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Immunological study of hereditary

motor and sensory neuropathy

type 1a (HMSN1a)

C M 1, N A Gregson1, N W Wood2 and R A C 1

1 Department of Neuroimmunology, Guy's King's and St ' School of

Medicine, Hodgkin Building, Guy's Hospital,

London SE1 9RT, UK

2 Institute of Neurology, University College, London, UK

Correspondence to:

Professor R A C , Department of Neuroimmunology, Guy's King's and

St ' School of Medicine, Hodgkin

Building, Guy's Hospital, London SE1 1UL, UK;

richard.a.hughes@...

Received

20 March 2001

In final revised form

3 September 2001

Accepted

23 October 2001

ABSTRACT

Objectives: Fifty three patients were studied to investigate whether

autoimmune or inflammatory mechanisms could explain the phenotypic

heterogeneity of patients with hereditary motor and sensory neuropathy

type

1a (HMSN1a). Methods: Serum samples were examined for antibodies to

peripheral nerve myelin protein 22 (PMP22), ganglioside GM1 and cauda

equina homogenate, and interleukin-6 (IL-6) and soluble tumour necrosis

factor receptor 1

(sTNF R1) concentrations. Serological results were compared with those

from patients with

other neuropathies (ONPs, n=30) and with normal subjects (n=51).

Results: In the group as a whole, no relation emerged between clinical

severity and any immune

parameters. Immunohistochemical examination of four sural nerve biopsies

did not show

significant inflammatory infiltration. In a subset of 12 patients who

experienced stepwise

progression of disease, there was a trend towards a higher proportion

having anti-PMP22

antibodies (33% v 15% of those with gradual disease progression, 3%

ONPs, and no normal

controls) and complement fixing antibodies to human cauda equina (25% v

5% with gradual

progression, 8.6% ONPs, 3.9% normal controls, p=0.07).

Conclusions: Patients with HMSN1a and a stepwise disease progression may

have an

inflammatory, autoimmune component superimposed on the genetic

condition.

Keywords: HMSN1a; neuropathy; immune

Abbreviations: HMSN1a, hereditary motor and sensory neuropathy type 1a;

PMP22, peripheral

nerve myelin protein 22; IL-6, interleukin-6; sTNF R1, soluble tumour

necrosis factor receptor

1; ONPs, other neuropathies; EAN, experimental autoimmune neuritis; GBS,

Guillain-Barré

syndrome; CIDP, chronic inflammatory demyelinating

polyradiculoneuropathy; NDS,

neurological disability score; GNDS, Guy's neurological disability

score; CMAP, compound

motor action potentials; SNAPs, sensory nerve action potentials; NCVs,

nerve conduction

velocities; ECD1 and ECD2, first and second extracellular domain

peptides; AIDP, acute

inflammatory demyelinating polyradiculoneuropathy; IDP, inflammatory

demyelinating

polyradiculoneuropathy; DAB, 3,3'; diaminobenzidine

The early literature acknowledged great variation in age of onset,

rapidity of progression, nerve

conduction velocity, and neuropathological abnormalities in the

hereditary motor and sensory

neuropathies (HMSNs). The division of the commonest HMSNs into types 1

and 2 on the basis

of nerve conduction velocities1 was invaluable for future classification

studies and suggested

some clinical differences between these types, but did not explain the

phenotypic variation. Even

within the commonest genotype for HMSN, a 1.5 Mb duplication in

c17p11.2, (the gene for the

myelin protein PMP222–6), clinical variability both within and between

families is marked and

not yet explained.7–10

We have shown that recombinant, homologous PMP22 induces experimental

autoimmune neuritis

(EAN) and that these animals develop antibodies against the immunising

antigen.11 We have

recently identified anti-PMP22 antibodies in 52% of patients with

Guillain-Barré syndrome

(GBS) and 35% of those with chronic inflammatory demyelinating

polyradiculoneuropathy

(CIDP).12 Using a different assay others have detected anti-PMP22

antibodies in 70% of patients

with HMSN1a and 60% with HMSN2 as well as in those with other

neuropathies.13

We have now studied 55 patients with HMSN1a to establish whether

immunological

mechanisms might contribute to the phenotypic heterogeneity of this

group.

METHODS

Fifty five patients known to have the chromosome 17p11.2-p12 duplication

were interviewed and examined by one of us (CMG). Serological studies

were performed on 53 and neurophysiological assessment on 33. Patients

not

tested declined.

Clinical data

Patients were recruited between January 1995 and January 1997 from the

neuromuscular disease

clinic at Guy's Hospital, the Departments of Neurology and Neurogenetics

at the National

Hospital for Neurology and Neurosurgery, and the Charcot-Marie-Tooth

Society. The first 55

patients recruited by any of these means were included. All were

interviewed with a standard

questionnaire and underwent clinical examination. Three clinical scoring

systems were used:

The Medical Research Council (MRC) sum score,14 a modification of the

neurological disability

score (NDS)15 comprising reflex, sensory and weakness scores and the the

upper and lower limb

sections of the Guy's neurological disability score (GNDS).16, 17

Nerve conduction studies

The compound motor action potentials (CMAPs) of abductor pollicis brevis

and abductor

hallucis, the sensory nerve action potentials (SNAPs) of the right

median and sural nerve, and the

motor nerve conduction velocities (NCVs) of the right median and tibial

nerve were measured

(t Compass Portabook).

Serology

Serum samples from the 53 patients above, together with those from 30

patients with other

neuropathies (ONPs) and 51 normal control serum samples were collected

and stored at -70°C.

The ONP group included patients with idiopathic sensorimotor neuropathy,

HMSN2,

granulomatous neuropathies, hereditary neuropathy with liability to

pressure palsies, idiopathic

lumbar plexopathy, and vasculitis.

Anti-PMP22 antibodies

Titres of anti-PMP22 antibodies were measured by ELISA and western blot

in the serum

samples of all patients and controls as we have previously described.12

For the ELISA, MP22

first and second extracellular domain peptides (ECD1 and ECD2) were

cross linked to bovine

serum albumin (BSA) and used to coat ELISA plates. Plates were incubated

with patients' serum

and bound antibody detected with horse radish peroxidase (HRP)

conjugated rabbit anti-human

IgM, IgG or anti-pan Ig (antiIgG/Ig/IgA). Plates were developed with

o-phenylenediamine

dihydrochloride and H2O2 and the optical density read at 490 nm. For the

western blot,

suspended frozen sections of human cauda equina were fractionated by

SDS-PAGE, transferred

to nitrocellulose, incubated with patient's serum and then with HRP

conjugated rabbit anti-human

IgG or IgM and developed with diaminobenzidine hydrochloride and

cobalt-nickel enhancement.

Interleukin-6 and soluble tumour necrosis factor receptor 1

Serum interleukin-6 (IL-6) and soluble tumour necrosis factor receptor 1

(sTNF R1)

concentrations were measured in 52 HMSN1a subjects, 51 normal subjects,

10 ONPs and also in

eight patients with GBS, with a quantitative sandwich enzyme immunoassay

technique

(QuantikineTM, R and D Systems, Minneapolis, USA). Optical densities

were read at 450 nm

with 570 nm wavelength correction and concentrations calculated by

creating a standard curve

with the standards provided.

Complement fixation test

Serum samples were heat inactivated at 56°C for 30 minutes and tested

for complement fixing

activity to a predetermined optimal dilution of human cauda equina

homogenate.18 This was

performed on the serum from 52 patients with HMSN1a, 51 normal controls,

and 23 patients

with ONPs.

Anti-ganglioside antibodies

Serum samples from 52 patients with HMSN1a, 51 normal controls, and 23

patients with ONPs

were tested by enzyme linked immunosorbent assay (ELISA) using methods

previously

described.19, 20 Immulon-3 ELISA plates were coated with

ganglioside:cholesterol, blocked,

and incubated overnight with patients' serum. Bound antibody was

detected with anti-human IgM

or anti-IgG, plates were developed with p-nitrophenylphosphate, and the

optical density was

read at 405 nm.

Histology

Paraffin wax embedded sural nerve biopsies of four patients with the

c17p11.2 duplication were

available. Controls were biopsies of three patients with vasculitis (one

with polyarteritis

nodosa, two with non-systemic vasculitic neuropathy), three with

inflammatory demyelinating

neuropathy (one with acute inflammatory demyelinating

polyradiculoneuropathy (AIDP), two

with CIDP), and six with chronic idiopathic axonal polyneuropathy.

Transverse skip serial

sections (5 µm) were heated at 60°C overnight to assist adherence.

Antibodies against CD68

(monoclonal PGM-1), CD3 (polyclonal) and CD20 (monoclonal L26) in EPOS

(enhanced

polymer one step staining, DAKO) form were used. Sections were dewaxed

through xylene,

rehydrated, and blocked with 1% H2O2 in methanol. Before application of

anti-CD68 and

anti-CD20, sections were microwaved. Pretreatment for anti-CD3 was

incubation for 30

minutess in 0.1% trypsin at 37°C. Sections were blocked with normal goat

serum, incubated with

the EPOS antibodies for 1 hour, and visualised with

3,3'–diaminobenzidine (DAB)

counterstained with haematoxylin. Areas of the endoneurium and

epineurium/perineurium were

measured using a Freelance software image analysis programme. Numbers of

positive cells in

both areas were counted by an observer blind to the identity of the

section. The upper limit for

increased cellular infiltration in each compartment was defined as the

mean +3SD of that seen in

patients with chronic idiopathic axonal polyneuropathy.

Statistical analysis

Calculations were performed using GraphPad Prism® software with two

tailed tests of

significance. Differences in proportions were made using a 2 test or

Fisher's exact test.

Differences between two groups were determined by a t test or the

Mann-Whitney test. Other

differences between larger numbers of groups were made with one way

analysis of variance

(ANOVA, with Bonferroni's multiple comparison test for post hoc

analysis) if the groups were

normally distributed, or the Kruskall-Wallis (with Dunn's multiple

comparison test for post hoc

analysis) if they were not. Correlations between two groups were

performed with the Pearson

test if groups were normally distributed and the Spearman test if they

were not.

RESULTS

Disease progression

Most patients gave a history of slowly progressive disease. However, in

12

patients progression was in a stepwise rather than gradual fashion. Five

of

these were sporadic cases and none of those with a family history were

in

the same family. One patient had an IgM paraprotein,21 and three others

had

a history of improvement with immunosuppression. One had worsened

significantly during each

of her pregnancies.

Clinical neurophysiology

Sural nerve SNAPs were absent in all patients and the mean median SNAP

amplitudes reduced

at 0.7 µV (range 0–13.6 µV). The mean CMAP amplitude of the abductor

pollicis brevis was 3.1

mV (range 0.1–12.7 mV) with a mean median motor NCV of 23 (12–32) m/s.

The CMAP

amplitude of the abductor hallucis was more severely reduced, mean 0.19

mV (range 0.03 -1.7).

The maximum tibial motor NCV in the lower limb was reduced to a similar

extent as in the upper

limb (mean 21m/s, range 15–28).

Serological results

Anti-PMP22 antibodies

Fourteen out of 53 patients with HMSN1a had antibodies detected by ELISA

against either of the

PMP22 extracellular domains compared with two of the 51 normal subjects

(p=0.002) and three

of those with ONPs (p=0.09, table 1). The diagnoses in the ONP group

with positive

anti-PMP22 antibodies were alcohol related axonal neuropathy,

adrenomyeloneuropathy, and

idiopathic axonal neuropathy (with a history of sarcoidosis). One of the

normal subjects had

worked with myelin proteins in the laboratory for many years.

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Table 1 Details and ELISA results in each group examined

for

anti-PMP22 antibodies.

Western blotting confirmed 10 out of 14 of the positive ELISA results

from the group of patients

with HMSN1a (fig 1). Five patients had IgG antibodies alone, two had IgM

antibodies alone,

and three had both IgM and IgG antibodies confirmed by both ELISA and

western blot. Western

blotting did not confirm the presence of anti-PMPM22 antibodies in the

two normal control

subjects with a positive ELISA but did identify a 22 kDa band with the

serum from one other

normal subject.

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Figure 1 Western blot of human cauda equina

incubated

with serum from representative patients with

HMSN1a. The

blot was incubated with the serum of patients with

HMSN1a

(lanes a-g) or normal control subjects (lanes

h-l). The lane

marked IgM represents a blot with the IgM

secondary

antibody alone (no primary). Bands indicating a

protein of

22 kDa are indicated by the filled arrowhead

(lanes b, e, f,

g). Some patients (lanes b, d, e, f, g) had

antibodies against

proteins of about 30 kDa (empty arrow head). Some

subjects (lanes a, c, g, h, j) had antibodies

directed against a

smaller protein of 16 kDa (arrow).

By western blotting, serum also bound to a protein band of about 30 kDa

(range 30–36 kDa) in

six patients (five IgG antibodies, one IgM) with HMSN1a and one (IgG)

with ONP which was

not bound by the serum of any normal subjects. A band of approximately

16 kDa was also

detected in the serum of four patients (all IgM) with HMSN1a and eight

normal controls (four

IgM, four IgG), but not that from any of the patients with ONPs.

There were no significant differences in any of the measures of severity

or neurophysiological

indices in the 10 patients with HMSN1a with anti-PMP22 antibodies

confirmed by western blot

and ELISA compared with the rest. s

TNF R1

There was no significant increase in the concentration of sTNF R1 in

patients with HMSN1a

compared with normal subjects (fig 2 A). Four patients had particularly

high sTNF R1

concentrations (arrowed). The patient with HMSN1a was a woman aged 54

with mild disease

although moderate resting tremor, who did not have anti-PMP22

antibodies. The patients with

ONPs had polyarteritis nodosa, inactive sarcoidosis, and chronic

idiopathic axonal

polyneuropathy.

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Figure 2 (Top) Graph showing sTNF R1

concentrations.

Arrows indicate patients discussed in text.

(Bottom) Graph

showing IL-6 concentrations in all groups

examined.

Arrows indicate patients discussed. Bars on both

graphs

indicate mean (SE)

IL-6

There were no significant increases in the concentrations of IL-6 in

patients with HMSN1a

compared with normal subjects (fig 2 . Five patients had particularly

high concentrations,

three with severe GBS and two normal subjects. Two of the patients with

GBS had antibodies to

PMP22.12 The normal subjects with high IL-6 concentrations were healthy

women, neither with

anti-PMP22 antibodies.

Anti-GM1 antibodies and complement fixation test against human nerve

Antibodies to ganglioside GM1 and a positive complement fixation test

against human cauda

equina were not more common in patients with HMSN1a. However, two

patients with HMSN1a

had very high titres by complement fixation test. One of these (titre

1/16364) was known to have

an IgM paraprotein21 the other (titre 1/65456) was one of the patients

with a stepwise disease

progression who had responded to immunosuppression.

Serological results in the group reporting stepwise disease progression

Serological results of these 12 patients were compared with those in

whom progression was

gradual (table 2). There were no significant differences with regard to

anti-PMP22 antibodies,

sTNF R1, or IL-6 concentrations. Three (25%) patients with a stepwise

progression had a

positive complement fixation test compared with two out of 40 (5%) of

those with gradual

disease progression (p=0.07).

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Table 2 Serological results in patients with a stepwise

disease

progression compared with those with a gradual

progression

Histological studies

Patients with HMSN1a had no evidence of increased infiltration of T

lymphocytes (CD3). Three

patients with HMSN1a, one with IDP and one with vasculitis had small

numbers of endoneurial

B cells (from 0.7–3.3 /µ2). Epineurial B cells were also seen in small

numbers (from 0.2–5.7 µ2

) in two biopsies of patients with HMSN1a, two with IDP and one with

vasculitis. Biopsies from

two patients with HMSN1a who reported stepwise deterioration were

examined. One showed

no evidence for cellular infiltration, the other was known to have an

IgM paraprotein and his

biopsy did show some epineurial macrophage infiltration and a few

epineurial B cells. Electron

microscopic examination of this patient's biopsy had previously shown a

demyelinating

neuropathy with hypertrophic changes (concentric Schwann cell

proliferation), widely spaced

myelin, and IgM deposition on the myelin sheath.21

CONCLUSIONS

Clinical,22–24 serological,25, 26 electrophysiological,27 and

histological28–32 studies have suggested the existence of an

inflammatory

component in HMSN. Immune deficiency in a mouse model of a hereditary

demyelinating neuropathy results in a less severe neuropathy.33 We have

shown that antibodies to important nerve constituents or increased

cytokine

concentrations are present in the serum of only a minority of patients.

For all serological

measurements, there were no differences in severity of disease between

those with positive

results (or high concentrations) and those without.

Anti-PMP22 antibodies

We hypothesised that an increase in PMP22 protein expression in

HMSN1a34, 35 might lead to

immune responses directed against this protein. We previously showed

that anti-PMP22

antibodies are found in 35%-52% of patients with inflammatory

neuropathies.12 Recently, using

different techniques, a high proportion of patients with different types

of peripheral neuropathy

including HMSN were found to have anti-PMP22 antibodies.13

Ten patients had antibodies against PMP22 detected by both ELISA and

western blot. Of these,

six also had antibodies against a 30 kDa protein, likely to represent

antibodies against P0, which

have been described in other peripheral neuropathies.36, 37 Antibodies

against PMP22 were

more common in patients with HMSN1a than in normal subjects, but not

more than in those with

other neuropathies. These results are similar to those of Ritz et al.13

As no clinical differences were detected between those with anti-PMP22

antibodies and those

without, it seems unlikely that clinical phenotypic differences can be

ascribed to a humoral

response directed towards PMP22. It is possible that the finding of

anti-PMP22 antibodies in

HMSN1a is usually a non-specific reaction to nerve damage rather than of

primary pathological

importance. It would be interesting to determine whether patients with

HMSN1a have antibodies

directed towards P0 in similar numbers and titre to confirm this.

Cytokine concentrations

Previous studies had shown increased plasma concentrations of a

leukotriene, decreased

concentrations of arachidonic acid, and raised levels of inflammatory

cells in HMSN25, 26

suggesting a potential for immune mediated damage by cellular

mechanisms. Neither the " Th2

cytokine " IL-6 which stimulates B cells, nor the " Th1 cytokine " sTNF R1,

which corresponds to

raised TNF concentrations,38 were raised, suggesting that neither

pathway is activated in

HMSN1a.

Histology

Demyelination in HMSN 1a is most active in childhood when macrophage

associated myelin

removal ( " active " demyelination) has been described,28–30 similar to

that seen in GBS39 and

CIDP.40 In adults, isolated clusters of mainly T cells have been found

in 12% of patients with

HMSN1a. Endoneurial oedema, which may be prominent in CIDP,22 has been

described in 21%

of patients with HMSN1a30 and onion bulbs may be seen in CIDP as well as

HMSN1a.30, 41

Our histological study did not confirm previous reports of increased

numbers of T cells in

HMSN,30, 31 as none of the patients with HMSN1a had more epineurial or

endoneurial cells than

in chronic idiopathic axonal polyneuropathy. Only one patient with

HMSN1a had increased

numbers of macrophages,28, 32 and he was known to have an IgM

paraproteinaemic

neuropathy.21 Although numbers of B cells were small in all biopsies,

they were found most

often in HMSN1a, although as the finding was marginal we think that it

would be inappropriate

to advance hypotheses for isolated B cell infiltration in HMSN1a.

Patients with stepwise disease progression

In 12 patients, all from different families, the progression of the

disease was stepwise, with

months in which progression in symptoms was rapid, followed by months or

years of seemingly

quiescent disease. One patient was known to have an IgM paraprotein,21

but none of the others

had any additional known causes for their " relapses " .

Three patients had been treated with immunosuppression (IVIg in one

patient and this together

with plasma exchange in the other two patients) as the pattern of their

illness fitted that of either

AIDP (in one case, similar to recently reported cases42, 43) or CIDP

(two cases). All responded

favourably. Two groups have described beneficial responses to

prednisolone in patients with

HMSN type 122, 23 but it is not known whether these patients had the

HMSN1a genotype. Partial

steroid responsiveness has also been recently reported in a family with

a mutation in the myelin

protein zero gene.44

The characteristics of the group with a stepwise progression with regard

to weakness, areflexia,

sensory loss, or disability were no different from the group as a whole,

although only half of

them were examined during what they described as a relapse. There was a

trend towards more

patients having anti-cauda equina antibodies in this group compared with

those with a gradual

progression. Although not significant, twice as many patients with

stepwise progression had

anti-PMP22 antibodies (33% compared with 15% with gradual progression).

This compares

with 52% of those with GBS and 35% of those with CIDP.12

The subgroup with stepwise progression may represent patients in whom a

heightened humoral

immune response occurs, directed against myelin proteins. There are

several possible

explanations for this. It could be that these patients have an

additional immunosusceptibility to an

inflammatory demyelinating neuropathy. Because they have altered or

overexpressed PMP22,

which already renders their peripheral nerves liable to demyelination, a

superimposed

inflammatory demyelinating disorder may be more likely to occur in them

than in genetically

normal subjects. Similar susceptibilities have been implicated in

adrenoleukodystrophy45, 46 and

facioscapulohumeral dystrophy47, 48 and have been reported for EAN in

inbred strains of rats.49

Alternatively the inherited neuropathy may expose myelin antigens, or

the c17p duplication may

contain genes that modify the immune response in some patients. In mice

heterozygously deficient

in the myelin protein zero gene, T cells show enhanced reactivity to

myelin components and

immune deficiency results in less severe peripheral nerve disease.33 It

is plausible but seems

less likely that these patients represent a subgroup of pure HMSN1a

responsive to

immunosuppression. Of course, it remains possible that these patients

with a stepwise disease

progression simply have coincidental inflammatory neuropathy and HMSN1a,

but our results

suggest that, in this group, immune mediated mechanisms relate the two

conditions.

ACKNOWLEDGEMENTS

CMG was supported by a research fellowship from the British Brain and

Spine Foundation. We

thank Professor PK for referring patients, CMT International UK

for allowing us to

advertise for patients, Dr Robin Posner for assistance with image

analysis and Ian Gray and

Alan Hartigan for technical assistance.

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