Neuromuscular Disorders
Volume 8, Issue 6 , Pages 426-431, August 1998

2nd Workshop of the European CMT Consortium: 53rd ENMC International Workshop on Classification and Diagnostic Guidelines for Charcot-Marie-Tooth Type 2 (CMT2–HMSN II) and Distal Hereditary Motor Neuropathy (Distal HMN–Spinal CMT)

26–28 September 1997, Naarden, The Netherlands

Laboratory of Neurogenetics, University of Antwerp (UIA), Department of Biochemistry, Universiteitsplein 1, B-2610 Antwerpen, Belgium

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1. Introduction 

Major breakthroughs have been achieved in the study of hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1). Mutations in the peripheral myelin genes, peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) were identified as the cause of autosomal dominant HMSN I and mutations in Connexin 32 (Cx32) are associated with X-linked HMSN I [1]. The pace of progress in the study of hereditary motor and sensory neuropathy type II (HMSN II) or Charcot-Marie-Tooth disease type 2 (CMT2) and the distal hereditary motor neuropathy (distal HMN–spinal CMT) has been much slower. Therefore, on September 26–28 1997 a group of neurologists, neuropathologists and geneticists met in Naarden, The Netherlands at a multidisciplinary workshop on the `Classification and diagnostic guidelines for HMSN II and distal HMN'. This workshop was sponsored by a European concerted action and co-organized by the European Neuromuscular Center (ENMC). The workshop aimed to discuss the classification and molecular genetic data that underlie the clinical, neurophysiological and histopathological features of CMT2 and distal HMN. Diagnostic criteria for CMT2 and distal HMN were designed and evaluated. Results obtained on the current linkage data were discussed to pool resources for a genome wide search to identify additional loci.

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2. HMSN II or CMT 2 

2.1. Classification 

HMSN II or CMT2 is clinically characterized by a typical peroneal muscular atrophy syndrome. Electrophysiologically, CMT2 shows normal or slightly reduced motor and sensory nerve conduction velocities (NCV) and decreased amplitudes of evoked motor and sensory responses. CMT2 is genetically heterogeneous and can be inherited as an autosomal dominant or autosomal recessive trait. A complicated form of CMT2 with mental retardation and deafness is inherited as an X-linked recessive trait [2]. Four loci for autosomal dominant CMT2 have been mapped. The first locus CMT2A was localized on chromosome 1p35–p36 [3]. The families linked to this locus show a classical CMT2 phenotype. A second locus, CMT2B was mapped to chromosome 3q13–q22 [4]. CMT2B patients have in combination with weakness of the distal muscles, prominent sensory abnormalities with ulcerations leading to amputations of distal parts of the lower limbs [5]. CMT2C is a clinical entity associated with vocal cord paralysis [6]. Recently a third locus, CMT2D, was assigned to chromosome 7p14 in a single large pedigree. The phenotype in the latter family is unusual since the disease starts in the hands where it predominates [7]. A novel type of axonal HMSN with predominantly proximal involvement (HMSN-P) was recently described in a few Japanese families, and the gene locus was mapped to chromosome 3p14.1–q13 [8]. A locus for recessive X-linked CMT2 with deafness and mental retardation was mapped to chromosome Xq24–q26 [9]. No genes for these CMT2 types are identified yet.

2.2. Epidemiology and clinical features 

The inherited peripheral neuropathies are relatively common and, according to published data, all types combined have a prevalence of 20–40:100 000 10, 11. At this workshop, the prevalence of CMT2 was reported to be much lower than CMT1, e.g. in Sweden 3.9:100 000 and in Cantabria (Northern Spain), 12:100 000.

In an Italian family with suggestive linkage to chromosome 1p35–p36 (possibly CMT2A), patients showed a classical CMT phenotype. Younger generations seemed to be affected at an earlier age, but these younger patients were not more severely affected than their older relatives. The possibility of anticipation in this family was discussed. Motor median NCVs varied between 40 and 63 m/s, and were usually higher than 49 m/s (lower limit of normal range). One family with suggestive positive LOD scores with the CMT2B locus at 3q13–q22 showed prominent sensory abnormalities, ulcerations and eventually amputations of the distal parts of the limbs [12]. The differential diagnosis between CMT2B and hereditary sensory neuropathy type I (HSN I), linked to chromosome 9q22.1–q22.3 [13], was discussed and differences were observed in the clinical evolution, presence of pain attacks, ulcerations, ataxia, and abnormalities of pain, temperature and position sense. Several other families with a CMT2B or HSN phenotype were presented at this workshop, but since genetic studies were not yet completed, it was difficult to make genotype-phenotype correlations in these pedigrees. CMT2C with vocal cord paralysis is usually inherited as an autosomal dominant trait [2]. At the workshop, two brothers with a severe paresis of the limbs and vocal cord paralysis were described. Their parents were clinically normal which suggests an autosomal recessive mode of inheritance. Clinical heterogeneity was observed in autosomal recessive HMSN II; some families had a mild neuropathy while others presented a severe phenotype with onset in childhood. The combination of CMT2 with neuromyotonia was observed in another sibling and may represent a novel clinical entity.

CMT1X patients with Connexin 32 mutations (Cx32) and especially female patients, are sometimes diagnosed as CMT2 since NCVs can fall within the range of CMT2 14, 15. A French study compared female patients of autosomal dominant CMT2 families with CMT1X females carrying Cx32 mutations and found that the former group was more severely affected in terms of muscle weakness, wasting and areflexia.

2.3. Electrophysiology 

Studies within large CMT2 families showed two electrophysiological phenotypes. Some families have normal (>49 m/s) or homogeneously slowed motor median NCVs, but always higher that 40 m/s. Other families have more variable NCVs, varying from normal to severely slowed and even less than 30 m/s (38 m/s is usually considered to be the cut-off value for CMT1). It is well known that such variable NCVs are often associated with Cx32 mutations, but a similar electrophysiological phenotype was also observed in pedigrees with autosomal dominant inheritance. In some of these autosomal dominant families, mutations in the MPZ gene were identified (this report). In severely affected patients with extreme atrophy of the distal muscles, NCVs can be severely slowed due to axonal loss. It was suggested that in these cases measurements of the latencies in more proximal segments of the nerves can help to distinguish between a primarily axonal or demyelinating pathology.

Follow-up studies of an at risk individual in a Spanish CMT2 family showed that NCVs and concentric needle EMG were initially normal [16], while several years later, when discrete clinical signs appeared, the EMG showed some neurogenic alterations and the distal motor latencies of the peroneal nerve were increased.

2.4. Pathology 

Morphological data on CMT2 exclusively derive from older studies that predate molecular genetic diagnosis. This discrepancy precludes genotype/phenotype correlations. In general, sural nerve biopsies of CMT2 patients show chronic axonal atrophy with clusters of small regenerated fibers. Gross abnormalities of the axons are usually absent except for alterations of axon caliber with an increase of small fibers and loss of large fibers [17]. Some CMT2 patients have tomacula and a few onion-bulbs. The non-myelinated fibers may be involved. More clusters of remyelinating axons and less pronounced loss of large myelinated fibers were observed in autosomal dominant CMT2 patients compared with autosomal recessive CMT2 cases. Rare autosomal dominant CMT2 cases with neurofilament accumulation have been described [18]. Classical giant axonal neuropathy also shows accumulation of neurofilaments but this disorder is inherited as a childhood onset autosomal recessive disease. In some early onset severe autosomal recessive CMT2 cases a striking lack of large fibers was observed without axonal degeneration, clusters or demyelination. These findings could be interpreted as a developmental or maturation defect of the large axons.

2.5. Molecular genetics 

2.5.1. Linkage studies in CMT2 

At this workshop, suggestive positive LOD scores with the CMT2A locus were reported in only one family and another family showed suggestive linkage to the CMT2B locus. In genetic linkage studies comprising more than 20 large CMT2 families, no linkage was found with the CMT2A, CMT2B and CMT2D loci, further supporting genetic heterogeneity in CMT2. A genome wide search is on-going to identify additional CMT2 loci.

2.5.2. Cx32 mutations in `CMT2' 

NCVs in female CMT1X patients or Cx32 mutation carriers vary widely from severely reduced to normal. In clinical practice, female CMT1X patients are often diagnosed as CMT2 based on normal or slightly reduced NCVs although the underlying pathology is different from axonal autosomal dominant CMT2. In male CMT1X patients, NCVs are usually severely slowed. However, at this workshop, a young boy with CMT1X was reported who had normal NCVs. It was already suggested to screen female CMT2 patients for Cx32 mutations if no male to male transmission was observed in the pedigree [14]. This guideline should now be broadened to male CMT2 patients without a family history of a father to son transmission. Mutation analysis in French CMT2 patients with NCVs between 30 and 40 m/s, designated as `intermediate NCVs', showed Cx32 mutations in 40% of the cases 19, 20.

2.5.3. MPZ mutations in `CMT2' 

At the workshop, two MPZ mutations were reported in patients with a phenotype different from classical CMT1B. In an extended Sardinian pedigree with a Ser44Phe mutation the age at onset varied between 40 and 50 years [21]. The motor median NCVs in mutation carriers ranged from 23 to 57 m/s. Some young mutation carriers were clinically and electrophysiologically normal. A Thr124Met mutation in MPZ was found in five apparently unrelated Belgian families. Patients also showed late onset in the 4th or 5th decade and some patients became wheel-chair dependent. Several patients had severe hearing loss and Argyll–Robertson pupils were observed in most patients. Motor median NCVs ranged from 24 to 59 m/s (normal >49 m/s).

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3. Distal HMN or spinal CMT 

3.1. Classification 

HMN is an exclusively motor neuropathy characterized by a classical peroneal muscular atrophy syndrome and normal or slightly reduced motor NCVs. Sensory NCVs are always normal. Distal HMN is clinically and genetically heterogeneous and a classification in seven types based on mode of inheritance, age at onset and clinical progression was proposed 22, 23. At the workshop, several families with distal HMN types I, II, V and VII were presented. Distal HMN type I is characterized by juvenile onset between 2 and 20 years and distal HMN type II has an adult onset between 20 and 40 years. A locus for distal HMN type II was assigned to chromosome 12q24 in a large Belgian family [24]. Distal HMN type V is characterized by upper limb predominance and the locus was localized on chromosome 7p in a large Bulgarian family [25]. Distal HMN type VII has associated vocal cord paralysis. The gene loci for distal HMN type I and VII have not yet been identified.

3.2. Clinical features 

The clinical phenotypes in the distal HMN types I, II, V and VII families were similar as described in the literature. At this workshop, two families with congenital non-progressive distal HMN and contractures were re-examined 26, 27. The clinical phenotype of these two families is not included in the current HMN classification [23], and linkage analysis showed that this type is a separate genetic entity (discussed below).

3.3. Pathology 

The study of a sural nerve biopsy of an older distal HMN II patient, belonging to a large pedigree linked to 12q24 [24], showed only a somewhat reduced diameter of myelinated fibers. This finding was considered to be non-specific and might be due to the older age of the patient.

3.4. Molecular genetics 

Linkage analysis in a few families with distal HMN type I showed negative LOD scores with 12q and 7p markers indicating that distal HMN type I is not allelic with the distal HMN types II and V. Suggestive but non-conclusive linkage with chromosome 14q11.2 markers was obtained in a Dutch family with mild, childhood onset distal HMN. An update on the linkage analysis on the large Belgian chromosome 12q24 linked distal HMN II family was presented. A YAC contig spanning the 13 cM candidate region is being constructed. At this workshop evidence for genetic heterogeneity in distal HMN type V was reported. Two small Italian distal HMN V families showed slightly positive LOD scores with markers flanking the 7p region, while large Dutch and Spanish distal HMN V families showed no linkage to 7p. Both the 7p and 12q loci were excluded in a large French distal HMN type V family. One of the two families with congenital, non-progressive distal HMN showed linkage to the chromosomal region 12q23–q24, proximal to the region of distal HMN type II, the other family was excluded for this locus. It is interesting to note that a novel gene locus for scapuloperoneal spinal muscular atrophy was recently mapped to the same chromosomal region [28].

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4. Diagnostic criteria 

At the end of the workshop, diagnostic criteria were formulated and requirements defined for families to be included in the linkage analyses. Detailed notes for guidance are described below. Inclusion criteria are indicated. `I' and `E' denote exclusion criteria and `C' stands for comment.

4.1. Diagnostic criteria of hereditary motor and sensory neuropathy type II (HMSN II) or Charcot-Marie-Tooth type 2 disease (CMT2) 

4.1.1. Clinical criteria 

Family history

I. Autosomal dominant, recessive or X-linked inheritance.

C. Isolated cases have either recessive CMT2 or are the result of a de novo mutation of dominant CMT2.

Age at onset

I. Wide range of onset, usually in the first two decades.

Muscle wasting and weakness

I. Muscle wasting and weakness of predominantly the distal parts of the lower limbs, usually symmetrical.

I. Extensors of feet and toes, as well as intrinsic foot muscles are usually earlier and more severely affected than calf muscles.

C. Later, wasting and weakness of the intrinsic hand muscles and the distal part of the medial vastus muscle and other parts of the quadriceps muscle may develop.

C. Weakness of the hands is a rare presenting symptom.

C. Some patients, in particular autosomal recessive cases, may develop shoulder amyotrophy.

C. Calf muscle hypertrophy may be present.

Other associated features

C. Impaired sensation is frequently observed but is not an obligatory feature.

C. Pes cavus, scoliosis, tremor, ulcerations, sensorineural deafness, mental retardation, diaphragmatic and vocal cord paralysis.

E. Predominant CNS involvement including pyramidal tract or cerebellar signs.

Course and severity

I. Slowly progressive with variable severity.

4.1.2. Laboratory criteria 

Metabolic studies

E. Metabolic and acquired cause for neuropathy

E. Markedly elevated CPK.

Electrophysiology

I. Median motor NCV >38 m/s in at least one affected person in the family.

I. Small or absent sensory nerve action potentials.

I. Neurogenic pattern at concentric needle EMG.

C. Median motor NCV <38 m/s in some family members does not militate against the diagnosis CMT2.

C. Electromyographic evidence of denervation is often present.

C. Reduced compound muscle action potentials are usually observed.

C. Motor NCV in single nerves (usually peroneal) may be not measurable in advanced cases due to important muscle atrophy.

Sensory nerve biopsy

I. Reduction of density and total number of large myelinated fibers.

I. Clusters of thinly myelinated regenerating fibers.

C. Extensive loss of large myelinated fibers and a diminished total transverse fascicular area.

C. Small onion bulbs may occasionally be present.

Molecular genetics

E. Exclusion of the CMT1A duplication.

C. CMT2 loci have been identified on chromosomes 1p35–p36 (CMT2A), 3q22–q23 (CMT2B) and 7p14 (CMT2D).

4.2. Diagnostic criteria of distal hereditary motor neuropathy (distal HMN) or spinal Charcot-Marie-Tooth disease 

4.2.1. Clinical criteria 

Family history

I. Autosomal dominant or recessive inheritance.

C. Isolated cases have either autosomal recessive distal HMN or are the result of a de novo mutation of autosomal dominant distal HMN.

Age at onset

I. Usually in the first decade of life.

C. There is a wide range of onset; varying from congenital to late onset.

Muscle wasting and weakness

I. Muscle wasting and weakness of predominantly the distal parts of the extremities.

C. Onset of muscle weakness and wasting usually in the distal parts of the lower limbs, initially in the peroneal compartment and intrinsic foot muscles.

C. In some families, weakness and wasting of calf muscles preceding weakness of ankle dorsiflexion may be the earliest sign.

C. In a small proportion of patients onset of weakness of the muscles of hands and forearms is the presenting symptom.

C. Asymmetrical onset may occur.

C. In the case of onset with muscle weakness of the distal part of the lower limbs, wasting and weakness of the intrinsic hand muscles and proximal muscles of the lower limbs may develop in the latest stage of the disease.

C. Calf muscle hypertrophy may be present.

E. Predominant proximal muscle weakness.

Other associated features

C. Arthrogryposis, pes cavus, scoliosis, tremor, progressive sensorineural deafness, vocal cord paralysis.

E. Impaired sensation.

E. Significant involvement of CNS, including pyramidal tract.

Course and severity

I. Slowly progressive with variable severity.

C. Stationary in congenital type.

4.2.2. Laboratory criteria 

Metabolic studies

E. Metabolic and acquired cause for neuropathy

E. Markedly elevated CPK.

Electrophysiology

I. Normal or slightly reduced motor NCVs.

I. Normal sensory NCVs.

I. Neurogenic abnormalities on needle EMG.

C. Motor NCV in single nerves (usually peroneal) may be not measurable in advanced cases due to important muscle atrophy.

E. Myopathic abnormalities in distal muscles.

Pathology

C. Sural nerve biopsy is normal except for age related changes.

Molecular genetics

E. Exclusion of mutations in the survival motor neuron gene (SMN) associated with proximal spinal muscular atrophy on chromosome 5q11.2–13.3.

C. Distal HMN loci have been identified on chromosomes 12q24 (distal HMN type II) and 7p (distal HMN type V).

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5. Workshop advisors 

A. Brice (Paris, France)

(Amsterdam, The Netherlands)

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6. Workshop participants 

M. Auer-Grumbach (Graz, Austria)

J. Berciano (Santander, Spain)

J. Beuten (Antwerpen, Belgium)

G.J. Braathen (Oslo, Norway)

C. Van Broeckhoven (Antwerpen, Belgium)

K. Christodoulou (Nicosia, Cyprus)

C. Cianchetti (Cagliari, Italy)

P. De Jonghe (Antwerpen, Belgium)

O. Dubourg-LeGuern (Paris, France)

B. van Engelen (Nijmegen, The Netherlands)

U. Ericson (Stockholm, Sweden)

A. Gabreëls-Festen (Nijmegen, The Netherlands)

E. LeGuern (Paris, France)

L. Van Maldergem (Loverval, Belgium)

J.-J. Martin (Antwerpen, Belgium)

F. Palau (Valencia, Spain)

M. Reilly (London, England)

N. Rizzuto (Verona, Italy)

J.M. Schröder (Aachen, Germany)

T. Sevilla-Mantecon (Valencia, Spain)

V. Timmerman (Antwerpen, Belgium)

M. Villanova (Siena, Italy)

M. Zappia (Catanzaro, Italy)

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Acknowledgements 

This workshop was made possible by the financial support by the European Union BIOMED2 grant: `Clinical, genetical and functional analysis of peripheral neuropathies: an integrated approach' (CT961614 and CT960055) and the European Neuromuscular Centre (ENMC) and its main sponsors and associate members. We are grateful to Prof. em. A.E.H. Emery for his scientific help, and to Mrs. Janine de Vries and Mr. Michael Rutgers for the organizational assistance of the ENMC. Prof. C. Van Broeckhoven is the coordinator of the European CMT consortium.

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PII: S0960-8966(98)00025-X

Neuromuscular Disorders
Volume 8, Issue 6 , Pages 426-431, August 1998

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