Further clinical and genetic characterization of SPG11: hereditary spastic paraplegia with thin corpus callosum

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders leading to progressive spasticity of the lower limbs. Clinically, HSPs are divided into "pure" and "complicated" forms. In pure HSP, the spasticity of the lower limbs is the sole symptom, whereas in complicated forms additional neurological and non-neurological features are observed. Genetically, HSPs are divided into autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) forms. Up to date, 30 different HSPs are linked to different chromosomal loci and 11 genes could be defined for AR-HSP, AD-HSP and XL-HSP. SPG11, an AR-HSP (synonym: HSP11), is a complicated HSP associated with a slowly progressive spastic paraparesis, mental impairment and the development of a thin corpus callosum (TCC) during the course of the disease. SPG11 has been previously linked to chromosomal region 15q13 - 15. First, we applied rigid diagnostic criteria to systematically examine 20 Turkish families with autosomal recessive HSP for characteristic features of SPG11. We detected four large Turkish families with AR-HSP and TCC consistent with SPG11. Subsequent genetic linkage analysis of those 4 families refines the SPG11 locus further down to a small region of 2.93 cM with a maximum lod score of 11.84 at marker D15S659 and will guide further candidate gene analysis.     

Abnormal corticomotor excitability assessed in biceps brachii preceding pronator contraction post-stroke.

OBJECTIVE: To assess corticomotor (CM) excitability of the antagonist biceps brachii (BB) post-stroke in preparation for pronator contraction. In healthy subjects, we previously demonstrated that prior to pronator contraction CM excitability of the antagonist BB was suppressed. METHODS: Transcranial magnetic stimulation (TMS) was used to assess pre-contraction changes in motor evoked potential (MEP) amplitude of the BB, when BB was acting either as an antagonist or an agonist. TMS was applied 100-200ms prior to rhythmic isometric BB or pronator contractions in chronic stroke survivors and age/gender matched healthy control subjects. RESULTS: Prior to pronator contraction, MEPs in BB were elicited in the stroke group but were absent in healthy controls indicating that CM excitability of the antagonist BB was increased post-stroke. The extent of the abnormal increase in excitability positively correlated with the extent of upper limb motor impairment. CONCLUSIONS: Our results suggest that an alteration of cortical control mechanisms regulating motor excitability of the antagonist BB may contribute to the impairment of upper limb motor coordination post-stroke. SIGNIFICANCE: This study offers a unique approach to study the potential for a cortical origin of post-stroke motor discoordination.     

Motor and somatosensory evoked potentials in Autosomal Dominant Hereditary Spastic Paraparesis (ADHSP) linked to chromosome 2p, SPG4

The aim of our study was to evaluate Motor Evoked Potentials (MEPs) and cortical excitability, using Transcranial Magnetic Stimulation (TMS) as well as short latency Somatosensory Evoked Potentials (SEPs) in Autosomal Dominant Hereditary Spastic Paraparesis (ADHSP) patients. MEPs were recorded from upper and lower limb muscles in 12 patients (7 m and 5f) affected by ADHSP with spastin mutation (SPG4). We measured: (i) motor threshold (MTh); (ii) total motor conduction time (TMCT); (iii) direct and indirect central motor conduction time (d-CMCT and i-CMCT) calculated by subtracting from the cortical latency those obtained on magnetic spinal stimulation (d-PMCT) and via the F-wave method (i-PMCT); (iv) MEP amplitude (MEP/Mmax ratio%) and (v) duration of the cortical silent period (CSP). Latency, amplitude and persistence of the F-wave obtained with electrical nerve stimulation were also considered; H reflex was also tested from lower extremities. SEPs were recorded from spine and scalp sites following median and posterior tibial nerve stimulation; conventional latency and amplitude measurements were performed. In a comparison with the control group, the MTh recording from lower limbs was significantly higher (67.5 +/- 7.7% versus 52.5 +/- 6.9%), MEPs were absent in one case and showed reduced amplitude in the remainders (22.9 +/- 12.6% versus 66.3 +/- 25.9% of M wave); TMCT resulted to be abnormal (36.5 +/- 3.9 ms versus 27.1 +/- 1.4 ms) and d-CMCT as well as i-CMCT were significantly prolonged (23.1 +/- 3.5 ms versus 13.8 +/- 1.3 ms; and 20.1 +/- 3.4 ms versus 10.6 +/- 1.3 ms, respectively). The CSP, which was normal from the hands, was significantly shortened from the legs and correlated with spasticity scoring (Ashworth scale). Cortical SEPs from lower limbs were abnormal in all cases, whereas SEPs by stimulation of median nerves were normal; F-wave parameters from upper limbs showed no abnormalities, whereas an increased persistence was detected from lower limbs; H reflex amplitudes resulted larger compared with controls. Moreover, shortening of the CSP, being correlated with the Ashworth scale, can be considered an electrophysiological marker of spasticity that seems to arise from impairment of the supraspinal or intracortical inhibitory pathways with an additional contribution of increased segmental motor neuron excitability. These data prove the existence of comparable neurophysiological abnormalities in ADHSP with spastin mutation (SPG4) when long ascending and descending pathways are involved.     

Genetics of hereditary spastic paraplegias

Hereditary spastic paraplegias (HSPs) are clinically and genetically highly heterogeneous. The key symptom of spastic paraparesis of lower limbs can be complicated by a variety of signs and symptoms including cognitive impairment, optic atrophy, cerebellar ataxia, peripheral nerve involvement, or seizures. At least 48 loci have been identified, termed SPG1-SPG48. Ten genes for autosomal dominant HSP are currently known, SPG4 being by far the most common subtype accounting for ～50% of cases. SPG3 is especially common in young-onset cases. Autosomal recessive HSP seems to be even more heterogeneous. The known 12 autosomal recessive HSP genes collectively explain about one third of cases only. The most common causes for pure autosomal recessive HSP are SPG7 and SPG5. Mental retardation and thin corpus callosum on magnetic resonance imaging point toward SPG11 and SPG15. The authors provide an overview on clinical, neurophysiologic, and neuroradiologic characteristics of the more common HSP subtypes. More details are given in the tables for quick reference, and a genetic testing strategy is proposed.     

Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia

BACKGROUND: Hereditary spastic paraplegias are disorders that are very heterogeneous, both clinically and genetically. The atlastin1 gene has recently been implicated in SPG3A, a form of autosomal dominant pure spastic paraplegia. Atlastin1 mutations have been identified in 8 families so far. OBJECTIVES: To determine the relative frequency, phenotype, and mutation spectrum of SPG3A in patients with pure autosomal dominant spastic paraplegia and onset before age 20 years. PATIENTS AND METHODS: We sequenced the atlastin1 gene in a large series of patients (31 families) in which mutations in the spastin gene, corresponding to the frequent SPG4 locus, had previously been excluded. The phenotype was compared with 126 SPG4 patients. RESULTS: We identified 12 families (39%) including 34 patients with 9 different missense atlastin1 mutations, 7 of which are newly described. The main clinical characteristic of these SPG3A patients was pure spasticity with very young onset of symptoms (mean age, 4.6 +/- 3.9 years) and slow progression. However, additional signs such as decreased vibration sense and wasting in lower limbs, sphincter disturbances, and scoliosis were found in a minority of patients. In addition, several gene carriers were clinically affected but still asymptomatic (n = 5) or had no clinical signs (n = 2), indicating incomplete penetrance. Compared with patients from other families meeting the same diagnostic criteria (43 patients) and families with SPG4 (126 patients), the major form of autosomal dominant spastic paraplegia, SPG3A patients had earlier symptom onset, less frequently increased reflexes in the upper limbs, decreased vibration sense in the lower limbs, and fewer sphincter disturbances, but more frequently observed wasting in the lower limbs and scoliosis. These particularities, as well as frequent abnormal motor evoked potentials, could help identify patients to be screened for atlastin1 gene mutations. CONCLUSIONS: This study enables us to estimate the frequency of the SPG3A mutations in France at 39% in families with young-onset autosomal dominant spastic paraplegia after exclusion of SPG4 cases. So far, most mutations have been private, although they were all found in exons 7, 8, 12, and 13. These exons should be given priority when performing molecular diagnoses for SPG3A.     

Peripheral neuropathy in hereditary spastic paraplegia due to spastin (SPG4) mutation--a neurophysiological study using excitability techniques

ObjectiveTo identify peripheral nerve abnormalities in hereditary spastic paraplegia (HSP) due to mutations in the spastin gene (spastic paraplegia 4, SPG4) using standard nerve conduction (NCS) and novel tests of axonal excitability.MethodsEleven patients with known mutations in spastin were assessed with NCS for the upper and lower limbs, and axonal excitability testing on the median nerve.ResultsStandard nerve conduction studies revealed a sensorimotor neuropathy in two patients. Excitability studies on median motor axons showed an isolated abnormality (increased strength-duration time constant), but those on sensory axons were normal in nine patients with normal routine nerve conduction studies.ConclusionsPeripheral neuropathy occurs in HSP patients with SPG4 mutations, but axonal excitability studies provide limited additional evidence for subclinical peripheral nerve dysfunction, and add little further to standard nerve conduction studies.SignificanceThe features of HSP due to SPG4 mutations include sensorimotor polyneuropathy. The value of excitability studies is limited in individual patients.     

Eight novel mutations in SPG4 in a large sample of patients with hereditary spastic paraplegia

BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous disorders characterized by progressive spasticity of the lower limbs. Mutations in the SPG4 gene, which encodes spastin protein, are responsible for up to 45% of autosomal dominant cases. OBJECTIVE: To search for disease-causing mutations in a large series of Italian patients with HSP. DESIGN: Samples of DNA were analyzed by direct sequencing of all exons in SPG4. Samples from a subset of patients were also analyzed by direct sequencing of all exons in SPG3A, SPG6, SPG10, and SPG13. SETTING: Molecular testing facility in Italy. PATIENTS: Sixty unrelated Italian patients with pure (n = 50) and complicated (n = 10) HSP. MAIN OUTCOME MEASURES: Mutations in SPG4, SPG3A, SPG6, SPG10, and SPG13. RESULTS: We identified 12 different mutations, 8 of which were novel, in 13 patients. No mutations of any of the other HSP genes tested were found in 15 patients with sporadic pure HSP who did not have mutations in the SPG4 gene. CONCLUSIONS: The overall rate of mutation in the SPG4 gene within our sample was 22%, rising to 26% when only patients with pure HSP were considered. The negative result obtained in 15 patients without mutations in SPG4 in whom 4 other genes were analyzed (SPG3A, SPG6, SPG10, and SPG13) indicate that these genes are not frequently mutated in sporadic pure HSP.     

The effect of coordination mode on use-dependent plasticity.

OBJECTIVE: To evaluate the role of coordination mode on the generation of use-dependent plasticity (UDP) within the primary motor cortex (M1). METHODS: Ten healthy volunteers performed brisk repetitive thumb movements for 30 min in the opposite direction to those evoked by transcranial magnetic stimulation (TMS) prior to training. This practice was synchronized or syncopated with a 1 Hz auditory metronome in two separate sessions. Motor evoked potentials (MEPs) were recorded from 3 intrinsic thumb muscles, to assess changes in corticomotor excitability. RESULTS: Both synchronized and syncopated motor practice induced changes in the direction of TMS-evoked thumb movements, away from the baseline direction toward the trained direction. MEP amplitude increased following synchronized, but not syncopated, motor practice. Changes in movement direction and corticomotor excitability lasted for at least 30 minutes. CONCLUSIONS: UDP can be elicited in the presence or absence of changes in corticomotor excitability. SIGNIFICANCE: Motor practice that is synchronized with external pacing may promote UDP and facilitate corticomotor excitability in patient populations with reduced corticomotor output, such as stroke. Training that is syncopated with external pacing may promote UDP without increasing corticomotor excitability. This could be relevant for individuals with disorders characterized by maladaptive plasticity.     

Ipsilateral corticomotor excitability is associated with increased gait variability in unilateral transtibial amputees

Ipsilateral primary motor cortex (M1) reorganisation after unilateral lower‐limb amputation may degrade function of the amputated limb. We hypothesised unilateral lower‐limb amputees would have a bilateral increase in corticomotor excitability, and increased excitability of ipsilateral M1 would be associated with increased step‐time variability during gait. Twenty transtibial amputees (16 male) aged 60.1 years (range 45–80 years), and 20 age‐ and gender‐matched healthy adult controls were recruited. Single‐pulse transcranial magnetic stimulation assessed corticomotor excitability. Two indices of corticomotor excitability were calculated. An index of corticospinal excitability (ICE) determined relative excitability of ipsilateral and contralateral corticomotor projections to alpha‐motoneurons innervating the quadriceps muscle (QM) of the amputated limb. A laterality index (LI) assessed relative excitability of contralateral projections from each hemisphere. Spatial‐temporal gait analysis was performed to calculate step‐time variability. Amputees had lower ICE values, indicating relatively greater excitability of ipsilateral corticomotor projections than controls (P = 0.04). A lower ICE value was associated with increased step‐time variability for amputated (P = 0.04) and non‐amputated limbs (P = 0.02). This association suggests corticomotor projections from ipsilateral M1 to alpha‐motoneurons innervating the amputated limb QM may interfere with gait. Cortical excitability in amputees was not increased bilaterally, contrary to our hypothesis. There was no difference in excitability of contralateral M1 between amputees and controls (P = 0.10), and no difference in LI (P = 0.71). It appears both hemispheres control one QM, with predominance of contralateral corticomotor excitability in healthy adults. Following lower‐limb amputation, putative ipsilateral corticomotor excitability is relatively increased in some amputees and may negatively impact on function.     

Modulations in corticomotor excitability during passive upper-limb movement: is there a cortical influence?

Modulations in the excitability of corticomotor pathways to forearm musculature have previously been demonstrated during passive wrist movement [Brain Res. 900 (2001) 282]. Investigations were conducted to determine the level of the neuroaxis at which these modulations arise, and to establish the influence of proprioceptive task constraints on pathway excitability. Forearm motor evoked potentials (MEPs) in response to transcranial magnetic stimulation (TMS) were examined during passive wrist movement while subjects maintained a low-level muscle activation, thus stabilising the excitability of the motoneuron pool. Modulations in response amplitude during movement were evident in both forearm flexor and extensor muscles. The pattern of modulation generally mirrored that seen in quiescent musculature during movement, with responses potentiated during the phases where the muscle was in a shortened position. Variations in MEP amplitude were not detected while the wrist was constrained statically at various joint angles. This suggests a dynamic influence of movement, most likely mediated by spindle receptors, arising at a supraspinal level. We also investigated the influence of a kinesthetic tracking task on corticomotor excitability during passive movement of the wrist joint. MEPs were recorded from the target driven limb while the contralateral limb was stationary, while the contralateral limb actively tracked the movements of the target limb, and while the contralateral limb moved actively in time with a metronome. The results revealed no differences in MEP characteristics in the driven limb between the three conditions. Placing the movement elicited afferent information in an active movement context does not appear to enhance the modulations in cortical excitability.     

Interaction Between Simultaneously Applied Neuromodulatory Interventions in Humans

BackgroundTranscranial direct current stimulation (tDCS) is a neuromodulatory technique with the potential to enhance the efficacy of traditional therapies such as neuromuscular electrical stimulation (NMES). Yet, concurrent application of tDCS/NMES may also activate homeostatic mechanisms that block or reverse effects on corticomotor excitability. It is unknown how tDCS and NMES interact in the human primary motor cortex (M1) and whether effects are summative (increase corticomotor excitability beyond that of tDCS or NMES applied alone) or competitive (block or reduce corticomotor excitability effects of tDCS or NMES applied alone).ObjectiveTo investigate corticomotor excitability in response to NMES after concurrent application of tDCS protocols that enhance (anodal tDCS) or suppress (cathodal tDCS) excitability of M1.MethodsWe used transcranial magnetic stimulation (TMS) to examine corticomotor excitability before and after the concurrent application of: i) NMES with anodal tDCS; and ii) NMES with cathodal tDCS. Effects were contrasted to four control conditions: i) NMES alone, ii) anodal tDCS alone, iii) cathodal tDCS alone, and iv) sham stimulation.ResultsConcurrent application of two protocols that enhance excitability when applied alone (NMES and anodal tDCS) failed to induce summative effects on corticomotor excitability, as predicted by homeostatic plasticity mechanisms. Combined cathodal tDCS and NMES suppressed the enhanced excitation induced by NMES, an effect that might be explained by calcium dependent anti-gating models.ConclusionsThese novel findings highlight the complex mechanisms involved when two neuromodulatory techniques are combined and suggest that careful testing of combined interventions is necessary before application in clinical contexts.     

Changes in corticomotor excitability after fatiguing muscle contractions

To investigate whether the type and duration of activity influences corticomotor excitability following fatiguing exercise, we compared motor evoked potential (MEP) responses of the biceps brachii to transcranial magnetic stimulation (TMS) during recovery from two different exercise regimens. Responses were recorded in both the resting state and during a weak contraction. Ten subjects performed a 60-s maximal voluntary contraction (MVC) and, on a subsequent occasion, a sustained 20% MVC to the point of exhaustion. Resting MEP amplitude declined following maximal and submaximal protocols, reaching 34% and 31% of pre-exercise means, respectively (P < 0.001 for both). In contrast, mean facilitated MEP amplitude showed a smaller and more transient decrement following the sustained submaximal effort (64%; P < 0.05), but not the 60-s MVC. Abolition of the postexercise depression in resting MEP amplitude by a weak tonic contraction indicates that decreases in excitability at the spinal level contribute to the reduced corticomotor excitability observed after fatiguing exercise.     

Corticomotor organisation and motor function in multiple sclerosis

Our objective was to determine whether there are changes in the corticomotor map for the hand in multiple sclerosis, and whether these changes correlate with indices of motor function and measures of corticomotor conduction or excitability. Transcranial magnetic stimulation (TMS) maps, motor evoked potential (MEP) latency and amplitude, motor threshold and EDSS and Purdue-pegboard measurements were made in 26 subjects with relapsing-remitting multiple sclerosis. Correlations were sought between these measurements using the Pearson product-moment correlation with a level of significance of p = 0.05 (two-tailed). Map displacement was positively correlated with MEP latency (p = 3 x 10(-4)) and EDSS (p = 0.007), and negatively correlated with Purdue score (p = 4 x 10(-4)). Purdue scores correlated with all MEP parameters (latency, p = 4 x 10(-10); threshold, p = 4 x 10(-6); amplitude, p = 0.003). We conclude that motor reorganisation is associated with impaired corticomotor conduction and may reflect a process of neural plasticity associated with axonal demyelination in MS. An understanding of motor function in MS should incorporate models of both axonal demyelination and conduction deficits as well as neural plasticity.     

Connecting clinical aspects to corticomotor excitability in restless legs syndrome: a TMS study

We assessed corticomotor excitability in the primary motor cortex (M1) of participants with moderate-to-severe restless legs syndrome (RLS) symptoms using transcranial magnetic stimulation (TMS) in relation to the clinical and sleep aspects of the disease. Thirty-five participants (20 F; mean age: 59.23 ± 1.66 years; range: 42–78 years) affected by primary RLS (off medications) and 31 age-matched controls (19 F; mean age: 57.90 ± 1.50 years; range: 43–79 years) underwent TMS following two nights of polysomnography (PSG). Paired-pulse TMS measures [short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), and intracortical facilitation (ICF)] of the dominant M1_hand and M1_leg muscles were collected and analyzed in relation to clinical features of RLS and PSG. We found decreased corticomotor excitability in M1_hand, whereas it was increased in M1_leg, which was greater in patients with more severe RLS. Participants with RLS with a history of dopamine-agonist–induced symptom augmentation showed decreased LICI (reduced inhibition) compared to nonaugmented participants with RLS for M1_leg. None of the TMS measures (M1_hand or M1_leg) correlated with the PSG parameters. This study shows hyperexcitability in M1_leg, and this appears related to RLS disease severity and decreased excitability in M1_hand. The results provide new insight into the complex neurobiology of RLS, particularly in more advanced stages of the disease.     

Brain functional reorganization in children with hemiplegic cerebral palsy: Assessment with TMS and therapeutic perspectives

Transcranial magnetic stimulation (TMS) can be a useful tool for the assessment of the brain functional reorganization in subjects with hemiplegic cerebral palsy (HCP). In this review, we performed a systematic search of all studies using TMS in order to explore the neuroplastic changes that occur in HCP patients. We aimed at investigating the usefulness of TMS to explore cortical excitability, plasticity and connectivity changes in HCP. Children with HCP due to unilateral lesions of the corticospinal system had ipsilateral motor evoked potentials (MEPs) similar to those recorded contralaterally. TMS studies demonstrated that occupational and constraint-induced movement therapy were associated with significant improvements in contralateral and ipsilateral corticomotor projection patterns. In addition, after intensive bimanual therapy, children with HCP showed increased activation and size of the motor areas controlling the affected hand. A TMS mapping study revealed a mediolateral location of the upper and lower extremity map motor cortical representations. Deficits in intracortical and interhemispheric inhibitory mechanisms were observed in HCP. Early hand function impairment correlated with the extension of brain damage, number of involved areas, and radiological signs of corticospinal tract (CST) degeneration. Clinical mirror movements (MMs) correlated with disability and CST organization in subjects with HCP and a positive relationship was found between MMs and MEPs strength. Therefore, TMS studies have shed light on important pathophysiological aspects of motor cortex and CST reorganization in HCP patients. Furthermore, repetitive TMS (rTMS) might have therapeutic effects on CST activities, functional connectivity and clinical status in children with HCP.     

Changes in corticomotor excitation and inhibition during prolonged submaximal muscle contractions

Changes in motor evoked potential (MEP) amplitude, post-MEP silent period duration, and interpolated twitch torque were measured using transcranial magnetic (TMS) and electrical (TES) stimulation during a 20% maximum voluntary contraction of the elbow flexors sustained to exhaustion. TMS- and TES-induced MEP amplitude increased progressively over the contraction period up until the point of exhaustion. The TMS-induced silent period was prolonged only during the second half of the contraction period, the time course being different from that of the MEP responses, whereas the TES-induced silent period did not change. The findings indicate that corticomotor excitability increases during a sustained submaximal voluntary contraction and that, as fatigue develops, there is a progressive buildup of intracortical inhibition. This may represent a mechanism whereby corticomotor output is maintained at an appropriate level to preserve optimal motor unit firing frequencies during a fatiguing contraction. © 1997 John Wiley & Sons, Inc. Muscle Nerve 20:1158–1166, 1997     

Analysis of motor pathway involvement in konzo using transcranial electrical and magnetic stimulation

To elucidate the involvement of motor pathways in konzo, 21 konzo subjects (mean age 22 years) underwent transcranial electrical stimulation (TES) in 1998. Fourteen konzo subjects (mean age 21 years) underwent transcranial magnetic stimulation (TMS) in 2000. Three subjects underwent both TES and TMS. Motor evoked potentials (MEPs) were recorded in the abductor pollicis brevis (APB) muscle with TES, and in the abductor digiti minimi (ADM) and tibialis anterior (TA) muscles with TMS. APB-MEPs were normal in 2 of 21 subjects and absent in 9; central conduction time (CCT) was prolonged in 10. Resting ADM-MEPs were absent in 9 of 14 subjects with clinically preserved upper limbs. Among these nine, seven subjects responded after facilitation. Most subjects (13 of 14) failed to show TA-MEPs. Of the subjects who underwent both types of stimulation, one had normal TES-MEP but abnormal ADM-MEP with TMS. These findings suggest involvement of both corticomotoneurons and motor descending pathways in konzo.     

A single dose of sulthiame induces a selective increase in resting motor threshold in human motor cortex: A transcranial magnetic stimulation study

Sulthiame is a carbonic anhydrase inhibitor that is widely used to treat partial and myoclonic seizures. In 11 healthy adults, we applied transcranial magnetic stimulation (TMS) to the primary motor cortex. Using a cross-over study design, we found that a single oral dose of sulthiame (5 mg/kg) produced a significant increase of resting motor threshold relative to placebo. No other TMS measure of corticomotor excitability was altered after a single dose of sulthiame. The selective increase in motor threshold suggests that sulthiame produces its antiepileptic effect by reducing the axonal excitability of cortical neurons.     

Autosomal recessive spastic paraplegia (SPG45) with mental retardation maps to 10q24.3–q25.1

Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity in the lower limbs. They are clinically heterogeneous, and pure forms as well as complicated forms with other accompanying clinical findings are known. HSPs are also genetically heterogeneous. We performed clinical and genetic studies in a consanguineous family with five affected members. A genome scan using 405 microsatellite markers for eight members of the family identified candidate gene loci, and subsequent fine mapping in 16 members identified the gene locus responsible for the HSP. The clinical manifestations were very early onset spastic paraplegia (SPG) accompanied by mental retardation and ocular signs. The gene locus was identified as the interval 102.05–106.64 Mbp on chromosome 10. Gene MRPL43 was analyzed in the patients. No mutation but high levels of mRNA were detected. We have mapped a novel autosomal recessive complicated form of HSP (SPG45) to a 4.6-Mbp region at 10q24.3–q25.1 with multipoint logarithm of odds scores >4.5.