Neurogenetic Disorders

Question 1

Rett Syndrome - inheritance pattern

Answer 1

*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)

Question 2

Rett Syndrome - genetic defect

Answer 2

*MECP2 gene located on the X chromosome

Question 3

Rett Syndrome - clinical features

Answer 3

*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

Question 4

Rett Syndrome - treatment

Answer 4

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

Question 5

Fragile X syndrome - inheritance pattern

Answer 5

*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)

Question 6

Fragile X syndrome - genetic mechanism

Answer 6

*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

Question 7

Fragile X syndrome - clinical features (full mutation repeats)

Answer 7

*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

Question 8

Fragile X syndrome - clinical features (premutation alleles)

Answer 8

*premutation alleles (55-200 repeats)

-males: Fragile X Tremor Ataxia syndrome (FXTAS)

-females: premature ovarian failure

Question 9

mucopolysaccharidoses (MPS) - overview

Answer 9

*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

Question 10

mucopolysaccharidoses (MPS) - common features

Answer 10

*normal at birth
*coarse facial features
*joint contractures
*short stature
*some may have:
-developmental delay
-neurologic disease
-hepatosplenomegaly

Question 11

Hunter syndrome - clinical features

Answer 11

*coarse facial features
*short stature
*“claw-like” hands
*hepatosplenomegaly
*developmental delay
*macrocephaly
*hearing loss
*sometimes hydrocephalus

note - similar features to Hurler syndrome

Question 12

Hurler syndrome - clinical features

Answer 12

*CORNEAL CLOUDING
*coarse facial features
*short stature
*“claw-like” hands
*hepatosplenomegaly
*developmental delay
*macrocephaly
*hearing loss
*sometimes hydrocephalus

note - similar features to Hunter syndrome

Question 13

Hunter syndrome - unique features

Answer 13

*X-linked (“the hunter aims for the X”)
*enzyme = iduronate 2-sulfatase

Question 14

Hurler syndrome - unique features

Answer 14

*corneal clouding (hunters need to see to hunt, so it can’t be hunters)
*enzyme = alpha-L-iduronidase

Question 15

Hunter & Hurler syndromes - treatment

Answer 15

*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

Question 16

Tay-Sachs disease - inheritance pattern

Answer 16

*autosomal recessive
-high carrier frequency in Asheknazi Jewish population
*caused by mutations in the HEXA gene

Question 17

Tay-Sachs disease - genetic mechanism

Answer 17

*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

Question 18

Tay-Sachs disease - clinical features

Answer 18

*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

Question 19

Tay-Sachs disease - treatment

Answer 19

studies of gene therapy ongoing

Question 20

Friedrich Ataxia - inheritance pattern

Answer 20

*autosomal recessive
*caused by trinucleotide GAA repeats in the FXN gene

Question 21

Friedrich Ataxia - genetic mechanism

Answer 21

*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

Question 22

Friedrich Ataxia - clinical features

Answer 22

*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

Question 23

Friedrich Ataxia - treatment

Answer 23

*Skyclarys (Omaveloxolone) - transcription factor activates gene that promotes mitochondrial function
*decreases disease progression by about 50%
*decreases symptoms in the first year