Approach to Inherited Neuropathies - McGill University

Approach to Inherited Neuropathies - McGill University

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 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 (vsSeminars CMT1D) Siskind and Shy,

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 or primary part of the disorder

CharcotMarieTooth 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 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 Classicclinical phenotype: lengthdependent 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 Patzk and Shy. Curr Neurol Neurosci Rep. 2011

Patzk 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?

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]

Recently Viewed Presentations

  • Diapositive 1 - WordPress.com

    Diapositive 1 - WordPress.com

    Calames Histoire naturelle, anatomie et dissection Calames et l'ABES Calames = Catalogue en ligne des archives et des manuscrits de l'enseignement supérieur ABES = Agence bibliographique de l'enseignement supérieur Sudoc (monographies, périodiques…) PeB Calames (manuscrits, archives) Star (workflow des thèses...
  • Circulation Did you know?  In one day, blood

    Circulation Did you know? In one day, blood

    Figure 42.6 The mammalian cardiovascular system: an overview. Heart: central engine. ... Clot can break away and travel to brain (cause stroke) or to lung, heart, or other areas. Anticoagulants, compression stockings, periodic breaks to stand up and get blood...
  •  Mark E. Damon - All Rights Reserved  Mark

    Mark E. Damon - All Rights Reserved Mark

    Scores Chinese Rebellions Final Jeopary Question In 756 CE, this Turkish-Chinese general in charge of the Northern Army marched his troops towards Chang-an in an effort to topple
  • Proper Installation &amp; Maintenance of Shade Trees &amp; Palms

    Proper Installation & Maintenance of Shade Trees & Palms

    This project is made possible by a grant through the 2011 National Urban and Community Forestry Grant Program and the Florida Department of Agriculture and Consumer Services, and the Florida Forest Service.
  • The Voynich Manuscript as a MesoAmerican Herbal Jules

    The Voynich Manuscript as a MesoAmerican Herbal Jules

    The Voynich Manuscript as a MesoAmerican Herbal. Jules Janick and Arthur O. Tucker. Department of Horticulture & Landscape Architecture, Purdue University, West Lafayette, Indiana, USA. EmeritusProfessor and Co-Director Claude E. Phillips Herbarium, Delaware State University, Dover, Delaware, USA
  • Prezentacja programu PowerPoint

    Prezentacja programu PowerPoint

    Early plant succession in the post brown cole miningareaChickenCreak. 2005. 2010. Successionstarts with colonisingspecies from a . regional. species. pool. and from the initial
  • Middle Powers During Great Power Transitions: China&#x27;s Rise ...

    Middle Powers During Great Power Transitions: China's Rise ...

    Middle Powers During Great Power Transitions: China's Rise and the Future of Canada-U.S. Relations Bruce Gilley, Portland State University China's Rising Power Relative Shares of World GDP (%) CHINA CHINA CANADA Power vs. Purpose Power Transitions China seeks to expand...
  • Chapter1: Intro To Macro - QED

    Chapter1: Intro To Macro - QED

    Small Open Economy Under a fixed exchange rate system: Fiscal policy accompanied by a monetary expansion/contraction is effective for stabilization purpose, but it has larger impact on output. Monetary policy is ineffective, but factors that shift LM curve has no...