Neurogenetic Disorders Flashcards
Rett Syndrome - inheritance pattern
*X-linked dominant disorder
*typically lethal in males (only seen in females)
*usually isolated and sporadic mutation in the population (because affected individuals usually do not reproduce)
Rett Syndrome - genetic defect
*MECP2 gene located on the X chromosome
Rett Syndrome - clinical features
*developmental REGRESSION starting at age 6-18 months
*acquired microcephaly (slowing of head growth)
*stereotypic hand movements: hand wringing, hand washing movements, clapping/tapping movements
*absent speech
*seizures
*irregular breathing patterns
Rett Syndrome - treatment
NEW TX:
*Daybue (trofinetide)
*MOA is unknown but seems to decrease neuroinflammation and support synaptic function
OLD TX: supportive, seizure tx; avg age of death about 24 years
Fragile X syndrome - inheritance pattern
*X-linked (dominant vs. recessive is unclear, but affects males more than females)
*caused by trinucleotide repeats (CGG) in the FMR1 gene (# of repeats determines the phenotype)
Fragile X syndrome - genetic mechanism
*caused by trinucleotide repeats (CGG) in the FMR1 gene (# of repeats determines the phenotype)
*most common INHERITED cause of intellectual disability & most common single gene cause of autism spectrum disorder
Fragile X syndrome - clinical features (full mutation repeats)
*full mutation repeats ( >200 repeats):
-males: intellectual disability, hypotonia, ADHD, autism spectrum disorder; after puberty, long face, large ears, macroorchidism (large testicles)
-females: depending on x-inactivation, features can range from completely normal to as severely affected as males
Fragile X syndrome - clinical features (premutation alleles)
*premutation alleles (55-200 repeats)
-males: Fragile X Tremor Ataxia syndrome (FXTAS)
-females: premature ovarian failure
mucopolysaccharidoses (MPS) - overview
*a subset of lysosomal storage disorders
*caused by deficiency of one of the enzymes required to break down glycosaminoglycans
*includes: Hunter syndrome, Hurler syndrome, Sanflippo syndrome, Morquio syndrome, Morateaux-Lamy syndrome, and Sly syndrome
mucopolysaccharidoses (MPS) - common features
*normal at birth
*coarse facial features
*joint contractures
*short stature
*some may have:
-developmental delay
-neurologic disease
-hepatosplenomegaly
Hunter syndrome - clinical features
*coarse facial features
*short stature
*“claw-like” hands
*hepatosplenomegaly
*developmental delay
*macrocephaly
*hearing loss
*sometimes hydrocephalus
note - similar features to Hurler syndrome
Hurler syndrome - clinical features
*CORNEAL CLOUDING
*coarse facial features
*short stature
*“claw-like” hands
*hepatosplenomegaly
*developmental delay
*macrocephaly
*hearing loss
*sometimes hydrocephalus
note - similar features to Hunter syndrome
Hunter syndrome - unique features
*X-linked (“the hunter aims for the X”)
*enzyme = iduronate 2-sulfatase
Hurler syndrome - unique features
*corneal clouding (hunters need to see to hunt, so it can’t be hunters)
*enzyme = alpha-L-iduronidase
Hunter & Hurler syndromes - treatment
*enzyme replacement therapy (given by IV infusion; cannot cross blood-brain barrier)
*delays but does not stop disease progression
*death typically due to respiratory compromise
Tay-Sachs disease - inheritance pattern
*autosomal recessive
-high carrier frequency in Asheknazi Jewish population
*caused by mutations in the HEXA gene
Tay-Sachs disease - genetic mechanism
*caused by mutations in the HEXA gene, which encodes the beta-hexosaminidase A
*leads to accumulation of GM2 ganglioside in the brain and nerve cells
*autosomal recessive
Tay-Sachs disease - clinical features
*3-6 months: progressive loss of motor skills, progressive weakness
*6-10 months: decreased visual attentiveness, exaggerated startle response, cherry red spots visible on the retina, loss of motor skills
*12+ months: further deterioration of skills, development of seizures
*2-5 years: death from central apnea or respiratory infection
Tay-Sachs disease - treatment
studies of gene therapy ongoing
Friedrich Ataxia - inheritance pattern
*autosomal recessive
*caused by trinucleotide GAA repeats in the FXN gene
Friedrich Ataxia - genetic mechanism
*caused by trinucleotide GAA repeats in the FXN gene, which encodes for Frataxin
*Frataxin is predominantly located in the MITOCHONDRIA and binds to iron and is used in the synthesis of the respiratory chain complexes I-III
*leads to cerebellar atrophy, small dorsal root ganglia, and loss of corticospinal and spinocerebellar tracts
*66-1300 repeats = full mutation
Friedrich Ataxia - clinical features
*onset typically between 10-15 years of age
*progressive ataxia of gait and limbs
*dysarthria
*decrease or loss of position sense and/or vibration in lower limbs
*muscle weakness
*hypertrophic cardiomyopathy
*diabetes mellitus
*life expectancy: 30-37 years; typical cause of death in cardiomyopathy or respiratory infection
Friedrich Ataxia - treatment
*Skyclarys (Omaveloxolone) - transcription factor activates gene that promotes mitochondrial function
*decreases disease progression by about 50%
*decreases symptoms in the first year
