Day 30: Triplet Repeats

HD, spinocerebellar ataxia, spinal bulbar muscular atrophy, fragile x, friedrech's ataxia, myotonic dystrophy, facioscapulohumeral

What are the features of Friedreich’s ataxia?

• slow to progress ataxia

• dysarthria: slow or stuttered speech

• cardiomyopathy in 2/3 of cases

• diabetes in 1/3 of cases

• scoliosis

• deafness

What is the AOO in Friedreich’s ataxia?

<25yo

What is the inheritance of Friedreich’s ataxia?

AR, w/o anticipation

• generally only one person per fam affected

What gene is associated with Friedreich’s ataxia?

FXN

What is the mechanism of disease for Friedreich’s ataxia?

GAA repeats in FXN

• Typical = <33

• Premutation = 34-65

• Reduced penetrance = 44-66

• Pathogenic = >66

How do you genetic test for Friedreich’s ataxia?

1. targeted analysis for GAA repeat in FXN

   1. if only 1 repeat identified —> seq analysis, reflex del/dup

   2. some cases, only 1 expanded allele + point mutation on other allele

2. multigene panel

How do you treat Friedreich’s ataxia?

• PT/OT/SP

• prostheses/walking aids/wheelchairs for ambulation

• hearing aids

What are the features of spinocerebellar ataxia?

• progressive cerebellar ataxia

• uncoordinated muscle movement

• loss coordination of the eyes, hands, speech

• shaky gait

What is the AOO for spinocerebellar ataxia?

30-40yo

What is the life expectancy for spinocerebellar ataxia?

dependent on when symptoms appear

What is the inheritance of spinocerebellar ataxia?

AD

What genes are associated with spinocerebellar ataxia?

ATXN genes

• Ex: Type 1 = AXTN7/1, Type 3 = AXTN3

What is the mechanism of disease for spinocerebellar ataxia?

CAG repeats in ATXN genes

How do you treat spinocerebellar ataxia?

supportive care, no cure

• physical activity wih PT/OT

• walking aids

• speech therapy

How do you survey spinocerebellar ataxia?

• neuro exam annually

• nutrition

• social supports

What are the features of spinobulbular muscular atrophy?

• progressive neuromuscular degenerations of lower motor neurons

• muscle weakness, atrophy, fasciculations of bulbar and limbs

• gynecomastia

• testicular atrophy

• reduced fertility

What is the inheritance of spinobulbular muscular atrophy?

X-linked

What is the mechanism of disease for spinobulbular muscular atrophy?

CAG repeat in AR

• Normal = <34

• Premutation = —

• Reduced penetrance = 37

• Full penetrance = 38<

How do you treat spinobulbular muscular atrophy?

• walking aids

• standard tx for dysarthria and dysphagia

  • anti-androgen drugs in clinical trial

How do you survey spinobulbular muscular atrophy?

• assess strength, mobility, ADLs, speech, and feeding issues annually

• eval for cardio/pulmonary functions

How do you genetic test for spinobulbular muscular atrophy?

targeted analysis of CAG repeats in AR

What are the features of Fragile X?

• ID/DD/BD— autism, 50-70%

• long face

• prominent ears

• large head circumference

• macroorchidism: large testes

• hypotonia

What is the mechanism of disease for Fragile X?

LOF, abnr. promotor methylation —> silencing of gene

CGG (CheckGiantGonads) repeats in the FMR1 gene

• Normal = 5-44

• Intermediate = 45-54

• Pre-mutation = 55-200

• Full mutation = >200

maternal anticipation

If someone is a carrier for Fragile X and is found to be in the pre-mutation range, what symptoms my they have? How many repeats?

pre-mutation = 55-200 CGG repeats

• AFAB = 20% risk of FXPOI, primary ovarian insufficiency

  • occurs <40yo, ovaries stop working

• FXTAS = 40% risk in AMAB, 16-20% risk in AFAB, tremor/ataxia syndrome

  • occurs 60yo, progressive cerebellar ataxia w/ tremor + cognitive impairment

What kind of expansion anticipation is Fragile X?

Maternal, more likely to expand when maternally inherited

Can the risk of expansion in Fragile X be reduced? How?

Yes, presence of AGG interruptions in the CGG repeat region

• lower chance of expansion in offspring

What gene is associated with Fragile X?

FMR1

What is the inheritance of Fragile X?

X-linked

• males > females

• more severe and more frequent, but females can have sx

What are the features of a carrier with Fragile X?

50% of women have milder sx due to X inactivation or dosage compensation

• ID/DD

How do you genetic test for Fragile X?

PCR w/ reflex to southern blot

• PCR observes # of repeats

• southern blot can also determine methylation status of promotor region

What are the features of classic myotonic dystrophy type 1?

• muscle weakness and wasting

• slowly progressive

• myotonia

• cardiac conductive defects

• cataracts

• baldness

What are the AOO for myotonic dystrophies?

classic = 10-30yo

congenital = prenatal

type 2 = 30s

What are the features of congenital myotonic dystrophy?

if lives, develop to classic DM1

• reduced fetal movement

• hypotonia at birth

• general muscle weakness

• respiratory compromise

• ID

What gene is associated with myotonic dystrophy type 1?

DMPK

What is the inheritance of myotonic dystrophy type 1?

AD w/ anticipation

• >34 CTG repeats (CheckTheGrip)

  • expansion in meiosis, more likely in egg than sperm

• more repeats = less stability —> higher chance for expansion

What are the features of Huntington disease?

movement, cognitive, and psych abrn. —> degeneration of nerve cells in the brain

• movement: chorea, loss of voluntary movements

• cognitive changes

  • language, last to be affected

• behavioral: aggression, outbursts, apathy

  • ˆlater in the disease

• severe impairments requiring full dependency in end

• suicide common

What is the inheritance of Huntington disease?

AD, 10% de novo

• w/ anticipation and age dependent penetrance

What gene is associated with Huntington disease?

HTT, CAG repeat

• Normal = <26

• Intermediate = 27-35

• Reduced penetrance = 36-39

• Pathogenic = >40

• Juvenile = >60

What is the AOO for Huntington disease?

~45yo, adult

Describe the mechanism of the diease for Huntington disease.

• expansion is more likely when inherited paternally

• contraction possible, tho rare

• less repeats = older AOO

  • ex: 40-55 repeats —> adult onset, >60 = juvenile onset

What is juvenile Huntington disease?

onset before 20yo

How frequent is juvenile Huntington disease?

5-10% of Huntington disease cases

Describe the genetic testing protocol for Huntington disease?

1. Visit 1: GC visit, informed consent, mental health assessment

2. Visit 2: neuro exam, blood draw

3. Visit 3: result disclosure w/ support person, arrange follow up

What considerations should be made prior to testing for Huntington disease?

• psychiatric problems must be resolved before testing

  • GC may decide to terminate testing if unfit

• local counselor should be notified

• support persons recommended

  • GC may exclude from testing if one is not present

What are the features of facioscapulohumeral muscular dystrophy?

affects face, shoulder, upper arm, abs, lower leg muscles

• asymmetric weakness

• retinal vasculopathy

• HL

• rarely impacts heart+respiratory systems

How do you treat/survey facioscapulohumeral muscular dystrophy?

• PT/OT for routing exercise

• foot orthoses/wheelchair to improve mobility

• surgical intervention to improve mobility

• manage pain, audiology, ophthalmology

What is the inheritance of facioscapulohumeral muscular dystrophy?

AD, 10-30% de novo

What is the mechanism of disease in facioscapulohumeral muscular dystrophy?

inappropriate expression of DUX4

1. contraction of D4Z4 contraction on chr 4 (95%, FSHD1)

   1. Normal = ≥12 repeat

   2. Contracted, reduced penetrance = 10-11 repeats on permisive

   3. contracted, full penetrance = ≤9 repeats on permissive

1. hypomethylation of D4Z4 from PV in SMCHD1 (<5%, FSHD2)

What is a permissive allele? What condition?

functional allele in facioscapulohumeral muscular dystrophy

What genes are associated with facioscapulohumeral muscular dystrophy?

DUX4, SMCHD1 (<5%)

How do you genetic test for facioscapulohumeral muscular dystrophy?

1. concurrent haplotype analysis w/ targeted analysis of contracted D4Z4 repeats via southern blot

2. methylation analysis

3. sequence analysis for SMCHD1