Neuromuscular Disorders
Volume 9, Issue 4 , Pages 279-287, 1 June 1999

4th Workshop of the European CMT-Consortium – 62nd ENMC International Workshop: Rare forms of Charcot-Marie-Tooth disease and related disorders. 16–18 October 1998, Soestduinen, The Netherlands

  • Jean-Jacques Martin

      Affiliations

    • Laboratory of Neuropathology, Born-Bunge Foundation, University of Antwerp(UIA), Universiteitsplein 1, Antwerpen, Belgium
    • Corresponding Author InformationCorresponding author
    • ,
  • Alexis Brice

      Affiliations

    • INSERM U289, Hôpital de la Salpêtrière, Bâtiment Pharmacie, Boulevard de l‘Hôpital, Paris, France
    • ,
  • Christine Van Broeckhoven

      Affiliations

    • Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), Laboratory of Neurogenetics, Born-Bunge Foundation, Department of Biochemistry, University of Antwerp, Universiteitsplein 1, Antwerpen, Belgium

Article Outline

 

Back to Article Outline

1. Introduction 

The autosomal recessive types of Charcot–Marie–Tooth (CMT) disease are rarer than the classical dominant forms in Western Europe but they are reported in many different places and especially in the Mediterranean countries. Experts in the field were brought together to discuss the classification and molecular genetic data that underlie the clinical, neurophysiological and histopathological features of different disorders like autosomal recessive Charcot–Marie–Tooth disease type 1 (CMT 1), hereditary motor and sensory neuropathy type V (HMSN V), giant axonal neuropathy (GAN), hereditary sensory neuropathies (HSN), hereditary sensory autonomic neuropathies (HSAN) and hereditary neuralgic amyotrophy (HNA).

Other forms of CMT that are not included in the HMSN classification were recently studied in more detail and some novel entities were described in highly inbred North African, Saudi Arabian, Sudanese and Bulgarian families. These forms include autosomal dominant CMT 2 with hyperkeratosis, autosomal recessive CMT with glaucoma, several recessive forms of HSN and CMT 2. Linkage analyses in these pedigrees are expected to lead to the identification of new chromosomal loci and genes for peripheral neuropathies. Special attention was also paid to new disease entities such as HMSN-LOM disease that were recently ascertained in highly inbred families with a gene locus which is already known.

This multidisciplinary workshop had also the purpose to stimulate new or intensify existing collaborations among the participants and to enhance the research into this group of inherited peripheral neuropathies. A table gives a preliminary estimate of the number and type of CMT families in some countries (Table 1).

Table 1. Estimates of the number and type of CMT families
CountryAutosomal dominantAutosomal recessiveX-linkedUnknown/sporadicHMSN-LOMCCFDNTotal
Italy6512065 142
Morocco611014 31
Tunisia181140 33
Algeria2040UnknownUnknown Unknown
Saudi ArabiaUnknown6UnknownUnknown Unknown
Turkey181706 41
Bulgaria 25 + 719

De Jonghe (Antwerpen, Belgium) described the general clinical features of the autosomal recessive forms of CMT. Most older studies of autosomal recessive hereditary motor and sensory neuropathies (HMSN) include isolated cases. It is usually assumed that these isolated cases represent genuine autosomal recessive HMSN cases particularly when the parents are consanguineous. Molecular genetic studies however, have recently shown that a large number of these isolated cases are due to de novo mutations in known peripheral myelin genes and related genes [1]. The majority of these de novo cases have the 1.5 Mb CMT 1A duplication but point mutations in peripheral myelin 22 (PMP22), myelin protein zero (P0), connexin 32 (Cx 32) and the early growth response 2 (EGR2) genes have also been documented. Patients, homozygous for the CMT 1A duplication or some P0 mutations tend to have a more severe phenotype. The heterozygous parents always show at least some subclinical involvement. More recently, siblings homozygous for a PMP22 mutation and sibs homozygous for an EGR2 mutation have been reported [2], [3]. The consanguineous parents, heterozygous for the mutation, were clinically and electrophysiologically normal. These sibs represent true cases of autosomal recessive CMT 1. In conclusion, isolated cases should be screened for mutations in genes implicated in CMT 1 and sibs with autosomal recessive CMT 1 can be screened for mutations in PMP22 and EGR2.

Gabreëls-Festen (Nijmegen, The Netherlands) described the neuropathological features observed in autosomal recessive HMSN. Autosomal recessive forms of HMSN include myelin/Schwann cell disorders (HMSN type 1) and neuro-axonal disorders (HMSN type 2). Both types are markedly heterogeneous in clinical, morphological and genetic aspects. Until recently, classification of these rare forms was based merely on clinical and morphological features. In the last few years several gene loci have been identified in HMSN type 1, each with a rather typical combination of clinical and morphological features.

1.1. Autosomal recessive HMSN type 1 

At present, four different phenotypes can be discerned in autosomal recessive HMSN type 1 on morphological criteria: (1) congenital hypomyelination; (2) focally folded myelin; (3) few classic onion bulbs; (4) involvement of myelinated and unmyelinated Schwann cells. However, on-going investigations likely will demonstrate additional morphological expressions in autosomal recessive forms.

1.Severe hypomyelination of the peripheral nerves with a congenital disease onset was reported in a number of sporadic and autosomal recessive cases of unknown etiology. Axons show no or only very thin myelin sheaths and are surrounded by ‘onion bulbs’ of single or double basal membranes. Recently, this phenotype was reported in a few (hetero- and homozygous) P0 and PMP22 mutations carriers [4], [5] and in one case homozygous for a EGR2 mutation [2].

2.The forms with focally folded myelin are characterised by the occurrence of abundant focal outfoldings of the myelin sheath [6], [7]. These structures are in many respects different from the hereditary neuropathy due to pressure palsies (HNPP) tomacula. This phenotype results from different genetic defects: heterozygous P0 mutations [8], other unknown autosomal dominant mutations [9] and in at least three distinct autosomal recessive forms with different gene loci [10], [11], [12].

3.One definite autosomal recessive case with a few classic onion bulbs in a nerve biopsy was described by Harding and Thomas [13]. Some of the cases with newly described gene loci also show few and small onion bulbs and are often marked by a severe and early loss of myelinated axons, dominating the pathology in adult cases [14].

4.The fourth type, characterised by an involvement of myelinated and unmyelinated Schwann cells was described in 1992 [15]. Nerve biopsies show a chronic demyelinating neuropathy with few and small classic onion bulbs. Onion bulbs consist of multiple basal membranes, sometimes intermingled with few Schwann cells lamellae. Schwann cells of myelinated but especially of unmyelinated Schwann cells show multiple cytoplasmic extensions. An identical morphology was found in one biopsied case of the Algerian families with a disease locus on 5q23–33 [16]. Subsequent testing for the 5q region confirmed a gene locus in a region between D5S643 and D5S670 in these patients of five Dutch and one Turkish family with this pathological phenotype. This disorder is defined by a precocious and rapidly progressing scoliosis in combination with a relatively mild neuropathy and a unique pathology.

1.2. Autosomal recessive HMSN type 2 

There are only a few reports of HMSN type 2 or neuronal HMSN with an autosomal recessive mode of inheritance [17]. Pathology in the described cases is marked by a near total loss of large diameter fibres from early age on, and hardly any signs of regeneration, which contrasts with the autosomal dominant form of HMSN type 2 [18]. At present, no gene loci have been identified. Recently, autosomal recessive neuronal types with a milder phenotype were reported in consanguineous North-African families [19].

Back to Article Outline

2. Classification of the disorders 

2.1. Autosomal recessive conditions 

2.1.1. Pure forms 
2.1.1.1. Myelinopathies with known genetic loci 
2.1.1.1.1. Chromosome 5q. 

The examination of two large consanguineous Algerian families by Grid (Evry, France) has enabled the definition of a peculiar phenotype linked to chromosome 5q23–33 [20]. The disorder starts before the age of 10 years and is characterised by a precocious and severe deformity of the spine requiring very often a surgical correction. The other peculiar clinical feature is the very slow progression producing a milder invalidity by comparison with the other autosomal recessive neuropathies. The morphological study shows small onion bulbs and myelinated or unmyelinated axons surrounded by numerous single or duplicated basal membranes, realising basal lamina onion bulbs. The clinical and neurophysiological features are similar to those described in Dutch families linked to the same locus [15]. Four other families from Morocco, Tunisia and France, also linked to locus 5q23–33, present with the same phenotype despite minor variations. Unfortunately, they do not permit to reduce the candidate region. As there are no evident candidate genes by function in the databases, a physical map of the 5q31–33 region has been constructed based on the report of Li et al. [21]. Using additional YACs, ten microsatellite markers which cover a 6 cM interval have been ordered on the contig. The most probable candidate interval which corresponds to the minimal region of homozygosity is covered by 7 YACs with an estimated size of 1400 Kb. This region has been mapped to 5q32 by FISH analysis. In order to identify candidate genes by their position, 10 out of 40 genes previously assigned to 5q31–33 have been tested on the contig. Two genes are located on YACs which overlap the candidate region but no mutation has been detected by sequence analysis in the Algerian families.

2.1.1.1.2. Chromosome 8q. 

Clinical, genealogical, electrophysiological and nerve biopsy analysis of patients with CMT disease has allowed Hentati (Tunis, Tunisia) to describe 26 patients belonging to 11 Tunisian families with autosomal recessive inheritance. Three groups could be distinguished according to nerve conduction velocity (NCV) and nerve biopsy findings: (1) group A including five families and 15 patients; (2) group B with two families and six patients and (3) group C with four families and ten patients. The group A patients presented delayed motor development and symptoms were noticed by the end of the first year of life in all patients. The clinical examination, realised at mean age of 13.6 years, showed a marked distal weakness and atrophy of lower and upper limbs, absent deep tendon reflexes and moderate distal sensory loss. Three of the patients became wheelchair-bound between the age of 10 and 12 years. Motor NCVs were unobtainable in the upper limbs of seven patients. Sensory action potentials were absent in the median and saphenous nerve in four patients. When present the motor and sensory NCVs were respectively reduced to 30±2.91 m/s and 17.25±3.8 m/s for the median nerve. Nerve biopsies showed variable reductions in the number of large myelinated fibres and typical onion-bulb formation. This CMT form type 4A, CMT 4A, was mapped to chromosome 8q13. The other groups (B and C) were not fully discussed.

2.1.1.1.3. Chromosome 11q. 

HMSN with focally folded myelin sheaths, or CMT type 4B (CMT 4B), is a distinct clinical and genetic entity belonging to the heterogeneous group of autosomal recessive demyelinating neuropathies. A. Gambardella (Catanzaro, Italy) described a large inbred pedigree with ten patients affected by CMT 4B [10], [22]. This hereditary demyelinating neuropathy represents a distinct clinical and genetic entity with an autosomal recessive pattern of inheritance. The clinical picture observed in the affected individuals is uniform and characterised by infantile onset with progressive symmetric distal and proximal muscular weakness starting in the lower extremities and eventually involving the hands and forearms. Cranial nerve involvement is an additional feature observed in most of the patients. All these findings are very similar, further supporting the notion that familial cases with CMT 4B display a rather homogeneous clinical spectrum in age at onset and progression of the disease. A striking feature of all these familial cases is the non random nature of age at onset, with the majority clustering around two years of age.

Using homozygosity mapping and haplotype sharing analysis, Bolino et al. [10] found evidence for linkage to chromosome 11q23. Gambardella et al. [23] then identified a second unrelated family in which two individuals were affected with CMT 4B. Although the clinical findings were similar to those previously reported, they excluded the disease locus segregating in this smaller pedigree from the 11q23 region. Evidence was thus provided for genetic heterogeneity with a second locus causing the CMT 4B phenotype [23].

Also, Gabreëls-Festen et al [8] recently found different mutations in P0 in three sporadic unrelated patients, whose clinical and neuropathological findings were highly characteristic of CMT 4B. Therefore, all these findings clearly indicate that CMT 4B is phenotypically quite homogeneous but genetically heterogeneous.

2.1.1.1.4. HMSN-LOM. 

Thomas (London, UK) reported the features of the hereditary motor and sensory neuropathy - LOM type (HMSN-LOM). HMSN-LOM, named after the city in northwest Bulgaria where the initial cases were identified, is an autosomal recessive neuropathy that is observed mainly in Balkan gypsies. It is characterised by an onset in the first decade of distal weakness in the legs, followed by distal upper limb weakness in the second and deafness in the third decade of life. All sensory modalities are affected. Severe disabilities develop by the fifth decade, although sometimes as early as the second decade. NCV studies indicate a demyelinating neuropathy. This was confirmed by nerve biopsy observations that show poorly developed onion bulbs and progressive severe axonal loss. Brainstem auditory potential recordings suggest demyelination both in the 8th nerve and in the central auditory pathways.

Kalydjieva (Joondalup, Western Australia) commented on genetic epidemiology, population genetics and social anthropology of Balkan gypsies. All indicate that common single gene disorders in gypsies are likely to be genetically homogeneous and caused by single founder mutations. At the same time, high gene frequencies, divergence between gypsy groups and possible old age of disease mutations with resulting haplotype divergence, complicate the picture and make approaches such as homozygosity mapping and searching for segment sharing inappropriate for localising disease genes in gypsies. Since the mapping of HMSN-LOM to 8q24 [14], a large number of additional families with the disorder were diagnosed in many countries, bringing the number of affected individuals to over 80. The molecular analysis of these families for known and newly identified microsatellite markers in the region, has helped to identify recent and historical recombinations and narrowed down the critical interval. A contig of bacterial artificial chromosomes (BAC) clones is under construction by sequence tagged sites mapping. About 400 kb of the previously defined HMSN-LOM region were excluded. Radiation hybrid mapping data indicated that the size of the remaining gap in the BAC contig is about 300–400 kb. Genes and expressed sequence tags (ESTs) roughly mapped to the 8q4 region are being tested against the BAC contig clones.

Merlini (Bologna, Italy) reported on 142 CMT families studied at the Rizzoli Orthopaedic Institute, Bologna, Italy. Rizzoli is a 350 orthopaedic bed hospital with 18,000/year in-patients, 8,000 surgery and 38 000 out-patients. Of the 142 CMT families, 103 were type 1 (demyelinating forms with motor NCV<35 m/s) and 39 type 2 (axonal/neuronal with motor NCV>40 m/s, distal denervation and absent or reduced amplitude's sensory action potential). In the type 1 group, 90 were non-consanguineous and 13 were consanguineous families. In the type 2 group, ten families showed a clear dominant inheritance, while the other 29 were small families or sporadic cases, none were consanguineous. Molecular genetic studies allowed the identification of 21 families with CMT 1A, 2 with CMT 1B, 7 with HNPP and 2 with HMSN-LOM. In the Italian gypsy family with HMSN-LOM [24], four (aged 8, 11, 13, and 14 years) out of five siblings were affected. Onset was in the first years of life with foot deformity and clumsy gait. Distal muscle wasting and weakness became evident at the end of the first decade with a progressive course. In the oldest affected sibling, hearing loss was noticed at age 12 years when proximal weakness became also evident. Motor NCV was between 6 to 15 m/s in the upper limbs. Sensorineural hearing loss was documented with audiometry and brain stem evoked potentials. Sural nerve biopsy showed axonal loss and onion bulbs. The second family was consanguineous and of Rumanian gypsy origin. The two patients were in their third decade and showed a very severe distal and proximal muscle wasting and weakness with foot deformity. Both families showed linkage to chromosome 8q24 and segregate a conserved haplotype.

2.1.1.2. Myelinopathies with unknown genetic loci. 

Salih (Riyadh, Saudi Arabia) reported on demyelinating (type 1) and neuronal (type 2) autosomal recessive forms of HMSN or CMT disease which are relatively frequent in Saudi Arabia and North Africa because of a high rate of consanguinity. A variant of autosomal recessive demyelinating CMT manifested a prominent pathological feature characterized by excessive myelin outfolding. He reported on the clinical, electrophysiologic and neuropathologic features of two unrelated Saudi kindreds affected with this variant of CMT. The first kindred extended for six generations and four of its members had the disease, including 2 children (a boy and a girl) and a 23-year-old man. The fourth (a female) died at the age of 14 years. The second kindred extended over five generations and two of its members were affected. These were a 14-year-old adolescent and a female who died of the disease at the age of 20 years. The associated proximal weakness of the lower limbs seemed to be a prominent feature of this CMT form, as well as facial weakness, high-arched palate and thick lips. Motor milestones were usually delayed and there was a precocious involvement of the upper limb muscles in the first decade.

Neurophysiological findings were characterised by severely reduced motor NCVs and absence of sensory action potentials. Median motor NCV ranged between 9.3 and 18.9 m/s in the young patients and no compound muscle action potentials could be obtained at the age of 14 years. There was also evidence of involvement of the phrenic nerve, the 8th cranial nerve and the visual tracts. Genetic studies in the first kindred confirmed linkage to chromosome 11q23 and refined the location of the gene between D11S1311 and D11S917, a 3.3 cM region. Genotyping studies in the second family are pending.

2.1.1.3. Axonopathies with unknown genetic loci. 

The axonal form of autosomal recessive CMT disease is rare. Up to date, the genetic defect(s) of this subtype have yet to be determined. Birouk (Rabat, Morocco) analysed this phenotype of CMT neuropathy in 13 patients belonging to three families of Moroccan ancestry. The parents of each affected individual were consanguineous and had normal clinical and electrophysiologic examinations confirming the recessive transmission. The clinical severity in terms of age at onset, functional disability and the existence of skeletal deformities were widely variable between families. Electrophysiology showed characteristics of the axonal form of CMT disease such as slightly reduced motor NCV, abnormal sensory nerve action potentials and reduced recruitment pattern with fibrillation potentials by needle electromyography examination. Evoked potentials studied in one family were abnormal. Pathological study performed in two families showed axonal neuropathy with no abnormal myelin proliferation. Molecular genetic studies consisted of exclusion of the known loci responsible for demyelinating autosomal recessive CMT (8q13–21, 8q21, 11q23, 5q23–33) and the loci responsible for axonal autosomal dominant CMT (3q13–22, 7p14, 1p35–36). A genome wide search using homozygosity mapping allowed to demonstrate linkage of the first family to a new locus. This locus was excluded in the second family. Thus the axonal form of autosomal recessive CMT disease is phenotypically and genetically heterogeneous.

2.1.1.4. Various disorders not yet classified. 

Topaloglu (Ankara, Turkey) has analysed the clinical features of families with several forms of autosomal recessive neuropathies. He and his co-workers excluded patients with giant axonal neuropathy, neuroaxonal dystrophy and leucodystrophies. The cohort consisted of 17 families. Consanguinity was present in 15 families and six families were multiplex. Age of onset was from birth to 7 years. Current ages of the patients ranged from 45 days to 16 years. All but two were ambulant. None of the patients had mental retardation. In most instances, electroneuronomyography helped to distinguish the sub-types. Nerve biopsies were carried out in the two youngest patients. Seven families were classified as demyelinating and three as axonal forms. There was one family with congenital hypomyelinating neuropathy, one with congenital dysmyelinating neuropathy, one demyelinating associated with severe deafness, one demyelinating plus nail dystrophy and one with congenital insensitiviy to pain. Two families could not be classified. Nerve biopsies and DNA examinations are currently being performed

2.1.2. Complex forms 
2.1.2.1. Congenital cataracts, facial dysmorphism, neuropathy (CCFDN). 

Thomas (London, UK) described the congenital cataracts – facial dysmorphism – neuropathy (CCFDN) syndrome which is also of autosomal recessive inheritance and is mainly encountered in Wallachian gypsies. It is recognised from birth by the presence of congenital cataracts and microcorneae. A predominantly motor neuropathy beginning in the lower limbs and later affecting the upper limbs develops during childhood and leads to severe disability by the third decade. Associated neurological features include a moderate non-progressive cognitive deficit in most affected individuals, together with mild chorea and pyramidal signs in some. Accompanying non-neurological features include short stature, a characteristic facial dysmorphism and hypogonadotrophic hypogonadism. Nerve conduction and nerve biopsy studies indicate a hypomyelinating/demyelinating neuropathy with later axonal degeneration.

Kalaydjieva (Joondalup, Western Australia) mapped the CCFDN gene by using a set of six affected sib pairs and an affected family with a peculiar configuration where four patients, related to each other in different ways, were expected to share alleles for a linked marker. After the initial genome scan, candidate regions were investigated on all affected families in the collection. The CCFDN gene was localised to 18q23-quater near marker D18S1141 (lod score 9.02 at θ=0.00). Haplotype analysis suggests genetic homogeneity, with all patients homozygous for the same allele of D18S70 (immediately telomeric to D18S1141) and a highly conserved haplotype in a large proportion of disease alleles.

2.1.2.2. With mental retardation and epilepsy. 

Another three families (two Sudanese and one Saudi) with neuronal autosomal recessive CMT were also described by M. Salih (Riyadh, Saudi Arabia). The onset of the disease ranged between birth (with foot deformities) in six individuals and 6–7 months in another two. Despite interfamilial clinical heterogeneity, both Sudanese families revealed evidence of linkage to markers on chromosome 8q. The two Sudanese girls of the first family (aged 10 and 12 years, respectively) were mentally retarded, had epilepsy, showed distal and proximal muscle weakness and were bed-ridden. The two boys who belonged to the second Sudanese family were mentally normal and had distal muscle weakness of the lower limbs associated with scoliosis. Their phenotype was generally similar to the Saudi family with four affected siblings (two males, two females). Genetic studies in the latter family are pending. In these three families, neurophysiologic studies revealed median motor NCV ranging between 34.5 and 66.8 m/s. Peroneal motor NCV ranged between 40.5 and 59.5 m/s. Amplitude of the compound muscle action potentials varied from 0.35 to 0.56 mV. The peroneal compound muscle action potentials could not be recorded in two of seven patients. The sural sensory compound action potential was absent in five cases and abnormal in another one. Neuropathologic features were characterised by myelinated fibre loss of varying degrees which was not associated with the presence of tomacula, hypermyelination, onion-bulb formation or basal lamina proliferation. The known loci for recessive CMT were tested in both families. The loci 11q23, 5q23–33 and 8q21 were excluded. But in the first family, both patients shared the same genotypes and a homozygosity region was observed, overlapping the candidate region on chromosome 8q13. These results suggested a possible linkage. In the second family, both patients had the same genotypes for the 8q13 markers so that also in this family the 8q13 locus could not be excluded.

The importance of detailed neurophysiological investigations of both parents is emphasised by highlighting examples of cases in two families with first degree consanguineous parents. These were initially presumed to have autosomal recessive CMT but later proved to be affected with dominant forms. The index case in the first family had features suggestive of HNPP whereas the second family had two daughters with HMSN and spastic paraplegia (HMSN type V).

2.1.2.3. With glaucoma. 

Gouider (Tunis, Tunisia) reported an inbred family with four affected children from 10 to 18 years of age who presented with HMSN associated with juvenile glaucoma (iridogoniodysgenesis, abnormal trabeculum, megalocorneae and buphthalmos) [25]. The peripheral neuropathy was characterised by early onset age (5–11 years), hand muscles and peroneal atrophy, abolition of deep tendon reflexes in lower limbs and pes cavus. A kyphoscoliosis was also noted but there was a large intrafamilial variability. A dysgenesis of the iridocorneal angle was noted in the four affected members leading in one case to a high ocular tonus and a severe visual loss. The motor NCVs were 13–18 m/s for the median nerve and 10–15 m/s for the peroneal nerve. The sensory nerve action potentials were absent in the four limbs and somatosensory evoked potentials were not elicitable. The disease was transmitted in an autosomal recessive mode. Indeed all parents of the affected children in this inbred family had normal clinical and electrophysiologic examinations. Clinically unaffected siblings had normal NCVs. Previously published loci of dominant and recessive demyelinating CMT disease, as well as loci of autosomal recessive glaucoma were excluded, confirming the genetic specificity of this phenotype.

2.1.2.4. With deafness (some X-linked). 

Deafness is a symptom which is not rare in classical CMT 1 and CMT 2 and also in complex forms of HMSN where other disturbances such as pyramidal signs, optic atrophy, pigmentary retinopathy can be present. In the last years, a few pedigrees have been described where CMT was associated with deafness and mental retardation. Mancardi (Genova, Italy) described a family where two brothers, sons of cousins, had a severe form of CMT associated with deafness and mental retardation [26]. Deafness became apparent at the age of 5 or 6 years. The intellectual quotient was ±50. Motor NCVs were markedly delayed and sensory nerve action potentials were not recorded from the sural nerve. Biopsy of sural nerve showed a nerve composed only of small myelinated fibres while the larger ones were absent, without signs of demyelination. The histogram was shifted to the left and the morphometric study confirmed the presence of only small axons. Few other cases, completely similar to the cases reported by Mancardi et al. [26] were recently reported by Sabatelli et al. [27]. Cowchock et al. [28] described in the past a large family with seven males affected by CMT type 2, deafness and mental retardation. The disease locus in this family was later mapped to chromosome Xq24–26. The biopsy findings of the cases described by Cowchock et al. [28] were however completely different from those reported by Mancardi et al. [26] and Sabatelli et al. [27]. The genetic study of these last cases is in progress and is mainly focused on the study of the connexins.

2.2. Autosomal dominant conditions 

2.2.1. HMSN type V 

HMSN type V (HMSN V) is a very rare disease in which familial spastic paraplegia is associated with HMSN [29]. HMSN V is inherited as an autosomal dominant trait with usually incomplete penetrance. As yet no data is available in the literature mapping this disease. In a large Italian family, Rampoldi (Padua, Italy) collected DNA samples from 32 individuals, of which 12 are affected. Although the index case presented a clear association of the two phenotypes, the other affected subjects showed heterogeneous clinical signs, either with predominant pyramidal traits or a main involvement of the peripheral nervous system. The onset of the disease was usually after the third decade with a different degree of progression and severity. Rampoldi excluded by linkage analysis the association of the disease with all known loci for autosomal dominant CMT 2 (CMT 2A on 1p35–36, CMT 2B on 3q13–22 and CMT 2D on 7p14), pure autosomal dominant familial spastic paraplegia (SPG3 on 14q12–q23, SPG4 on 2p21-p24, SPG6 on 15q11.1) and pure recessive familial spastic paraplegia (8q12–q13 and 16q24.3). They performed a genome wide search using a set of 320 fluorescently-labeled microsatellite markers and ruled out 80 % of the genome. They found a positive linkage (lod score of 4.87, θ=0, penetrance 0.95) for the marker D1S242 on chromosome 1q24. Unfortunately, this result was not confirmed by the analysis of several flanking markers and the haplotype reconstruction. Although the finding of a lod score of 4.87 seemed to represent a chance finding without any real significance, different participants felt that this locus deserved reconsideration after completing the rest of the genome search.

2.2.2. HSAN 

A family with hereditary sensory autonomic neuropathy (HSAN) was presented and a possible locus on chromosome 9q22.1–22.33 was found after exclusion of the locus 3q13–q22, discovered for a form of CMT 2B with ulcerating features [30], [31]. There was some discussion as to the clinical picture because motor signs were associated to the sensory loss and the dysautonomic signs.

LeGuern (Paris, France) reported on the clinical, electrophysiological, and genetic features of five patients from a single French family with HSAN 1 linked to chromosome 9. Age at onset is highly variable, from 20 to 52 years. All patients but one experienced trophic alterations with poorly healing ulcers of the feet, developing after a painless skin injury. Sensory deficit concerns especially the distal part of the lower limbs. It predominantly affects sensation of touch, pain and temperature. Motor deficit is always present. Areflexia is limited to ankle jerk in four patients, and pes cavus is noted in three patients. Dysautonomia is not observed, although excess of sweating is mentioned for three patients. Electrophysiological findings are consistent with an axonal motor and sensory neuropathy. Since the CMT 2A and CMT 2B loci have been excluded and the same haplotype for 9q markers is shared by all patients, linkage to the HSAN 1 locus is highly suspected in this family despite the phenotype of axonal motor and sensory neuropathy [32].

2.3. CMT related disorders 

2.3.1. HNA 

Hereditary neuralgic amyotrophy (HNA) is a rare autosomal dominant recurrent focal neuropathy [33]. The age at onset is most commonly in the second decade, although, children in the first decade can be affected. Episodes are characterised by pain in the affected limbs, followed by weakness and atrophy of the affected muscles. Sensory disturbances may occur. Recovery is usually complete after weeks to months. There is no evidence for a generalised neuropathy. Single episodes are often preceded by flu-like infections or immunisations, suggesting a possible role of the immune system in the pathogenesis. Episodes can be associated with parturition. Minor dysmorphic features can be associated with the HNA phenotype, although co-segregation has not yet been proven.

Meuleman (Antwerpen, Belgium) reported that a HNA locus was originally assigned to chromosome 17q25–q24 by Pellegrino et al. [34]. He and co-workers confirmed linkage to chromosome 17q25–q24 [35], [36] and defined a 16 cM candidate region on 17q25 [36]. This linkage interval has been refined to 4 cM [37]. Because nearly nothing is known about the pathogenesis of HNA, it is very difficult to choose appropriate candidate genes based on their function. Therefore, every positional candidate gene has to be considered a potential candidate gene for HNA, unless its expression is restricted to tissues certainly not involved in the HNA pathogenesis. Up to now, four candidate genes for HNA have been excluded. Using radiation hybrid mapping [38], Meuleman and co-workers were able to localise the prolyl-4-hydroxylase-β polypeptide gene (P4HB) and the CD 7 gene 9.5 cM telomeric to the HNA locus. Therefore these genes are positionally excluded as HNA candidate genes. By direct DNA sequencing they excluded two other positional candidate genes: a cDNA encoding a putative sialyltransferase (GenBank Acc. U14550) and the general splicing factor SFRS2 (GenBank Acc. M190104) [39].

Therefore, the gene and mutation causing HNA are still unknown. Meuleman and co-workers are currently constructing a clone contig for the linkage interval, using yeast artificial chromosome (YAC) and P 1 derived artificial chromosome (PAC) clones. This physical map will enable the group to assign candidate genes and ESTs, and find new genes in the HNA candidate region by cDNA selection and exon trapping. Mutation analysis of these genes should lead to the identification of the disease causing mutations.

2.3.2. GAN 

Koenig (Strasbourg, France) presented data concerning giant axonal neuropathy (GAN). GAN is a sensorimotor neuropathy associated with central nervous system involvement such as pyramidal signs and mental retardation. A very striking associated feature was the presence of kinky fragile hair and eyelashes. GAN is typically an early onset childhood disease with rapid progression and death before 30 years. The mode of inheritance is autosomal recessive. Diagnosis is made by peripheral nerve biopsy which reveals very large caliber axons distended by the accumulation of neurofilament masses. GAN is in fact an intermediate filament (to which neurofilaments belong) disease with associated biochemical abnormalities of other types of intermediate filaments (desmin, vimentin, keratin). A variant form, with neither kinky hair nor mental retardation and with prolonged survival beyond 50 years has been reported in a large inbred Tunisian family. This family as well as two other Tunisian families were used to localise the GAN gene to chromosome 16q24.1 in a 5 cM interval [40]. This genetic localisation excludes the neurofilament genes, located on chromosomes 8 and 22 as candidate genes for GAN. A genetic homogeneity for GAN was demonstrated by the localisation of five non-Tunisian, rapidly progressing, consanguineous GAN families to the same 5 cM interval on 16q24.1. These families were of widespread geographic origin. Linkage dysequilibrium studies of the Tunisian families are in progress, in order to narrow down the linked interval for gene cloning purposes.

Back to Article Outline

3. Conclusion 

In the Mediterranean countries, the over-representation of the autosomal recessive forms of CMT versus the rest of Europe results from their high consanguinity rate. It could also be due in part to the fact that these autosomal recessive forms are severe while the autosomal dominant forms, being less severe, have less chances to be examined. The patients affected by autosomal dominant disorders will be less prone to complain and part of them will not seek medical attention, bringing a bias in the selection of the disorders.

Since the conditions discussed here presented many different features, it was felt necessary to prepare a questionnaire to be filled out by clinicians in order to start a data base of the autosomal recessive forms of CMT. This questionnaire was prepared by Birouk in collaboration with De Jonghe and will be made available.

Future aims and priorities are: (1) to make an inventory of the rare forms of CMT with the help of the questionnaire; (2) to develop a clinical classification useful for clinicians, geneticists and patients; (3) to develop an appropriate genetic nomenclature; (4) to elaborate a strategy for the diagnosis (including flow-chart, guidelines with inclusion and exclusion criteria, clinical symptoms and signs, laboratory tests including electrophysiology, nerve biopsy and DNA testing) and (5) to perform systematic testing of known genes and to establish the relative frequencies of the different types of autosomal recessive CMTs.

Back to Article Outline

4. Workshop advisors 

Eric LeGuern (Paris, France), Peter De Jonghe (Antwerpen, Belgium)

Back to Article Outline

5. Workshop participants 

N. Birouk (Rabat, Morocco)

A. Brice (Paris, France)

C. Van Broeckhoven (Antwerpen, Belgium)

A. Gabreëls-Festen (Nijmegen, The Netherlands)

A. Gambardella (Catanzaro, Italy)

R. Gouider (Tunis, Tunisia)

D. Grid (Evry, France)

F. Hentati (Tunis, Tunisia)

P. De Jonghe (Antwerpen, Belgium)

L. Kalaydjieva (Joondalup, Western Australia)

M. Koenig (Strasbourg, France)

E. LeGuern (Paris, France)

GL. Mancardi (Genova, Italy)

J-J. Martin (Antwerpen, Belgium)

L. Merlini (Bologna, Italy)

J. Meuleman (Antwerpen, Belgium)

L. Rampoldi (Padua, Italy)

M. Salih (Riyadh, Saudi Arabia)

P.K. Thomas (London, UK)

H. Topaloglu (Ankara, Turkey)

Back to Article Outline

Acknowledgements 

This workshop was made possible by the financial support of the European Union Biomed II grant: ‘Clinical, genetical and functional analysis of peripheral neuropathies-an integrated approach’ (CT96-1614 and CT96-0055) and the European Neuromuscular Centre (ENMC) and its main sponsors and associate members. We are grateful to Prof.Dr. A.E.H. Emery for his scientific help, and to Mrs Janine de Vries and Mr. Michael Rutgers for the organisational assistance of the ENMC. Prof. C. Van Broeckhoven is the co-ordinator of the European CMT consortium.

Back to Article Outline

References 

  1. De Jonghe P, Timmerman V, Nelis E, Martin JJ, Van Broeckhoven C. Charcot–Marie–Tooth disease and related peripheral neuropathies. J Periph Nerv Syst. 1998;2:370–387
  2. Warner LE, Mancias P, Butler I, et al.  Mutations in the early growth response 2 (EGR 2) gene are associated with hereditary myelinopathies. Nature Genet. 1998;18:382–384
  3. Parman Y, Planté-Bordeneuve V, Mantel A. Clinicopathological and genetic study of patients with the Dejerine–Sottas phenotype. J Neurol. 1998;245:465–466
  4. Ouvrier R. Correlation between the histopathologic, genotypic, and phenotypic features of hereditary peripheral neuropathies in childhood. J Child Neurol. 1996;11:133–146
  5. Warner LE, Hilz MJ, Appel SH. Clinical phenotypes of different MPZ (P0) mutations may include Charcot–Marie–Tooth type 1B, Dejerine–Sottas, and congenital hypomyelination. Neuron. 1996;17:451–460
  6. Ohnishi A, Murai Y, Ikeda M, Fujita T, Furuya H, Kuroiwa Y. Autosomal recessive motor and sensory neuropathy with excessive myelin outfolding. Muscle Nerve. 1989;12:568–575
  7. Gabreëls-Festen AAWM, Joosten EMG, Gabreëls FJM, Stegeman DF, Vos AJM, Busch HFM. Congenital demyelinating motor and sensory neuropathy with focally folded myelin sheaths. Brain. 1990;113:1629–1643
  8. Gabreëls-Festen AAWM, Hoogendijk JE, Meijerink PHS, et al.  Two divergent types of nerve pathology in patients with different P0 mutations. Neurology. 1996;47:761–765
  9. Umehara F, Takenaga S, Nakagawa M, et al.  Dominantly inherited motor and sensory neuropathy with excessive myelin folding complex. Acta Neuropathol. 1993;86:602–608
  10. Bolino A, Brancolini V, Bono F, et al.  Localization of a gene responsible for autosomal recessive demyelinating neuropathy with focally folded myelin sheaths to chromosome 11q23 by homozygosity mapping and haplotype sharing. Hum Mol Genet. 1996;5:1051–1054
  11. Ben Othmane K, Rochelle JM, Johnson E, et al. Autosomal recessive Charcot–Marie–Tooth disease: Clinical and genetic aspects. AAN 50th anniversary annual meeting, Minneapolis, MN, April 25–May 2, 1998. Neurology 1998;50 (Suppl. 4):4122 (abstract).
  12. Gambardella A, Bolino A, Muglia M, et al.  Genetic heterogeneity in autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths (CMT4B). Neurology. 1998;50:799–801
  13. Harding AE, Thomas PK. Autosomal recessive forms of hereditary motor and sensory neuropathy. J Neurol Neurosurg Psychiatry. 1980;43:669–678
  14. Kalaydjieva L, Hallmayer J, Chandler D, et al.  Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24. Nature Genet. 1996;14:214–217
  15. Gabreëls-Festen AAWM, Gabreëls FJM, Jennekens FGI, Joosten EMG, Janssen-van Kempen TW. Autosomal recessive form of motor and sensory neuropathy type 1. Neurology. 1992;42:1755–1762
  16. LeGuern E, Guilbot A, Kessali M, et al.  Homozygosity mapping of an autosomal recessive form of demyelinating Charcot–Marie–Tooth disease to chromosome 5q23-q33. Hum Mol Genet. 1996;5:1685–1688
  17. Dyck PJ, Lambert EH. Lower motor and primary sensory neuron disease with peroneal muscle atrophy. II. Neurologic, genetic and electrophysiologic findings in various neuronal degenerations. Arch Neurol. 1968;18:619–625
  18. Gabreëls-Festen AAWM, Joosten EMG, Gabreëls FJM, Jennekens FGI, Gooskens RHJM, Stegeman DF. Hereditary motor and sensory neuropathy of neuronal type with onset in early childhood. Brain. 1991;114:1855–1870
  19. Birouk, N., Belaidi, H., Benomar, A., et al. The axonal form of autosomal recessive Charcot–Marie–Tooth (CMT) disease: a phenotype study of 4 Morocan families. Neuromusc Disord 1997;7:470 (abstract).
  20. Kessali M, Zemmouri R, Guilbot A, et al.  A clinical, electrophysiologic, neuropathologic and genetic study of two large Algerian families with an autosomal recessive demyelinating form of CMT disease. Neurology. 1997;48:867–873
  21. Li X, Wise CA, Le Paslier D, et al.  A YAC contig of approximately 3 Mb from human chromosome 5q31–q33. Genomics. 1994;19:470–477
  22. Quattrone A, Gambardella A, Bono F, et al.  Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths. Clinical, electrophysiologic, and genetic aspects of a large family. Neurology. 1996;46:1318–1324
  23. Gambardella A, Bono F, Muglia M, Valentino P, Quattrone A. Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths (CMT 4B). Neurology. 1999;in press
  24. Merlini L, Villanova M, Sabatelli P, et al.  Hereditary motor and sensory neuropathy LOM type in an Italian Gypsy family. Neuromusc Disord. 1998;3-4:182–185
  25. Gouider R, Dogui T, Fredj M, LeGuern E, Ben Ammou S, Mrabet A. Recessive sensory and motor hereditary neuropathy associated with a juvenile glaucoma. Neuromusc Disord. 1997;7:471–472(abstract NAP14)
  26. Mancardi GL, Di Rocco M, Schenone A, et al.  Hereditary motor and sensory neuropathy with deafness, mental retardation and absence of large myelinated fibers. J Neurol Sci. 1992;110:121–130
  27. Sabatelli M, Mignogna T, Lippi G, et al.  Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity. Am J Med Genet. 1998;75:309–313
  28. Cowchock FS, Duckett SW, Streletz LJ, Graziani LJ, Jackson LG. X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder. Am J Med Genet. 1985;20:307–315
  29. Harding AE, Thomas PK. Peroneal muscular atrophy with pyramidal features. J Neurol Neurosurg Psychiatry. 1984;47:168–172
  30. Kwon JM, Eliott JL, Yee WC, et al.  Assignement of a second Charcot–Marie–Tooth type 2 locus to chromosome 3q. Am J Hum Genet. 1995;57:853–858
  31. De Jonghe P, Timmerman V, Fitzpatrick D, Spoelders P, Martin JJ, Van Broeckhoven C. Mutilating neuropathic ulcerations in a chromosome 3q13–q22 linked Charcot–Marie–Tooth disease in type 2B family. J Neurol Neurosurg Psychiatry. 1997;62:570–573
  32. Nicholson GA, Dawkins JL, Blair IP, et al.  The gene for hereditary sensory neuropathy type 1 (HSAN-I) maps to chromosome 9q22.1–q22.3. Nature Genet. 1996;13:101–104
  33. Windebank AJ, et al.  Inherited recurrent focal neuropathies. In:  Dyck PJ,  Thomas PK,  Griffin JW, et al. editor. Peripheral neuropathy. 3rd edn.. 1993;p. 1137
  34. Pellegrino JE, Rebbeck TR, Brown MJ, Bird TD, Chance PF. Mapping of hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) to distal chromosome 17q. Neurology. 1996;46:1128–1132
  35. Wehnert M, Timmerman V, Spoelders P, Meuleman J, Nelis E, Van-Broeckhoven C. Further evidence supporting linkage of hereditary neuralgic amyotrophy to chromosome 17q. Neurology. 1997;48:1719–1721
  36. Stögbauer F, Young P, Timmerman V. Refinement of the hereditary neuralgic amyotrophy (HNA) locus to chromosome 17q25. Hum Genet. 1997;99:685–687
  37. Pellegrino JE, George RA, Biegel J, et al.  Hereditary neuralgic amyotrophy: evidence for genetic homogeneity and mapping to chromosome 17q25. Hum Genet. 1997;101:227–283
  38. Stewart EA, McKusick KB, Aggarwal A, et al.  An STS-based radiation hybrid map of the human genome. Genome Res. 1997;7:422–433
  39. Kuhlenbaümer G, Meuleman J, Schirmacher A, et al.  Mutation analysis of a putative sialyltransferase gene, the SFRS2 splicing factor gene and the c-myb ET-locus in two families with hereditary neuralgic amyotrophy (HNA). Ann Human Genet. 1999;in press
  40. Ben Hamida C, Cavalier L, Belal S, et al.  Homozygosity mapping of giant axonal neuropathy gene to chromosome 16q24.1. Neurogenetics. 1997;1:129–133

PII: S0960-8966(99)00017-6

Neuromuscular Disorders
Volume 9, Issue 4 , Pages 279-287, 1 June 1999

Article Tools