Behavioral genetics discussion

I. Mendelian disorders

Mendelian disorders = rare and usually inherited, typically caused by mutation in a single gene

Almost all Mendelian intellectual disabilities are x-linked

Fragile X syndrome is the most common x-linked cognitive disability (1 in 5000 males, 1 in 8000 females)

Fragile X Syndrome

Results in:

Intellectual disability

Most well-known cause of autism

67% of boys with FXS have AD/ASD

Behavioral abnormalities

Anxiety, ADHD, atypical sociality

Fragile X Syndrome

Associated with an expansion of a trinucleotide repeat (CGG) in the 5’- noncoding region of a gene that encodes an RNA binding protein called FMR1 – it is repeated >200 times in cases of FXS, and typical is just 1—40!

In the normal brain, FMR1 protein is found in nearly all neurons and is likely important for translation and mRNA export

It plays a role in the maturation and pruning of dendritic spines during brain development – so in the case of FXS, TOO MANY synapses occur and that’s not a good thing

We need to have normal pruning of synapses to fine-tune our connections

Rett’s Syndrome

Progressive neurological disorder that affects females almost exclusively

Mutations found in methyl-CpG-binding protein 2 (MeCP2) gene, which is located on the X chromosome

The development and severity of Rett’s syndrome depends on the location and type of mutation on the MeCP2 gene

Rett’s Syndrome

MeCP2 gene makes the MeCP2 protein that is necessary for the development of the brain and normal nervous system function

Rett’s syndrome results in not enough MeCP2 being produced, which disrupts the normal function of neurons and other cells in the brain

Less than 1% of cases are inherited

Rett’s Syndrome

Symptoms:

Abnormal respiratory patterns

Absent speech development

Loss of developmental milestones

Global developmental delay

High-pitched cry

Bradykinesia

Difficulty walking, dystonia, seizure, apraxia

Skeletal muscle atrophy

Alpha-thalassemia X-linked mental retardation syndrome (ATRX)

Mutations in ATRX result in severe MR, facial dysmorphism, urogenital abnormalities, and alpha-thalassemia (a blood disorder that reduces the production of hemoglobin), speech delay, hypotonia

Occurs almost exclusively in males

ATRX gene codes for a protein that plays an essential role in development and is suggested to regulate the expression of HBA1 and HBA2 genes, which are necessary for normal hemoglobin production

Reduced HBA1 and HBA2 genes cause alpha thalassemia

II. Chromosomal aberrations

Down’s syndrome (trisomy 21)

Edward’s syndrome (trisomy 18)

Down’s syndrome (Trisomy 21)

An extra copy of chromosome 21 results in an error of cell division, causing Down’s syndrome, the most frequent form of intellectual disability

Clinical features: dysmorphic features, seizures, psychomotor slowing, and congenital malformations

There are at least 16 genes on chromosome 21 that are linked to mitochondrial energy generation and reactive oxygen metabolism

Several studies have linked mitochondrial dysfunction with Down’s syndrome and Alzheimer’s disease

Edward’s syndrome (Trisomy 18)

Very high mortality rate

Slow growth before birth and low birth weight, heart defects, organ abnormalities

Small, abnormally shaped head, small jaw and mouth, clenched fist with overlapping fingers