triplet repeat and neurogenetics

spinocerebellar ataxia type 1 main features

progressive cerebellar ataxia, uncoordinated muscle movement, less coordination of eyes, hands, speech, shaky gait, adult onset (30-40y), lifespan depends on when symptoms appear

general features of dystrophinopathies

glower sign, pseudohypertrophy of calf, elevated CK (creatine phosphokinase) levels

pantothenate kinase-associated neurodegeneration gene and mode of inheritance

PANK2, AR

list the repeat ranges of fragile x syndrome from typical to full mutation

normal: 5-44,
intermediate: 45-54,
pre-mutation: 55-200,
full mutation: more than 200,

friedrichs ataxia main features and onset

slowly progressive ataxia of gait and limbs with adolescent/adult onset (before 25 years), slow or slurred speech (dysarthia), scoliosis (some cases), muscle weakness, diabetes (1/3 cases), hypertrophic cardiomyopathy (2/3 cases), involuntary eye movements/deafness

what are the nucleotides that repeat in fragile x syndrome

CGG

what are the nucleotides that repeat in friedrichs ataxia

GAA

myotonic dystrophy type 1 gene and mode of inheritance

DMPK, AD

main features of classic myotonic dystrophy type 1

cataracts, baldness, muscle weakness and wasting, myotonia, cardiac conduction issues, shortened lifespan, onset 10-30

list the repeat ranges of myotonic dystrophy from premutation to full mutation

premutation: 35-49,
mild: 50-150,
classic: 100-1000,
congenital: more than 1000

what are the nucleotides that repeat in myotonic dystrophy

CTG

myotonic dystrophy type 2 gene and mode of inheritance

CNBP, AD

list the repeat ranges of myotonic dystrophy type 2 from typical to full mutation

typical: less than 30
gray zone: 27-29
premutation: 30-74
pathogenic: more than 75

spinocerebellar ataxia type 1 main genes and mode of inheritance

ATXN1 and 7, AD

what are the nucleotides that repeat in spinocerebellar ataxia

CAG

what are the nucleotides that repeat in huntington disease

CAG

list the repeat ranges of huntington disease from typical to full mutation (including juvenile onset)

typical: less than 26,
intermediate: 27-35,
reduced penetrance: 36-39,
pathogenic: more than 40,
juvenile: more than 60 (5-10% of cases and onset is before 20y)

dystrophinopathy associated gene and mode of inheritance

DMD, XL

8% of DMD carriers will develop _________ and can have higher ______ levels

dilated cardiomyopathy (DCM), CK

facioscapulohumeral muscular dystrophy genes and mode of inheritance

DUX4 (D4Z4 region), SMCHD1, AD

clinical findings and onset of BMD

progressive symmetric muscle weakness (proximal > distal) starting at legs/pelvis often with calf hypertrophy, activity induced cramping, flexion contractures of elbows, wheelchair dependency, adolescent/adult onset (after 16y), preservation of neck flexor muscle strength

Limb Girdle Muscular Dystrophy (LGMD) inheritance

type 1: AD
type 2: AR

Limb Girdle Muscular Dystrophy (LGMD) main features

affects proximal muscles around hips and shoulders, waddling gait, trouble standing and with stairs, raising arms, may eventually need mobility assistance, cardiomyopathy and arrhythmias, elevated CK

oculopharyngeal muscular dystrophy gene and mode of inheritance

PABPN1, AD

how to test for Limb Girdle Muscular Dystrophy type 2 (LGMD)

multigene panel that includes ANO5 and other genes of interest

oculopharyngeal muscular dystrophy features and onset

affects eyelids (ptosis and limitation of upward gaze), throat, face, and limbs. Difficulty swallowing and keeping eyes open, some mobility issues. Adult onset (4-5th decade). muscle weakness in later years

genetic findings suggestive of oculopharyngeal muscular dystrophy

heterozygous GCN trinucleotide repeat expansion of 11 to 18 repeats in the first exon of PABPN1 (~90% of affected individuals) or biallelic GCN trinucleotide repeat expansions that are either compound heterozygous (GCN[11] with a second expanded allele) or homozygous

emery dreifuss muscular dystrophy modes of inheritance

XL, AD (de novo in 65%), AR (rare)

suggestive findings and onset of emery dreifuss muscular dystrophy

early contractures in elbows, neck, and heels, waisting of shoulders, upper arms, and calves cardiac conduction defects/cardiomyopathy, childhood onset (by 10y)

Charcot-Marie-Tooth disease (CMT) testing strategy

start with del/dup of PMP22 gene, reflex to gene panel

Ataxia telangiectasia (AT) main features

gait and truncal ataxia, head tilting, slurred speech, inability to follow an object across visual field (oculomotor apraxia), telangiectasia in eyes, immunodeficiency, hypersensitivity to ionizing radiation

walker warburg syndrome gene and mode of inheritance

POMT 1 and 2, AR

walker warburg syndrome main features and onset

onset at birth, muscular dystrophy, brain and eye anomalies (lissencephaly, encephalocele), hypotonia, DD, ID, seizures

tuberous sclerosis genes and mode of inheritance

TSC1 and 2, AD (2/3 de novo, variable expressivity)

renal features of tuberous sclerosis

angiomyolipomas (80%), cysts, polycystic kidney disease (PKD), renal cell carcinoma (rare)

wilson disease main features

improper copper metabolism causing liver disease, movement disorders, psychiatric issues, kayser-fleisher rings

NF2 diagnostic criteria

-bilateral vestibular schwannomas OR

-unilateral vestibular schwannomas with any TWO of the following:

-meningioma, schwannoma, glioma, neurofibroma, cataract

schwannomatosis genes and mode of inheritance

SMARCB1, LZTR1, AD

early-onset Alzheimer's disease genes, mode of inheritance and age of onset

APP, PSEN2, AD, before 65y

general symptoms of
Leukodystrophies

issues with balance, breathing, cognition, swallowing, hearing, vision, speech, coordination

CADASIL gene and mode of inheritance

NOTCH3, AD

CADASIL main features

cerebral autosomal dominant artriopathy with cub-cortical infarcts and leukoencephalopathy, recurrent ischemic stroke, cognitive decline/dementia, migraine with aura, mood disturbance

testing strategy for triplet repeat disorders

PCR with reflex to southern blot

pros and cons of PCR when testing for triplet repeats

PCR determines number of repeats but cannot tell the number of repeats when there is a large number/pathogenic expansion

pros and cons of southern blot when testing for triplet repeats

southern blot can tell how much protein is present and therefore how many repeats there are but cannot tell the number of repeats when there is a small number

which sex is affected more often and more severely in Fragile X syndrome

males

fragile x syndrome main symptoms

ID, long narrow face and prominent ears, marcoorchidism (large testicles), hypotonia, autism

in fragile x syndrome, expansion is more likely when inherited from which parent

mother

what stage of mutation are children of parents with intermediate mutations at risk of?

pre-mutation

what are the 2 main features of fragile x pre-mutations?

FXTAS (tremor/ataxia) and FCPOI (primary ovarian insufficiency)

excluding fragile x syndrome, triplet repeats are more likely to expand when they come from which parent?

father

fragile x syndrome gene and mode of inheritance

FMR1, XL

friedrichs ataxia gene and mode of inheritance

FXN, AR

list the repeat ranges of friedrichs ataxia from typical to full mutation

typical: less than 33,
premutation: 34-65,
reduced penetrance: 44-66
pathogenic: more than 66

if repeat expansion is not detected in someone with symptoms of friedrichs ataxia, what test should be ordered which finds pathogenic variants in 4% of cases?

gene sequencing with del/dup analysis

definition of myotonia

inability to release closed grip

features of mild myotonic dystrophy type 1

mild myotonia, normal lifespan, onset 10-30 years

main features of congenital myotonic dystrophy type 1

hypotonia at birth, respiratory insufficiency and early death, ID

features of myotonic dystrophy type 2

myotonia, adult onset (20-30s), (less common: cataracts, cardiac conduction defects, type 2 diabetes)

true/false: myotonic dystrophy type 2 has no correlation between pathogenic repeat size and onset of severity

true

huntington disease gene and mode of inheritance

HTT, AD

huntington disease main features and onset

progressive motor disability with chorea (involuntary movement of limbs and facial muscles), cognitive decline, personality changes, depression, adult onset (~45 years)

can there be a contraction or reduction of repeats in huntington disease?

yes but it is very rare

what are the components of the HD predictive genetic testing process recommended by the huntington's disease society of america?

1. telephone contact informing them of the process.
2. visit 1: genetic counseling (informed consent, mental health assessment, neuro exam, blood draw).
3. visit 2: disclose results in person and arrange follow up.
4. follow up

what are the two dystrophinopathies

Duchenne and Becker

testing strategies for dystrophinopathies

del/dup of DMD gene (80% cases caused by del) followed by sequencing

dystrophinopathies: in frame deletions of the DMD gene cause _________ while out of frame deletions cause ________

BMD (less severe), DMD

in the absence of family history, the mother of a child with a dystrophinopathy has a __/__ risk of being a carrier

2/3

to determine if a deletion is likely to result in DMD or BMD, look at the ________ on either side of the deletion

exons

in frame deletions are likely to cause BMD because a ______ protein with __________ material is produced

functional, missing

out of frame deletions are likely to cause DMD because everything after the deletion is ______ ____ ________ , resulting in a _________ protein

out of frame, truncated

main features of facioscapulohumeral muscular dystrophy

asymmetric weakness affects muscles of face, shoulder blades, upper arms, abs, and lower legs. Rarely effects heart or respiratory system

clinical findings and onset of DMD

progressive symmetric muscle weakness (proximal > distal) starting at legs/pelvis and effecting shoulders and neck, often with calf hypertrophy, childhood onset (before 5y), wheelchair bound before 13y, possible motor or DD, eventual respiratory issues

Charcot marie tooth (CMT) mode of inheritance and genes

50% have dup in PMP22 gene (AD). other types can be AR or XL. Over 100 other genes can also cause CMT

Charcot-Marie-Tooth disease (CMT) main features

progressive distal neuropathy of the arms and legs, weakness in feet or hands, high arched feet, can have sensorineural hearing loss

Hereditary neuropathy with liability to pressure palsies gene and mode of inheritance

deletion in PMP22 (80% and sequence variant in 20%), AD inheritance

Hereditary neuropathy with liability to pressure palsies main features

recurrent neuropathy in a single or multiple nerves, some may have mild to moderate pes cavus (high arch) foot deformity

Hereditary neuropathy with liability to pressure palsies genetic testing method

del/dup of PMP22, reflex to sequencing

Ataxia telangiectasia (AT) gene, mode of inheritance, and onset

ATM, AR, early childhood onset (1-4y)

carriers of Ataxia telangiectasia (AT) are at increased risk of what cancers?

breast, ovarian, and pancreatic cancer

in tuberous sclerosis, ____________s can grow in multiple organs

haratomas

cerebral features of tuberous sclerosis

cortical tubers, seizures (in 85%), higher chance for ID

cardiac features of tuberous sclerosis

rhabdomyoma (in over 50-80%)

skin features of tuberous sclerosis

Facial angiofibroma, shagreen patch, and ungual fibromas, hypopigmented spots (ash leaf macules), bumps around finger/toenails (periungual fibromas)

what causes the eye of the tiger sign on MRI?

abnormal accumulation of iron in brain

what condition can have eye of the tiger sign as feature

PKAN (pantothenate kinase-associated neurodegeneration)

wilson disease gene and mode of inheritance

ATP7B, AR

NF1 gene and mode of inheritance

NF1, AD (50% de novo)

NF1 diagnostic criteria

2 or more of the following:

-6+ cafe au lait macules

-2+ neurofibromas

-axillary/ingunal freckling

-optic glioma

-2+ lisch nodules

-osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis

-affected 1st degree relative

-pathogenic NF1 variant

true/false ID can be a feature of NF1

true

true/false: NF1 patients can be at increased risk of breast cancer

true

legius syndrome gene and mode of inheritance

SPRED1, AD

legius syndrome main features

skin findings of NF1 without neuro involvement

NF2 gene and mode of inheritance

NF2, AD (50% de novo)

true/false: NF2 doesn't have skin findings

true

what is the penetrance of NF2

complete/100% penetrane

schwannomatosis main features and onset

2+
-schwannomas across the body, usually without vestibular, ocular, or cutaneous
-meningiomas
-adolescence to adult onset

what percent of alzheimer's disease is familial

25%

___________ alleles have a significant association with
alzheimer's disease, but genotyping is not diagnostic

APOE

1st degree relatives of those with familial
alzheimer's disease are at how much of an increased risk?

1.5-2x