View
3
Download
0
Category
Preview:
Citation preview
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?
Recommended