Approach to Inherited Neuropathies

Jodi Warman Chardon, MD, MScNeuromuscular 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

3

Clinical-Clues to Inherited Neuropathy

• 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:– initial sporadic mutation – expression can be variable– penetrance incomplete– late-onset disease

• family members available for study may be pre-symptomatic• 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 orprimary 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 multisystemdisorder

• Familial amyloid polyneuropathy• Disturbances of lipid metabolism• Porphyrias• Disorders with defective DNA• Neuropathies associated with mitochondrial

diseases• Neuropathies associated with hereditary

ataxiasReilly 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. 2011http://neuromuscular.wustl.edu/time/hmsn.html accessed September 15th, 2012

Patzko and Shy, Continuum 2012Shy M. Inherited Peripheral Neuropathies. Continuum. 2011

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

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?

• 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)

MerciQuestions?

jwarman@cheo.on.ca