Brain, Vol. 124, No. 12, 2393-2406,
December 2001
© 2001 Oxford University Press
Abnormal corticospinal function but normal axonal guidance in human L1CAM mutations
1 Developmental Neuroscience, Department of Child Health, University of Newcastle upon Tyne, 2 Department of Medicine, University of Cambridge and 3 Medical Genetics, St Mary's Hospital, Manchester, UK
Correspondence to:
Professor J. A. Eyre, Professor of Paediatric Neuroscience, Department of Child Health, The Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE2 4LP, UK E-mail: J.A.Eyre{at}ncl.ac.uk
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L1 cell adhesion molecule (L1CAM) gene mutations are associated with X-linked ‘recessive’ neurological syndromes characterized by spasticity of the legs. L1CAM knock-out mice show hypoplasia of the corticospinal tract and failure of corticospinal axonal decussation and projection beyond the cervical spinal cord. The aim of this study was to determine if similar neuropathology underlies the spastic diplegia of males hemizygous for L1CAM mutations. Studies were performed on eight carrier females and 10 hemizygous males. Transcranial magnetic stimulation excited the corticospinal tract and responses were recorded in biceps brachii and quadriceps femoris. In contralateral biceps and quadriceps the responses had high thresholds and delayed onset compared with normal subjects. Ipsilateral responses in biceps were smaller, with higher thresholds and delayed onsets relative to contralateral responses. Subthreshold corticospinal conditioning of the stretch reflex of biceps and quadriceps was abnormal in both hemizygous males and carrier females suggesting there may also be a reduced projection to inhibitory interneurones. Histological examination of post-mortem material from a 2-week-old male with an L1CAM mutation revealed normal corticospinal decussation and axonal projections to lumbar spinal segments. These data support a role for L1CAM in corticospinal tract development in hemizygous males and ‘carrier’ females, but do not support a critical role for L1CAM in corticospinal axonal guidance.
L1CAM; corticospinal; ipsilateral; man; TMS
CAM = cell adhesion molecules; CMCD = central motor conduction delay; C-t = condition to test interval; EPSP = excitatory postsynaptic potential; GAP43 = growth associated protein 43 kilodaltons; IPSP = inhibitory post-synaptic potential; PMCD = peripheral motor conduction delay; TMCD = total motor conduction delay; TMS = transcranial magnetic stimulation
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Introduction |
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The neural cell recognition molecule L1 cell adhesion molecule (L1CAM), a member of the immunoglobulin superfamily of CAMs, is expressed on the surface of glial cells and neurones in the developing nervous system (Lemmon and McLoon, 1986
; de la Rosa et al., 1990; Moscoso and Sanes, 1995; Weiland et al., 1997). L1 protein is found at high levels along major axonal pathways such as the corticospinal tract, corpus callosum and optic nerve (Hortsch, 2000). It has been implicated in a variety of processes important for axonogenesis, including neuronal migration (Lindner et al., 1983), neurite growth and fasciculation (Stallcup and Beasley, 1985; Lagenaur and Lemmon, 1987), myelination (Wood et al., 1990), axonal guidance (Castellani et al., 2000) and synaptic plasticity (Luthl et al., 1994; Fields and Itoh, 1996).
The gene encoding L1CAM is located near the telomere of the long arm of the X chromosome (Xq28) (Djabali et al., 1990). In man, mutations in the L1CAM gene are responsible for a clinically variable, X-linked disorder, described variously as X-linked hydrocephalus, MASA (mental retardation, adducted thumbs, spastic paraparesis, agenesis of the corpus callosum) syndrome, X-linked agenesis of the corpus callosum or spastic paraplegia type 1 (Rosenthal et al., 1992; Jouet et al., 1994, 1995; Vits et al., 1994). The most consistent features in affected males are lower limb spasticity, mental retardation, hydrocephalus and flexion deformity of the thumbs (Kenwrick et al., 1996, 2000; Fransen et al., 1997), and it is now recognized that together these syndromes represent phenotypic variability of L1CAM mutations. Perhaps the most striking pathological observation is hypoplasia or apparent absence of two long axonal tracts, the corticospinal tract and corpus callosum (Chow et al., 1985; Yamasaki et al., 1995; Graf et al., 2000).
The L1CAM protein in mice is very similar in sequence to human L1CAM protein and two transgenic mouse models have been generated that have a targeted null mutation in the L1CAM gene (Cohen et al., 1997; Dahme et al., 1997). These mutations produce a phenotype similar to that observed in man. As in the human condition, the central nervous system of the mice was largely intact with major malformation limited to hypoplasia of the corticospinal tract, corpus callosum and cerebellar vermis and a degree of ventricular enlargement (Cohen et al., 1997; Dahme et al., 1997; Fransen et al., 1998; Demyanenko et al., 1999). The mutant mice had a reduced size of the medullary pyramids (Dahme et al., 1997) consistent with an overall reduction in the corticospinal projection, and no corticospinal axons were detected in the spinal cord caudal to the cervical level (Cohen et al., 1997). Cohen and colleagues also found that a substantial proportion of corticospinal axons failed to cross the midline at the medullary decussation and instead passed ipsilaterally into the dorsal column (Cohen et al., 1997). No abnormalities of decussation were found in the corpus callosum, optic chiasm or spinal commissural projection of L1CAM knock-out mice. This led to the suggestion that the ventral midline of the pyramidal decussation expresses a specific guidance cue, which functions as a ligand for L1CAM, facilitating crossing of corticospinal axons over the midline. Thus, L1CAM was hypothesized to have a highly specific effect on the guidance of axons of the corticospinal tract at the pyramidal decussation.
The aim of this study was to investigate if there was abnormality of corticospinal decussation in human subjects with L1CAM mutations, and to determine whether failure of projection of the corticospinal tract to the lumbar enlargement underlay the spastic paraparesis observed in hemizygous males. Females with known L1CAM mutations were also studied to determine if L1CAM mutation was an X-linked recessive disorder or whether ‘carriers’ expressed abnormalities in corticospinal tract neurophysiology and function.
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The Joint Ethical Committee of Newcastle upon Tyne University and Health Authority gave ethical approval. Informed written consent was obtained from the subjects and their parents, where appropriate.
Neurophysiological studies
Subjects
Eight mother–son pairs, two with two affected sons, were recruited. All subjects had either class two or class three mutations (Yamasaki et al., 1997). Class two mutations comprise missense point mutations in the extracellular domain of L1CAM. Class three mutations include nonsense or frameshift mutations that produce a premature stop codon in the extracellular domain. Mutant L1CAM molecules in Class 3 do not remain integrated in the plasma membrane and thus L1CAM would not be expressed. The clinical details of the subjects are summarized in Table 1.
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Normative data for the threshold for evoking ipsilateral and contralateral responses following trancranial magnetic stimulation (TMS) and their central motor conduction delays (CMCDs) to biceps brachii were obtained from previous studies of normal subjects (Conway, 1995
; Eyre et al., 2000, 2001b). Normal values for cortical conditioning of the phasic stretch reflex in biceps were obtained for contralateral conditioning from the study by Eyre and colleagues (Eyre et al., 2000), and for ipsilateral conditioning from 25 normal subjects, 11 males and 14 females, aged from 8 to 30 years. Normative data for the threshold for evoking responses and their CMCDs to quadriceps femoris were obtained from 100 normal subjects: 65 children, 32 males and 33 females, aged from birth to 16 years; and 35 adults, 20 males and 15 females, aged from 18 to 55 years. Normal values for cortical conditioning of the phasic stretch reflex in quadriceps were obtained from 20 normal subjects, 10 males and 10 females aged from 12 to 30 years.
Surface electromyography
The EMGs of left biceps and quadriceps were recorded using miniaturized, skin-mounted differential amplifiers. A –3 dB bandpass of 5–1500 Hz was applied and the signals were sampled at 5000 Hz for computer analysis. For each muscle the EMG was also rectified and integrated (time constant 1 s) and displayed as a horizontal line on an oscilloscope. The maximum voluntary contraction of each muscle was recorded as the greatest level of rectified, integrated EMG obtained by the subject in three attempts separated by 1-min intervals. During testing the subject contracted the muscle to raise the EMG display to meet a target line set at 10% maximum voluntary contraction.
Positioning of subjects and generation of background muscle activity
Subjects were seated with their head in the midline. Contraction of biceps was obtained with the arm adducted, the elbow held in 90° of flexion from full extension, and the hand supinated. Straps placed over the wrist resisted elbow flexion. Contraction of quadriceps was obtained with the legs adducted and the knee flexed in 90° from full extension. Straps placed over the ankle provided resistance to knee extension.
Excitation of motor pathways projecting to biceps
Corticospinal tracts
. TMS (MagStim Company Ltd, Whitland, UK), using a figure-of-eight coil with each circle having a diameter of 55 mm (SPC-ENG 8618; MagStim Company Ltd), was used to excite corticospinal neurones (Winter et al., 1989; Edgley et al., 1990, 1997; Eyre et al., 2000, 2001a) projecting to left biceps 
-motoneurones. The left (ipsilateral) and right (contralateral) motor cortices were stimulated. The induced current flow was maintained in posterior to anterior direction, approximately perpendicular to the central sulcus, by orientating the handle of the stimulating coil posteriorly and parallel to the parasagittal axis. To ensure accurate and reproducible coil placement, the method in a study by Metman and colleagues was used (Metman et al., 1993). The site with the lowest threshold for evoking responses in contracting left biceps was determined for the right (contralateral) and left (ipsilateral) motor cortex. To define the threshold for evoking responses, the intensity of TMS was increased until responses were evoked in the contracting target muscle in 50% of trials. Twenty stimuli at 1.2 times their respective thresholds were delivered and responses recorded. The shortest onset latency of responses following TMS of the right (contralateral) and left (ipsilateral) motor cortex was determined to estimate the total motor conduction delay (TMCD) from each cerebral hemisphere (Fig. 1A and B).
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Peripheral motor nerves
. Magnetic stimulation using a 50 mm diameter circular coil (S/N ENG 014, MagStim Company Ltd) placed over the spines of C5–8 vertebrae was used to excite cervical spinal motor roots. The longest onset latency of at least 20 responses in biceps was determined to estimate the peripheral motor conduction delay (PMCD; Fig. 1D
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Excitation of motor pathways projecting to quadriceps
Corticospinal tracts
. To excite corticospinal neurones projecting to left quadriceps -motoneurones, a ‘butterfly coil’ (loop diameter 14 cm) was used and the centre of the coil was placed over the vertex of the skull (Jalinous, 1991; Eyre and Miller, 1992; Terao and Ugawa, 1994). Twenty stimuli at 1.2 x threshold were delivered and responses recorded. The shortest onset latency of responses was determined to estimate the TMCD (Fig. 1C).
Peripheral motor nerves
. A significant proportion of the path of motor nerves projecting to quadriceps lies within the cauda equina, and hence magnetic excitation of these nerves at their point of emergence through the intervertebral foramina (L2–4) will provide an underestimate of the PMCD (Eyre and Miller, 1992). The PMCD to quadriceps was therefore estimated from the onset of its homonymous phasic stretch reflex (Fig. 1F). The shortest onset latency of the quadriceps stretch reflex was determined (see below). One millisecond was subtracted for trans-synaptic delays, and the peripheral conduction delay was scaled according to the relative mean conduction velocity for age in motor and Group Ia afferent nerves (Vecchierini-Blineau and Guiheneuc, 1979; Eyre and Miller, 1992).
Central motor conduction delay
Subtraction of PMCD from TMCD estimated the CMCD for responses in biceps and quadriceps (Fig. 1G and I).
Corticospinal conditioning of biceps and quadriceps phasic stretch reflex
The studies were only carried out in subjects aged 8 years and older, since we have previously shown that the pattern of response in biceps does not achieve adult values until 8 years (Conway, 1995). These studies could also only be undertaken in subjects who had demonstrated responses to TMS, since an estimate of CMCD was required.
Homonymous phasic stretch reflex
A hand-held electromechanical tapper (model 201; Ling-Altec Ltd, Royston, UK) delivered small taps to the tendon of biceps or quadriceps. The tapper was held at right angles to the tendon. A force transducer (type ELF-500 miniature load cell; Entran, Watford, UK), was mounted in series with the stylus of the tapper to encode the force profile of each tap delivered to the muscle tendon. The static force with which the tapper pressed on the muscle tendon was kept at ~2 N, indicated on a meter visible to the experimenter. The peak force achieved in each tap was fed to the computer for off-line analysis. The peak force of the tap was increased until a phasic stretch reflex was evoked in 50% of trials, defined as threshold (Fig. 1E and F). Using this technique the mean amplitude and onset latency of 20 phasic stretch reflexes in biceps evoked at 1.2 x threshold have been shown to be consistent within a subject, both when recorded consecutively within the same session and when recorded at different experimental sessions (Miller et al., 2001). In addition the threshold is highly reproducible. When consecutive estimates of threshold were made in 20 adults, the mean difference between repeat measurements made within the same experimental session was 0 ± 0.22 N (mean ± standard error of the mean), and between different experimental sessions was 0 ± 0.25 N (O'Sullivan, 1991).
Corticospinal conditioning of the phasic stretch reflex (Eyre et al., 2000)
CMCD estimated the delay from TMS to the onset of the corticospinal excitatory post-synaptic potential (EPSP) at biceps or quadriceps -motoneurones. The delay from the tap to arrival of the Group Ia EPSP was estimated by subtracting PMCD from the shortest onset latency of the stretch reflex. TMS at 0.8 x threshold (conditioning stimulus, C), tap to biceps or quadriceps at 1.2 x threshold (test stimulus, t) and the two stimuli together at a defined condition to test interval (C-t interval) were delivered in sequence. Trials, comprising 20 repeats of the sequence, were conducted over a range of C-t intervals such that the corticospinal EPSP was estimated to arrive at biceps -motoneurones from 2 ms before (C-t interval –2 ms) to 8 ms after (C-t interval +8 ms) the estimated arrival of the Group Ia EPSP (Fig. 2). The phasic stretch reflex in left biceps was conditioned by subthreshold TMS of the left (ipsilateral) and right (contralateral) cortex, and that of left quadriceps was conditioned by TMS over the vertex.
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Functional studies
Hand and leg dominance were assessed using the criteria of Porac and Coren (Porac and Coren, 1977). Manual dexterity was assessed using the nine-hole pegboard and the Purdue pegboard (Sharpless, 1976
; Mathiowetz and Weber, 1985). Normal control data were obtained from Mathiowetz and Weber (1985) for the nine-hole pegboard and from Tiffin and Asher for the Purdue pegboard (Tiffin and Asher, 1948). A nine-pad footboard was used to assess dexterity of leg and foot movements (Dobson, 1999). The board comprised a 3 x 3 array of 1.8 cm diameter pads, with 10 cm between the centres of each pad. The subjects were timed whilst they completed depressing each of the pads, returning between each to press a ‘home’ pad. The dominant leg was tested first and one practice run was allowed for each leg. The test was repeated for each foot, first using the area over the first metatarsal (the ball of the foot) to press the pads, and then the first toe. Normal data were obtained from 100 subjects (45 males and 65 females) aged from 3 to 45 years.
Neuroanatomical study
Subject
A male child hemizygous for a class 3 L1CAM mutation, who died aged 2 weeks. The genetics and clinical details of this child have been published (Jouet et al., 1995) (Case 9 in Table 1).
Methods
Formalin-fixed and paraffin-embedded post-mortem samples of the medulla and lumbar spinal cord were provided by Dr M. V. Squier, Department of Neuropathology, Radcliffe Infirmary, Oxford, UK. Sections from each sample were either immunostained for neurofilaments, using a polyclonal antiserum to all neurofilament sub-units (Affiniti Research Products, Manhead, Exeter, UK) diluted 1 : 1000 or, for growth associated protein 43 kilodaltons (GAP43), using a monoclonal antiserum clone GAP-7B10 (Sigma) diluted 1 : 1000. Standard immunocytochemical procedures were followed. Appropriate biotinylated secondary antibodies and blocking sera, and streptavidin horseradish peroxidase were obtained from Vector Laboratories (Newcastle upon Tyne, UK). Finally, sections were reacted with diaminobenzidine to visualize the immunostaining.
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Neurophysiological studies
Studies were performed on all subjects with the exception of the son of case family 3 who refused to take part in the neurophysiological studies but completed the functional tests.
Responses in left biceps evoked by TMS of the right (contralateral) motor cortex
L1CAM mutation hemizygous males
. Responses were evoked in all subjects following stimulation of the right (contralateral) motor cortex (Fig. 1A). The CMCDs were either abnormally prolonged or at the upper limit of the normal range in all subjects aged 13 years or less, but for the older four subjects CMCDs were within the normal range (Fig. 1G). Although the thresholds were within the normal range, they were abnormally distributed towards high values (Fig. 1H), giving a mean standard deviate score of 0.95 with 95% confidence limits of +0.22 to +1.66.
L1CAM mutation carrier females
. Responses were evoked in all subjects following TMS of the right (contralateral) motor cortex who had thresholds and CMCDs within the normal adult range (Fig. 1G and H).
Responses evoked in left biceps by TMS of the left (ipsilateral) motor cortex
L1CAM mutation hemizygous males
. Responses following TMS of the left (ipsilateral) motor cortex were obtained in only four of the nine subjects tested. The CMCDs were within the normal range for two subjects and abnormally prolonged in two (Fig. 1G). The thresholds of these responses lay within the normal range for age (Fig. 1H).
L1CAM mutation carrier females
. Responses following TMS of the ipsilateral (left) motor cortex were obtained in only one subject with a CMCD and threshold within the normal range (Fig. 1G and H).
Responses evoked in quadriceps by TMS over the vertex of the skull
L1CAM mutation hemizygous males
. Responses were obtained in eight out of nine subjects tested. The CMCDs and thresholds for these subjects were either greater than or at the upper limit of the normal range for age (Fig. 1I and J). Responses could not be obtained in Case 5 aged 10 years.
L1CAM mutation carrier females
. Responses were obtained in all subjects. While thresholds and CMCDs lay predominantly within the normal adult range, the CMCDs and thresholds were abnormally distributed towards the upper limits of normal (standard deviate score: thresholds, mean +1.13, 95% confidence limits +0.25 to +1.99; CMCD, mean +0.67, 95% confidence limits –0.20 to +1.52 (Fig. 1I and J).
Corticospinal conditioning of biceps and quadriceps stretch reflexes (Fig. 2)
In normal subjects, hemizygous males and carrier females with L1CAM mutations, subthreshold TMS of the ipsilateral and contralateral cortex for biceps, or the vertex for quadriceps, led initially to facilitation of the stretch reflexes in biceps and in quadriceps at C–t intervals appropriate for coincidence of corticospinal and Group Ia afferent EPSPs at the -motoneuronal pools (Fig. 2).
Conditioning of left biceps stretch reflex by subthreshold TMS of the right (contralateral) motor cortex
. In normal subjects, the initial facilitation peaked within 1 ms of its onset. It was followed by significant depression of the biceps stretch reflex that reached a maximum of 3 ms after the onset of facilitation (Fig. 2C and E). For both hemizygous males and carrier females of the L1CAM mutation, the peak of the facilitation occurred 1 ms later than for normal subjects and it was significantly greater than normal for hemizygous males (P < 0.05). The mean duration of the facilitation was also prolonged (hemizygous males >6 ms, carrier females 4 ms) and there was no period of depression of the test reflex (Fig. 2C and E).
Conditioning of left biceps stretch reflex by subthreshold TMS of the left (ipsilateral) motor cortex
. The period of facilitation was brief in both normal subjects and those with L1CAM mutations, so that the conditioned reflex amplitude had returned to baseline by 2 ms for all subject groups (Fig. 2C). The peak facilitation for males hemizygous for L1CAM mutations was significantly less than for normal subjects (Fig. 2D; P < 0.05).
Conditioning of quadriceps stretch reflex by subthreshold TMS of the vertex
. In normal subjects, cortical facilitation of the quadriceps stretch reflex peaked within 1 ms of its onset and had a mean duration of 3 ms (Fig. 2F). For both hemizygous males and carrier females of L1CAM mutation the peak of the facilitation occurred 1 ms later than for normal subjects and it was significantly greater than normal for hemizygous males (P < 0.05). The duration of the initial facilitation was prolonged (hemizygous males 6 ms, carrier females 4 ms) and there was no period of depression of the test reflex.
Functional tests of dexterity
To allow comparison between the tests of dexterity, the individual scores were converted to standard deviate scores, based on the mean and standard deviation score for normal subjects (Fig. 3).
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Nine-hole pegboard (Fig. 3A
)All carrier females and hemizygous males were able to complete the test. Carrier females had normal test scores, while those for hemizygous males were significantly abnormal for both their dominant (P < 0.01) and non dominant hands (P < 0.01).
Purdue pegboard (Fig. 3B)
Males hemizygous for L1CAM mutations were unable to complete the Purdue pegboard tests. Carrier females were able to complete the tests. Although their scores fell predominantly within the normal range, the scores were abnormally distributed towards lower dexterity, such that the 95% confidence limits for mean standard deviate scores for each component of the test did not include zero.
The nine-pad footboard (Fig. 3C)
Although the hemizygous males were able to complete the test using the ball of their foot to depress the footboard pads, their scores were significantly abnormal (dominant foot P < 0.001, non-dominant foot P < 0.01). They were unable to complete the test using their first toe to depress the footboard pads. Female carriers completed both components of the nine-pad footboard test. While their individual scores lay predominantly within the normal range, the scores were skewed towards the lower limits of normality for dexterity, since the 95% confidence limits for their mean standard deviate scores approached but did not include zero.
Neuroanatomical study
Anti-neurofilament immunocytochemistry gave clear labelling of corticospinal fibres, which were visible in the medulla and could be seen crossing over the midline in both directions at the normal point of decussation (Fig. 4A and B). Far fewer corticospinal axons were GAP43 positive at this level (Fig. 4C). In the lumbar spinal cord the lateral corticospinal tract was identifiable and contained a mixture of neurofilament-positive and GAP43-positive axons (Fig. 4D and E).
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Functional corticospinal projections to cervical and lumbar spinal segments are present in males hemizygous for the L1CAM mutation
TMS has been shown in man and subhuman primates to excite corticospinal tract axons, both directly and trans-synaptically at the level of the cortex (Edgley et al., 1990
, 1997; Burke et al., 2000). In hemizygous males, the responses evoked in biceps and in quadriceps following TMS of the motor cortex establish that functional corticospinal projections extending to the lumbar segments of the spinal cord can be present in subjects with L1CAM mutations. This conclusion is supported by histological evidence of clearly visible lateral corticospinal tracts in the lumbar spinal cord of Subject 9 (Fig. 4D and E). All but one of the reports of absent medullary pyramids in association with severe X-linked hydrocephalus have been made at post-mortem in children who died aged <3 months, or in foetuses who either died or were terminated in utero (Chow et al., 1985; Yamasaki et al., 1995; Chow, 1996; Graf et al., 2000). Absence of corticospinal projections may therefore occur in cases with the most extreme phenotypes associated with early death. Another possible explanation is marked delay in the development of the corticospinal projection, so that at the time of death insufficient numbers of corticospinal axons have projected to the midbrain to form clearly identifiable pyramids in severely affected foetuses and infants. Such developmental delay would be consistent with the slow fasciculation observed in neurones where there is a class 2 or 3 mutation of the L1CAM gene (Stallcup and Beasley, 1985; Lagenaur and Lemmon, 1987). The present study also provides support for delayed corticospinal tract development, since the CMCDs of responses evoked in biceps and quadriceps were most likely to be abnormal in the youngest subjects (Fig. 1G and I).
The majority of corticospinal axons decussate in hemizygous males
In primates, including man, the majority (~90%) of corticospinal axons decussate in the medulla. The minority (~10%) descend into the ipsilateral spinal cord, mainly in the dorsolateral column, but also in the ventromedial column (Nathan et al., 1990; Galea and Darian-Smith, 1994; Darian-Smith et al., 1996; Armand et al., 1997). Reflecting this predominance of crossed projections, TMS of the motor cortex normally evokes responses in contralateral muscles significantly more frequently than in ipsilateral muscles, and these responses have significantly lower thresholds and shorter CMCDs than responses evoked in ipsilateral muscles (Wassermann et al., 1994; Eyre et al., 2001b; Fig. 1). Cohen and colleagues have proposed that the ventral midline of the pyramidal decussation expresses a specific guidance cue, which functions as a ligand for L1CAM, permitting crossing of corticospinal axons over the midline (Cohen et al., 1997). If this hypothesis is correct, then males hemizygous for class 2 or class 3 L1CAM mutations would be expected to have a greatly reduced decussation, i.e. the majority of fibres would not cross the midline but would have an ipsilateral projection to the spinal cord. In these circumstances, TMS of the cortex would evoke responses more readily in muscles ipsilateral to the motor cortex than in contralateral muscles. In all of the hemizygous males tested we found evidence to the contrary. Following TMS of the motor cortex, responses in ipsilateral biceps occurred less frequently, were smaller (Fig. 1A and B) and had very much higher thresholds and longer CMCDs than responses evoked in contralateral biceps (Fig. 1G and H). Indeed, the neurophysiological data of the present study imply a reduced rather than increased ipsilateral corticospinal projection in the presence of L1CAM mutations. In normal subjects, ipsilateral responses in biceps can be obtained in all subjects under 12 years of age (Muller et al., 1997; Eyre et al., 2001b), and in 65–100% of adults (Wassermann et al., 1994; Eyre et al., 2001b). In the present study, however, ipsilateral responses were obtained in only four out of nine (44%) males hemizygous for L1CAM mutations and in only one out of eight (13%) carrier females. While subthreshold TMS of the cortex led to facilitation of the phasic stretch reflex in ipsilateral biceps in hemizygous males, the peak facilitation was significantly less than that observed in normal adult subjects, consistent with a reduced corticospinal excitatory input to the ipsilateral motoneuronal pool. The possibility that the motoneuronal pool is less responsive to corticospinal input in subjects with L1CAM mutations is excluded by the significantly increased facilitation of the biceps stretch reflex observed following subthreshold TMS of the contralateral cortex.
The conclusion that the majority of corticospinal axons decussated is supported by the neuroanatomical findings in Subject 9. These revealed apparently normal decussation of corticospinal axons at the medullary pyramid with no evidence of the formation of substantial ipsilateral corticospinal tracts (Fig. 4A and B). Subject 9 had a nonsense mutation affecting the Ig domain 6 and was thus unlikely to express L1CAM at the cell membrane.
Evidence for abnormal corticospinal function in males hemizygous for the L1CAM mutation
The responses elicited in contralateral biceps in hemizygous males had CMCDs within the normal range, except for those aged 13 years or less, in whom CMCDs were abnormally prolonged. The thresholds were abnormally skewed to lie in the upper limits of normal. Responses evoked in quadriceps had CMCDs at or above the upper limit of normal and abnormally high thresholds. In one subject, responses could be evoked in biceps following stimulation of the contralateral cortex, but not following ipsilateral TMS, nor could responses be obtained in the quadriceps. These data indicate pathophysiology of the corticospinal system, which affects the projection to the lumbar spinal segments more than that to the cervical segments. In light of the hypoplasia of the corticospinal tract, which has been demonstrated both histologically and radiologically in human subjects and in both of the knock-out L1CAM mouse models, the data of the present study would be consistent with a reduced but functional corticomotoneuronal projection to both the cervical and lumbar spinal segments (Chow et al., 1985; Yamasaki et al., 1995; Cohen et al., 1997; Dahme et al., 1997; Fransen et al., 1998; Graf et al., 2000).
TMS is most likely to excite axons within the cortex rather than cortical neurones (Di Lazzaro et al., 1998; Matthews, 1999). There is increasing evidence that members of the L1CAM sub-family play a role in the clustering of voltage-gated sodium channels at the initial segment of the axon and at the nodes of Ranvier (Bennett and Lambert, 1999). Voltage-gated sodium channels in these domains are essential for the efficient initiation and propagation of action potentials, and failure to appropriately locate these ion channels would also lead to a higher threshold for activation of corticospinal axons and slower saltatory conduction, thus increasing conduction delays.
In hemizygous males, cortical conditioning with TMS led to both an increased peak and a prolonged duration of facilitation of both biceps and quadriceps phasic stretch reflexes. These findings at first appear incompatible with the high threshold and prolonged CMCDs of responses evoked by TMS alone, and previous morphological findings of hypoplasic corticospinal tracts (Chow et al., 1985; Yamasaki et al., 1995; Graf et al., 2000) in subjects with L1CAM mutations. In the macaque monkey, cortically evoked composite EPSPs recorded in -motoneurones have durations of up to 15 ms, unless followed by an inhibitory post-synaptic potential (IPSP) mediated by corticospinal projections to Group Ia inhibitory interneurones (Jankowska et al., 1975, 1976). The very brief durations of cortical facilitation of biceps and quadriceps stretch reflexes in normal subjects and the significant cortical depression of biceps stretch reflex, beginning within 1 ms of the onset of facilitation (Fig. 2F–I), are consistent with the arrival of an IPSP 1–2 ms after the onset of the EPSP (Jankowska et al., 1975, 1976; Eyre et al., 2000). To support this conclusion, subthreshold TMS has been demonstrated to evoke inhibition of biceps -motoneurones in man via monosynaptic corticospinal projections to Group Ia inhibitory interneurones (Eyre et al., 2000). The increased peak and prolonged duration of the cortical facilitation of the phasic stretch reflex observed in hemizygous males may have arisen because a reduced corticospinal projection to the Group Ia inhibitory interneurones resulted in a significantly smaller IPSP following TMS. This conclusion is supported by the absence of significant depression of biceps phasic stretch reflex in the hemizygous males. However, since L1CAM is expressed by sensory nerves during development, it is also possible that there are abnormalities of muscle sensory afferent projections, leading to changes in the rise time of the Group Ia EPSP at the -motoneuronal pool (Honig and Rutishauser, 1996). Finally, a further possibility is that of abnormal development of spinal inhibitory interneurones and their projections to -motoneurones. To discriminate between these possibilities, further studies will be required.
Impaired dexterity of both upper limb and lower limb function in hemizygous males
Hemizygous males showed impaired manual dexterity as well as abnormal dexterity of lower limb function (Fig. 3). A degree of cognitive deficit will have contributed to their poor performance; however, skilled movements of the hand and feet in primates have been shown to rely upon the integrity of the corticospinal system (Kuypers 19621981;Lawrence and Hopkins, 1976; Bortoff and Strick, 1993). The impairment of dexterity in hemizygous males is similar to that documented in the affected limbs of patients with spastic hemiplegia who do not have a cognitive deficit (Tinnion, 1999), and it is consistent with the demonstrated abnormalities of corticospinal neurophysiology.
Impaired corticospinal tract function in female carriers of L1CAM mutations
Females with L1CAM mutations are described as being asymptomatic and thus the syndromes associated with L1CAM mutations are thought to be X-linked recessive disorders (Kenwrick et al., 1996; Fransen et al., 1997). However, the present neurophysiological studies reveal abnormalities of corticospinal tract function, which are similar in pattern but less severe in nature to those observed in hemizygous males. Subtle abnormalities were also demonstrated in dexterity of both upper and lower limb function, which would be unlikely to be manifest in clinical examination, or to significantly impede the skill of performance of activities of daily living. In this context it is interesting to note the much higher incidence of left-handedness in carrier females and hemizygous males than occurs in the normal population. A much higher incidence of left-handedness has been shown to occur in children with clumsiness and mild cognitive impairment (Saigal et al., 1992). Our findings in carrier females are corroborated by the occasional clinical reports of ‘expressing females’ (Bianchine and Routtenberg, 1974; Halliday et al., 1986; Kaepernick et al., 1994), which may represent both phenotypic variation and/or skewed X-chromosome inactivation in these individuals.
There are discrepancies between the observations in man and the knock-out mouse models
The present study demonstrates significant abnormality in corticospinal function in subjects with L1CAM mutations, as might be expected from the evidence for corticospinal tract hypoplasia observed both in man and in the knock-out mouse models (Chow et al., 1985; Yamasaki et al., 1995; Cohen et al., 1997; Dahme et al., 1997; Fransen et al., 1998; Graf et al., 2000) and the clinical signs of spasticity (Kenwrick et al., 1996; Fransen et al., 1997). There are two observations in this study, however, which are inconsistent with those made in the knock-out mouse by Cohen and colleagues (Cohen et al., 1997). First, corticospinal projections have been demonstrated both neurophysiologically and histologically to the lumbar spinal segments, and secondly, there is no anatomical or neurophysiological evidence to support significant failure of decussation of corticospinal axons. These discrepancies are unlikely to arise from differences in the site of the mutation between the knock-out mouse and our subjects, since we have included in the study hemizygous males with class 3 mutations who, like the knock-out mouse of Cohen and colleagues (1997), would not have expressed L1CAM protein (Cases 2, 3, 5 and 9). Indeed, Case 9, the subject for the neuroanatomical study, had a nonsense mutation affecting Ig domain 6, and this is very similar to the mutation used to create the knock-out mouse of Dahme and colleagues (Dahme et al., 1997). The histological evidence in Case 9 for decussation of the majority of corticospinal axons at the medulla, combined with neurophysiological evidence in the remaining cases that the majority of corticospinal axons projecting to biceps motoneurones decussated, makes it unlikely that there is a critical role for L1CAM proteins in corticospinal axon guidance at the pyramidal decussation. An alternative explanation may be that significant delay in the projection of corticospinal axons, secondary to slow fasciculation, led to the corticospinal axons in the knock-out mouse arriving at the medulla too late for the optimal expression of guidance cues for decussation. Slow fasciculation might also explain the failure of projection of corticospinal axons to the lumbar cord observed in the knock-out mouse. Since this projection is the longest in the central nervous system, the axons may arrive too late to be competitive in establishing synapses on motoneurones and interneurones, and are thus predominantly or even completely withdrawn (Stanfield et al., 1982; Martin and Lee, 1999; Eyre et al., 2001b). The findings in the present study that the neurophysiological abnormalities were more marked in the corticospinal projection to the quadriceps -motoneurones than to biceps -motoneurones would be consistent with this hypothesis. Axons projecting to biceps motoneurones would arrive relatively earlier and would therefore have been more likely to be competitive in the establishment of their synaptic projection. Finally, there is increasing evidence that CAMs, including L1CAM, have a pivotal role in activity-dependent establishment of synapses (Hoffman, 1998). The corticospinal projection to the lumbar segments of the spinal cord must therefore be the most vulnerable to abnormalities in L1CAM protein expression, since the axons are likely to arrive late and dysfunction in cell adhesion will further compromise synapse formation.
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TopAbstractIntroductionMaterial and methodsResultsDiscussionAcknowledgementsReferences |
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We thank all the subjects and physicians who gave permission to study their patients. The study was supported by The Wellcome Trust.
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Received March 28, 2001. Revised June 4, 2001. Accepted July 10, 2001.
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