9 CMT presentations at San Francisco Conference

[Guest guest]

The following 9 research papers/topics with corresponding authors will

be presented at the American Academy of Neurology meeting in San

Francisco April 29, 2004. This meeting runs from April 24 to May 1,

2004. This is a list of the 9 titles and the abstracts. I will keep you

up to date on additions/changes/and plenary sessions.

Wednesday, April 28:

The Use of Skin Biopsies in the Evaluation of Inherited Neuropathies

Jun Li, Marina Grandis, Xingyao Wu, E. Shy, Detroit, MI,

Jean-Michel Vallat, Limoges

OBJECTIVE: To investigate whether skin biopsy is suitable for studying

nerve morphology and gene expression in inherited neuropathies.

BACKGROUND: Charcot Marie Tooth disease (CMT), a group of genetically

inherited peripheral neuropathies, is a common neurological condition,

with a prevalence of one in 2500. Mutations causing CMT have been

identified in 17 different genes and chromosomal loci have been

identified for more than 25 others. Effective treatment for CMT,

however, is not yet available, in part because the molecular and

cellular mechanisms by which the identified mutations cause neuropathy

are not known. One important reason for lack of progress in this area is

the paucity of pathological material from patients with CMT. Until now

the major source of patient nerve specimens has been obtained from sural

nerve biopsy, an invasive, painful procedure, no longer required for

diagnosis, and which cannot be repeated proscribing its use in

longitudinal studies. Skin biopsies are currently utilized in the

evaluation of sensory neuropathies, because skin contains significant

numbers of sensory nerve fibers, most of which are unmyelinated. Skin,

however, also contains myelinated nerve fibers that could be evaluated

in patients with CMT.

DESIGN/METHODS: To begin this evaluation we are performing

immunohistochemistry, electron microscopy, immunoEM, and quantitative

RT-PCR to analyze the morphology and patterns of gene expression of

myelinated nerves from glabrous skin biopsies. RESULTS: Our preliminary

studies show that individual myelinated axons stained with PGP9.5

antibodies are reproducibly observed innervating Meissers capsules. P0

and myelin basic proteins are detected in the internodes of these

nerves. Semithin sectios with Toluidine Blue staining reveal that dermal

nerve bundles have myelinated fibers. These myelinated fibers are

further examined under EM and show compacted myelin wrapping similar to

those in sural biopsies. Moreover, real-time PCR found that myelin gene

expression in Schwann cells ensheathing these nerves is similar to the

myelin gene expression from Schwann cells ensheathing sural nerves.

CONCLUSIONS: These data suggest that skin biopsy evaluation can be used

to evaluate myelinated nerves in inherited neuropathies.

Thursday, April 29, 2004

7:30 AM Room: Gateway Ballroom 103-104

A Novel Insertional Mutation in the Connexin 32 Gene Causes CMTX with

Unusual Elecetrophysiological Findings

Lan Zhou, Cleveland, OH, Ahmet Hoke, Baltimore, MD

OBJECTIVE: To report a novel in-frame insertional mutation in the

Connexin 32 gene that causes motor greater than sensory, non-uniform

demyelinating polyneuropathy with unusual electrophysiological findings.

BACKGROUND: X-linked dominant Charcot-Marie-Tooth disease (CMTX) is the

second most common form of CMT. It is caused by mutations in the

Connexin 32 gene which encodes a noncompact myelin gap junction protein.

So far, 264 different mutations have been identified, 11 of which are

insertional mutations http://molgen-www.uia.ac.be/CMTMutations). CMTX is

a notable exception of the heritable demyelinating neuropathies such

that demyelination can be non-uniform.

DESIGN/METHODS: We performed nerve conduction study on a patient with

long-standing distal weakness, foot deformity, and a strong family

history of similar symptoms. He was subsequently tested for

demyelinating CMT gene mutations. RESULTS: A 60-year-old man has had

slowly progressive distal weakness since childhood. Examination showed

prominent bilateral pes cavus and hammer toes, wasting and weakness of

the distal leg (MRC 2-3/5) and intrinsic hand (4/5) muscles, reduced

pinprick and vibration sensation in a stocking-glove pattern, and

areflexia. Similar condition has affected his maternal family in a

dominant fashion with no male-to-male transmission. NCS of this patient

showed a motor greater sensory, non-uniform demyelinating

polyneuropathy. The conduction velocities were in the range of 30.1 to

39.3 m/s in the upper extremity and 28.9 m/s in the sural nerve. While

motor responses of the lower extremities were absent, the sural sensory

nerve action potential (SNAP) amplitude was surprisingly normal at 13.8

uV. The SNAP amplitudes were also normal in the median (15.5 uV) and

radial (17.7 uV) nerves but was mildly reduced in the ulnar nerve (6.9

uV). The ulnar distal motor latency was normal (3.05 ms), the F-wave

latency was prolonged (42.2 ms), and the compound muscle action

potential (CMAP) amplitude was normal (6.1 mV). The median distal motor

latency was markedly prolonged (6.25 ms) and the CMAP amplitude was

severely reduced (0.3 mV). There was no conduction block. The gene test

by Athena Diagnostics (Worcester, MA) revealed a novel 3-basepair

insertion of TCA at the nucleotide position 634 with resultant in-frame

addition of Serine between Thr191 and Val192, an area of Connexin 32

which is highly conserved among different species indicating its

structural and functional importance. There were no macro- or

micro-mutations in the peripheral myelin protein-22 (PMP-22), myelin

protein zero (MPZ), or early growth response gene 2 (EGR2) genes.

CONCLUSIONS: While patients with CMTX clinically manifest a symmetrical

length-dependent sensorimotor deficit, demyelination and axonal

degeneration on NCS can be non-length-dependent and highly variable

among different nerves and different segments of an individual nerve. It

can more severely affect motor nerves than sensory nerves as seen in the

present case with a novel insertional mutation in the Connexin 32 gene.

Thursday, April 29, 2004

7:30 AM

Room: Gateway Ballroom 103-104

Electrophysiologic Critieria Defining Charcot-Marie-Tooth Disease with

Intermediate Conduction Velocities

Agnes Acsadi, E. Shy, Krajewski, A. ,

Detroit, MI

OBJECTIVE: This study is designed to determine the range of conduction

velocities that optimally defines Charcot-Marie-Tooth Disease (CMT) with

Intermediate Conduction Velocities and differentiates it from CMT-1 and

CMT-2.

BACKGROUND: Bradley et al. (Brain 1977) identified a group of patients

with CMT who had conduction velocities that were intermediate between

those that we would now label as CMT-1 and CMT-2. They defined this

intermediate group as having median motor velocities of between 25 and

45 m/sec. It is now clear that CMT-X represents many patients with

intermediate slowing but there remain a number of other patients with

unknown genetic disorders. CMT-Int is being used without a clear

definition (www.ncbi.nih.gov/omim). To be meaningful, the term should

define a group of patients with distinct characteristics that separate

it from CMT-1 and CMT-2. This study is designed to determine whether

there is a range of velocities that best discriminates patients with

CMT-Int from CMT-1 and CMT-2 and guide genetic testing.

DESIGN/METHODS: We reviewed median conduction velocity (CV) studies of

214 patients with dominant CMT. The number of patients with genetically

determined CMT-1 (CMT-1A, MPZ mutations) and CMT-X were compared using 6

different criteria for intermediate conduction (25 to 45 and 50; 30 to

45 and 50; and 35 to 45 and 50). CMT-2 was defined by autosomal dominant

inheritance, and mildy slow NCS (> 40m/sec).

RESULTS: When 25- 50 m/sec was the criteria for CMT-Int, there were 22

out of 118 (19%) with PMP-22 duplications (CMT-1A), 23/24 (96%) with

CMTX, 22/42 (52%) with CMT-2 and 6/9 (67%) with MPZ mutations. Changing

the range to 30-50 m/sec reduced those with CMT-1A to 8%, CMTX to 92%,

and MPZ to 56% . Changing to 35-50 m/sec, excluded all but 1 CMT-1A

patient (0.8%), but also reduced those with CMTX to 63%, and MPZ to 44%.

With 35-45 m/sec there was no change in the CMT-1A or MPZ groups, but

there were only 11/24 CMTX patients (45%)and 10/42 (24%) with CMT-2.

Thus, increasing the lower limit from 25-35 excludes virtually all

CMT-1A but also some CMT-X. Lowering the upper limit from 50- 45 also

excluded some CMT-X.

CONCLUSIONS: These results suggest that CMT-Int, as a subset of CMT, can

discriminate between disorders with known mutations and may be useful to

identify new disorders. It appears that the optimal may be 30-45 m/sec

which maintains the most CMT-X patients while excluding many CMT-1A and

2. The range of 35-45 excludes virtually all CMT-1A but also excludes

more CMT-X. This, in part, is due to the variability of NCS and gender

differences in CMT-X. Optimally, criteria would exclude virtually all

CMT-1A and include all CMT-X. We will analyze the data correlating NCS

to CMAP and investigating gender differences to see if this will improve

the discrimination of these disorders.

Thursday, April 29, 2004

7:30 AM

Room: Gateway Ballroom 103-104

DI-CMTC: Dominant Intermediate Charcot-Marie-Tooth Disease Type C. A

Neurophysiologic Study of 2 Families in Bulgaria and the USA

C. Rao, V. Guergueltcheva, F. A. A. Gondim, I. Tournev, L. J. Kinsella,

B. Ishpekova, Y. Pan, A. Jordanova, I. Litvinenko, I. Kremensky, Sofia,

Bulgaria, V. Timmerman, P. De Jonghe, Antwerp, Belgium, F. P. , St

Louis, MO

OBJECTIVE: Describe the EMG/NCS features of dominant intermediate

Charcot-Marie-Tooth disease type C (DI-CMTC) in 2 families.

BACKGROUND: CMT encompasses many forms of hereditary sensory and motor

neuropathy, classified by EMG/NCS and histologic criteria as CMT1 with

nerve conduction velocities (NCV) <38m/s and de- and remyelination, and

CMT2 with near-normal NCV and axonal changes. Intermediate NCVs, first

described in 1978, occur in families with MPZ, Cx32, GDAP1 and NF-L

mutations and in DI-CMTA and DI-CMTB linked to chromosomes 10q24.1-q25.1

and 19p12-p13.2. Having recently reported linkage of DI-CMTC to

chromosome 1p34-p35, we present EMG/NCS studies in this new disease

entity.

DESIGN/METHODS: EMG/NCS was performed prospectively and retrospectively

in 29 Bulgarian (age 12-67) and U.S. (age 6-78) subjects. Evolution of

NCS was analyzed longitudinally and across age groups. RESULTS: Motor

NCS were abnormal in all U.S. adults and 5/6 minors. All 25 median motor

NCVs were abnormal in adults, 19 <38m/s, 6 40-45m/s. CMAPs were

unobtainable in 7/9 peroneal and 11/14 tibial NCS. In children, 3/7

median, 5/7 peroneal and 4/8 tibial motor NCVs were abnormal. No

disproportionate slowing was seen across ulnar and peroneal entrapment

sites; but 17/28 median DMLs were prolonged disproportionately vs. ulnar

DMLs, suggesting entrapment at the wrist. Median motor NCVs plotted

cross-sectionally against age (1st to 4th decade) revealed a decline

from normal to 35m/s. No significant sex difference was observed in the

rate of decline, but women retained higher NCVs. Serial studies at 2-15

year intervals revealed median DML prolongation and motor NCV slowing in

5/6 subjects, but stable CMAP amplitudes. Low or absent SNAPs were

common. EMG showed denervation/reinnervation in leg but not arm muscles.

In Bulgarian subjects, median motor NCVs were 33 to >48m/s, 2 <38m/s.

CMAPs were unrecordable in 5/9 peroneal and 4/7 tibial studies; motor

NCVs were abnormal in 4/9 peroneal and 2/9 tibial nerves. SNAP were of

low amplitude. Serial studies at 6-11 year intervals revealed motor NCV

slowing in 3/3 subjects and stable CMAP amplitudes in 2/3.

CONCLUSIONS: We found intermediate NCVs in all adults and slowly

progressive slowing. Similar slowing with age was reported with certain

MPZ mutations, but was more rapid in DI-CMTA. Sex differences occur also

in CMTX1 and other subtypes. CMAP amplitudes in the arms were generally

normal in contrast to CMTX1 where they are significantly reduced.

Identifying the functions and mutations of the gene responsible for

DI-CMTC should elucidate the pathomechanisms of intermediate NCVs.

Thursday, April 29, 2004

7:30 AM

Room: Gateway Ballroom 103-104

Seven Novel Mutations and One Family with Both Cx32 and EGR2 Mutations

on Genetic Analysis in the PMP22, MPZ, Cx32, EGR2, and NEFL Genes in CMT

Patients

Byung Ok Choi, Ki Wha Chung, Kongju, Korea, Kee Duk Park, Seoul, Korea

OBJECTIVE: To find the PMP22, MPZ, Cx32, EGR2, and NEFL gene mutations

in Korean Charcot-Marie-Tooth (CMT) patients, and investigate their

phenotypic characteristics.

BACKGROUND: CMT disease is a clinically and genetically heterogeneous

disorder. It is well known that mutations in the PMP22 gene cause CMT1A,

MPZ gene, CMT1B, and Cx32 gene, CMTX disease. Mutations in the EGR2 gene

are associated with CMT type 1, Desserin-Sottas syndrome, and congenital

hypomyelination neuropathy. The NEFL gene mutations are recently

reported as a cause for CMT2E, but they have been also reported to

relevant with CMT type 1.

DESIGN/METHODS: We performed the mutational analysis in 211 unrelated

CMT patients from 51 families of Korean origin. Mutational analysis was

carried out to find the mutation of PMP22 duplication at chromosome

17p11.2-p12, and also the missense mutations of PMP22, MPZ, Cx32, EGR2,

and NEFL genes.

RESULTS: In this study, we found seven novel mutations. The PMP22

duplication was found in fifteen families. In MPZ, one family had a

novel missense mutation with CMT1B, and one family had a novel mutation

at the last nucleotide of intron 3 causing abnormal splicing. We also

found three novel missenses, two silents, and six polymorphisms in Cx32

gene with CMTX. In EGR2, one missense mutation was found in CMT type 1

family. We discovered two novel missense mutations in CMT type 1 and

CMT2E families in NEFL gene. In addition, we found a novel family with

both V136A mutation in Cx32 and R359W mutation in EGR2. Daughter with

two different gene mutations showed more severe clinical,

electrophysiological and histopathological phenotypes than her father

with only EGR2 mutation.

CONCLUSIONS: From screening for mutations in the PMP22, MPZ, Cx32, EGR2,

and NEFL genes in Korean CMT patients, we found seven novel missense

mutations, and one family with both Cx32 and EGR2 mutations. Moreover,

EGR2 and Cx32 mutations cause different phenotypes within one CMT

family.

Thursday, April 29, 2004

7:30 AM

Room: Gateway Ballroom 103-104

A CMT1C Family with Gly112 Ser Mutation in LITAF/Simple: Mild Phenotype,

Minimal Axonal Loss and Slow Conduction Velocities

A. , Krajewski, Rosemary Shy, Detroit, MI, Mustafa

Saifi, Lupski, Houston, TX, E. Shy, Detroit, MI

OBJECTIVE: We define the clinical and electrophysiologic phenotype of

the neuropathy in a family with a Gly 112Ser mutation in LITAF/SIMPLE

(CMT-1C). We demonstrate that this mutation causes slow motor conduction

velocities but only mild clinical manifestations and minimal motor

axonal loss based on compound motor action potential amplitudes (CMAP)

and motor unit number estimation (MUNE).

BACKGROUND: Charcot-Marie-Tooth disease 1 (CMT-1) is a heterogeneous

group of inherited neuropathies typically caused by mutations in genes

encoding Schwann cell myelin proteins. It has become clear that the

clinical deficits in the most common form, CMT-1A, correlate more with

motor axonal loss than with conduction slowing. Recently mutations in

LITAF/SIMPLE on 16p13.1-p12.3 have been shown to cause CMT-1C. A

detailed clinical analysis of patients with CMT-1C has yet to be

determined. We have evaluated and analyzed a family with a Gly 112Ser

mutation in which motor axonal loss is minimal despite significant

conduction slowing.

DESIGN/METHODS: We evaluated 5 patients from two generations with

neurologic examinations, nerve conduction studies (NCS), MUNE and

quantitative sensory testing (QST) and compared these results to other

patietns with CMT-1A.

RESULTS: All 5 patients, ranging in age from 26 to 72, presented with a

classic, but mild CMT-1 phenotype as defined by Harding and

(Brain, 1980). Early milestones were normal but mild symptoms began in 3

patients in the first 2 decades and in 2 patients as an adult. All

patients had only mild motor signs and none used ambulation aids on

presentation. The 2 patients over the age of 70 had moderate vibration

and position sense deficits. 4 patients rated themselves as 90% capable

of normal activities of daily living. One rated himself at 80%. NCS were

uniformly slow with median motor NCS of 24 4 m/sec with normal CMAP of

7.6 2.2 millivolts. MUNE of the ulnar innervated intrinsic hand muscles

ranged from 82 to 128 (normal > 100). QST by Case IV showed vibration

JND thresholds of 7.9 3.7 in the hands and 19.8 4.3 in the feet.

CONCLUSIONS: This family with a Gly 112Ser mutation in LITAF/SIMPLE has

mild clinical disability that presents in a classic CMT-1A pattern that

is distinct from most patients with point mutations in myelin protein

zero, PMP-22 or EGR2. The conduction slowing was indistinguishable from

CMT-1A but the degree of motor axonal loss, as manifested by CMAP

amplitude and MUNE, was much less than seen in the majority of our

CMT-1A patients ( et al; Muscle Nerve 2003). This suggests that

this mutation may have less of an effect on Schwann cell-axonal

interactions than does PMP-22 duplication. It is unclear whether other

mutations in LITAF/SIMPLE have similar findings.

Thursday, April 29, 2004

7:30 AM

Room: Gateway Ballroom 103-104

Exogenous Brain Derived and Ciliary Neurotrophic Factors in the Wildtype

and Trembler-j Mouse, a Model for CMT1A

D. Weiss, Gregg Meekins, J. Emery, Seattle, WA

OBJECTIVE: To test whether exogenous brain derived (BDNF) and ciliary

(CNTF) neurotrophic factors improve myelination or axonal functioning in

wildtype and trembler-j mice.

BACKGROUND: The trembler-j mouse, a spontaneously occurring

demyelinating mutant resulting from a point mutation in the gene for

peripheral-myelin protein 22, is considered a model for

Charcot-Marie-tooth disease type 1A (CMT1A) by pathology and

electrophysiology. There is no specific therapy for CMT1A, a frequently

debilitating disease. Because recent studies have suggested that BDNF

plays a role in remyelination after injury and CNTF has a trophic

influence on nerve axon, these neurotrophic factors could also

potentially benefit CMT1A patients.

DESIGN/METHODS: Wildtype and trembler-j mice were injected

subcutaneously with 50 or 500 ng of BDNF or CNTF, or normal saline

(placebo), twice weekly. Sciatic nerve conduction was assessed before

and after 6 weeks of treatment. For stimulation, steel needle electrodes

were placed subcutaneously just above the left ankle and in the left

sciatic notch. Recording electrodes were placed in the left foot pad at

the base of the second toe. Conduction velocity and distal and proximal

motor latency, compound muscle action potential (CMAP) amplitude, and

duration were assessed from recordings made after supramaximal

stimulation. The animals were studied in a blinded fashion and

subsequently genotyped after the last nerve conduction study was

performed.

RESULTS: In comparison to before treatment, wildtype animals receiving

placebo (n = 7) had increased CMAP duration (+ 66%). However, all

wildtype animals receiving CNTF (n = 12) and BDNF (n = 13) had a

significant relative reduction of CMAP duration (- 77%) versus placebo

(p < .02). For wildtype mice following six weeks of treatment, those

receiving CNTF or BDNF versus placebo tended to have greater increases

in conduction velocity (+ 30%) and CMAP amplitude (+ 2 to 3 fold), and a

2 fold greater decreased distal motor latency; however these group

differences did not reach significance. In similarity to wildtype

animals, CNTF treated trembler-j mice (n = 10) as compared to

placebo-treated mice (n = 8) tended to have greater increased conduction

velocity (+ 45%) and CMAP amplitude (+ 50%), and a 3 fold greater

decreased distal motor latency. CNTF treated mutants demonstrated a

relatively reduced CMAP duration (- 60%) versus placebo. BDNF treated

mutants (n = 9) versus placebo also tended to have a greater distal

motor latency (+ 2-3 fold). However, differences between trembler-j

treatment groups failed to reach statistical significance. CONCLUSIONS:

Exogenous BDNF and CNTF appear to increase motor unit performance in

both trembler-j and wildtype mice, perhaps by altering the population or

caliber of motor nerve axons. The trend of increased conduction

velocity, decreased CMAP latency, and preserved CMAP duration in treated

mutant mice may indicate improved myelination. Both BDNF and CNTF may

ultimately prove useful in the treatment of CMT1A.

Thursday, April 29, 2004

7:30 AM

Room: Gateway Ballroom 103-104

Clinical, Pathological and Molecular Phenotype of a Human MPZ Mutation:

An Autopsy Study

Jun Li, Marina Grandis, M. Krajewski, Emilia Ianokova, J.

Kupsky, E. Shy, Detroit, MI

OBJECTIVE: To describe clinical, pathological, and molecular

architectural alterations in an autopsy from a patient with late onset

CMT1B.

BACKGROUND: Myelin protein zero (MPZ) is the major myelin protein

expressed by Schwann cells (SC) and probably mediates myelin compaction

via homotypic adhesion. Mutations in the gene cause Charcot-Marie-Tooth

disease type 1B (CMT1B). We have recently demonstrated that certain MPZ

mutations cause early onset neuropathy with severely slowed conduction

velocities (CV) where other mutations cause late onset neuropathy with

mildly reduced CV but pronounced axonal degeneration (Shy et al. Brain,

in press). Why late onset mutations cause axonal damage with minimal

physiologic features of demyelination is unknown. We have the

opportunity to address this issue in an autopsy of a patient with a late

onset neuropathy caused by a His10Pro MPZ mutation.

DESIGN/METHODS: A 73-year-old woman developed weakness and sensory loss

after age 40. Nerve conductions were only mildly slowed with evidence of

axonal degeneration. She developed progressive respiratory failure. An

autopsy was completed within 3 hours of her death. The following tissues

were harvested: ventral/dorsal roots, phrenic, sciatic, femoral, tibial

and sural nerves, cervical and lumbar spinal cord, and diaphragm muscle.

Tissues were divided into blocks for routine histological studies,

immunohistochemistry, and electron microscopy.

RESULTS: Initial results with immunohistochemistry of teased nerve

fibers demonstrated a reorganization of the axolemma and the development

of axonal enlargement, particularly at the paranodes. Nodes were

identifiable by sharply demarcated narrow bands of sodium channels

suggesting that the nodal structure is largely preserved. However, some

internodes were shortened, consistent with, but not proving,

remyelination. Moreover, conspicuous alterations of Caspr staining at

paranodal regions were present in many myelinated fibers. Caspr staining

flanking each side of the node was often asymmetric, or spread out of

the paranodal region; in some cases it was non-detectable. Studies

investigating length dependent axonal loss, the extent of demyelination,

and other molecular abnormalities are currently underway.

CONCLUSIONS: Preliminary results suggest that abnormalities in the

organization of the axolemma are involved in the pathogenesis of late

onset neuropathy in our patient. These abnormalities, particularly at

paranodes, may disrupt the concealment of current through potassium

channels at juxtaparanodes, and place increased energy demands on

neurons. Ongoing studies will explore the relationship between these

findings and the degree of demyelination and axonal loss in this

patient.

Thursday, April 29, 2004

7:30 AM

Room: Gateway Ballroom 103-104

A Sensory and Motor Neuropathy with a Predominant Proprioceptive Ataxia

O. Anne, H. Hazzedine, D. , La Rochelle, France, A. Vital, C.

Barhoumi, G. in, E. Le Guern, Paris, France, A. Lagueny, Bordeaux,

France

OBJECTIVE: To characterize a new sensory motor neuropathy with

predominant proprioceptive ataxia phenotype segregating with an

autosomal dominant mode of inheritance in a large French family.

BACKGROUND: Sensory ataxia is very rarely a major symptom of hereditary

neuropathies with dominant autosomal transmission. In most cases,

sensory ataxia is associated with either a cerebellar syndrome in the

context of spinocerebellar atrophy (SCA), or a superficial sensory

deficit in the framework of Charcot-Marie-Tooth diseases (CMT) and

Hereditary Sensory Neuropathies of type I (HSN I).

DESIGN/METHODS: We describe a French family in which segregated an

autosomal dominant sensory and motor neuropathy, characterized by late

onset of symptoms and sensory ataxia. This family comprises 96 members

including 26 affected individuals in four generations. This family was

screened for 40 microsatellites markers covring 8 loci: the most

frequent CMT loci (CMT 1A, 1B, 2A, 2B), HSN loci (HSN1A and HSN1B),

Sensory motor neuropathy with ataxia SMNA/SCA18 and, Spinocerebellar

ataxia 25 (SCA25). Genotyping was performed on an ABI-Prism 377

sequencer. Assignement of the family to each locus was established by

haplotyping and linkage analysis.

RESULTS: In 14 examined patients the muscle strength was normal except

in 9 cases in were a mild weakness in distal lower limbs was observed.

In all cases, vibratory and pinprick sensations were decreased or

abolished in distal limbs and deep tendon reflexes were absent or

depressed. Electrophysiological examination showed mildly reduced motor

and sensory nerve conduction velocities with severely decreased compound

muscle action potential (CMAP) and sensory nerve action potential

amplitudes. Peroneal nerve biopsy showed a severe loss of myelinated

fibbers with clusters of regeneration and few onion bulb formations.

These findings are consistent with a primary axonal degeneration with

some demyelinating features. At the genetic level, the 8 previous loci

were excluded.

CONCLUSIONS: We suggest that this family correspond to a new phenotype

variant of CMT2. A genome wide search is in progress in order to

localise the responsible gene.