Transcript Approach to Inherited Neuropathies

Approach to
Inherited Neuropathies
Jodi Warman Chardon, MD, MSc
Neuromuscular Fellow, McGill University
Neurogenetics Fellow, University of Ottawa
Objectives
• Develop approach to inherited neuropathies
– Appropriate history
– Relevant physical exam
– Review of electrodiagnostic testing
• Develop appreciation for benefits and erroneous
conclusions due to genetic testing
• At the end, discussion of career or fellowship
options if you would like
• Please provide feedback: written or oral, positive
and especially negative
Disclosures
• No disclosures
Quiz
• HMSN patients usually have primarily positive
sensory symptoms at onset T/F
• With ROS on focused exam, it is necessary to
review symptoms of visual changes, hearing
loss, dysphagia and hoarseness T/F
• GJB1 is most common mutation causing
inherited neuropathy T/F
• Patients with HMSN most often have decreased
amplitudes and preserved conduction velocities
and latencies on NCS T/F
Case X
• 65 year old man, diabetic, smoker, alcoholic
• 4 year history of sensory loss in his feet
• Exam: MS, CN N
– Motor: pes cavus, distal weakness, length
dependent
– Sensory: distal pp decreased to ankles, vibration
decreased to MM
– Reflexes: 1+ symm reflexes except absent Achilles
• What other information do you need?
Clinical approach to any neuropathy
Hx:
• Negative motor symptoms weakness, fatigue
and wasting
• Positive motor symptoms include cramps,
twitching and myokymia
• Negative sensory symptoms: hypesthesia and
gait abnormalities such as ataxia
• Positive sensory symptoms include burning or
lancinating pain, paresthesias, “buzzing,”
“tingling”
Alport and Sander, Continuum, 2012
Clinical-assess for acquired causes
• Exposures with
– occupation (possibility of toxic exposures to
solvents, glues, fertilizers, oils, and lubricants)
– sexual history
– recreational drug use
– excessive alcohol intake
– dietary habits
– smoking
Alport and Sander, Continuum, 2012
General PMHx (r/o acquired)
• Medical (FHx) neuropathy focus:
endocrinopathy (DM, hypothyroidism), renal
insufficiency, hepatic dysfunction, CTD, and cancer.
• Surgical history: bariatric surgery, multiple
orthopedic procedures, and multiple surgeries for
‘‘entrapped nerves’’
• Medication list: (temporal) HAART, chemotherapy,
Abx, herbal, etc
• ROS: rash/skin changes, arthralgias, dry eyes and mucous
membranes, orthostasis, GI, and constitutional symptoms
(fever, weight loss, night sweats).
Alport and Sander, Continuum, 2012
Family History
• Not just “no neuromuscular conditions…”
unless clearly acquired cause
• Draw pedigree
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Clinical-Clues to
Inherited Neuropathy
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Any symmetric, generalized polyneuropathy (+HNPP)
….Family history
Symptoms less obvious to patient
Lack of positive sensory symptoms
Early age at onset, delayed milestones/ development
– Ankle weakness (difficulty skating), stumble, running
difficulties, balance difficulties vs later adult onset *
• Associated skeletal abnormalities
– Foot deformities
– Scoliosis
• Very slowly progressive
– Lower, 10 years delay upper extremities (vs CMT1D)
Siskind and Shy, Seminars in Neurology, 2011
Alport and Sander, Continuum, 2012
Causes of Negative Family History
• Family data are frequently not available,
incomplete, or unknown, a genetic cause is not
ruled out:
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initial sporadic mutation
expression can be variable
penetrance incomplete
late-onset disease
• family members available for study may be presymptomatic
• older relatives may have other comorbidities that confound
the phenotype
• older relatives may also pass away before evaluation
Lawson & Gharibshahi, Seminars in Neurology, 2010
Pathophysiological Approach
Suter and Scherer. Nature Reviews Neuroscience, 2003
Neuropathy is the sole or
primary part of the disorder
• Charcot–Marie–Tooth disease (CMT)=
Hereditary Motor Sensory Neuropathy (HMSN)
• Hereditary neuropathy with liability to pressure
palsies (HNPP)
• Hereditary sensory and autonomic
neuropathies/hereditary sensory neuropathies
(HSAN/HSN)
• Distal hereditary motor neuropathies (dHMN)
• Hereditary neuralgic amyotrophy (HNA)
Reilly and Shy, J Neurol Neurosurg Psychiatry, 2009
Neuropathy part of a widespread
neurological or multisystem
disorder
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Familial amyloid polyneuropathy
Disturbances of lipid metabolism
Porphyrias
Disorders with defective DNA
Neuropathies associated with mitochondrial
diseases
• Neuropathies associated with hereditary
ataxias
Reilly and Shy, J Neurol Neurosurg Psychiatry, 2009
CMT
• Charcot-Marie-Tooth disease (CMT) disease =
Hereditary Motor Sensory Neuropathy (HMSN)
– encompasses inherited neuropathies that
demonstrate both genetic and phenotypic
heterogeneity
– i.e. PMP-22 [CMT1a, CMT1e, HNPP, early onset CMT
(~CMT3 (previously known as Dejerine-Sottas)
Congenital Hypomyelinating Neuropathy]
• CMT results from mutations in more than 50
genes expressed in Schwann cells and neurons
causing overlapping phenotypes
Choi et al. Human Mutation, 2012
Complex CMT Genetics
• 60% of all
CMT=CMT1
– (80-90% is
CMT1A with
PMP 22
duplication>
point mutation
CMT
• “Classic”clinical phenotype:
length-dependent degeneration
characterized by
– distal sensory loss and weakness
– deep tendon reflex abnormalities
– and skeletal deformities (foot,
scoliosis)
• Vs. “CMT-Plus” syndromes:
– Optic atrophy, cataracts, glaucoma,
deafness, dysphagia, respiratory,
UMN etc
Patzkó and Shy. Curr Neurol Neurosci Rep. 2011
Patzkó and Shy. Curr Neurol Neurosci Rep. 2011
Electrodiagnostic studies (Classic)
Demyelinating
• Decreased conduction
velocity {<38 M/s}
• Conduction velocities
• Uniformly slow in all
nerves (Mean 17 to 20
M/s)
• Onset before clinical
signs appear
• Usually NO abnormal
temporal dispersion or
conduction block (≠
HNPP)
• i.e. CMT 1 (AD) and 4
(AR)
Intermediate
(much less common)
• NCS velocities between
25-35 M/s
• =Dominant or recessive
Intermediate CMT
Axonal
• Electrodiagnostic:
Usually Axonopathy
• Median NCV
• Velocity: Slightly
decreased; > 38 M/s
• CMAP amplitude:
Reduced
• SNAP amplitude:
Reduced
• EMG: Denervation in
distal muscles
• i.e. CMT 2 (AD) and 4
(AR)
Shy M. Inherited Peripheral Neuropathies. Continuum. 2011
http://neuromuscular.wustl.edu/time/hmsn.html accessed September 15th, 2012
Current Organization of CMT
• CMT1=AD demyelinating <38 M/s
• CMT2=AD axonal >38 M/s
• CMT3=no longer used
– Previously Dejerine-Sottas
• CMT4=AR demyelinating or axonal
– (Previously Refsum disease, but now Refsum not
considered part of CMT)
• X-linked
• Dominant Intermediate (meaning CV between
25-35 M/s
Patzko and Shy, Continuum 2012
Shy M. Inherited Peripheral Neuropathies. Continuum. 2011
Demyelinating Nerve Pathology
Approach to CMT Genetic Testing
• > 80% PMP22, MPZ, GJB1, MFN2
Siskind and Shy, Seminars in Neurology, 2011
Patzko and Shy, Continuum 2012
Approach to CMT Testing
Siskind and Shy, Seminars in Neurology, 2011
Hereditary neuropathy with liability
to pressure palsies (HNPP)
• Usually due to PMP 22 deletion (vs duplication
with CMT1a)
• Clinical features:
– transient and recurrent motor and sensory
mononeuropathies, usually at entrapment sites,
such as the carpal tunnel, ulnar groove, and fibular
head
– duration: last hours, days or weeks or occasionally
longer
– HNPP can progress to long-term peripheral
neuropathy phenotypically indistinguishable from
CMT1
Siskind and Shy, Seminars in Neurology, 2011
Hereditary sensory and autonomic
neuropathies/hereditary sensory
neuropathies (HSAN/HSN)
– Distribution: Distal > proximal; Symmetric;
Legs > Arms
– Sensory Loss
– Pain & Temperature (Small fiber)
– Large fiber loss also occurs
– Progressive
• Spontaneous sensations
– Lancinating pains, burning
• Autonomic & reflex loss
• Edx studies usually only useful later in disease
www.neuromuscular.wustl.edu/sensory-small.html#hsan1 accessed Sept 13th, 2012
Patzko and Shy, Continuum, 2012
Distal hereditary motor
neuropathies (dHMN)
• Heterogeneous group of diseases with
length-dependent predominantly motor
neuropathy.
– +/- minor sensory abnormalities and/or a
significant upper-motor-neuron component,
– often an overlap with CMT2 and with juvenile
forms of ALS and HSP.
Rossor et al., Neuromuscular disorders, 2012
Why would you perform genetic
testing in CMT?
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Family planning and counselling
Diagnostic certainty
Relevance of unusual clinical features
Avoidance of potential iatrogenic toxicities
Scientific study
Lawson & Gharibshahi, Seminars in Neurology , 2010
To choose no genetic testing
• Identification of a mutation in a
presymptomatic or mildly affected individual
• Social stigmatization
• Selection of appropriate and rational testing
• Cost
• Genetic heterogeneity
Lawson & Gharibshahi, Seminars in Neurology 2010
Causes of Negative Genetic Testing
• Disease may be heterogeneous and the
wrong gene has been tested
• Techniques used may be insufficiently
sensitive to detect the causative mutation in
that individual/family
• Mutation of unclear pathogenic significance
may be found
Eccles, Practical Guide to Neurogenetics, 2008
Inheritance Pattern?
• 45 year old male with large fibre sensory
loss, with myoclonus and hearing loss
Mitochondrial
• Mitochondria are almost always inherited
from the mother.
– If a female has a mitochondrial trait, all of her
offspring inherit it.
– If a male has a mitochondrial trait, none of his
offspring inherit it.
• Complex phenotype, heteroplasmy
• Mitochondrial inheritance not followed if
nuclear mutations cause mitochondrial
dysfunction
Inheritance Pattern?
• 12 year old female with with slowly
progressive sensory loss in feet>hands with
5- weakness in l/e, palpable peroneal nerves
• Demyelination pattern in EDx
Autosomal Recessive
• Affected offspring are usually born to
unaffected parents
• Appears in both sexes with equal
frequency
• Trait tend to skip generations
• When both parents are hetrozygous,
approx. 1/4 of the progeny will be
affected
• Appears more frequently among the
children of consanguinous marriages
Inheritance Pattern?
• 5 year old boy with progressive, length
dependent sensory and motor signs with
NCS demonstrating demyelination
Autosomal Dominant
• Appears in both sexes with equal
frequency
• Both sexes transmit the trait to their
offspring
• Does not skip generations (but penetrance
may not be 100%
• Affected offspring must have an affected
parent unless they posses a new mutation
• When one parent is affected (het.) and
the other parent is unaffected, approx.
1/2 of the offspring will be affected
• Unaffected parents do not transmit the
trait
Inheritance Pattern?
• 18 year old boy with demyelination in S/M
nerves on biopsy and progressive weakness
and sensory loss; sisters and female cousins
less affected
X-Linked Dominant
• Both males and females are affected; often
more females than males are affected
• Does not skip generations.
– Affected sons must have an affected mother;
– Affected daughters must have either an affected
mother or an affected father
– Affected fathers will pass the trait on to all their
daughters
• Affected mothers if heterozygous will pass the
trait on to 1/2 of their sons and 1/2 of their
daughters
Inheritance Pattern?
• 30 year old male with 18 year history of
progressive distal l/e weakness, now
complaining of more hand weakness;
mother has high arches and no weakness
X-Linked Recessive
• More males than females are affected
• Affected sons are usually born to unaffected
mothers, thus the trait skips generations
• Approximately 1/2 of carrier mothers’ sons
are affected
• It is never passed from father to son
• All daughters of affected fathers are carriers
Inheritance Pattern?
• For the sake of completeness:
– 30 year old male, thought he was in the urology
clinic (mistake with neurology clinic by the clerk)
due to infertility
Y-linked dominant
• Only males are affected
• It is passed from father to all sons
• It does not skip generations
Quiz
• HMSN patients usually have primarily positive
sensory symptoms at onset F
• With ROS on focused exam, it is necessary to
review symptoms of dysphagia and hoarseness,
etc T
• GJB1 is most common mutation causing
inherited neuropathy F
• Patients with HMSN most often have decreased
amplitudes and preserved conduction velocities
and latencies on NCS F
Summary
• Hereditary neuropathies can easily be
misdiagnosed as acquired due to negative or
incomplete family history
• Hereditary neuropathies exhibit both genetic
and phenotypic heterogeneity
• Hereditary neuropathies have important
consequences for prognosis, familial
consequences (…and future molecular
therapies)
Merci
Questions?
[email protected]