.

Intriguingly, these ASD-related genes influence a major signaling pathway for regulating cell metabolism, growth, and proliferation, the mTOR pathway. This suggests a very real potential for treating autism with drugs that target the mTOR pathway. For example, mouse models with mutations in PTEN show traits similar to humans with these gene variants: altered sociability, anxiety, and repetitive behaviors. These behaviors can be relieved or reversed by drugs that inhibit the mTOR pathway. Clinical trials of these drugs (rapamycin and lovastatin) are underway.

The genetics of autism is very complicated in most cases, involving dozens of genes, leading to a unique condition in nearly every person.

Despite this progress, autism genetics is so complicated that it can’t be used to diagnose the condition. And unlike diabetes, kidney disease, or thyroid disease, there are no biochemical or other biomarkers of autism. Currently, autism diagnosis is based on behavioral analysis, but efforts are underway to use more objective criteria such as tracking eye movements and functional neuroimaging, which can even be done in infants.

How early can autism be detected? Parents often notice developmental issues before their child’s first birthday, and autism can be reliably diagnosed based on behavioral characteristics at age 2. Despite these possibilities for early detection, most American children aren’t diagnosed until they’re about 4½ years old. With evidence mounting that interventions are more effective the earlier they begin, researchers are hoping that more objective measures will enable earlier diagnoses and interventions.

Although the molecular causes and characteristics of autism are unclear, it appears that the condition results from unusual cellular development within the cerebral cortex — a brain region that is crucial to memory, attention, perception, language, and other functions. Both white and gray matter of the brain show consistent, but subtle, alterations in people with ASD. Long-term studies also have found that a minority of children on the autism spectrum have abnormally large brain volumes and faster brain growth. Other toddlers with autism have shown unusual development and network inefficiencies at the back of the cerebral cortex. There is evidence that some atypical activity occurs in the cortex of people with ASD from older childhood into adulthood, and information might not be integrated in the usual way across distributed brain networks.

At this point, no medications have been proven to reverse autism. Some people get symptomatic relief from drugs designed for other uses, such as anxiety conditions, and several studies have reported social benefits from treatment with oxytocin — a hormone known to improve social bonding — but the findings have been mixed. For this challenging disorder, behavioral therapies are still the only proven treatments for autism, and early interventions are the most effective.

ATTENTION DEFICIT HYPERACTIVITY DISORDER

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed childhood conditions. In 2014, approximately 11 percent of American parents with a child between the ages of 4 and 17 reported that their son or daughter had received an ADHD diagnosis. In at least 30 percent of those diagnosed with ADHD, the disorder continues into adulthood.

ADHD is usually characterized by inattentiveness, as well as hyperactivity or impulsive behaviors. Although all young children can be hyperactive, impulsive, and inattentive from time to time, these symptoms are more extreme and last longer in children with ADHD. They often struggle to form strong friendships, and their grades in school can reflect their behavior instead of their academic ability. Executive functions, such as finishing what they start, remembering to bring homework back to school, and following multistep directions, can be especially challenging for those with ADHD. Young people with ADHD also have lower rates of high school graduation and a higher risk of suicide.

No objective diagnostic test exists for ADHD, so diagnosis requires a comprehensive evaluation, including a clinical interview and parent and teacher ratings. Because problems with attention and hyperactivity can be caused by other conditions such as depression, sleep issues, and learning disorders, careful evaluation is always needed to determine whether ADHD is truly the cause of the symptoms. To warrant an ADHD diagnosis, attention and behavioral problems must be severe enough that they interfere with normal functioning. In addition, the behavioral issues must be present in more than one context — not only at home or at school, but in both settings.

Although ADHD tends to run in families, no well-defined set of genes is known to be responsible for the condition. Environmental risk factors, such as extreme early adversity, exposure to lead, and low birthweight, can also be involved. People with ADHD do not demonstrate any obvious brain alterations, but research has found that people with ADHD might have differences in the structure of brain cells and in the brain’s ability to remodel itself. Some people with ADHD show unusual activity in brain cells that release dopamine, a chemical messenger involved in rewarding behavior.

ADHD has no cure, but treatments include drugs, behavioral interventions, or both. Interestingly, ADHD medications include stimulants such as methylphenidate, as well as newer, non-stimulant drugs. The drugs are available in long-acting formulations so children do not have to interrupt the school day to take their medication. Determining the right drug and the right dose might require a period of experimentation and support from a specialist, since dosage is adjusted to how fast a child metabolizes the drug, and to minimize the side effects. Nevertheless, most children with ADHD are diagnosed and treated by their pediatricians. Effective behavioral treatments include organizational support, exercise, and meditation.

DOWN SYNDROME

Down syndrome is named for the English physician who first described it in 1866, but nearly 100 years passed before scientists determined what caused the condition: possessing an extra copy of all or part of the 21st chromosome. People with this syndrome have three copies of this genetic material, instead of two. In some cases, the extra copy, or trisomy, does not occur in every cell, producing what’s known as mosaicism. Currently, about 250,000 people in the United States are living with Down syndrome.

There is no clear cause of the genetic glitch, although maternal age is a major risk factor for Down syndrome. Mothers older than 40 are 8.5 times more likely to have a child with Down syndrome than mothers aged 20 to 24. Advanced paternal age has also been linked to higher incidence of Down syndrome.

Since late 2011, fetuses can be screened for Down syndrome using the mother’s blood. In the past, the risk of test procedures meant that only older mothers (whose likelihood of having a Down syndrome child was known to be higher) should be screened. Younger mothers didn’t know until delivery whether their child would have Down syndrome. The new blood test, unlike amniocentesis and chorionic villus sampling, poses no risk to the baby, so it can also be used for younger mothers whose chance of having a child with Down syndrome is quite small.

Children born with Down syndrome have distinctive facial features, including a flattened face and bridge of the nose, eyes that slant upward, and small ears. They usually have small hands and feet, short stature, and poor muscle tone as well. The intellectual abilities of people with Down syndrome are typically low to moderate, although some graduate from high school and college, and many successfully hold jobs. Other symptoms of Down syndrome can include hearing loss and heart defects, and virtually everyone born with Down will develop early-onset Alzheimer’s disease, often in their 40s or 50s. Chromosome 21 contains the gene that encodes amyloid precursor protein (APP), an Alzheimer’s disease risk factor, and possessing an extra copy of this gene might cause the early onset of this fatal disease. Interestingly, people with mosaic Down syndrome seem to have milder symptoms and are more likely to live past 50.

There is no real treatment for Down syndrome, nor any clear explanation of what occurs in the brain. Poor connections among nerve cells in the hippocampus, the part of the brain involved in memory (and the first brain area affected by Alzheimer’s disease), are believed to be a key factor in brain or intellectual differences in Down syndrome. Dysfunction in the mitochondria, the cell’s power plants, might also play a role in development of related disorders that involve energy metabolism, such as diabetes and Alzheimer’s.

Scientists have grown stem cells from fetuses with Down syndrome and used them to test potential treatments and confirm which molecular pathways are involved in the condition. In one such laboratory study, researchers took a gene that normally inactivates the second X chromosome in female mammals and spliced it into a stem cell that had three copies of chromosome 21. In these cells, the inactivation gene muted the expression of genes on the extra chromosome 21, believed to contribute to Down syndrome. Although this is a long way from any clinical applications, the model is being used to test the changes and cellular problems that occur with the tripling of the 21^st chromosome, in hopes of eventually finding a treatment.

DYSLEXIA

Dyslexia is the most common and best-studied of the learning disabilities, affecting as many as 15 to 20 percent of all Americans. People with dyslexia have a pronounced difficulty with reading despite having normal intelligence, education, and motivation.

Symptoms include trouble with pronunciation, lack of fluency, difficulty retrieving words, poor spelling, and hesitancy in speaking. People with dyslexia might need more time to respond orally to a question and might read much more slowly than their peers. Dyslexia is usually diagnosed in elementary school, when a child is slow to read or struggling with reading. Although reading skills and fluency can improve, dyslexia persists lifelong.

Deciphering printed letters and words and recalling their sounds and meaning involves many areas of the brain. Brain imaging studies indicate these areas can be less well connected in people with dyslexia. One of these areas is a region on the left side of the brain called the “word-form area,” which is involved in the recognition of printed letters and words. People with dyslexia also show less brain activity in the left occipitotemporal cortex, which is considered essential for skilled reading. Researchers believe that the brain differences are present before the reading and language difficulties become apparent — although it is possible that people with dyslexia read less and, therefore, their brains develop less in regions associated with reading. Those with dyslexia appear to compensate for reduced activity on the left side of the brain by relying more heavily on the right side.

Genetic analyses have revealed a handful of susceptibility genes, with animal models suggesting that these genes affect the migration of brain cells during development, leading to differences in brain circuitry. Dyslexia runs in families, with roughly half of dyslexics sharing the condition with a close relative. When one twin is diagnosed with dyslexia, the second twin is found to have the condition 55-70 percent of the time. But the genetics of dyslexia is complex, and likely involves a wide range of genes and environmental factors.

Treatment for dyslexia involves behavioral and educational intervention, especially exercises like breaking words down into sounds and linking the sounds to specific letter patterns. Some researchers use a child’s ability to rapidly and automatically name things as an early indicator of dyslexia. This rapid automatic naming, and the ability to recognize and work with the sounds of language, are often impaired in people with dyslexia. Both skills can be used in preschoolers and kindergartners to predict their later reading skills. Research suggests that treatments targeting phonology, as well as multiple levels of language skills, show the greatest promise.

Epilepsy has many possible causes and thus is considered a spectrum rather than a single disorder.

EPILEPSY

If someone has two or more seizures that cannot be explained by a temporary underlying medical condition such as a high fever or low blood sugar, their medical diagnosis will be “epilepsy” — from the Greek words meaning to “seize,” “attack,” or “take hold of.” About 1 percent of American children and 1.8 percent of adults have been diagnosed with this brain disorder. Seizures result from irregular activities in brain cells that can last five or more minutes at a time. Some seizures look like staring spells, while others cause people to collapse, shake, and become unaware of what is going on around them. The pattern of symptoms and after-seizure brain recordings using EEGs are used to distinguish between different types of epilepsy and determine whether the true cause of the seizures is epilepsy or a different medical condition.

Seizures are classified by where they occur in the brain. Generalized seizures affect both sides of the brain. They include absence or petit mal seizures, which can cause rapid blinking or a few seconds of staring into space, and tonic-clonic or grand mal seizures, which can make someone fall, have muscle spasms, cry out, and/or lose consciousness. Focal or partial seizures are localized to one area of the brain. A simple focal seizure can cause twitching or a change in sensation, triggering strange smells or tastes. Complex focal seizures can leave a person confused and unable to answer questions or follow directions. A person can also have so-called secondary generalized seizures, which begin in one part of the brain but spread to become generalized seizures. In some patients with severe epilepsy, multiple types of seizure can occur at the same time.

Epilepsy has many possible causes and thus is considered a spectrum rather than a single disorder. Causes include premature birth, brain trauma, and abnormal development due to genetic factors. Attributes of epilepsy patients such as head size, movement disorders, and family history suggest that genetics is involved.

Seizures can also accompany or cause intellectual or psychiatric problems. For example, some seizures may suppress the growth of dendrites, leaving the person emotionally unsettled or less able to learn.

Treatments for epilepsy are directed toward controlling seizures with medication or diet. For most patients, a single medication is enough to control seizures, although a significant minority cannot get adequate control from drugs. About half of epilepsy patients, particularly those with generalized epilepsy, can reduce their seizures by eating a ketogenic diet, which relies heavily on high-fat, low-carbohydrate foods, although it’s unclear why this diet is effective. For severe cases that are not relieved by medication, doctors might recommend surgery to remove or inactivate the seizure-initiating part of the brain. In the most severe cases, if one side of the brain triggers seizures on the other side, surgeons may perform “split-brain surgery,” cutting the corpus callosum, a thick band of white matter that connects the two sides of the brain. Once their seizures are controlled, people with epilepsy can resume their normal lives.