Genetics E2- Neuro & Muscular Dystrophies

What autosomal dominant condition is a fatal, progressive neurodegenerative disease of the CNS?

Huntington’s Disease

What causes Huntington’s disease / chorea?

Expansion of CAG trinucleotide in the HTT gene on 4p16.3 that encodes huntingtin

When does Huntington’s disease most commonly onset?

30-60 y/o

What symptoms are seen in Huntington’s?

Progressive chorea & insidious impairment of intellectual function (psychiatric → dementia)

What are brief, abrupt, involuntary, non stereotyped movements that involve the face, trunk, & limbs?

*key feature of Huntington’s disease

Chorea

What is the treatment for Huntington’s disease?

VAMT2 inhibitors (use antipsychotics if depression), SSRIs

*no disease-modifying therapies available

What drugs are VMAT inhibitors?

Tetrabenazine, duetetrabenazine

How do VMAT2 inhibitors treat chorea that interferes with function?

Inhibit presynaptic DA, thereby inhibiting release of DA at the synapse

When should VAMT2 inhibitors be avoided in the treatment of Huntington’s?

If depression is present → use antipsychotics instead

What does CADASIL stand for?

Cerebral autosomal dominant arteriopathy w/ subcortical infarcts & leukoencephalopathy

What autosomal dominant condition is a microangiopathy affecting mainly the brain, and is also the MC inherited cause of stroke & vascular dementia?

CADASIL

What causes CADASIL?

NOTCH3 gene on 19p13.2 → missense variants (MC) or cysteine-altering variants (causes vascular lesions in small arts&caps)

What clinical features are seen with CADASIL?

Migraine w/ aura (initial manifestation), acute reversible encephalopathy, ischemic episodes (MC manifestation), cognitive impairment & dementia, psychiatric disturbances

What is the typical clinical course of CADASIL?

Age 30: migraine w/ aura

40-60: TIA, ischemic strokes, mood d/o

50-60: dementia

~60: gait difficulty

What are the 2 major typical findings of CADASIL on an MRI?

Small, circumscribed regions isointense to CSF on T1 & T2 weighted images

Less well demarcated T2 hyperdensities/T1 hypodensities clearly distinct from CSF

What is the treatment for CADASIL?

CVA: tx acute stroke, HTN, hypercholesterolemia; low dose ASA for prevention

Dementia: donepezil

Migraine: NSAIDs, avoid triptans

What are causes of familial early onset Alzheimer’s disease?

PSEN1 chromosome 14q (MC, ~43 y/o onset), PSEN2 chromosome 1q, APP chromosome 21q

*autosomal dominant, very high penetrance)

What clinical manifestations are seen in familial early onset AD?

Memory impairment, poor judgement, agitation, withdrawal, confusion, language difficulties, occasionally parkinsonian features & seizures

When should genetic testing for familial early onset AD be done?

If symptomatic or if an asymptomatic pt has a FHx suggesting inheritance

What are progressive conditions characterized by motor incoordination d/t dysfunction of the cerebellum & it’s connections, often accompanied by wide-based gait, dysarthria, & nystagmus?

*can be AD, AR, X-linked, or mitochondrial inheritance

Hereditary ataxias

Which hereditary ataxia is autosomal dominant & characterized by intermittent periods of unsteady gait, lasting several hours, with nystagmus and dysarthria?

Episodic ataxias

Which condition is an autosomal recessive progressive ataxia of all limbs d/t loss of function mutation on the FXN gene on 9q13?

*MC hereditary ataxia

Friedreich ataxia

What clinical features are seen in Friedreich ataxia?

*Dx’d w/ genetic testing

Progressive ataxia of all limbs, neurological dysfunction, cardiomyopathy, DM, life expectancy ~ 40-50 yrs (some can live beyond 60s)

What is another name for Charcot-marie-tooth disease (CMT)?

Multiple hereditary sensory & motor neuropathies (HSMN)

What spectrum of disorders are caused by mutations in genes whose protein products are expressed in myelin, gap junctions, or axonal structures w/in peripheral nerves?

characterized by slowly progressive distal muscle weakness & wasting - “stork legs”

CMT

What are clinical features of CMT?

Distal weakness & atrophy of intrinsic muscles(MC initial sx) -foot drop, pes cavus, stork legs, hammer toes; & sensory symptoms (less prominent)

How is CMT diagnosed?

EMG → confirm w/ genetic testing

What is another name for amyotrophic lateral sclerosis (ALS)?

Lou Gehrig disease

What presents with focal asymmetric weakness in the extremities or bulbar signs such as dysphagia or dysarthria?

ALS

What is the average age of onset & survival of ALS?

56 y/o; 1-5 years after dx

What kind of inheritance pattern does familial ALS have?

MC autosomal dominant but can be autosomal recessive or X-linked

*but most cases are sporadic not familial (90-95%)

What genes are MC implicated in familial ALS?

C9ORF72: assoc w/ high risk FTD

SOD1: ranges from rapid progression (< 2 yrs) to slow (10-20 yrs)

also TARDBP & FUS

How does ALS affect the nervous system?

Degeneration & death of motor neurons → gliosis replaces lost neurons → spinal cord becomes atrophic → ventral roots become thin → affected muscles show denervation atrophy, unable to contract

What signs may be seen on PE in a patient with ALS?

LMN: weakness, fasciculations, muscular atrophy, dec muscle tone

UMN: inc tone, spasticity, inc DTRs, +babinski, pseudobulbar affect (inappropriate laughing, crying, forced yawning)

What is the Gold Coast diagnostic criteria for ALS?

1. Progressive motor impairment

2. Presence of either UMN & LMN sx in atleast 1 limb/body segment OR progressive LMN sx in atleast 2 body segments

3. Absence of electrophysiologic, neuroimaging, and pathological evidence of other diseases

What are the treatment options for ALS?

Riluzole: slows progression, modest survival

Edaravone: slow functional decline in early stages

Tofersen: targets SOD1 gene mutations

What is another name for Neurofibromatosis type 1 (NF1)?

Von Recklinghausen disease

What is a benign, unencapsulated tumor composed of a mixture of cell types from the nerve sheath (Schwann cells, fibroblasts, mast cells)?

Neurofibromatosis

How many features of the diagnostic criteria must be present for a diagnosis of NF1?

• cafe au lait macules, neurofibromas, Crowe sign, optic pathway glioma, linch nodules or choroidal abnormalities, distinctive osseous lesion, heterozygous variant

2 or more

What autosomal dominant condition is due to a mutation in the NF1 gene on 17q11.2, leading to a lack of tumor suppression which results in the growth of neurofibromas?

*50% have FHX, 50% de novo

NF1

What is a de novo mutation?

Spontaneous genetic alteration that appears for the first time in a family, not inherited from either parent

*ex- 50% of NF1 cases

What is the treatment for NF1?

Lifelong surveillance, targeted therapies (selumetinib for plexiform neurofibromas), & surgery for symptomatic neurofibromas

What is the prognosis of NF1?

Life expectancy reduced 8-15 yrs, median survival ~ 70 y/o

What condition is characterized by the following clinical findings?

• Hallmark: BL VS on vestibular portion CN VIII → progressive hearing loss, tinnitus, & balance dysfunction

• Ocular: juvenile posterior subcapsular or cortical cataracts, epiretinal membranes

• Cutaneous:n skin schwannomas, cafe au lait macules

NF2

What other tumors are commonly associated with NF2?

Multiple meningiomas (cranial & spinal), schwannomas on other cranial/spinal/peripheral nerves, & spinal ependymomas (intramedullary)

When does NF2 typically onset?

Late teens-early 20s & most develop BL VS by age 30

How is NF2 diagnosed?

Manchester criteria or identification of pathogenic variant

What autosomal dominant condition is caused by a mutation of the NF2 gene on chromosome 22, disrupting merlin activity & leading to the formation of schwannomas?

NF2-SWN

What is the management for NF2-SWN?

Annual MRI, spinal MRI q 2-3 yrs, surgery, Bevacizumab

*progressive condition, median survival 60-70s+

What protein product is involved in NF1?

Neurofibromin (tumor suppressor, widely expressed)

What protein product is involved in NF2-SWN?

Merlin (aka Schwannomin; cell membrane related protein that acts as tumor suppressor)

What conditions are prominent X-linked recessive dystrophinopathies that are caused by mutations of the dystrophin gene on Xp21.2 & occur primarily in males?

DMD & BMD

What are genetically inherited diseases that cause progressive muscle wasting and weakness & result from gene mutations affecting critical muscle proteins essential for muscle structure & function?

Muscular dystrophies

Which muscular dystrophy involves absent/deficient dystrophin?

Duchenne (DMD)

Which muscular dystrophy involves abnormal/reduced dystrophin?

Becker (BMD)

Which muscular dystrophy presents with a more severe clinical phenotype & earlier onset?

Duchenne (DMD)

What is a rod shaped cytoplasmic protein that acts as an anchor connecting each muscle cell’s cytoskeleton with the extracellular matrix?

*deficiency causes muscles fibers to be destroyed → replaced by fat & fibrous tissue

Dystrophin

What clinical presentation is seen with DMD & BMD?

*more severe in DMD

Progressive muscle weakness, awkward gait, inability to run, difficulty rising from floor (gower’s sign), pseudo hypertrophy of calves

What is the prognosis of DMD?

Boys present 2-4 y.o; wheelchair dependence by early-mid teens, median survival 30s; rarely reproduce

What are the chances of a son of a carrier mother inheriting a pathogenic allele for DMD (X-linked recessive)?

50%

What is the chance of a daughter of a carrier mother & unaffected father of becoming a carrier of DMD (X-linked recessive)?

50%

What gene is affected in DMD?

DMD gene on Xp21.2

What is the prognosis for BMD?

Ambulation maintained into mid-adulthood (40s-50s) or longer; life expectancy into middle age (50s-60s) or beyond

*cardiac health is key determinant

What is the diagnosis for DMD & BMD?

Gold standard: genetic testing for DMD mutations; if inconclusive → muscle bx

Early indicator: elevated CK in early childhood

What is the treatment for DMD & BMD?

Glucocorticoids to slow decline of motor & pump function

Novel mutation specific therapies (DMD) to restore dystrophin- exon skipping, stop-codon read-through, gene therapy

What drug is an monoclonal antibody, angiogenesis inhibitor that is shown to reduce the size of vestibular schwannomas & spinal tumors?

*used for NF2-SWN

Bevacizumab