Sontheimer, H. (2015). Diseases of the Nervous System. Academic Press. 

Diseases of the Nervous System 

Sleep problems and seizures are common comorbidities seen in Fragile X Syndrome.

Comorbidities of Fragile X Syndrome

In these mice, mGLUR5 proteins are reduced by 50% and thus symptoms of Fragile X Syndrome are seen. However, when you cross a *FMR1* knockout mouse with a mouse that has a heterozygous deletion of mGLUR5, it leads to expression of only 1 intact mGLUR5 allele and this led to the reversal of all Fragile X symptoms except for enlarged testes. Additionally, this transgenic mouse model is being used to look at pharmacological treatments of Fragile X Syndrome.


Mouse Model: *FMR1* Knockout

Currently, there are no clinically proven treatments that directly affect the disease. Most proven treatments are for the comorbidities seen with Fragile X rather than the condition itself. However, there are many pharmacological treatments being tested for treatment of Fragile X - and many of these are already approved for treatment of other mental or physical conditions:
- Fenobam 
- Baclofen 
- Arbaclofen
- Acamprosate 
- Minocycline
- Lithium 
- MPEP
- CTEP
Some studies that use animal models have found ways to reduce the severity of symptoms like impaired cognition and seizures by conducting trials with metabotropic glutamate receptor 5 pathway antagonists. The severity of these symptoms correlate with the severity of the FMRP (fragile X mental retardation protein) deficit (Hagerman et al., 2009). Further research into this deficit and the methylation needed to prevent it may reveal more about possible treatments in the future.  

Emerging Treatments for Fragile X Syndrome

- Anatomical signs
- Cognitive and behavioral symptoms

Symptoms of Fragile X Syndrome

- Enhanced long-term depression (LTD)
- Protein targets affected by the balance of mGluR5-FMRP balance

Neurobiology of Fragile X Syndrome

Fragile X syndrome is perhaps the most common genetic form of intellectual disability. It results when the trinucleotide repeats (i.e., CGG repeats) in the long arm of the X chromosome number more than 200 repeats, as opposed to the normal 6-50 repeats. This extension of repeats leaves this region of DNA fragile, or prone to breakage. Specifically, the overexpansion causes methylation and transcriptional repression of the Fragile X Mental Retardation 1 gene (*FMR1*), which encodes an important RNA-binding protein that inhibits RNA translation into proteins known as fragile X retardation protein (FMRP). The condition affects 1 in 3600 males and 1 in 8000 females. The reason for this large discrepancy between incidences in biological sexes is due to the fact that genetic females have two X chromosomes rather than one X like genetic males do. Generally speaking, females have one normally functioning *FMR1* on the non-mutated chromosome in each cell, which allows their symptoms to be milder since the amount of abnormal *FMR1* is more variable than in males.

Macalester College

Brandeis University

Smith College

- Intellectual and Developmental Disabilities (IDD)
- Learning disabilities
- Autism Spectrum Disorder (ASD)
- Downs Syndrome
- Fetal Alcohol Syndrome (FAS)
- Cerebral Palsy
- Attention-Deficit Hyperactivity Disorder (ADHD)
- Phenylketonuria (PKU)
- Hypoxia
- Fragile X Syndrome (FXS)
- Rett Syndrome
- Developmental Dyslexia
- Auditory Processing Disorder (APD)

Examples of developmental disorders

Autism Spectrum Disorder is a neurodevelopmental disorder that affects communication and behavior. It displays symptoms such as impaired communication, lack or impairment in social skills and interactions, and repeated patterns of behaviors that interfere with an individual's ability to cognitively function. These symptoms are almost always present in early development, and are considered to be on a 'spectrum' because of the differences in severity of these symptoms.


Although autism can be diagnosed at any age, it is said to be a “developmental disorder” because symptoms generally appear in the first two years of life. Boys tend to be diagnosed more often than girls by approximately 4x. There is also an overrepresentation of transgender or gender nonconforming people with ASD.

Autism Spectrum Disorder

This list includes disorders or conditions that are related to autism or autistic states/features but are not currently directly or officially included in the DSM. These disorders include:

- Williams Syndrome
- Fragile X Syndrome
- Landau - Kleffner Syndrome
- Prader - Willi Syndrome
- Angelman Syndrome
- Rett Syndrome
- Tardive Dyskinesia


List of Other Recognized Autism Spectrum and Related Disorders

Breedlove, S. & Watson, N. (2017). Behavioral neuroscience, eighth edition. Oxford University Press.

Behavioral Neuroscience 8th Edition

Phenylketonuria (PKU) is a recessive hereditary disorder, meaning that two copies of the mutated gene implicated in PKU disease processes must be inherited in order for an individual to display symptoms of this disorder. It’s one of the most common inherited metabolic disorders. The mutated genes cannot produce the enzyme that normally metabolizes the compound phenylalanine, found in certain food products, into tyrosine. The build-up of phenylalanine in the brain can become toxic, leading to intellectual disability when the build-up interferes with myelination in the central nervous system. If a baby with PKU ingests food with phenylalanine, the build-up during the post-birh period stunts brain development. Because of its preventable nature, and because the test is inexpensive and accurate, many governments have passed laws for mandatory PKU testing shortly after birth, and this has prevented many cases of intellectual disability.
PKU can be prevented by regulating the level of phenylalanine intake, especially early in life. After the post-birth brain development period has passed, the low phenylalanine diet can be relaxed somewhat since the danger to brain development has passed. 
For pregnant women with PKU, however, this isn’t the case. When a fetus is in utero, it’s protected by its mother’s metabolism. For non-PKU having mothers, this means the baby is especially protected during this time. However, if the mother has PKU and ingests a diet with typical or high levels of phenylalanine - while it won’t damage HER brain - it will cause improper brain development in the fetus. 

Phenylketonuria (PKU)

Hypoxia describes a deficiency in oxygen. If newborns experience birth complications such that they experience a lack of oxygen at birth, they are more likely to have an intellectual disability, or significant difficulties with intellectual functioning and adaptive behavior. 

Hypoxia

Fragile X Syndrome

Down syndrome is a developmental disorder that causes varying degrees of physical and cognitive disability. It is the most common genetic condition and is caused by a chromosomal abnormality in which there is an extra copy of chromosome 21. 

Down Syndrome

Fetal Alcohol Syndrome is a specific diagnosis within the broader Fetal Alcohol Spectrum Disorder. It occurs when a mother consumes alcohol during pregnancy, especially during the critical period of the 3rd or 4th week of gestation. This exposure damages the developing nervous system, leading to distinct anatomical and behavioral abnormalities.

Fetal Alcohol Syndrome (FAS)

Learning disabilities are cognitive disorders that impact specific areas of cognition, such as language or reading. They are classified as specific neurological impairments, distinguishing them from global intellectual or developmental disabilities. A key characteristic is that they often affect individuals with average to above-average intelligence, meaning the disability is confined to a particular cognitive area and is not an indicator of overall intellectual capability.

Learning Disabilities

Attention-Deficit Hyperactivity Disorder (ADHD) is characterized by inattention and hyperactivity-impulsivity and is divided into three subtypes:
- primarily inattentive
- primarily hyperactive-impulsive
- combined

Attention-Deficit Hyperactivity Disorder (ADHD)

Cerebral Palsy is the most common motor disability in children, and it is caused by abnormal development or damage to the brain. This results in an impaired ability to move and maintain posture. In mild cases, individuals may walk a bit awkwardly while severe cases may need a caretaker and special equipment.

Cerebral Palsy

Rett Syndrome is a rare X-linked disorder usually caused by spontaneous (de novo) mutations in the methyl-CpG-binding protein 2 (*MeCP2*) gene. It affects almost exclusively genetic females (1 in 10,000 females). This is because genetic males only have one X chromosome and therefore don’t have dosage compensation occurring, lessening the amount of the mutated gene circulating. Genetic males with the syndrome either die in utero or in infancy due to the severity of the mutation phenotype. For 6 - 18 months persons with Rett Syndrome experience normal development, hitting the usual developmental milestones, until said development suddenly stops and regression begins. There’s usually a mild improvement in some social skills at around age 5, but regression (mental and physical) will continue for the rest of the person’s life.


Rett Syndrome

Individuals with Intellectual and Developmental Disabilities

IDD 

A 10-year-old student consistently scores in the high-average range on intelligence tests that measure problem-solving and abstract reasoning. However, the student struggles significantly with reading, frequently confusing letters and having difficulty sounding out words, which is well below the expected level for their age and overall intelligence. Which of the following best categorizes this student's specific challenge?

In a foundational 1943 paper, psychiatrist Leo Kanner detailed a unique neurodevelopmental condition he termed "early infantile autism." His observations in a group of children highlighted key characteristics, including an inability to form close emotional bonds, abnormalities in speech and language, repetitive behaviors, and a strong intolerance for minor changes in their environment or routines.

Leo Kanner's 1943 Description of Early Infantile Autism

Verbal

Gestures

Pictures

Text

Drawing

Communication Styles

A 1981 epidemiological study conducted by Lorna Wing to examine sex ratios in children diagnosed with autism revealed the following:
- difference b/w men and women in language and social impairments, and in the way they reacted to their respective environments
- prompted further sex ratio research

Ehlers and Gillberg (1998):
- study on epidemiology of Asperger's syndrome
- found smaller male:female ratio than expected

Matille et. al, (2007):
- hypothesizied that women with autism display superficial social skills and this is what causes them to be misdiagnosed

Koenig and Tsatsanis (2005):
- found that most autism research stemmed from male experiences alone
- Hartrung and Widiger (1998): concluded that when a disorder's symptoms change based on gender, diagnosis will be skewed towards those who outwardly express symptoms that are out of the social norm



Gender Bias in Autism and Asperger's Syndrome

When diagnosed with ASD, one is further classified as level 1, 2, or 3. These classifications correspond with severity of symptoms and dependency, particularly indicating how much support is necessary for that individual’s daily functioning. 

- ASD Level 1
- ASD Level 2
- ASD Level 3
- Limitations of the ASD Levels

Three Functional Levels of ASD

The most common co-occurring disorders with Autism Spectrum Disorder include epilepsy/seizures, sleep disorders, gastrointestinal disorders, ADHD, anxiety, depression, and bipolar disorder. Often, these can go undetected due to the overlapping symptoms of ASD and/or inability to communicate these symptoms. This inability to communicate other discomforts can often result in coping mechanisms consisting of inappropriate behaviors, thus a shift in behavior can indicate presence of a comorbid disorder. 

- ASD and Epilepsy

ASD Co-morbidity with Other Disorders

As our understanding of Autism Spectrum Disorder has evolved, our definition and explanations have evolved as well, modifying diagnostic criteria and labels. Most likely, it will continue to adapt and evolve as we learn more about it, as our current understanding is incomplete. 

ASD Definitions Through Time

There is no medical test for ASD. Rather, experts must study an individual's development and behavior and, using their best logic and existing criteria, suggest a diagnosis. Generally, diagnoses are more likely to be accurate by age 2 or older. 

ASD Diagnosis Techniques

People with autism and those with intellectual disability often experience stigma and barriers to forming intimate romantic relationships due to deficits in complex social skills, despite often having the same needs for intimacy and sexuality as typically-developing people.

Forming romantic relationsihps as an individual with ASD

- About 50-60% of transition-age youth and adults with autism spectrum disorder obtain work opportunities following participation in vocational rehabilitation programs, mainly working part-time and for low wages
- Programs primarily focus on modifying behavior as opposed to modifying work environments and practices
- The structures of VR programs, availability of services, eligibility criteria, and funding differ greatly by state, as well as how tailored they are to individuals with ASD
- A shift to a knowledge-based economy makes VR services for individuals on the autism spectrum a necessity

Vocational Rehabilitation for Individuals on the Autism Spectrum

Many autistic individuals have at least one other co-occuring psychological condition. Some common co-morbidities of Autism Spectrum Disorder include: 

- Attention-Deficit Hyperactivity Disorder 
- Obsessive-Compulsive Disorder 
- Depression 
- Anxiety Disorders 

Co-occuring Psychological Conditions in Autism Spectrum Disorder 

Applied behavioral analysis, or ABA therapy, is rooted in understanding learning and behavior. This therapy is intended to help people with ASD learn skills and behaviors to help them live more fulfilling lives. Such as:

- coping mechanisms
- social skills
- communication skills
- self-care
- play, leisure activities
- motor skills

ABA Therapy

The DSM-5 criteria for children with ASD includes deficits in sensory processing, specifically sensory modulation. Any sensory modality may be affected but some evidence suggests that individuals with ASD have a greater frequency of sensory deficits in the domains of taste and smell, as well as tactile sensitivity. 

- neurobiology of sensory symptoms in ASD

Sensory Processing Deficits in Autism Spectrum Disorder

- mental/speech deficits or impairment
- sleep difficulties
- if smiling, laughing, and/or head flapping is a repetitive behavior this could also be a symptom of autism since repetitive behaviors are a part of autism.

Angelman Syndrome and Autism Spectrum Disorder: Common Symptoms

Social Anxiety Disorder and Autism Comparison

Reference for Autism and Social Anxiety Disorder

Avoidant Personality Disorder and Autism Comparison

Neff, M. (n.d.). Avoidant Personality Disorder vs Autism. Neurodivergent insights. https://neurodivergentinsights.com/misdiagnosis-monday/avoidant-personality-disorder-vs-autism




Avoidant Personality Disorder and Autism Comparison Reference 

Autism Spectrum Disorder (ASD) is a category of neurodevelopmental disorders defined by core challenges in social interaction and communication, alongside the presence of restricted and repetitive patterns of behavior.

Autism Spectrum Disorder (ASD) Core Deficits

The capacity for independent living among adults with Autism Spectrum Disorder varies. While individuals with more developed language and intellectual skills may be able to live and work on their own, this is not the reality for the majority. For many, the persistence of ASD symptoms creates significant impairments in various life domains, making it difficult to manage essential daily tasks like personal hygiene, finances, and meal preparation.

Independent Living and Daily Life for Individuals with Autism Spectrum Disorder

A disorder characterized by fluent linguistic function but poor performance on standard IQ tests and great difficulty with spatial processing. This syndrome is caused by the absence of about 28 genes from one of the two chromosomes numbered 7.

Williams syndrome

A disorder characterized by involuntary movements, especially involving the face, mouth, lips, and tongue. Can be caused by prolonged use of antipsychotic drugs, like chloropromazine

Tardive Dyskinesia

A rare form of epilepsy that manifests through loss of language. It develops when the child is between 3-7 years old. It is twice as common in males than in females. Individuals generally lose their ability to comprehend first and then lose the ability to speak. 

Some autistic traits seen with this syndrome include aggression, poor eye contact, insistence on sameness, and sleep problems. 

The cause of LKS is not known but many suggest it could be a dysfunctional immune system, virus exposure, or brain trauma. 

Landau - Kleffner Syndrome

Initial symptoms manifest in the first year of life and become more visible during early childhood. 

It derives from a missing portion of chromosome 15 from the maternal side. 


Angelman Syndrome

Core features of this disorder:
- impulsive eating, which can lead to being overweight
- compact body build
- undeveloped sexual characteristics
- poor muscle tone

Some Behaviors common with Autism:
- delays in motor development
- learning disabilities
- feeding problems 
- sleep disturbances
- skin picking
- temper tantrums

People who have this disorder are missing a portion of chromosome 15 but unlike Angelman Syndrome, receive this from the paternal side. 

Learn Before

Related

Learn After