What is CMT? • Neuropathies: Primary diseases of nerve

• Peripheral Nerves

– Demyelinating Neuropathy – Axonal Neuropathy

• Clinical Hallmarks

– Distal muscle weakness and atrophy – Loss of proprioception and sensation – Classical steppage gait, pes plannus or pes cavus – Fatigue and depression can often accompany disease

• Genetic heterogeneity

– Over 50 known genetic causes

Chromosomes

Chromosomes Are Found In Each Cell

Cell

Nucleus

Chromosomes - Female

Chromosomes - Male

Chromosome Gene DNA

C A T G A A T G G C A

C A T G A A T G G C A

Code

Inherited neuropathies: chromosomes and genes (June 2012)

CMT

Demyelinating (Type 1)

Axonal (Type 2)

Autosomal Dominant X-Linked Autosomal Recessive

Demyelinating OR Axonal (Type 4)

Intermediate (Type X)

CMT “Subtypes” Demyelinating Axonal

• CMT1 – AD – 1A – 1B – 1C – 1D

• CMTX - XLD • HNPP – AD • CMT4 – AR

– 4A – 4B – 4C – 4D – 4E – 4F

• CMT2 – AD – 2A – 2B – 2C – 2D – 2E

CELLULAR PATHWAYS IN CMT (Klein et al. 2013)

CLINICAL APPROACH TO CMT A Multidisciplinary Effort

• MDA Healthcare Service Coordinators – Maggie Segal, Julie Campbell, Denise Gant

• Genetic Counselors – Shawna Feely, Lindsey Miller, Carly Siskind

• Pros: – Tailoring prognoses

and recommendations – Access to clinical trials – Relief of uncertainty

and anxiety – Facilitating reproduction

decisions – Determine if other

family members are at risk

Genetic Testing Cons • Positive test may not be completely informative:

– Variability of disease severity – Conditions with incomplete penetrance

• May have inconclusive results

– Unknown or unclear results • May not have a genetic test available

• Emotional impact of positive or negative results • Genetic Discrimination

• COST !!!!!!!

Genetic Information Nondiscrimination Act (GINA)

• What does GINA do? – Title I: Health Insurers can not:

• Require individual/family genetic information for eligibility, coverage, underwriting, or premium-setting decisions

• Collect genetic information to make enrollment or coverage decision

• Require individual/family to undergo genetic testing

• Use genetic information as a preexisting condition *

– Title II: Employers can not: • Use genetic information in hiring, promotion,

compensation, or termination decisions

• Use genetic information to aid in determining accessibility to training programs

• Limit, segregate or classify an employee on the basis of genetic information

• Request or require genetic information

• What does GINA not do? – GINA does not regulate:

• Life Insurers • Disability Insurers • Long-Term Care Insurers

– GINA does not protect: • Patients manifesting a

condition: – If they are experiencing symptoms – Being treated for a condition – Or, if a condition has been

diagnosed

• Members of the US military • Veterans obtaining insurance

through VA • Indian Health Service

Heath Insurance Portability and Accountability Act (HIPAA)

• What does HIPAA do? – Helps those with a preexisting condition get health coverage

• Group Health Insurers can only use preexisting conditions to deny health coverage for up to 6 months

• If patients did not receive medical advice, diagnosis, care, or treatment within the past 6 months, then the Health Insurer can not use that condition for exclusion

– Helps to prevent a preexisting condition from being excluded from health coverage • Group Health Insurers can only exclude a preexisting condition from health coverage plan for

up to 12 months • A preexisting condition exclusion relates only to benefits for a patient’s preexisting condition;

patients will receive coverage for the plan’s other benefits during that time – Protects applying a preexisting condition exclusion to pregnancy, genetic information,

and certain children – Prevents Health Insurer from charging more than similarly situated individuals based

on any health factors

• What does HIPAA not do? – Does not require that employers offer health coverage – Does not guarantee that ANY condition patients have or have had are covered – Does not prohibit an employer from imposing a preexisting condition exclusion period

if treatment for a condition has occurred during the past 6 months – No protections for Life, Disability, or Long-Term Care Insurances

Genetic Testing

• Other issues:

– Should we test a child? – Impact on the family system

– Research based testing

– Cost!

CMT subtype Gene HNPP PMP22 (deletion)

CMT1A PMP22 (duplication)

CMT1B MPZ

CMT1C LITAF/SIMPLE

CMT1D EGR2

CMT1E PMP22 (point mutation)

CMT1X GJB1 (Cx32)

CMT2A MFN2

CMT2B RAB7

CMT2D GARS

CMT2E NFL

CMT2F HSP27/HSPB1

CMT2L HSPB8

CMT4A GDAP1

CMT4B1 MTMR2

CMT4B2 SBF2

CMT4C SH3TC2

CMT4D NDRG1

CMT4E EGR2

CMT4F PRX

CMT4J FIG4

dHMN V GARS and BSCL2

HSN SPTLC1

Subtypes of CMT

CMT subtype Gene HNPP PMP22 (deletion)

CMT1A PMP22 (duplication)

CMT1B MPZ

CMT1C LITAF/SIMPLE

CMT1D EGR2

CMT1E PMP22 (point mutation)

CMT1X GJB1 (Cx32)

CMT2A MFN2

CMT2B RAB7

CMT2D GARS

CMT2E NFL

CMT2F HSP27/HSPB1

CMT2L HSPB8

CMT4A GDAP1

CMT4B1 MTMR2

CMT4B2 SBF2

CMT4C SH3TC2

CMT4D NDRG1

CMT4E EGR2

CMT4F PRX

CMT4J FIG4

dHMN V GARS and BSCL2

HSN SPTLC1

Subtypes of CMT

Total Cost for Complete CMT Panel:

$21,000

COST EFFECTIVE TESTING

• Use the phenotype to focus testing • Not every affected patient in the family needs

genetic testing • Patient Protection Program (20% cost) • Moderate reduction in costs for MDA

• ONE SIMPLE APPROACH:

– USE NCV (38 m/s) AND FREQUENCIES OF SUBTYPES

Phenotypic Approach • CLASSICAL

– Early milestones normal – Mild symptoms 1st 2 decades – Slowly progressive

• EARLY ONSET (DEJERINE-SOTTASl CONGENITAL HYPOMYELINATION) – Early milestones delayed – Severe phenotype before age 20

• ADULT ONSET (OFTEN>40 YRS OF AGE)

• PURE SENSORY • PURE MOTOR

Nerve Conductions in Arms

• Slow: 15-35 m/s • Very slow: <15 m/s • Intermediate NCV: 35-45 m/s • Normal: > 45m/s

• SNAPS often unobtainable in uppers • CMAPS and SNAPS often absent in lowers

Nerve Conductions in Arms

• Slow: 15-35 m/s • Very slow: <15 m/s • Intermediate NCV: 35-45 m/s • Normal: > 45m/s

• SNAPS often unobtainable in uppers • CMAPS and SNAPS often absent in lowers

>90% positive diagnoses in one of four genes

• PMP22, GJB1, MPZ, MFN2

• Saporta et al. 2011; Ann Neurol • Murphy et al. 2012; JNNP • Latour et al. 2006; JPNS

PMP22 functions • Structural protein of

peripheral myelin • Unknown function

Peripheral Myelin Protein 22 (PMP22)

From: Nelis et al. 1999

Duplication of PMP22 F CMT1A (overexpression of the protein)

50 % of all CMT

Deletion of PMP22 F HNPP (underexpression of the protein)

Initial Problems

• Normal onset of walking – rarely on toes

• Other milestones normal

• Clumsy as child

• Tripped often, sprained ankles frequently

• Riding bike/ice skating difficult

• Trouble finding shoes that fit

Sensory Abnormalities

• Loss of feeling – Can distinguish hot/cold

– Can feel sharp objects

• Abnormal sensations in minority – Burning, tingling, numbness, neuropathic pain

• Proprioceptive problems in most

CMT1A NCV

• Symmetrically slow • 20-25 /sec • Rarely > 30 m/sec • Peroneal/sural NR

> 100 Different Mutations In all domains of the protein Genotype Phenotype Correlations ? Role of Adhesion ? 29 AA signal peptide

MPZ mutations cause Charcot Marie Tooth Disease type 1B (CMT1B)

Patient CS

• 54 year old female • Delayed motor milestones, failure to thrive as an

infant • First walked after age 3 • Requires walker or wheelchair • Gly94Cys mutation in MPZ • NCV < 15 ms

Cx32 Mutations at WSU

• X-linked dominant • No male to male

transmission • Marked distal leg

and hand wasting • Intermediately slow

NCV • Motor often

>>Sensory

CMTX1

MFN2

• Mitochondrial outer membrane protein • Function: mitochondrial fusion • MFN2 mutations à impaired

mitochondrial fusion à mitochondrial dysfunction and mislocalization à cellular function defect à Autosomal dominant axonal Charcot-Marie-Tooth type 2A (CMT2A)

Initial Problems

• Walked at about a year but “slid” his toes

• AFOs by 2 years of age

• Decreased hand strength

– Fist grasp rather than pincer grip

Nerve Conductions Nerve Tested

MNCV CMAP SNAP DML

Ulnar (L) 44 m/s 1.1 mV 4.0 ms

SNCV

Ulnar (L) 40 m/s 10.3 mV

CMT4A

GDAP1

Defects in mitochondrial dynamics à several neurodegenerative diseases

AD optic atrophy (ADOA)

CMT2A

Mitophagy: Parkinson disease

GDAP1 à CMT4A/ CMT2K

AR HINTS • Polymorphisms are frequent, and compound

heterozygous mutations can be disease causing. Often multiple family members must be screened to ensure mutations are disease causing.

• Identifying demyelination by NCV can be difficult. RECORD FROM PROX MUSCLES

• Severe early scoliosis in CMT4C (SH3TC2) • Focally misfolded myelin in CMT4B1. CMT4B2 • CMT4F (periaxin) predominant sensory & dysmyelination • CMT4D (NDRG1) mainly Balkan gypsy lineage • LMNA and GDAP1 only known axonal CMT4

A 25-year-old man CC: Scoliosis, foot deformity and slowly progressive distal

muscle weakness o During childhood

• Early milestone was on time, hand tremor • Delayed walking 18 months of age, not toe walker • Slowest runner and difficulty with balance • Scoliosis and pes cavus with bracing

o During teenager • Scoliosis: rapidly progressive, rod placement at 20 years

old • Tendon transfer, osteotomy and corrected hammer toes

at 16 years old

Left ulnar motor responses

Motor and sensory nerve conduction velocities (NCV) were uniformly slowed 14-19 m/s

OPA = stop codon Nonsense mutation

Truncate protein