Interpreting diagnostic genetic Tests Flashcards
Why is it relevant - just send for a panel
- pathogenic
- likely pathogenic
- variant of uncertain significance
- likely benign
- benign
Pitfalls:
- in some countries VUS are not reported
- poor coverage of duplication and deletions/ repeat expansions
- wrong panel
Probability of a VUS being disease causing
Hot - 81%
Warm - 67.5%
Tepid - 50%
Cool - 32.5%
Clinical presentation of CMT
Length dependent weakness or sensory loss
Slow progression
Onset varies from childhood to late adult
Often but not always a family history:
- de novo mutations
- non paternity
- late onset
Neurophysiology
Is there a neuropathy
- sometimes only detected on EMG
Is there involvement of motor and sensory nerve fibres
- hereditary motor AND sensory neuropathy (CMT) vs HMN or HSN
Is the neuropathy demyelinating or axonal?
- <38m/s upper limb CV
Nomenclature of hereditary neuropathies
Hereditary weakness or numbness
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Neurophysiology
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Demyelinating - CMT1
Axonal
- sensory predominant HSN
- mixed motor and sensory CMT2
- motor predominant HMN
CMT1A = chromosome 17p duplication
Childhood onset
Disability from foot deformity
Variable disease severity
- neurophysiology always abnormal (slow NCV)
- some asymptomatic adults
Charcot Marie tooth
- duplication of 17p
X linked CMT (CMTX1)
- mutations in GJB1 encoding connexin 32 (channel protein)
- 2nd commonest form of CMT
CMT (X)
- clinically similar to CMT1
- no male to male transmission
- males more severe than females
- males demyelinating/ females axonal
- patchy clinically (may mimic CIDP on NCS)
- sometimes upper limb dominant
- CNS
Split hand in CMTX
- weakness and wasting of APB> ADM or FDIO
CMT2
Mutations in the MFN2 are the commonest cause of axonal CMT (10-20%)
Majority autosomal dominant
- can be recessive
- associated with optic atrophy in a minority
Traditionally severe
For CMT2, hereditary sensory neuropathy and hereditary motor neuropathy, most patients do not have a genetic diagnosis (~50%)
Non-length dependent CMT2
Autosomal dominant
Neurofilament heavy chain NEFH
- onset 2/3rd decade
- distal/proximal weakness
HMSN-proximal (Okinawa type)
-TFG mutations
- onset 4th decade
- proximal > distal weakness
- Death by 7th decade
Autosomal recessive
Membrane metalloendopeptidase MME
- onset 5th decade
- distal = proximal
Often require wheelchair
May mimic CIDP (no slowing)
What is a complex genetic disease
Disease in which peripheral neuropathy is part of a clinical syndrome
- usually neurological - spasticity, ataxia, developmental delay
- other organ involvement e.g cardiac
Disease in which peripheral neuropathy is a significant feature of the syndrome
May present with peripheral neuropathy
Global developmental delay and peripheral neuropathy
- large number of diseases including metabolic leukodystophies
- commonly linked to mutations in microtubule transport based on motor proteins (diseases of cortical migration)
Global developmental delay and peripheral neuropathy
- large number of diseases including metabolic leukodystophies
- commonly linked to mutations in microtubule transport based on motor proteins (diseases of cortical migration)
Lower limb spasticity and upper limb motor neuropathy
- upper limb > lower limb denervation
- wrist extensor weakness with SIGMAR1
BSCL2 - misfolds in ER (dominant)
(Silver syndrome)
REEP1 - ER protein (dominant)
RTN2 - ER protein (recessive)
SIGMAR1 - ER protein (recessive)
May need to request HSP panel
Spasticity/ ataxia and neuropathy with slow nerve conduction velocities
Autosomal recessive spastic ataxia of Charlevoix-saguenay (ARSACS)
- recessive mutations of the SACS gene
- spasticity, ataxia, seizures, retinal nerve fibre hypertrophy ,
Late onset ataxic neuropathy (CANVAS)
(Cerebellar ataxia neuropathy vestibular areflexia syndrome)
Most common cause of late onset ataxia and sensory neuropathy
- recessive pentanucleotide expansion (AAGGG) in RFC1
- carrier frequency 5/560
What are amyloidoses
There are a heterogenous group of disorders characterised by the extreme extracellular deposition of insoluble amyloid deposits in tissues
Amyloidoses can be acquired or inherited, and systemic or localised
The most common types of systemic amyloidosis are categorised by pathogenic proteins:
- AL type (immunoglobulin light chain)
- AA type (serum amyloid A)
- ATTR type (wild type and hereditary)
