Inherited Neuropathies

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P0 12/30/2012 CMT & HMSN: Demyelinating CMT & HMSN: Axonal CMT + Intermediate NCV Inherited Neuropathies Victoria Lawson, MD The Ohio State University Medical Center Columbus, Ohio October 15, 2008

. CMT 1A: PMP-22; 17p11 CMT 1B: P0 protein; 1q22 CMT 1C: LITAF; 16p13 CMT 1D: EGR2; 10q21 CMT 1E: P0 protein; 1q22 CMT 1F: Neurofilament light chain; 8p21 HNPP: PMP-22 deletion; 17p11 HMSN 3

8q21 CMT 4B: MTMR2; 11q23 CMT 4B2: SBF2; 11p15 CMT 4C: SH3TC2 (KIAA1985); 5q32 CMT 4D (Lom): NDRG1; 8q24 CMT 4E: EGR2; 10q21 CMT 4F: Periaxin; 19q13 HMSN-Russe (4G): 10q23 CMT 4H: FGD4; 12q12 CMT 4J:

1 P0 12/30/2012 CMT & HMSN: Demyelinating CMT & HMSN: Axonal CMT + Intermediate NCV Inherited Neuropathies Victoria Lawson, MD The Ohio State University Medical Center Columbus, Ohio October 15, 2008 Just remember these simple facts.. CMT 1A: PMP-22; 17p11 CMT 1B: P0 protein; 1q22 CMT 1C: LITAF; 16p13 CMT 1D: EGR2; 10q21 CMT 1E: P0 protein; 1q22 CMT 1F: Neurofilament light chain; 8p21 HNPP: PMP-22 deletion; 17p11 HMSN 3 (Dejerine-Sottas) PMP-22; P0; 8q23; EGR2 Thermosensitive PNS & CNS hypomyelination: SOX10; 22q13 Sensory PN + Hearing loss: Connexin-31; 1p35 Hypomyelin, No symptoms: ARHGEF10; 8p23 CMT 4A: GDAP1; 8q21 CMT 4B: MTMR2; 11q23 CMT 4B2: SBF2; 11p15 CMT 4C: SH3TC2 (KIAA1985); 5q32 CMT 4D (Lom): NDRG1; 8q24 CMT 4E: EGR2; 10q21 CMT 4F: Periaxin; 19q13 HMSN-Russe (4G): 10q23 CMT 4H: FGD4; 12q12 CMT 4J: FIG4; 6q21 HMSN 3 (Dejerine-Sottas) P0; PMP-22; EGR2; Periaxin HMSN + Juvenile glaucoma Cataracts (CCFDN): CTDP1; 18qter Cockayne's: 5 Congenital hypomyelinating P0, PMP-22 & EGR-2 Farber's lipogranulomatosis: Ceramidase; 8p22 Glycosylation deficient, Ia: PMM2; 16p13 Krabbe: GALC; 14q31 MLD: ARSA; 22q13 PMP-22 point mutations Refsum's disease Childhood: PHYH; 10pter-p11.2 Adolescent-Adult: PEX7; 6q22 Infant: PEX1; 7q21 HMSN + CNS: Heterogeneous X-linked Connexin-32 (GJB1): Xq13 Pyramidal signs CMT 2A1: KIF1B; 1p36 CMT 2A2: MFN2; 1p36 CMT 2B: RAB7; 3q13-q22 CMT 2C: 12q23-q24 CMT 2D: GARS; 7p15 CMT 2E: Neurofilament light chain; 8p21 CMT 2F: HSPB1; 7q11-q21 CMT 2G: 12q12 CMT 2I: P0; 1q22 CMT 2J: P0; 1q22 CMT 2K: GDAP1; 8q21 CMT 2L: HSPB8; 12q24 HMSN-Proximal: 3q13 CMT 2: DNM2; 19p12 HMSN 5: Pyramidal signs HMSN + Optic atrophy HMSN + Deafness Connexin-31 (GJB3) Eye ± Ear dysfunction HMSN 6 (+ Visual loss): MFN2; 1p36 HSMN + Ulcero-mutilation HSAN I HSMN + Ataxia: 7q22 HMN 5B: BSCL2; 11q13 AR-CMT2A: Lamin A/C; 1q21 AR-CMT2B: 19q13.3 AR-CMT + Pyramidal signs (CMT 2H): 8q21.3 AR-CMT + Hoarseness (CMT 2K): GDAP1; 8q21 Acrodystrophy Andermann (Corpus callosum Δ): KCC3; 15q13 Ataxia with neuropathy: TDP1; 14q31 Giant axonal: Gigaxonin; 16q24 HMSN + Optic neuropathy ± Deafness Infantile axonal + Respiratory failure Lethal Neonatal Neuroaxonal dystrophy Ouvrier: onset Syndromes Childhood onset HMSN CNS + HMSN Deafness + HMSN X-linked Connexin-32 (Females): Xq13 2: Xp22.2 3: Xq26 4 (Cowchock): Xq24 5: PRPS1; Xq22 Sensory PN + Deafness: Xq23 CMT DIA: 10q24 CMT DIB: DNM2; 19p12 CMT DIC: tyrosyl-trna synthetase; 1p34 CMT DI3: P0; 1q22 CMT-X (Semi-dominant) CMT 2E: Neurofilament light chain; 8p21 CMT RIA: GDAP1; 8q21.1 Charcot-Marie-Tooth (CMT) Features: Comparative; General External link: Mutation database Other related names or disorders α-methylacyl-coa racemase (AMACR) Brachial plexopathy, Hereditary Childhood onset neuropathies CNS & Cranial nerve disorders Complex clinical syndromes Congenital Hypomyelinating EGR2: 10q21 P0: 1q22 PMP-22: 17p11 ARHGEF10; 8p23 Cowchock Dejerine-Sottas (HMSN 3) Focally folded myelin sheaths CMT 4B: MTMR2; 11q23 CMT 4B2: SBF2; 11p15 CMT 4E: EGR2; 10q21 CMT 4F: Periaxin; 19q13 P0: 1q22 Juvenile glaucoma Hereditary Distal motor neuropathies Sensory neuropathies Liability to pressure palsies Metabolic abnormalities Minifascicles & Gonadal dysgenesis HMSN HSN: DHH; 12q12 Myelin disorders; Myelin proteins Vertical talus: HOXD10; 2q31; Hereditary Neuropathies Symptoms Charcot-Marie-Tooth/HSAN/Others Common Genetic neuropathies constitute up to ½ of previously undiagnosed PN 3/10,000 CMT alone CMT largest group and consists of a number of different genetic entities Frequent tripping, falling Recurrent ankle injuries Slow running; difficulty with jumping Difficulty finding shoes that fit Gait disturbance ( walk like a duck ) FLF (funny-looking feet) As a child, leg cramps (especially nocturnal) Accelerated fatigue with walking even short distances Athletic divergence 1

Asymmetry Peroneal muscle atrophy Distal

2 High (pes cavus) or flat (pes planus) arches Hammertoes Champagne bottle legs Asymmetry Peroneal muscle atrophy Distal predominant Sensory loss without pain as prominent feature Distal weakness; if severe, steppage gait or drop foot Foot deformities Feet may be flat Decreased EDB bulk Thin ankles Ankle a- or hypo-reflexia; sometimes hyporeflexia more proximally Enlarged, palpable nerves in demyelinating forms Variable degress of interosseous wasting Increased angle of distal leg to dorsal foot Varus deformity Is it hereditary? Never know until you have a positive genetic test, or.. Family history! AD: ~1/2, both and AR: in sibs but not parents XL: no to transmission Beware of variable expression/age-dependent penetrance 2

and symptoms NCS abnormalities > clinical signs Foot and ankle deformities Suspect hereditary; now what?

3 Sporadic, recessive, insufficient family history? Other clues to genetic etiology Evidence of chronicity clumsiness, longstanding difficulty with specific physical activities, Signs > symptoms No pain or non-neuropathic pain Motor predominant signs and symptoms NCS abnormalities > clinical signs Foot and ankle deformities Suspect hereditary; now what? Mode of inheritance AD (CMT1, 2, DI) AR (CMT4) X (CMTX) Electrophysiology Axonal: Median MNCV >32 m/s Demyelinating: Median MNCV <32 m/s intermediate: m/s CMTX: 25-40m/s Genetic subtyping Letter designations correspond genes, OR chromosomal loci, OR distinctive phenotype Inheritance patterns Suspect hereditary; now what? Mode of inheritance AD (CMT1, 2, DI) AR (CMT4) X (CMTX) Autosomal dominant Each child will have ½ chance of being affected CMT1 or CMT2 Autosomal recessive Each child will have 1/4 chance of being affected CMT4 X-linked Each boy will have 1/2 chance of being affected; Each girl will have ½ chance of being a carrier Fathers cannot pass it along to sons Electrophysiology Demyelinating Uniform NCV slowing (Med MNCV< 38m/s) no conduction block or abnormal temporal dispersion Preservation of F-responses Axonal CMAP/SNAP: reduced amplitude mildly reduced or normal NCV (Med MNCV> 38 m/s) intermediate Intermediate NCV (25 to 50 m/s) CMAP/SNAPs: or Absent CMTX Moderate slowing (most severe 22 to 25m/s) Genetic subtyping Letter designations correspond genes, OR chromosomal loci, OR distinctive phenotype. CMTX 3

Uniform NCS slowing Pathology and Electrophysiology Median

Demyelinating CMT1 NCV slow Axonal CMT2 NCV near normal

AR (CMT4) X (CMTX) Electrophysiology Axonal: Median MNCV

25-50 m/s CMTX: 25-40m/s Genetic subtyping Letter

distinctive phenotype 70% 20% 10% CMT1:CMT2 = 2:1 CSF

4 Uniform NCS slowing Pathology and Electrophysiology Median nerve conduction study in CMT1A Normal nerve NCV normal Demyelinating CMT1 NCV slow Axonal CMT2 NCV near normal Median nerve conduction study in normal nerve Suspect hereditary; now what? Genetic Heterogeneity Mode of inheritance AD (CMT1, 2, DI) AR (CMT4) X (CMTX) Electrophysiology Axonal: Median MNCV >32 m/s Demyelinating: Median MNCV <32 m/s intermediate: m/s CMTX: 25-40m/s Genetic subtyping Letter designations correspond to genes, OR chromosomal loci, OR distinctive phenotype 70% 20% 10% CMT1:CMT2 = 2:1 CSF protein may be elevated! Foot deformities tend to be more classic NCS should not show significant progression with time 4

= peripheral myelin protein 2-5% PNS myelin protein 85% CMT1A patients have duplication of Some CMT1A patients have point mutations CMT is due to toxic gain of function CMT1A 2 copies 3 copies 1 copy

<38m/s Siblings within a family showed good concordance of NCVs Therefore, demyelinating and axonal phenotypes are closely related to the position and nature of MPZ mutation (Hattori et al, 03; Bird

5 = peripheral myelin protein 2-5% PNS myelin protein 85% CMT1A patients have duplication of Some CMT1A patients have point mutations CMT is due to toxic gain of function CMT1A 2 copies 3 copies 1 copy duplication deletion 4 copies CMT1B Position of MPZ mutations determines electrophysiologic characteristics Hattori and colleagues demonstrated a bimodal distribution of median MCVs; >38 m/s or <38m/s Siblings within a family showed good concordance of NCVs Therefore, demyelinating and axonal phenotypes are closely related to the position and nature of MPZ mutation (Hattori et al, 03; Bird et al, 97; Shy et al, 04) Chr 17 Normal CMT1A Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) Severe CMT1 (CMT3; DSS; CHN) HNPP: Hereditary Neuropathy with Liability to Pressure Palsies Onset, young adults Classic history is of episodic nerve paresis with minor trauma/compression (40%), exercise, stretching, on awakening, etc Associated with a mild axonal PN Differential includes Recurrent neuralgic amyotrophy Multiple lesions at common entrapment sites Patchy axonal neuropathy PMP-22 point mutation Pathologic hallmark: tomaculi CMT2 HMSN 6 Autosomal dominant Intermediate Autosomal recessive X linked Mode of Form Gene inheritance Specific phenotypic features Locus CMT2A1 KIF1Bβ AD axonal 1p36 CMT2A2 MFN2 AD Variable expressivity; optic atrophy 1p36.2 CMT2B RAB7 AD HSN-like 3q13 CMT2B1 LMNA AR axonal; proximal weakness 1q21 CMT2C? AD VC paralysis; respiratory distress 12q23 CMT2D GARS AD dsma-like; hand weakness 7p15 CMT2E NEFL AD axonal/demyelinating; hyperkeratosis 8p21 CMT2F HSPB1 AD trophic alterations of hand and feet 7q11 CMT2G? AD 12q12 CMT2H GDAP1 AR HSP-like 8q13 CMT2I MPZ AD axonal/demyelinating/di 1q21 CMT2J MPZ AD pupillary abnormalities 1q21 CMT2K GDAP1 AR no spasticity; hoarseness 8q13 CMT2L HSPB8 AD HMN-like 12q24 DICMTA AD Median MNCV 25-45m/s 10q24? DICMTB DNM2 AD Median MNCV 24-54m/s 19p12 DICMTC YARS AD 1p35 Median MNCV >33m/s DICMTD MPZ AD CMT4A GDAP1 AR demyelinating, severe 8q13 CMT4B1 MTMR2 AR focally folded myelin 11q22 CMT4B2 SBF2 AR glaucoma 11p15 CMT4C SH3TC2 AR demyelinating, severe CMT4D NDRG1 (LOM) AR deafness 8q24 CMT4E/ CHN MPZ or EGR2 AR 1q21; 10q21 CMT4F Periaxin AR demyelinating, severe 19q13 CMT4G? AR demyelinating, severe 10q23 CMT4H FDG4 AR demyelinating, severe 12p11 CMT4J FIG4 AR demyelinating, severe 6q21 CMTX GJB1 XD axonal in women Xq13 5

The fog is only slowly lifting Pareyson, D.; Neurol 2007: 68; 1649.

Rules: Buyer Beware! Hard to ever exclude MPZ!

predominant: RAB7, GARS (HSPB8) Axonal + hoarseness: 2C, GDAP1 Axonal + motor predominant: GARS, HSPB1,8 Axonal + optic atrophy: MFN2 Axonal + spasticity: GDAP1 Hereditary Sensory Autonomic

6 The fog is only slowly lifting Pareyson, D.; Neurol 2007: 68; AD HSPB1 LITAF EGR2 MPZ NEFL GJB1 MFN2 CMTX HSPB8 GARS HSN RAB7 GDAP1 Demyelinating Axonal MFN2 HSMN6 MPZ YARS DICMT DNM1 SBF2 NDRG1 MTMR2 PRX AR SH3TC2 GDAP1 LMNA dhmn HSPB1 GARS HSPB8 General Rules: Buyer Beware! Hard to ever exclude MPZ! Demyelinating + family history:, MPZ Demyelinating + little family history: CMT4, CMTX (GJB1) Mixed NCS: CMTX (GJB1), YARS, DNM2, MPZ Axonal +family history: MFN2, MPZ (NEFL) Axonal + sensory predominant: RAB7, GARS (HSPB8) Axonal + hoarseness: 2C, GDAP1 Axonal + motor predominant: GARS, HSPB1,8 Axonal + optic atrophy: MFN2 Axonal + spasticity: GDAP1 Hereditary Sensory Autonomic Neuropathies Sensory/autonomic disturbance out of proportion to motor Includes congenital insensitivity to pain Acral mutilations, foot ulcers, lost digits Autonomic features: Impaired or labile sweating (FUO or episodic fever) Labile BP, temperature, OH Impotence Hereditary Sensory & Autonomic Neuropathy Syndromes HSN Disorder Gene Chromosome Inheritance Onset Age I SPTLC1 9q22 > 20 years II WNK1/HSN2 12p13 Congenital, or Clinical features Pan-sensory loss Acromutilati on Sensory loss Acromutilati on III IKBKAP 9q31 Congenital Riley-Day Syndrome IV V TRKA/ NGF receptor 1q21 Absent pain NGF- 1p13 Inability to experience pain Congenital, or Congenital, or to Adult SCN 9A 2q24 Congenital Erythromelalgia SCN 9A 2q24 Childhood Biemond ataxia 19 to 30 years Sensory neuropathy Anhidrosis Absence of pain No anhidrosis Absence of pain No anhidrosis Absence of pain No anhidrosis Pain, distal Episodic Sensory loss Axon loss > Large Large & Large & C-axon Aδaxons Aδ- & C-axons None None Large axons Milder autonomic manifestations Severe autonomic manifestations HSAN1 Ataxic most common; only dominant After form 4th Sensory loss Large neuropathy decade Ataxia axons Normal or mildly abnormal NCS in 1, 5 to (NGF-associated) 30 Acromutilati Large & Ulcero-mutilation years on Most Spastic result in insensitivity to pain, while 1 to HSAN5 5 Acromutilati patients Large & are indifferent to pain 5p15 paraparesis years on Despite this, lancinating pains are prominent feature HSAN5 has normal NCS, QST, SSR 6

Other Hereditary Neuropathies Lysosomal storage disorders accumulation of lysosomal products (sphingolipids, mucolipids, etc) in neurons CNS>PNS Metachromatic Leukodystrophy, Krabbe Disease, Fabry

7 Other Hereditary Neuropathies Lysosomal storage disorders accumulation of lysosomal products (sphingolipids, mucolipids, etc) in neurons CNS>PNS Metachromatic Leukodystrophy, Krabbe Disease, Fabry Disease Peroxisomal disorders Peroxisomes have enzymes involved in FA oxidation, bile/cholesterol synthesis, aa metabolism ADL/AMN, RD (HMSN IV), Tangiers, CTX Hereditary ataxias FA, vitamin E deficiency, abetalipoproteinemia Defective DNA repair Ataxia-telangiectasia, Cockayne syndrome Other GAN, Infantile Neuroaxonal Dystrophy, Porphyria, Erythromelalgia Summary of important features Associated Inheritance Onset NCS Gene Lab features Lysosomal storage i. late infantile ii. Juvenile arylsulfatase A Metachromatic LD AR iii. adult Demyelinating Arylsulfatase A activity (urine) Dementia i. late infantile β-galactosidase Krabbe Disease AR ii. adult Mixed β-galactosidase activity (blood) Dementia Skin i. β-galactosidase angiokeratomas, Fabry Disease XL ii. early adult Axonal α-galactosidase activity (blood) early CVAs Peroxisomal disorders Peroxisomal transmembrane adenosine triphosphate-binding VLCFA (urine), cassette transporter gene (ABC + adrenal Dementia; may ALD/AMN XL early adult Axonal/ Normal transporter gene) insufficiency look like MS i. late infantile Phytanoyl-CoA α-hydroxylase Phytanic acids Ichthyosis, Refsum Disease AR ii. adult Demyelinating (PAHX) (serum) Anosmia Demyelinating/ ABC1 transporter (same fam as Tangier Disease AR Normal AMN) HDLs Orange tonsils Cerebrotendinous Tendon Xanthomatosis AR early adult Axonal/ Normal Sterol 27 hydroxylase cholestanol xanthomas Hereditary ataxias Gait ataxia; Friedreich ataxia AR Axonal Frataxin (trinuc repeat) dysarthria Vitamin E deficiency AR Sensory axonal αtocopherol transfer protein gene vit E ataxia Ataxia, RP, abetaliprotein steatorrhea, levels; distal extremity Abetalipoproteinemia AR Sensory axonal acanthocytosis sensory loss Disorders DNA repair oculocutaneous telangiectasias; frequent ATM gene (phosphatidyl inositol sinopulmonary Ataxia-telangiectasia AR Sensory axonal 3) αfetoprotein infections RNA polymerase II transcription Cockayne syndrome AR Demyelinating factors Progeria Misc ataxia; kinky Giant Axonal Neuropathy AR Axonal Gigaxonin hair intense Erythromelalgia AD any age Nav1.7 gene burning/warmth More general clues PN + Dementia: MLD, KD, ALD/AMN (GAN) PN + ataxia: FA, vitamin E, abetalipoproteinemia, GAN PN + angiokeratomas : Fabry PN + orange tonsils : Tangier Thanks for your attention! PN + tendon xanthomas PN + ichthyosis: Refsum : CTX Questions? 7

Table of Contents. 1 Architecture of the peripheral nerve P. Young, M. Boentert

Table of Contents. 1 Architecture of the peripheral nerve P. Young, M. Boentert Table of Contents z General part 1 Architecture of the peripheral nerve... 3 P. Young, M. Boentert Introduction... 3 1.1 Cellular components of the PNS... 3 1.2 Architecture of the myelin compartment..