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Inherited Peripheral Neuropathies Bristol Genetics Laboratory Kenneth Smith. SCOBEC A-Grade Training Day Cardiff 15 th October 08. Inherited Peripheral Neuropathies. Peripheral Neuropathies can be inherited or acquired.

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inherited peripheral neuropathies bristol genetics laboratory kenneth smith

Inherited Peripheral NeuropathiesBristol Genetics LaboratoryKenneth Smith

SCOBEC A-Grade Training DayCardiff 15th October 08

inherited peripheral neuropathies
Inherited Peripheral Neuropathies
  • Peripheral Neuropathies can be inherited or acquired.
  • The hereditary neuropathies are a clinically and genetically heterogeneous group of disorders with overall prevalence of 1 in 2,500.
  • This disease is characterised clinically by distal muscle wasting and weakness, distal sensory loss, reduced tendon reflexes, hypoflexia, variable amount of foot deformity and neurophysiological changes.
  • There are in excess of 40 causative genes associated with inherited peripheral neuropathies.
  • Age of onset and severity vary extensively.
  • AD, AR and XL forms
  • Broad overlap between genotype-phenotype correlation complicates testing strategy.

“Mutations in a single gene can cause different phenotypes, and the same phenotype can be caused by mutations in different genes”

Quote from Reilly MM. Sorting out the inherited neuropathies 2.

inherited peripheral neuropathies classification
Inherited Peripheral Neuropathies: Classification
  • Clinical classification of the Inherited Peripheral Neuropathies (IPN) is primarily based on the motor/ sensory involvement:
    • Hereditary Motor and Sensory Neuropathy (HMSN or CMT).
    • Hereditary Motor Neuropathy (HMN).
    • Hereditary Sensory Neuropathy (HSN).
  • Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) is genetically related to HMSN and is also considered under the inherited neuropathies.
  • Neurophysiological classification of the Inherited Peripheral Neuropathies (IPN) is primarily based on Nerve Conduction Studies (NCS):
    • type 1 (median NCV<38m/s) demyelinating.
    • type 2 (median NCV>38m/s) axonal.
    • an intermediate form is increasingly recognised.
  • Further classification can be made based on inheritance pattern and nerve biopsy.
  • Even after considering these factors may still be left with any one of a number of candidate genes or the genetic basis may remain unknown.
peripheral neuropathies testing strategy

CMT1

CMT2

Intermediate CMT

HNPP

abnormal myelin

MCV<38m/s

axonopathy

MCV>38m/s

combination of myelinopathy/ axonopathy

MCV 25-45m/s

AD or X-linked or isolated

AD or isolated

AD or isolated or X-linked

17p11.2 dosage

No male to male transmission

male to male transmission

Classical CMT2

CMT2 + sensory especially with pain

Positive FH or strong clinical indication

GJB1

MPZ

PMP22

MFN2

MPZ

SPTLC1

PMP22

GJB1

AD or isolated

- AD or sporadic

- CMT1 or severe early onset

NEFL

- AR CMT1/2 early onset/ severe with

vocal cord and diaphragm paralysis

- rare AD CMT2

- DSD or CHN

- AR CMT2 with proximal involvement

and rapid progression

GDAP1

(ION lab)

NEFL

MPZ

GDAP1

NEFL

EGR2

LMNA

(Exeter lab)

- AR or sporadic

- CMT1 or severe early onset or DSD

- often prominent sensory component

with ataxia and severe axonal loss

PRX

Peripheral Neuropathies: Testing Strategy
case 1 mpz family
Case 1: MPZ Family

I. 1 2 3 4 5

Ref: aged 88 yrs (02)

Clinically HMSN1

MPZ p.Lys108X

Ref: aged 72yrs (02)

Clinically unaffected

MPZ normal

Ref: aged 64yrs (02)

Clinically unaffected

MPZ p.Lys108X

Ref: aged 88 yrs (02)

Clinically unaffected

MPZ normal

II. 1 2 3 4 5 6

Ref: aged 58 yrs (01)

Clinically HMSN1

MPZ p.Lys108X

2

Ref: aged 65 yrs (05)

Clinically unaffected

MPZ p.Lys108X

III. 1 2

Ref: aged 28 yrs (01)

NCV <22m/s

Clinically HMSN 1

GJB1 mutation screen -ve

MPZ p.Lys108X

UV assumed pathogenic

Ref: aged 37 yrs (07)

MPZ p.Lys108X

case 1 mpz family1
Case 1: MPZ Family
  • 3 generation family with 3 affected individuals and 3 unaffected individuals all of which have the same UV in MPZ.
    • p.Lys108X had not previously been reported on the CMT database.
    • p.Lys108X reported as pathogenic based as nonsense and tracking with disease at the time.
  • Explanations:
    • Variable expressivity or reduced penetrance.
    • Clinical information is inaccurate.
    • UV is not pathogenic and the genetic basis of the peripheral neuropathy remain undetermined.
case 1 mpz family2

I. 1 2 3 4 5

Ref: aged 88 yrs (02)

Clinically unaffected

MPZ normal

Ref: aged 88 yrs (02)

Clinically HMSN1

MPZ p.Lys108X

Ref: aged 72yrs (02)

Clinically unaffected

MPZ normal

Ref: aged 64yrs (02)

Unaffected

MPZ p.Lys108X

II. 1 2 3 4 5 6

Ref: aged 58 yrs (01)

Clinically HMSN1

MPZ p.Lys108X

2

Ref: aged 65 yrs (05)

Unaffected

MPZ p.Lys108X

Ref: aged 28 yrs (01)

NCV <22m/s

Clinically HMSN 1

MPZ p.Lys108X

UV assumed pathogenic

III. 1 2

Ref: aged 37 yrs (07)

MPZ p.Lys108X

Case 1: MPZ Family
  • Current in silico analysis predicts the variant is pathogenic.
  • Clinical information was reviewed in September 08.
    • Individuals I.5 and II.1 mild signs of peripheral neuropathy and considered clinically affected.
    • III.2 is 37 years of age and is likely presymptomatic.
case 1 mpz family3

MPZ gene

MPZ gene

PTC

PTC

p.Lys108X (Exon 3)

Exons 1 2 3 4 5 6

Exons 1 2 3 4 5 6

7Kb

7Kb

Escapes to NMD

Dominant negative function

More severe phenotype

Subject to NMD

Haploinsufficiency

Less severe phenotype

Case 1: MPZ Family
  • Why is the age of onset so late?
    • Previous examinations had not detected mild signs of peripheral neuropathy.
    • Recently published paper1 proposing that Nonsense Mediated Decay (NMD) may influence disease severity depending on position of PTC in MPZ gene.
  • Highlights need for accurate and detailed clinical information and the need to review clinical data in order to interpret unclassified variants.
case 2 mpz pmp22 family

I. 1 2

II. 1

Ref: aged 13 yrs (00)

Dublin Lab

Severe DSS phenotype involving upper and lower limbs.

Onset: 3 yrs, wheelchair bound at 6 yrs.

Bilateral hearing loss.

Absent NCV.

Dublin lab found PMP22 duplication.

Genotype not consistent with DSS phenotype.

Referred to Bristol for extended testing.

Testing revealed: MPZ p.Arg67His

Variant not reported in CMT database.

Case 2: MPZ/PMP22 Family
  • Were the PMP22 duplication and the MPZ UV inherited or have they arisen de novo?
  • Was the variant a SNP in the Irish population?
  • Could p.Arg67His be eliciting a mild effect in a parent which is not evident on examination?
  • Could the combination of duplication in PMP22 and the variant in MPZ explain the phenotype or does a second contributing factor remain unidentified?
case 2 mpz pmp22 family1
Case 2: MPZ/PMP22 Family

II. 1 2

I. 1

Ref: aged 13 yrs (00)

Dublin Lab

Severe DSS phenotype involving upper and lower limbs.

Onset: 6 years, now wheelchair bound.

Dublin lab found PMP22 duplication.

Genotype not consistent with DSS phenotype.

Referred to Bristol for extended testing.

Testing revealed: MPZ p.Arg67His

Variant not reported in CMT database.

In silico analysis support variant not being pathogenic.

Pathogenic variants reported involving codon p.Arg67Pro

Mother

Unaffected carrier of UV p.Arg67His

Ref: aged 45 yrs

Father deceased but family recount information indicating he may have had mild symptoms of PN.

  • Mother was clinically unaffected and mutation analysis revealed she also had p.Arg67His variant.
  • Father was deceased. Duplication may have come from the father or may have arisen de novo.
  • The MPZ variant was not found in 50 population matched individuals or in our cohort of patients >100.
  • Published mutations involving this codon (but not this variant) with very variable phenotype.
  • In silico analysis supports this variant being benign.
peripheral neuropathies
Peripheral Neuropathies
  • These cases highlight:
    • The difficulty in ascertaining the effect of UV without functional studies particularly when there are so many different genes involved.
    • The need for accurate and up to date clinical information and a strategic reviewing process for all unexplained cases.
    • That until new technologies facilitate the testing of all known peripheral neuropathy genes an effective testing strategy is required.
  • Bristol Genetics Laboratory offers PMP22 duplication/deletion and MFN2 point mutation analysis to SCOBEC laboratories and mutation analysis of PMP22, MPZ, GJB1, NEFL, PRX, SPTLC1, EGR2 genes to all labs via the UKGTN.
  • References
  • 1. Reilly M. Sorting out the inherited Neuropathies. Pract Neurol. 2007 Apr;7(2):93-105
  • 2. Inoue K et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nature Genetics 2004; 36 (4):361-369.
    • CMT Mutation Database; http://www.molgen.ua.ac.be/CMTMutations/