Trinucleotide Repeat Disorders

What is Huntington's Disease?

movement disorder

What is myotonic Distrophy?

muscle disorder

Most trinucleotide repeat disorders involve which system?

nervous system

Which gene is abnormal in the Fragile X Syndrome?

FMR1 gene -fragile X mental retardation 1 gene -found on long arm of X chromosome

The diseased gene in trinucleotide repeat disorders have "unstable repeat expansions". What does this mean?

The number of repeats may increase in offspiring one generation --> next :more repeats key point: genetic abnormality changes over time

Myotonic Dystrophy is a multi system disorder that involves many non-muscle systems of the body. Which non-muscle features can be seen int his disease?

hypogonaidsm (primary) cataracts (high prevalence) cardiac arrhythmia frontal balding intellectual disabilities

What is the inheritance pattern of Fragile X syndrome?

x-linked dominant

What occurs during the endocrine involvement of myotonic dystrophy?

Primary hypogonadism -low testosterone -elevated FSH -oligospermia -infertility -testicular atrophy Insuline resistance

What is Myotonic Dystrophy type 2?

abnormal CNBP gene rare usually less severe than Type I CCTG (tetra nucleotide) repeat (not a trinucleotide repeat

What are sxs of Freidreich's Ataxia?

begins in adolescence w/progressive sxs cerebellar & spinal cord degenration -loss of balance -weakenss associated with hypertrophic cardiomyopathy physical deformities -kyphoscoliosis -foot abnormalities

What kind of nucleotide repeats are most common in Fragile X syndrome?

CGG normal. < 55 repeats full mutation. > 200 repeats

What is the tribucleotide expansion in Myotonic Dystrophy Type I?

CTG expansion

What kind of eye sxs are often seen in Myotonic Dystrophy?

Cataracts (high prevalence) -occur at younger age -often referred for regular slit-lamp exams for screening

Symptoms in ______ disease result from degeneration in the basal ganglia (striatum). This leads to chorea, dementia.

Huntington's -onset of sxs in 30s-40s -death after 10-20 yrs

Fragile X syndrome, Freidreich's ataxia, Huntington's Disease, and Myotonic dystrophy are all what type of syndromes?

Trinucleotide Repeat Disorders

What are the sxs of Fragile X syndrome?

anxiety, ADHD often has features of autism long, narrow face, large ears & jaw macroorchidism (large testicles) - classic feature

What may occur during Cardiac involvement of myotonic dystrophy?

arrhythmias and conduction disease are common First degree atrioventricular bloc k (20-30%) bundle branch block (10-15%) atrial flutter & atrial fibrillation

What's the inheritance pattern of Huntington's Disease?

autosomal Dominant

What's thee inheritance pattern of myotonic dystrophy?

autosomal dominant

What's the inheritance pattern of Freidreich's Ataxia?

autosomal recessive

How does Myotonic Dystrophy Type I present?

begins in adulthood -often tarts in 20s or 30s progressive muscle wasting & weakness Prolonged muscle contractions (myotonia) -can't relax muscles after use -cannot release grip -locking of jaw facial muscles often affected -gives characteristic facial appearance -caused by muscle weakness & wasting -long & narrow face -Hollowed cheeks

What intellectual disabilities can be seen in Myotonic Dystrophy?

common severity worse w/ younger age of onset -If disease presents in childhood --> severe cognitive impairment throughout their lives

What are common traits about the Diseased (abnormal) alleles in these disorders?

found in affected individuals Increased "expanded" number of repeats beyond the normal range likely due to slipped DNA mispairing

What are common traits about the Wild-type (normal) alleles in these disorders?

found in most individuals polymorphic - has many informs. that include variable nu mbar of repeats from person to person overall number of repeats is relatively low

What's the 2nd most common genetic cause of intellectual disability?

frágil X syndrome (Down syndrome # 1)

What is Fredreich's Ataxia?

hereditary ataxia mutation of frataxin gene on chromosome 9 -need for normal mitochondrial function -increased number of GAA repeats -leads to decreased frataxin levels Frataxin = a mitochondrial protein -hgih levels in brain, heart & pancreas -abnormal frataxin --> mitochondrionial dysfunction

What is the etiology of Fragile X syndrome?

leads to DNA methylation of FMR1 gene Gene silenced by methylation

Which organ is often involved with Myotonic Dystrophy?

lungs respiratory complications are common weakness/myotonia of respiratory muscles Decreased vital capacity Alveolar hypoventilation Respiratory failure can occur & can be amid of death

Fragile X syndrome is more frequent/severe among m or f?

males (absence of normal X)

What is Type I Myotonic Dystrophy?

most common caused by abnormal DMPK gene (chromosome 19) - dystrophia myotonic protein kinase -codes for myotonic dystrophy protein kinase abnormal gene transcribed to mRNA but not translated

Which gene is affected in Huntington's?

mutation in the HTT gene. -gene codes for Huntingtin protein mutation --> increased CAG repeat -CAG codes for glutamine -polyglutamine disorders": Huntington's, other rare CNS diseases. normal - 10-35 repeats Huntington's 36-120 repeats

What is anticipation?

occurs bc of unstable repeat expansions -disease severity worse in subsequent generations -earlier onset in subsequent generations associated w/ more repeats in abnormal gene