Expanded Repeat Disorders/Fragile X

Question 1

What is Fragile X Syndrome?

Answer 1

X-Linked
large CCG repeats in the non-coding portion of the FMR1 gene (Xq27.3)
most common cause of ID that is inherited
most common single gene associated with autism

Question 2

What is the repeat expansion cutoffs for Fragile X syndrome?

Answer 2

normal: <45
intermediate: 45-54
premature: 55-200
full mutation: >200

Question 3

What clinical manifestations are associated with Fragile X syndrome?

Answer 3

ID (almost all boys; 50% of girls)
delayed developmental milestones (first word, sit alone, walk)
prepubertal features: developmental delay especially speech, abnormal temperment (tantrums, hyperactivity, autism), ID (IQ of 30-50), abnormal craniofacies (long face, prominent forehead, large ears, prominent jaw)
post-pubertal features: macro-orchidism, abnormal behavior (shyness, gaze aversion), opthalmologic (strabismus), orthopedic (joint hpyerextensibility, pes planus)
other features: mitral valve prolapse, aortic root dilation, soft and smooth skin

Question 4

Describe the FMR1 gene expression for different levels of repeats.

Answer 4

normal= normal amount of mRNA and protein
premutation= increased mRNA leading to primary ovarian insufficiency and/or tremor/ataxia syndrome (methylation can decrease this to normal or too far and result in minor ID)
full mutation= guaranteed to have excessively methylated DNA which produces minimal mRNA which produces minimal FMRP proteins leading to full phenotype with cognitive impairment
AGG interruptions are stabilizing

Question 5

What detection methods are used to diagnose Fragile X syndrome?

Answer 5

targeted analysis for pathogenic variants with PCR/southern blot (99% detection) or AGG genotyping (100% detection of alleles with this structure)
methylation analysis of FMR1 promoter (100%)
FISH for large FMR1 deletions (<1%)
Deletion/duplication of FMR1 (<1%)
sequence analysis for FMR1 variants (<1%)

Question 6

What are the recurrence risks for Fragile X syndrome?

Answer 6

variable penetrance and clinical variability
males who are premutation carriers (“transmitting males”) will give premutation to all daughters and NO sons
females who are premutation carriers have 50% risk of transmitting premut or mut allele in each pregnancy
mother of affected (full mut) child is obligate carrier of pre or full mut
unaffected female with premut may have father who is premut carrier or mother who is premut/intermediate allele carrier

Question 7

What do the guidelines recommend for management of Fragile X syndrome?

Answer 7

special education and anticipatory management
early educational intervention, special education, vocational training
individual attention, small class size, and avoidance of sudden changes
pharmacological management of behavioral issues that significantly affect social interaction
medication management of strabismus, otitis media, GERD, seizures, mitral valve prolapse, and HTN

Question 8

What is Fragile X Associated Tremor/Ataxia Syndrome?

Answer 8

typically late-onset neurological symptoms in male premutation carriers of FMR1 alleles
50-59 repeats: 17%
60-69 repeats: 38%
70-79 repeats: 47%
>80 repeats: 75%

Question 9

What clinical manifestations are associated with Fragile X Associated Tremor/Ataxia?

Answer 9

heterogenous clinical presentation
gait ataxia
progressive intention tremor
short-term memory loss/deficits in working memory
cognitive decline
dementia
parkinsonism
peripheral neuropathy
lower limb weakness
executive function deficits
emotional difficulties (disinhibition/apathy)
psychiatric manifestations (social phobia, etc.)
autonomic dysfunction

Question 10

What are the main diagnostic features of Fragile X Associated Tremor/Ataxia?

Answer 10

MRI showing atrophy and white matter lesions in cerebral hemispheres and middle cerebellar peduncles (brain inclusions unique to FXATAS)

Question 11

What are the clinical manifestations of Fragile X Associated Primary Ovarian Insufficiency?

Answer 11

menopause/infertility before age 40 (in premutation carriers)
absent or irregular menses
symptoms of menopause (eg. hot flashes)

Question 12

What is C9orf72 Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia?

Answer 12

motor neuron disease upper and/or lower motor neuron that may or may not fulfill criteria for ALS
age of onset 30-70 years
pathogenic 60 G4C2 hexanucleotide repeat units
high penetrance

Question 13

What clinical manifestations are associated with C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia?

Answer 13

frontotemporal lobar degradation, changes in behavior, executive dysfunction, and/or language impairment
some degree of parkinsonism (akinetic rigid type without tremor)

Question 14

What are Hereditary Ataxias/Spinocerebellar Ataxias?

Answer 14

35+ AD disorders
typically adult onset
most common subtypes SCA1, 2, 3, 6, and 7
nucleotide expansion of CAG repeats

Question 15

What clinical manifestations are associated with Hereditary Ataxias/Spinocerebellar Ataxias?

Answer 15

highly heterogenous
gait ataxia
incoordination of eye movements
speech incoordination
hand movement incoordination
cerebellum atrophy

Question 16

What is Freidreich Ataxia?

Answer 16

AR
FXN
full penetrance of alleles with 66-1300 GAA repeats
progressive with onset before 25 y/o (average onset 10-15 y/o)

Question 17

What clinical manifestations are associated with Freidreich Ataxia?

Answer 17

dysarthria
muscle weakness
spasticity (esp. lower limbs)
bladder dysfunction
scoliosis
absent lower-limb reflexes
loss of position and vibration sense
cardiomyopathy
DM

Question 18

What is Huntington Disease?

Answer 18

AD
expansion of CAG repeats in coding sequence of HTT
gain of function due to polyglutamine tract
adult onset
anticipation effect (age at onset decreases through generations)
normal: 10-37
disease: 38-86

Question 19

What are the clinical features of Huntington disease?

Answer 19

personality changes
progressive abnormal movements (chorea)
progressive dementia
seizures