Brain Advance Access originally published online on June 23, 2003
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Brain, Vol. 126, No. 9, 2023-2033,
September 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg202
Clinical, electrophysiological and morphological findings of Charcot–Marie–Tooth neuropathy with vocal cord palsy and mutations in the GDAP1 gene
1 Departments of Neurology, 2 Clinical Neurophysiology and 3 Experimental Cellular Pathology, University Hospital La Fe, and 4 Laboratory of Genetics and Molecular Medicine, Instituto de Biomedicina, Consejo Superior de Investigaciones Científicas (CSIC), Valencia, Spain
Correspondence to: Dr Teresa Sevilla, Servicio de Neurología, Hospital Universitari La Fe, Avenida Campanar 21, 46009 Valencia, Spain E-mail: teresevillaus{at}yahoo.com
Received January 22, 2003. Revised March 29, 2003. Accepted April 16, 2003.
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Summary |
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Three Spanish families with an autosomal recessive severe hereditary motor and sensory neuropathy, showing mutations in the ganglioside-induced-differentiation-associated protein 1 (GDAP1) gene in the Charcot–Marie–Tooth (CMT) type 4A locus were studied. The disorder started in the neonatal period or early infancy with weakness and wasting of the feet and, subsequently, involvement of the hands, causing severe disability. By the late teens, some patients developed a hoarse voice and vocal cord paresis. Peripheral motor nerve conduction velocity (MNCV) could not be measured in many cases because of the absence of muscle response due to distal atrophy. However, latencies to proximal muscles were in the normal range; median MNCV was >40 m/s in those cases in which it could be measured. Sural nerve biopsy from two patients showed a pronounced depletion of myelinated fibres, regenerative clusters and signs of axonal atrophy. Additionally, a small proportion of thin myelinated fibres and proliferation of Schwann cells forming onion bulb structures were also found. Unmyelinated fibre population was markedly increased. These findings are indicative of a predominant axonal degeneration with some demyelinating features. These Spanish families share in the severe CMT clinical phenotype with some Tunisian families who also presented mutations in the GDAP1 gene and to which the CMT4A locus was originally assigned. However, our families differ in the presence of laryngeal involvement and values of MNCV and pathological features are more in line with CMT2 type. The possibility that GDAP1 gene mutations could be expressed under different phenotypes is a question to be resolved.
Keywords: Charcot–Marie–Tooth disease type 2; hereditary motor and sensory neuropathy type II; vocal cord paresis, autosomal recessive; GDAP1 gene
Abbreviations: CMAP= compound muscle action potential; GDAP1 = ganglioside-induced differentiation-associated protein 1; CMT = Charcot–Marie–Tooth; DL = distal latency; GJB1 = gap junction protein beta-1; HMSN = hereditary motor and sensory neuropathy; MRC = Medical Research Council; MCV = motor conduction velocity; MNCV = motor nerve conduction velocity; MPZ = myelin protein zero; NCS = nerve conduction studies; OB = onion bulbs; SNCV = sensory nerve conduction velocity; SNAPs = sensory nerve action potentials.
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Introduction |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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Hereditary motor and sensory neuropathy (HMSN) or Charcot–Marie–Tooth disease (CMT) was classically grouped into two main categories according to electrophysiological and nerve biopsy findings: (i) CMT1 showing a median nerve motor conduction velocity (MCV) of <38 m/s and nerve fibre demyelination with proliferation of Schwann cells forming onion bulbs (OB); and (ii) CMT2 with normal or near normal conduction velocities and pathological signs of axonal degeneration and regeneration (Harding and Thomas, 1980a
; Dyck and Lambert, 1968a, b). Other authors defined an intermediate group with conduction velocities ranging between 27 and 35 m/s, which did not gain wide acceptance at first. Dejerine–Sottas syndrome or CMT3 category was applied to early childhood-onset cases with sporadic or recessive transmission, presenting very slow motor nerve conduction velocity (MNCV) and severe demyelinating features (Dyck et al., 1993). A dominant X-linked category was also recognized and was included in the CMT1 group (Rozear et al 1987; Hahn et al., 1990). Examples of autosomal recessive CMT either demyelinating or axonal forms were also reported (Harding and Thomas, 1980b; Ouvrier et al., 1981; Gabreëls-Festen et al., 1991).
Genetic linkage studies discovered that HMSN categories were heterogeneous and that the CMT1 and CMT2 forms were sub-classified according to loci ascription (Reilly 2000; Boerkoel et al., 2002a). Furthermore, a CMT4 group emerged to include autosomal recessive CMT forms (Ben Othmane et al., 1993) and was rapidly enlarged with various subcategories (Bolino et al., 1996; Kalaydjieva et al., 1996; LeGuern et al., 1996; Delague et al., 2000). The discovery of the gene products lead to a rational approach to the study of the pathogenesis of the various CMT forms (Shy et al., 2002) but, at the same time, it has added complexity to the traditional concepts used to classify HMSN. For example, it has been shown that the Dejerine–Sottas phenotype may result from mutation of different genes (Hayasaka et al., 1993; Ionasescu et al., 1995; Bort et al., 1998; Timmerman et al., 1999). Conversely, mutations in certain genes like Gap junction protein beta-1 (GJB1) gene or myelin protein zero (MPZ) may produce demyelinating or axonal phenotypes (De Jonghe et al., 1999; Misu et al., 2000; Dubourg et al., 2001; Young et al., 2001; Boerkoel et al., 2002b).
Recently, two research groups simultaneously described CMT patients presenting mutations in the GDAP1 gene. In one case (Baxter et al., 2002), the mutations were found in Tunisian families and had been previously reported as CMT4A form and defined as a severe demyelinating neuropathy. The other group studied (Cuesta et al., 2002) consisted of Spanish families who also presented a severe clinical phenotype, but whose nerve conduction velocities and pathological pattern were consistent with an axonal neuropathy. Clinical, electrophysiological and nerve biopsy findings of the GDAP1 gene-related neuropathy in patients from these Spanish families are reported in detail in this study.
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Patients and methods |
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Clinical and electrophysiological examinations were carried out on 18 affected and non-affected members of three families: LF249, LF20 and LF38. Neuropathic symptoms and deficits were assessed by two of us (T.S. and J.J.V.). Genetic studies confirmed that all patients were either homozygous or compound heterozygous for mutations in the GDAP1 gene (Cuesta et al., 2002
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Nerve conduction studies (NCS) were tested with surface electrodes. Amplitudes of compound muscle action potential (CMAPs), distal latency (DL) and conduction velocity were recorded whenever possible from median, ulnar, peroneal, tibial and axillary nerves using conventional methods. Furthermore, motor nerve conduction studies of more proximal upper limb muscles like the palmaris longus muscle for the median nerve and flexor carpis ulnaris for the ulnar nerve were also tested. CMAP and DL from the diaphragm muscle were recorded by using phrenic nerve stimulation in the neck (Bolton, 1993). Recordings of sensory nerve action potentials (SNAPs) from median and ulnar nerves were performed orthodromically, but sural nerve was tested antidromically. Concentric needle electromyography was performed in the proximal and distal muscles of the upper and lower limbs.
Sural nerve biopsy was performed at ankle level after written consent. The sample was fixed in 2.5% glutaraldehyde–1% paraformaldehyde in 0.1M sodium cacodilate and post-fixed in 1% osmium tetraoxide, dehydrated in graded acetones and embedded in epoxy resin. Semi-thin sections stained with toluidine blue were prepared for evaluation under a light microscope. Ultrathin cut samples were contrasted with uranyl acetate and lead citrate for ultra structural study. Morphometry of myelinated fibres was performed on high-resolution (1600 x 1200 pixels) micrographic images obtained with a Polaroid DMC digital camera. Several pictures were obtained from each nerve fascicle; care was taken to ensure they did not contain overlapping fields. Measurement data were collected by means of Scion image analyst software (http://www.scioncorp.com). A threshold grey-scale level for myelin and axon profiles was defined and used to trace the border of the axon and outer edge of myelin; the software could then calculate their respective areas and diameters. To minimize the effects of shrinkage or irregular shape of the myelin ring, the mean of major and minor ellipse diameter was chosen. G-ratio was calculated by the quotient axon diameter/myelinated fibre diameter. OB formation was considered as supernumerary—more than one- layer of Schwann cells completing a full circle. Regenerative cluster was defined as two or more closely grouped small myelinated fibres in a delimited circular area. Quantification was expressed in terms of density or number of axons per mm2 and also as the percentage of myelinated fibres involved in OB or the cluster with respect to the total count. Electron microphotographs were taken randomly. Abnormal formations like OB, cluster or demyelinated axons were assessed at low power magnification (x3000). Pictures at higher magnification (x9000) were digitalized and used for quantification of unmyelinated fibres. Presence of structural abnormalities of myelin, axon, abnormal deposits in Schwann cell cytoplasm or macrophages, as well as the quantity of endoneural collagen was evaluated by inspection at the appropriate amplification. Microphotograph measurement calibration was performed by mean of stage micrometer, while electron micrograph magnification was calibrated by rule diffraction cross grating replica, both from Agar Scientific Ltd (Stansted, Essex, UK).
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Results |
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Clinical features
Fig. 1 represents the pedigrees of the three families and Table 1 summarizes clinical data.
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Kindred 1 (LF249)
The disorder in this family is inherited as an autosomal recessive form. There are three brothers affected out of six siblings (Fig. 1). The father died at 56 years of cancer; he had no neurological abnormalities at that time. The mother was clinically and electrophysiologically unaffected.
Patients started to walk at a normal age. Gait was clumsy and they had frequent falls. Each patient underwent orthopaedic surgery in his very first years of life before the diagnosis of a peripheral neuropathy was established. Hand weakness was a symptom reported during those first years. Patients were still able to walk at the end of their first decade, but all of them became chair-bound after the age of 12 years. Most patients were unable to remember at what specific age their voice changed, but it was usually in the second decade. Intelligence was normal in all patients.
Clinical assessment was scored according to MRC (Medical Research Council, UK) scale. All patients showed complete paralysis in the muscles below the knee and marked weakness in the thigh muscles (3/5 according to the MRC scale). Complete paralysis of the distal muscles groups was found (0/5 according to the MRC scale) in the upper limbs while flexion and extension of elbow was possible against mild resistance (4/5 according to the MRC scale). Strength in shoulder muscles was normal except in proband one. Spinal deformity was present in all patients and chest deformity in the proband only. Pes cavus, claw hands and contractures were also prominent. Cranial nerves were not involved except for hoarseness. Muscle stretch reflexes were absent. All modalities of sensation were affected. Pinprick and vibration were absent at hallux, ankle and knee; joint position sense was also absent at distal interphalangeal joints and ankle. Pinprick and vibration were also diminished in hands,but joint position sense was preserved. There was no clinical variability between the affected members (Table 1). The CSF protein determined in the proband resulted normal.
Kindred 2 (LF20)
There are two brothers affected out of four siblings in this family (Fig. 1). Parents were clinically unaffected. The electrodiagnostic examination was normal in both parents.
The propositus is a 39-year-old man. He was a floppy infant with delayed motor milestones who started walking at the age of 2 years and began to have frequent falls. He had to use orthopaedic devices. Difficulty manipulating objects with the hands was a prominent symptom from infancy. Intelligence was normal. He continued walking with the assistance of crutches until the age of 9 years. At this age, he became wheelchair dependent with marked weakness and atrophy in upper and lower limbs. Clinical examination was nearly identical to members of family LF249 (Table 1). Hoarse voice had been present since 14 years of age. An otolaryngologist studied the vocal cords and found paresis in both cords, the left one being more affected. Symptoms and clinical examination of his brother were identical (Table 1).
Kindred 3 (LF38)
This is a large family with nine affected members from four consanguineous marriages (Fig. 1). We have examined only four patients from this family. Their clinical data are summarized in Table 1. They are similar to those described for members of the other families, but the disease evolved at a slower pace. Indeed, the members of this family only needed crutches around age 18 years and become chair-bound around 30 years. One member of this family could even walk a few metres with supports at 43 years. Two members had had hoarseness since they were aged 30 years.
Electrophysiological studies
Table 2 summarizes EMG and NCV studies of the three families. EMG records from members of families LF249 and LF20 who were tested by us showed absence of motor unit action potentials (MUAPs) during voluntary contraction and fibrillation density reduced in all lower limb and distal upper limb muscles. In proximal upper limb muscles such as the deltoid and biceps, needle EMG showed evidence of chronic denervation with spontaneous fibrillation potentials, large polyphasic potentials and reduced recruitment pattern. Complex repetitive discharges were recorded in some instances.
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MNCVs were impossible to obtain in many instances. In affected members from families LF249 and LF20, peroneal, tibial, femoral, median, and ulnar CMAPs were not obtained on recording both proximal and distal innervated muscles. Axillary and phrenic nerve latencies were preserved in all tested cases, but some cases showed low CMAPs (Table 2). In two members of the LF38 family whose median motor NCV could be obtained, it was in the normal or near-normal range (Table 2).
Sural SNAP were absent in all patients. Amplitude of SNAPs and sensory nerve conduction velocities (SNCVs) from median nerve was obtained in two patients (LF249 II-4 and LF20 IV-14). The values of SNAPs were 1.3 and 0.2 µV, respectively (normal >16.5 µV); and SNCVs were 37 and 46.3 m/s, respectively (normal >43 m/s).
Sural nerve biopsies
Sural nerve biopsies were performed in probands from LF20 and LF249 families when they were 22 and 19 years old, respectively. A control nerve was obtained from a 27 year-old multiorgan donor without neuropathic or systemic disease history. Morphometric data are reported in Table 3. Semi-thin sections revealed a marked loss of myelinated fibres in both nerves; this was more pronounced in the LF20 proband patient (Fig. 2). Histograms of myelinated fibre size distribution (Fig. 3) showed a severe reduction of fibres of all sizes. No fibres >7 µm were observed in either nerve, yet both nerves displayed a population of very small myelinated fibres <2 µm, which were not present in the control nerve and probably represented regenerating sprouts.
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OB formation and regenerative cluster were occasionally present in both nerves, being rather more prominent in the LF249 proband nerve (Table 3). Most OB surrounded regenerative clusters; less often, they contained only a single myelinated axon (Figs 2 and 4). In detailed electron microscopic views, OBs were mainly made up of concentrically proliferated Schwann cells processes adopting a crescent shape. In general, the number of OB layers was small but thick in most cases, containing abundant Schwann cell cytoplasm and enclosing numerous unmyelinated axons (Fig. 5A). Basal membrane layers were not perceived.
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Myelin thickness was proportional to axon size in the majority of fibres from both nerves according to g-ratio figures (Table 3). However, the nerve of the LF20 proband presented a considerable proportion (20%) of myelinated fibres with a g ratio <0.4, indicating axonal atrophy; in turn, the nerve of the LF249 proband showed an increase (15%) of hypomyelinated fibres with g-ratio >0.7.
Myelinated fibres often adopted a distorted (not round) shape like boomerang forms and occasionally displayed internal or external myelin folding; only a tomaculum-like formation was seen. These findings were more prominent in the nerve of the LF20 patient and they were considered as indicative of myelin adaptation to axonal atrophy.
Neither demyelinated axons nor abnormalities in myelin compaction were observed. Only rare fibres were seen to undergo active axonal degeneration (Fig. 5B).
Most of the intrafascicular compartment of the nerve was occupied by collections of Schwann cells embedded in dense endoneural collagen deposits. These collections of Schwann cells sometimes showed a minor degree of concentric orientation, indicating their derivation from former OB (Fig. 6A), but this was not evident in the majority of cases (Fig. 6B). The density of unmyelinated fibres was higher (Table 3), although the counting undoubtedly included numerous non-myelinated regenerating sprouts derived from myelinated fibres.
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In summary, there were some quantitative and qualitative differences in both nerve biopsies. Nerve LF20 proband presented extreme depletion of myelinated fibres and many of the remaining fibres showed signs of axonal atrophy. Nerve LF249 proband showed a less severe axonal loss, but at the expense of regenerative sprouting, and a noticeable proportion of hypomyelinated fibres and abnormal Schwann cell proliferation forming OB as well.
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Discussion |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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The patients described in this report suffer from a chronically progressive motor and sensory neuropathy beginning in early childhood and resulting in severe disability at the end of their first decade in LF249 and LF20 families, and at the third decade in the large LF38 family. All of them presented mutations in the GDAP1 gene at the CMT4A locus: homozygotes for Q163X mutation in LF38 or compound heterozygotes for Q163X and S194X in LF249 and for Q163X and T288fsX290 in LF20 (Cuesta et al., 2002
). Their clinical picture is similar to a series of Tunisian families also harbouring mutations in the same gene and previously reported as corresponding to the CMT4A category (Baxter et al., 2002). However, our Spanish patients have two particular features: appearance of hoarseness due to vocal cord paresis, and electrophysiological and pathological evidence of an axonal neuropathy—thereby differing from the concept of CMT4A as a severe demyelinating neuropathy (Ben Othmane et al., 1993).
Hoarseness was a frequent symptom. It appeared late in the course of the disease in many affected members of our three families. Moreover, subclinical phrenic nerve impairment was also detected in some cases. Involvement of recurrent laryngeal and phrenic nerves does not seem to be a specific hallmark of GDAP1-related neuropathy. Vocal cord involvement has been reported to occur in different types of hereditary neuropathies like certain forms of distal motor neuropathy (Young and Harper,1980), CMT2C (Dyck et al., 1994; Yoshioka et al., 1996) and some CMT1 cases associated with either peripheral myelin protein (PMP22) (Thomas et al., 1997) or early growth response 2 (EGR2) gene mutations (Pareyson et al., 2000). It has been proposed that those nerves are rather long and the progression of a length-dependent severe neuropathy might explain their involvement (Thomas et al., 1997); other factors that may predispose to this particular regional involvement are not yet known.
Median NCV appeared >40 m/s in cases where it could be recorded. In other patients, it was not obtained due to a severe distal muscular atrophy of hand muscles, but proximal motor latencies were always preserved. Assuming that nerve conduction velocity is uniform along whole nerve in CMT demyelinating neuropathies (Kaku et al., 1993; Krajewski et al., 2000), our data are indicative of an axonal neuropathy or CMT2 type.
In a detailed analysis of the Tunisian patients harbouring GDAP1 gene mutations, the reported MNCV ranged between 27–35 m/s (Baxter et al., 2002), which appears less slower than would be expected in a severe infantile hypo or demyelinanting neuropathy (Gabreëls-Festen et al., 1990). Such values can be considered in the intermediate range that may be displayed by distinct CMT forms; some considered primarily demyelinating like GJB1 related cases (Nicholson and Nash, 1993; Dubourg et al., 2001) and others reported as axonal forms such as the recessive russe type neuropathy (Thomas et al., 2001). In the latest example, loss or damage to large calibre axons could be responsible for slowing conduction velocity to such a degree. The fact that some Tunisian patients showed a marked decrease of CMAP (0.3–0.2 mV) (Hentati et al., 2001) may indicate that axonal loss could have had some influence on nerve conduction results. In cases like this, testing of proximal motor latencies can give substantial information about the matter.
Sural nerve biopsy data from two of our patients showed that axonal loss was the most prominent finding. The presence of axonal atrophy and fibres undergoing axonal degeneration corroborate ‘axonal’ as the main pathological feature. The surviving myelinated fibres corresponded to the small size population showing large fibre vulnerability and, probably, replacement by regenerating fibres; in fact, cluster formation of small myelinated fibres were quite prominent, particularly in the nerve of the LF20 propositus. The notable increase of myelinated fibre population is also indicative of regenerating axonal sprout not reaching the myelinated condition. In addition both nerves, particularly that of the LF249 proband, showed a proportion of thinly myelinated fibres and OB formation that may be considered as demyelinating features. However, although teased fibre studies were not performed, the absence of demyelinated axon in transverse nerve sections precludes demyelination and secondary remyelination as the most probable source of hypomyelinated fibres. Many of these fibres may correspond to myelinated axonal sprouts or they could even result from a developmental myelination arrest.
OBs were quantitatively less frequent and qualitatively different to those observed in typical CMT1 neuropathies (Ouvrier et al., 1981; Gabreëls-Festen et al., 1992; Thomas et al., 1997). In our patients, most OBs were related to a regenerating cluster. The presence of OB formation is indicative of Schwann cell dysfunction and it usually appears in long-lasting demyelinating effects. Additionally, in experimental xenograft models, it has been demonstrated that abnormal Schwann cells tend to form OB when they try to myelinate axonal sprouting (Sahenk et al., 1999).
The nerve biopsy report of the Tunisian patients mentions a significant decrease in myelinated fibre density, predominantly in those of a large size. Apart from the presence of segmental demyelination in teasing preparation, the presence of hypomyelinated fibres and OB formation are also mentioned, but no quantification or detailed descriptions are available.
According to the histopathological data, the GADP1 alterations can interfere with axonal survival and induce an abnormal Schwann cell behaviour with minor or mild repercussion in myelin compaction. GDAP1 gene encodes a 358-amino acid protein that is expressed in the CNS and PNS (Baxter et al., 2002; Cuesta et al., 2002), but its exact cell location and function is not yet well understood; it probably intervenes in axon–Schwann cell interaction (Shy et al., 2002).
Some reports have recently been published describing families from different ethnic origin presenting several mutations at the GDAP1 gene. Nelis et al. (2002) described three families whose members affected displayed median MNCV >40 m/s except for one case who showed a MCV of 20 m/s; yet their distal CMAP amplitude was unknown and soon after it could not be obtained, suggesting an advanced axonal decay. Senderek et al. (2003) reported two patients from different families showing MCV in the intermediate range. The descriptions of pathological nerve features in both studies were similar to those found in our cases: loss of large myelinated fibres, presence of regenerative cluster and variable appearance of thin myelinated fibres and Schwann cell proliferation with OB formation.
Boerkoel et al. (2003) reported four families. Three of these were American Hispanic, sharing similar haplotypes and harbouring the Q163X mutation found in our Spanish families, suggesting a possible common founder mutation. As in our patients, MCV could not be obtained in most cases and, when it could be measured, was in the near normal range. The histopathological findings were also similar. It is also of interest to mention that two of their families (one harbouring the Q163X mutation) showed vocal cord paresis
In conclusion, according to the data available, GDAP1 mutations lead to severe early-onset neuropathy with remarkable axonal degeneration and a variable degree of demyelinating features. Vocal cord palsy may sometimes occur in a length-related fashion. Electrophysiologically this neuropathology may appear with near normal MCV or with mild slowing in the intermediate range. These features are known to occur with neuropathies associated with GJB1 mutations resulting in CMTX (Dubourg et al., 2001; Boerkoel et al., 2002a). A variable phenotypic presentation also occurs with MPZ mutations but, in this case, the typical CMT1 phenotype contrasts with a CMT2 form that appears in relation to specific mutations (De Jonghe et al., 1999; Misu et al., 2000; Young et al., 2001). At present, there is no reason to think that a similar allelic distinction may happen with the Q163X mutation present in all the Spanish and American Hispanic families who apparently show a greater predisposition to vocal cord palsy. Otherwise, more extensive clinical, biological and experimental studies are required to understand the pathogenesis of these diseases.
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Acknowledgements |
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We wish to thank the patients and their relatives for their collaboration and Encarnación Garcia for her help with sample patients. Dr Joaquin Piquero performed electrophysiological studies on a patient from family LF38. This work is supported by grants from the Comisión Interministerial de Ciencia y Tecnología (CICYT), Fondo de Investigación Sanitaria (FIS) and Fundació ‘la Caixa’, Spain.
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