LIFE AT THE PERIPHERY

Institue

Mary M Reilly

Hereditary Neuropathies

Alexander Rossor

Honorary consultant neurologist

MRC centre for Neuromuscular Diseases,

Institute of Neurology,

Queen Square, London, UK.

Contents of talk

1. Nomenclature of the hereditary neuropathies

2. Overview of the common subtypes

3. Illustrative clinical cases • Distinguishing inflammatory from genetic

demyelinating neuropathies • Determining pathogenicity of novel variants

Clinical presentation

• Length dependent weakness or sensory loss / paraesthesia

– Foot drop and hand weakness

• Slow progression

• Onset varies from childhood to late adulthood

• Often but not always a family history

– De novo mutations

– Non paternity

– Late onset

Neurophysiology

• Is there a neuropathy

– Sometimes only detected on EMG

• Is there involvement of motor and sensory nerve fibres

– Hereditary motor AND sensory neuropathy (CMT) vs HMN or HSN

• Is the neuropathy demyelinating or axonal?

Diagnostic algorithm Hereditary weakness or numbness

Motor predominant

Sensory predominant

Axonal Demyelinating

Neurophysiology

Mixed motor and sensory

HSN HMN CMT2 CMT1

Intermediate CMT (25-45 m/s) : commonest cause CMTX1 (GJB1)

CMT

CMT1 CMT2 X-linked Intermediate

CMT CMT

AD AR AD AR DI others (17p)

PMP22 GDAP1 MFN2 GDAP1 GJB1 DNM2 GJB1

MPZ MTMR2 KIFIBß LMNA PRPS1 YARS NEFL

LITAF MTMR13 RAB7 MED25 KARS MPZ

EGR2 SH3TC2 GARS NEFL GDAP1

NEFL NDRG1 NEFL MFN2

EGR2 HSPB1 HSPB1

PRX HSPB8 LRSAM1

CTDP1 MPZ HINT1

PMP22 GDAP1

MPZ TRPV4

FGD4 AARS

FIG4 LRSAM1

HK1

*Mitochondrial – Mt ATPase 6

CMT in most patients is due to a handful of genetic

mutations.

>80% autosomal dominant CMT1 is due to the 17 duplication

CMT 1

CMT1A = Chromosome 17p duplication

CMT1A Sensory µV m/s

Radial Absent

Median Absent

Ulnar Absent

Sural Absent

Superf. Peroneal

Absent

Motor Right Left Right Left

Median Common peroneal

DML 7.8 ms DML 10.8 ms 10.3 ms

CV (wrist-elbow)

22 m/s CV (fib neck - ankle)

20 m/s 20 m /s

CMAP (wrist) 4.4 mV CMAP (ankle) 2.1 mV 2.6 mV

Peripheral myelin protein 22 : PMP22

Hereditary Neuropathy With Liability to Pressure Palsies (HNPP)

• Autosomal dominant

• Chromosome 17p deletion (rarely PMP22 point mutations)

• Recurrent pressure palsies.

• Characteristic neurophysiology

• Care with alcohol and anaesthetics

• Avoid surgery for CTS unless refractory pain or progressive weakness

HNPP

Sensory µV m/s Motor Right Left

Radial 11 45 Common peroneal

Median 4 45 DML 3.0

Ulnar 3 51 CV (pop. Fossa – fib. Neck)

30 m/s

Sural 2 43 CMAP (fib. Neck) 4.7 mV

Superf. Peroneal 3 40 CMAP (pop. Fossa) 4.7 mV

Motor Right Left Right Left

Median Ulnar

DML 5.3 ms 4.5 ms DML 2.8 ms 2.6 ms

CV (wrist-elbow) 51 m/s 49 m/s CV (wrist-below elbow)

65 m/s 62 m/s

CMAP (wrist) 0.7 mV 1.8 mV CV (around elbow) 26 m/s 25 m/s

CMAP (wrist) 4.6 mV 8.7 mV

1. 17p duplication 2.PMP22 3. GJB1 4. MPZ 5. MFN2 (axonal)

6. SH3TC2 (recessive demyelinating)

CMT X

Clinically similar to CMT1 No male to male transmission Males more severe than females Males demyelinating / females axonal Patchy clinically (may mimic CIDP on NCS) Sometimes, upper limb predominant Central nervous system

CMTX Sensory µV m/s Motor Right Left

Radial Absent Common peroneal

Median Absent DML (EDB) 5.9 ms

Ulnar Absent CMAP (ankle) 0.1 mV

Sural Absent CMAP (pop. Fossa)

0.1 mV

Superf. Peroneal Absent

Motor Right Left Motor Right Left

Median Ulnar

DML 6.8 ms 6.4 ms DML 5.3 ms 5.4ms

CV (wrist-elbow)

24 m/s - CV (wrist-below elbow)

30 m/s 32 m/s

CMAP (wrist) 0.6 mV 0.1 mV CV (around elbow)

31 m/s 35 m/s

CMAP (elbow) 0.3 mV No response CMAP (wrist) 6.3 mV 2.2 mV

Split hand in CMTX1

Weakness and wasting of APB > ADM or FDIO

Non-coding mutations in GJB1 account for 10% of cases of CMTX Promoter region not covered in older panels or GJB1 sequencing (2012)

For CMT2, HSN and HMN, most genes are unknown

CMT2A (MFN2)

• Mutations in MFN2 are the commonest cause of axonal CMT (10-20%)

• Majority autosomal dominant

• Can be recessive

• Associated with optic atrophy in a minority

• Traditionally severe

• Young onset

• Wheelchair by 20

Copy number variations (deletions / duplications) will not be detected on most ‘hereditary neuropathy’ panels

MLPA

Ex 7 Ex 8

Deletion of MFN2 exons 7 and 8

Hereditary motor neuropathies

• 5q Spinal Muscular Atrophy (SMA) • Most common form

• Due to autosomal recessive mutations in SMN1

• Non 5q SMA (rarer)

• SMALED (DYNC1H1 and BICD2)

• Distal HMN (also called distal SMA)

• Lower limbs (HSPB1 and BSCL2)

• Upper Limbs (GARS and BSCL2)

Proximal > distal weakness (Non length dependent)

Distal > proximal weakness (Length dependent)

Non-5q SMA Spinal Muscular Atrophy Lower Extremity Dominant

(SMALED)

p.R399G in DYNC1H1 p.R501P BICD2

Distal hereditary motor neuropathy

• No agreed classification

• Dominant, recessive or X-linked

• Originally referred to as distal spinal muscular atrophy

• Selective motor nerve involvement thought to localise pathology to the motor neuron cell bodies in the spinal cord

• Now thought to be a ‘dying back’ axonopathy

Phenotypic clues in dHMN

• Lower limb onset dHMN (dHMN II or HMN II)

• Dominant mutations in the small heat shock protein (HSPB1)

• Molecular chaperone that prevents protein misfolding

• Predominant calf wasting

• Dominant mutations in BSCL2

• Spasticity

• Upper limb onset dHMN (dHMN V or HMN 5)

• Dominant mutations in GARS and BSCL2

Hereditary sensory neuropathy

• Commonly due to dominant mutations in serine palmitoyl transferase 1 (SPTLC1)

• Early pain and temperature loss

• NO autonomic involvement

• Motor involvement

• Motor conduction velocity slowing in males

HSN

Palmitoyl-CoA

NH2

OOH

C

H2

OH

Serine

Sphinganine (SA)

OHOH

NH2

CH3

Deoxy-Sphinganine (DoxSA) NH2

OOH

CH3

Alanine OH

NH2

CH3

CH3

Deoxy-methyl-Sphinganine (DoxmethSA) NH

2

CH2

OOH

Glycine OH

NH2

CH3

SPT

• Sphingolipids are a class of lipids important in signal transmission and cell recognition

• Mutations in the SPTLC1 subunit of SPT (Serine palmitoyltransferase) promote the substituion of serine by alanine or glycine and the production of toxic sphingolipids

•April 27, 2017

• Platform Session

• Peripheral Nerve Disorders

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DELAYED-START TRIAL TO EVALUATE THE SAFETY AND EFFICACY OF L-SERINE IN SUBJECTS WITH HEREDITARY SENSORY AND AUTONOMIC NEUROPATHY TYPE 1 (HSAN1) (S45.001) Neurology April 18, 2017 vol. 88 no. 16 Supplement S45.001

• Eighteen HSAN1 patients were equally randomized to L-serine or placebo for 1 year.

• Participants randomized to L-serine experienced a significant decline in the CMTNS over 1 year relative to placebo (−1.8 units, 95% CI −3.3 to −0.3, p = 0.02)

• 1-deoxySL levels declined significantly among subjects on L-serine vs. those on placebo

Illustrative clinical cases

Case 1.

• 52-year old right handed lady.

• Normal birth, walked at 10 months, able runner in the first decade.

• Aged 12 started to trip and was noted to be flat footed.

• Early 20s: Bilateral ankle osteotomies

• Late 20’s: Developed a waddling gait, prescribed ankle/foot orthoses.

• No family history

Neurophysiology aged 14

Case 1 • Early 30s: Started using a wheelchair.

– Unilateral vocal cord palsy

• Early 40s: No longer able to weight bear

– Re-investigated in the form of repeat neurophysiology, lumbar puncture (protein 0.7g) and a nerve biopsy.

– Neurophysiology:

• Median SAP of 5.9 , radial SAP of 7.1 • Temporal dispersion of the right median and ulnar nerves

– Sural nerve biopsy: “Severe axonal loss with some onion bulb formation. The onion bulb formation is irregular contrary to the usual appearances in CMT1…… and favours an acquired neuropathy.”

• Treated with steroids for one year with no improvement.

• Aged 45: Developed left sided trigeminal neuralgia – Commenced on non invasive ventilation

Case 1 • Aged 49:

– Stridor, but all other cranial nerves normal

– Proximal upper limb weakness (shoulder abduction grade 4).No movement of the intrinsic hand muscles.

– Grade 1 power at the hip and knee and grade 0 of ankle dorsi and plantar flexion.

– Areflexia

• Genetics: – 17p duplication, PMP22, MPZ, GJB1, LITAF, SH3TC2 all

negative

CMT1D due to mutation in EGR2

• c.1141C>T p.(Arg381Cys) heterozygous pathogenic mutation detected in EGR2

• Autosomal dominant and recessive mutations described

• May present as a severe early onset demyelinating neuropathy in the 1st/2nd decade

• Ophthalmoplegia, scoliosis, vocal cord palsy and deafness described.

Case 2

• 26-year old male

• Rapid development of a wasted left arm over a period of 2 years

• Previous diagnosis of a congenital hypomyelinating neuropathy (CMT1)

– walked late at 26 months of age

– wheelchair at 13 years of age

– Mild symmetric weakness and preserved function in both hands two years prior to presentation

• Healthy unrelated parents

Case 2

• No improvement in left arm function following a 5-day course of 500 mg methylprednisolone

• Nerve conduction studies performed at the age of 13 years, 19 years and at 26 years

• demyelinating neuropathy with dispersed proximal responses

• A fall in the conduction velocity in the right median nerve from 16 m/s to 4 m/s over 6 years

• Conduction block in the right median nerve.

• EMG: Fibrillations and PSW in left hand

- Frequent large thinly myelinated nerve fibres surrounded by concentric Schwann cell profiles (onion bulbs) - No inflammatory cell infiltrate

• Compound heterozygous mutations in FIG4

– I41T point mutation in exon 2

– 8-bp deletion in exon 8 (p.K278YfsX5)

Case report

Rapidly progressive asymmetrical weakness in Charcot–Marie–Tooth

disease type 4J resembles chronic inflammatory

demyelinating polyneuropathy

Ellen Cotteniea, M anoj P. M enezesa,b,⇑, Alexander M . Rossor a, Jasper M . M orrow a,Tarek A. Yousry c, David J. Dick d, Janice R. Anderson e, Zane Jaunmuktane f,Sebastian Brandner f,g, Julian C. Blakea,h, Henry Houlden a, M ary M . Reilly a

a M RC Centre for Neuromuscular Diseases, Department of M olecular Neurosciences, National Hospital for Neurology and Neurosurgery,

UCL Institute of Neurology, London, UKb Institute for Neuroscience and M uscle Research, Children’s Hospital at Westmead, Westmead, Australia

cLysholm Department of Neuroradiology, Division of Neuroradiology and Neurophysics, UCL Institute of Neurology, London, UKd Department of Neurology, Norfolk and Norwich University Hospital, Norwich, UK

eDepartment of Pathology, Addenbrooke’s Hospital, Cambridge, UKf Division of Neuropathology, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, UK

g Department of Neurodegenerative Disease, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, UKh Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, UK

Received 31 August 2012; received in revised form 25 November 2012; accepted 9 January 2013

Abstract

Charcot–Marie–Tooth disease type 4J (CM T4J), a rare form of demyelinating CM T, caused by recessive mutations in the

phosphoinositide phosphatase FIG4 gene, is characterised by progressive proximal and distal weakness and evidence of chronic

denervation in both proximal and distal muscles. We describe a patient with a previous diagnosis of CM T1 who presented with a

two year history of rapidly progressive weakness in a single limb, resembling an acquired inflammatory neuropathy. Nerve

conduction studies showed an asymmetrical demyelinating neuropathy with conduction block and temporal dispersion. FIG4

sequencing identified a compound heterozygous I41T/K 278YfsX5 genotype. CM T4J secondary to FIG4 mutations should be added

to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy,

especially if there is a background history of a more slowly progressive neuropathy.

Crown Copyright Ó 2013 Published by Elsevier B.V. All rights reserved.

Keywords: Charcot–Marie–Tooth disease; Chronic inflammatory demyelinating polyradiculoneuropathy; FIG4

1. Introduction

Charcot–Marie–Tooth disease (CM T) disease is a

clinically and genetically heterogeneous group of disorders

characterised by predominantly distal weakness, muscle

wasting and sensory loss. CM T is the commonest

inherited neuromuscular disorder affecting around 1 in

2500 individuals [1]. Based on upper limb motor

conduction velocities (M CV), CM T is divided into CM T1

(M CV < 38 m/s) and CM T2 (M CV > 38 m/s) [2]. I t is

usually straightforward to differentiate CM T1 from

chronic inflammatory demyelinating polyradiculopathy

(CIDP) which typically presents acutely, often with a

patchy non-homogeneous predominantly motor

neuropathy with associated demyelinating features on

0960-8966/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/j.nmd.2013.01.010

⇑ Corresponding author. Address: Institute for Neuroscience and

M uscle Research, Children’s Hospital at Westmead, Westmead, NSW

2145, Australia. Tel.: + 0061 2 98452652; fax: + 0061 2 98453905.

E-mail address: manoj.menezes@health.nsw.gov.au (M .P. M enezes).

www.elsevier.com/locate/nmd

Available online at www.sciencedirect.com

Neuromuscular Disorders 23 (2013) 399–403

Case report

Rapidly progressive asymmetrical weakness in Charcot–Marie–Tooth

disease type 4J resembles chronic inflammatory

demyelinating polyneuropathy

Ellen Cotteniea, Manoj P. Menezesa,b,⇑, Alexander M. Rossor a, Jasper M. Morrow a,Tarek A. Yousry c, David J. Dick d, Janice R. Anderson e, Zane Jaunmuktanef,Sebastian Brandner f,g, Julian C. Blakea,h, Henry Houlden a, Mary M. Reilly a

aMRC Centre for Neuromuscular Diseases, Department of Molecular Neurosciences, National Hospital for Neurology and Neurosurgery,

UCL Institute of Neurology, London, UKb Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Westmead, Australia

cLysholm Department of Neuroradiology, Division of Neuroradiology and Neurophysics, UCL Institute of Neurology, London, UKd Department of Neurology, Norfolk and Norwich University Hospital, Norwich, UK

eDepartment of Pathology, Addenbrooke’s Hospital, Cambridge, UKf Division of Neuropathology, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, UK

gDepartment of Neurodegenerative Disease, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London, UKh Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, UK

Received 31 August 2012; received in revised form 25 November 2012; accepted 9 January 2013

Abstract

Charcot–Marie–Tooth disease type 4J (CMT4J), a rare form of demyelinating CMT, caused by recessive mutations in the

phosphoinositide phosphatase FIG4 gene, is characterised by progressive proximal and distal weakness and evidence of chronic

denervation in both proximal and distal muscles. We describe a patient with a previous diagnosis of CMT1 who presented with a

two year history of rapidly progressive weakness in a single limb, resembling an acquired inflammatory neuropathy. Nerve

conduction studies showed an asymmetrical demyelinating neuropathy with conduction block and temporal dispersion. FIG4

sequencing identified a compound heterozygous I41T/K278YfsX5 genotype. CMT4J secondary to FIG4 mutations should be added

to the list of inherited neuropathies that need to be considered in suspected cases of inflammatory demyelinating neuropathy,

especially if there is a background history of a more slowly progressive neuropathy.

Crown Copyright Ó 2013 Published by Elsevier B.V. All rights reserved.

Keywords: Charcot–Marie–Tooth disease; Chronic inflammatory demyelinating polyradiculoneuropathy; FIG4

1. Introduction

Charcot–Marie–Tooth disease (CMT) disease is a

clinically and genetically heterogeneous group of disorders

characterised by predominantly distal weakness, muscle

wasting and sensory loss. CMT is the commonest

inherited neuromuscular disorder affecting around 1 in

2500 individuals [1]. Based on upper limb motor

conduction velocities (MCV), CMT is divided into CMT1

(MCV < 38 m/s) and CMT2 (MCV > 38 m/s) [2]. I t is

usually straightforward to differentiate CMT1 from

chronic inflammatory demyelinating polyradiculopathy

(CIDP) which typically presents acutely, often with a

patchy non-homogeneous predominantly motor

neuropathy with associated demyelinating features on

0960-8966/$ - see front matter Crown Copyright Ó 2013 Published by Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/j.nmd.2013.01.010

⇑ Corresponding author. Address: Institute for Neuroscience and

Muscle Research, Children’s Hospital at Westmead, Westmead, NSW

2145, Australia. Tel.: +0061 2 98452652; fax: +0061 2 98453905.

E-mail address: manoj.menezes@health.nsw.gov.au (M.P. Menezes).

www.elsevier.com/locate/nmd

Available online at www.sciencedirect.com

Neuromuscular Disorders 23 (2013) 399–403

Case 3

• 20 year old male

• Presented with delayed walking and poor balance in

the first decade of life.

• Slowly progressive course

• Distal amyotrophy predominantly involving the upper

limbs and lower limb spasticity (Silver syndrome).

• His past medical history is notable for congenital

cataracts, mild learning difficulties and left ventricular

impairment

Case 3

• Neurophysiology

– Normal sensory action potentials

– Small compound muscle action potentials of distal

muscles and neurogenic changes on EMG

– Consanguineous parents

– Affected sibling

Whole exome sequencing

• Filtering revealed 43 homozygous variants

present at a frequency of <1%

• Filtering of known CMT, dHMN, SMA, ALS, HSP

genes revealed 2 variants

• IKBKAP : MAF 0.5%, phenotype ≠ Riley-Day syndrome

(familial dysautonomia)

– RTN2, R191* : Novel, nonsense mutation in exon 4

– Heterozygous nonsense/missense mutations in RTN2

previously reported as a cause of HSP

c.1017C>A; R191fs

HSP type 12 postulated to be due to RTN2 halpo-insufficiency

Case 3

• However….

– Both parents heterozygous for RTN2, R191* loss of function allele and normal

– What is the risk of the proband’s offspring developing HSP/dHMN?

Case 3

• 43 loss of function alleles out of 250000 control alleles in GNOMAD (healthy control database)

• RTN2 deletion in original paper only reported in a sporadic case

• Therefore, haplo-insufficiency unlikely to be pathogenic

– Low risk for future generations

ACKNOWLEDGEMENTS

Mary Reilly Julian Blake James Polke Matilde Laura Sebastian Brandner Gita Ramdharry Zane Jaunmuktane

QUESTIONS?