Week 3 Combined Set

What are the three key aspects of neuromuscular conditions?

1. progressive muscle weakness

2. progressiv eneurodgeneration (in STR conditions)

3. Progressive loss of muscle function in muscular dystrophies

What is anticipation?

Concept where disease severity and symptom onsent increases with subsequent generations

T/F in myotonic dystrophy, large expansions are typically passed from males

False, usually passed from females

T/F Expansion occurs in the untranslated sequence for TRDs

True

The repeat inolved in polyglutamine Disorders

CAG

Location of the “fragile” site in Fragile X syndrome

5’ untranslated reigon of FMR1

Fragile x carrier rates for males and females

Males: 1;4,000
Females: 1:250

What percent of females with Fragile X have LD and/or mild ID

50%

The trinucleotide repeat involved in Fragile X syndrome

CGG

A person has 5-44 repeats of CGG in FMR1, do they have fragile X?

No, they have a normal allele

A person has 45-55 repeats of CGG in FMR1, do they have fragile X?

No, they have an intermediate amount of repeats

A person has 55-200 repeats of CGG in FMR1, do they have fragile X?

No, they have the premutation

A person has 206 repeats of CGG in FMR1, do they have fragile X?

Yes

Name the trinucleotide and the purpose of the “commas” in Fragile X repeats

AGG interruptions, stabilizes expanded region during transmission

What are some characteristic features of fragile X

ID/DD, seizures, macrocephaly, seizures

T/F Friedreich Ataxia is the most commonly inherited ataxia

True

T/F most clinical cases of Friedreich Ataxia have uniallelic expansions

False

T/F The clinical diagnosis of Friedrich Ataxia occurs usually with symptom onset in childhood

True

The most common COD for those with Friedrich Ataxia

Heart failure before age 40

Repeat, gene, location, inheritance in Huntington Disease

CAG in exon 1 of HTT, AD

Huntington’s Disease prevalence

1:10,000-20,000

DRPLA stands for?

Dantatorubaral-pallidolysian atrophy

Repeat location, gene, and inheritance pattern of DRPLA

CAG repeat in exon 5 of ATN1, AD

T/F DRPLA has a higher prevalance in Japanese population as compared to White/Latin populations

True

DRPLA normal allele has how many CAG repeats?

6-35

DRPLA affected allele has how many repeats?

48+

Spinobulbular Muscular Atrophy is also known as?

Kennedy disease

The trinucleotide repeat for Kennedy disease (Spinobulbular Muscular Atrophy) and Spinocerebellar ataxias

CAG

T/F Spinocerebellar ataxias have an androgen receptor related phenotype

False, its Kennedy disease that has an androgen receptor related phenotype

Kennedy disease repeat location, gene, inheritance

CAG repeat in exon 1 of AR, x-linked recessive

Kennedy disease prevalence

1:40,000 males

SCA1 trinucleotide, location/gene, and inheritance

CAG repeat in ATX1, AD

T/F SCA1 has a paternal anticipation bias?

True

Clinical presentation of SCA1

Progressive problems with movement and pain

SCA2 trinucleotide, gene, and inheritance

CAG in ATX2 , AD

T/F SCA2 has both recessive and dominant forms depending on the number of repeats

True

SCA3 is also known as

Machado Joseph disease

Trinucleotide repeat, gene, and inheritance for SCA3

CAG repeat in MJD , AD

Unique features of SCA3/Machado Joseph disease

Pyramial signs (spasticity, weakness, hyperreflexia), bulging eyes, impaired thermal and vibration sense, rigidity, bladder disturbances

SCA6 trinucleotide, gene and inheritance

CAG repeats in CACNA1A, AD

SCA6 clinical features

Ataxia, unsteady gate, tremors

T/F SCA6 usually presents with cognitive symptoms

False

SCA7 trinucleotide, gene, inheritance

CAG repeats in SCA7, AD

T/F SCA7 exhibits paternal anticipation bias

True

Unique clinical features of SCA7

Cone-rod retinal dystrophy (vision loss), macular degeneration, optic atrophy

SCA17 trinucleotide, gene, and inheritance

CAG repeats in TBP, AD

Unique features of SCA17

Psychiatric symptoms such as paranoia, depression, aggression, hallucinations, etc.

Dystrophionpathies are inherited in an ___ manner

x-linked

Dystrophinopathies prevalence

1:3,500-5,000 males a year

Most common mutations in Dystrophin are?

De novo deletions

Limb girdle muscular dystrophy clinical features

Progressive weakness in hips and shoulders

Facioscapulohumeral Muscular Dystrophy type 1 (FSHD1) gene, inheritance

D4Z4 MSI repeat array, AD

FSHD2 gene and relation to FSHD1 gene

SMCHD1 which causes D4Z4 hypomethylation

FSHD incidence

1:20,000

FSHD symptoms

Progressive shoulder girdle atrophy and progressive facial atrophy, hearing loss, eye problems. Most patients are non ambulatory by age 40

The 9 PolyQ diseases covered in class

Huntington’s disease, DRPLA, Kennedy, SCA1, SCA2, SCA6, SCA7, SCA17, and SCA3 (Machado-Joseph).

Myotonic dystrophy type 1 trinucleotide, location, gene and inheritance

CTG in the 3’ untranslated region of DMPK, AD

Myotonic Dystrophy Type 1 prevalence

1:8,000

Myotonic dystrophy Type 1 key clinical characteristics (6)

Myotonia, progressive muscle weakness, cardiac conduction defects, cataracts, sleep disturbances, behavioral abnormalities

How many CTG repeats is considered normal in Myotonic Dystrophy Type 1

5-37

How many CTG repeats is considered mildly affected in Myotonic Dystrophy Type 1

50-150

How many CTG repeats leads to Adult onset in Myotonic Dystrophy Type 1

100-1,000

How many CTG repeats leads to congenital Myotonic Dystrophy Type 1

>2,000

Friedreich Ataxia trinucleotide, gene, location, and inheritance

GAA expansion in intron 1 of FXN, AR

How many GAA repeats are in a normal allele in Friedreich Ataxia?

5-33 (but most are <12 repeats)

How many GAA repeats are considered a premutation for Freidreich Ataxia?

34-65

How many GAA repeats lead to full penetrance in friedreich ataxia?

66-1,300 (most are >600)

How many repeats of CAG will show reduced penetrance in Huntingtons?

36-39

How many repeats of CAG will lead to juvenile onset in Huntingtons?

60+

Key symptoms of huntingtons?

Progressive neurodegeneration, personality changes, bradykinesia

Charcot-Marie-Tooth 1A (CMT1A) inheritance and gene

PMP22, AD

CMT clinical features

progressive damage to peripheral nerves

T/F In CMT1A, nerve damage typically starts in upper limbs

False

T/F CMT disorders have multiple types of inheritance including AD, AR, X-linked

True

SMA inheritance and carrier frequency

Autosomal recessive, 1:50

SMA cause for more than 95% of SMA1 patients

A deletion of exon 7 in SMN1

T/F SMA can present with decreased fetal movements in pregnancy

True

Clinical features of SMA

Progressive muscle deterioration resulting in death <2yrs due to respiratory failure

Williams syndrome cause, inheritance

7q11.23 deletion, AD

Williams syndrome Clinical features:

ID/DD, hypotonia, hypersensitivity to sound, joint hypermobility, hoarse voice, characteristic facies (broad forehead, lacy iris pattern, strabismus, short nose, long philtrum, malocclusion, micrognathia, epicanthal folds).

Smith-Magenis Syndrome cause and inheritance

de novo deletion of 17p11.2 that includes RAI1 or intragenic RAI1, AD

Smith-Magenis Syndrome clinical characteristics

Brachycephaly, obesity, infantile hypotonia, impulsivity, attention-seeking behavior, hearing loss

Cri Du Chat Syndrome cause and inheritance

Partial or complete deletion of 5p (de novo)

Cri du chat clinical characteristics

High pitched cry, ID/DD, microcephaly, low birth weight, hypotonia, hypertelorism.

Wolf-Hirschhorn syndrome cause

4p- (NSD2, LETM1, MSX1)

Wolf-Hirschhorn clinical symptoms

“Greek warrior helmet” appearance (browd nasal bridge, large+protrudign eyes, high forehead, short philtrum, micrognathia) DD and mild to severe ID, skin changes, dental problems

1p36 deletion syndrome clinical characteristics

Severe ID, structural abnormalities of the brain, seizures, hypotonia, dysphagia

DMD age of onset vs BMD

Duchenne: muscle weakness appears in early childhood in boys
BMD: milder and more varied, later in childhood or in adolescense and slower decline

DMD and BMD are both associated with this key clinical characteristic

Cardiomyopathy

Gene associated with DMD and BMD and inheritance pattern

DMD, x-linked recessive