Skip to main content
Download PDF

Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)

Orphanet Journal of Rare Diseases volume 8, Article number: 158 (2013) Cite this article

Abstract

Background

Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP.

Methods

We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed.

Results

Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms.

Conclusions

Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials.

Background

Hereditary spastic paraplegias (HSPs) encompass a group of neurodegenerative disorders with lower limb spasticity due to degeneration of the corticospinal tract as most prominent sign. In addition to this “pure” form, additional neurological and non-neurological symptoms, such as mental retardation, dementia, epilepsy, cerebellar signs, extrapyramidal symptoms, sensory deficits, peripheral neuropathy, skin and skeletal abnormalities can be present (“complicated” forms) [1–4]. HSP is a rare disease with a prevalence of ~ 2–10: 100,000 inhabitants [5, 6]. To date, more than 50 loci (SPG1 – SPG57) and more than 30 genes have been described [7].

Electrophysiological features of HSP have been studied in rather small cohorts (maximum of 26 patients per study) with poor genetic characterisation. Motor evoked potentials were found to be abnormal to the legs in the majority of patients and to the arms in up to one third of patients [8–11]. Central and peripheral sensory tracts were affected to very variable degrees [9, 12–14]. First results hint to genotype-related changes in transcranial magnetic stimulation in the largest HSP subgroup, SPG4[15, 16].

To analyse the spread of long fibre tract affection in HSP and to explore potential effects of different pathomechanisms in distinct genotypes we studied motor and sensory involvement of the central and peripheral nervous system by clinical and electrophysiological means in a representative cohort of HSP patients.

Methods

Patients

128 patients (58 women, 70 men) from 109 families were recruited by specialised HSP outpatient clinics in Bochum, Kiel, and Tübingen, Germany, in the context of the German Network of Hereditary Movement Disorders (GeNeMove). Diagnostic criteria for HSP included (i) spastic paraparesis or spastic tetraparesis with legs earlier and more severely affected than arms or (ii) spastic paraparesis as early and prominent sign of a neurodegenerative multisystem disease after exclusion of other causes. To exclude secondary forms of spastic paraparesis standard diagnostic procedures covered MRI of head and spine, vitamin B12 and folic acid levels, very long chain fatty acids (VLCFA), neurometabolic screening (Krabbe disease, metachromatic leukodystrophy, GM1-gangliosidosis, GM2-gangliosidoses Tay Sachs and Sandhoff, Gaucher disease) and cerebrospinal fluid analysis. All participants gave their written informed consent. The study was approved by the ethics committee of the recruiting centres.

Mean age of patients at examination was 47.5 ± 14.9 years (13–80 years). Disease onset varied between 0 and 68 years (mean age at onset 29.6 ± 17.3 years), mean disease duration was 18.0 ± 13.1 years (0–64 years). At examination 35 patients used a walking aid, 15 patients were wheelchair-bound.

Family history was positive in 55 of 109 families, including 46 families with autosomal dominant (42%) and 9 families with autosomal recessive (8%) disease inheritance. The diagnosis was genetically confirmed in 54 of 128 cases (46%). In addition to 35 cases with SPG4 the following genotypes were identified: SPG3 (1), SPG5 (3), SPG7 (3), SPG8 (1), SPG10 (1), SPG11 (6), and SPG15 (4). SPG4 mutations were excluded in 34 of the 74 cases with unknown genotype (“non-SPG4 patients”).

Clinical severity was assessed by Spastic Paraplegia Rating Scale (SPRS) [17]. The sum of the point values for spasticity of hip adductor muscles, spasticity of knee flexion, weakness of hip abduction, and weakness of foot dorsiflexion were designated as “spastic subscore”. Pure HSP was diagnosed if spastic paresis was accompanied by impaired vibration sense and/or urinary urgency only (56% of patients in our cohort). Presence of other additional signs or symptoms resulted in classification as complicated HSP (44% of our patients) [2]. Peripheral motor neuropathy was clinically assumed by summing up the number of the following items: loss of muscle stretch reflexes to the upper limbs, loss of muscle stretch reflexes to the lower limbs, muscle wasting of the upper limbs, and muscle wasting of the lower limbs. Analogously, the sensory system was rated to be clinically affected (“clinical sensory deficit”) by summing up the number of the following affected parameters: touch sense, pinprick sensation, vibration sensation (< 6/8), joint position sense, and temperature discrimination.

Electrophysiological techniques

Motor evoked potentials (MEPs) were measured to the right and left abductor digiti minimi (ADM) and abductor hallucis (AH) muscle after muscle activation. For total motor conduction time (TMCT) stimulus was given with a circular coil over the vertex and stimulus intensity was chosen 20% above motor threshold at rest. Peripheral motor conduction time (PMCT) was calculated with the shortest F wave latency out of 16 trials after supramaximal stimulation of the ulnar nerve at the wrist or the tibial nerve at the medial malleolus respectively: PMCT = [(distal motor latency + F wave latency)/2] +1. Central motor conduction time CMCT = TMCT – PMCT.

Nerve conduction studies (NCS) with surface electrodes were performed on the right side, except local problems would have falsified the results. Motor NCS were performed of the ulnar and tibial nerve. Amplitudes of compound motor action potentials (CMAPs) were measured peak to peak. Stimulus intensity was increased in 5 mA steps to maximum response. Stimulus duration was adjusted 0.2 ms, and increased, if supramaximal stimulation was not reached otherwise. Recording electrode was placed over the abductor digiti minimi and abductor hallucis muscle respectively, distal stimulation was performed with the electrode 5 and 7 cm proximal to the recording electrode and proximal stimulation with the electrode at the elbow distal the sulcus ulnaris and at the popliteal fossa respectively.

Sensory NCS were recorded from the radial and sural nerve with antidrome technique and supramaximal stimulus intensity. Amplitudes of sensory nerve action potentials (SNAPs) were measured baseline to peak. The recording electrode was placed over the first dorsal spatium interosseum and behind the external malleolus respectively, stimulation electrode 15 cm and 14 cm proximal to the recording electrode respectively. Electrophysiologically peripheral neuropathy was assumed, if NCS were abnormal in two or more nerves.

Somato-sensory evoked potentials (SSEPs) of median and tibial nerve were acquired using surface electrodes over C3’/C4’ and Cz’ (3 cm posterior to Cz) respectively, and referred to Fpz. Electrode impedances were less than 5 kOhm. The constant current stimuli were rectangular electrical pulses of 0.2 ms duration, delivered 3 times per second at the medial side of the ankle and the wrist, respectively. Stimulus intensity was adjusted to produce a small muscle twitch. Overall bandpass was chosen 1 to 1500 Hz, analysis time was 100 ms. Two series of 200 potentials were recorded, averaged, superimposed, and checked for reproducibility. The latency was measured at Erb and N20 for median nerve, and L1 and P40 for tibial nerve.

Normal values and statistical analysis

Standard procedures and normal values were elaborated for NCS, MEP and SSEP in Tübingen, and transferred to the centres in Bochum and Kiel. Extreme values were checked for plausibility. Statistical analyses were performed using IBM SPSS Statistics 20.0 software (IBM Deutschland GmbH, Ehningen, Germany). Mean and standard deviation are given. Parameters were either normally distributed or slightly skewed (< 3.12), therefore parametric testing was applied. For continuous variables bivariate correlations were performed using the Pearson correlation coefficient, for categorised variables using Kendalls Tau-b. Significance was tested by one- or two-sided ANOVA, as appropriate. An alpha level of p < 0.05 was considered to be significant.

Results

Clinical characterisation

In our cohort, disease severity assessed by SPRS reached 1 to 44 points (mean 17.8 ± 8.5 points); the spastic items (“spastic subscore”, as described in Methods section) ranged from 0 to 14 points (mean 4.6 ± 2.5 points). A clinical sensory deficit was obvious in 56% of patients (including patients with only vibration sense deficits), a peripheral motor neuropathy was clinically suspected in 18% of patients, and 22% of patients had upper limb spasticity in addition to spastic paraparesis.

Central motor pathways

CMCT to upper and lower limbs correlated with each other (r = 0.595; p < 0.0001; see also Figure 1). Age had no influence on CMCT.

Figure 1
figure 1

Correlation of central motor conduction time (CMCT) to arm and leg. CMCT to the abductor digiti minimi muscle (ADM) and abductor hallucis muscle (AH) is correlated (r = 0.595; p < 0.0001). In (A) results for the left-hand side, in (B) for the right-hand side are shown. Patients with SPG4 mutations are indicated by red triangles, other patients by black squares.

Full size image

Although pyramidal tract affection to the legs is an obligatory feature and the primary hallmark of HSP, motor evoked potentials (MEPs) to the legs were normal in 27% of patients. 37% presented with prolonged CMCT. In 36% of patients no MEP could be evoked. CMCT to the legs correlated with total SPRS score (r = 0.176; p < 0.028) and spastic subscore (r = 0.241, p < 0.005, see also Figure 2). Pathologic CMCT to lower limbs correlated with disease duration (r = 0.231; p < 0.009).

Figure 2
figure 2

Conduction in motor evoked potentials correlate with clinical disease severity. In (A) Spastic Paraplegia Rating Scale (SPRS) [17], in (B) spastic subscore is correlated with central motor conduction time (CMCT) to the right abductor hallucis muscle (AH) (SPRS: r = 0.176; p < 0.028. Spastic subscore: r = 0.241, p < 0.005). Patients with SPG4 mutations are indicated by red triangles, other patients by black squares. Results to the left leg correlated accordingly; data not shown.

Full size image

In contrast, MEPs to the arms were surprisingly often pathologic in HSP (32%), including 28% with prolonged and 4% with not evocable MEPs. CMCT to the arms correlated with total SPRS score (r = 0.234, p < 0.005) and spastic subscore (r = 0.300, p < 0.0001), but not with disease duration.

A subgroup of seven patients (6%) showed very pronounced CMCT prolongation to the arms (≥ 15.0 ms, normal < 8.6 ms), and 17 (14%) to the legs (≥ 25.0 ms, normal < 16.1 ms) suggestive of a demyelinating process. Most of the patients were of unknown genotype, in two patients a mutation was found in the SPG5 and SPG7 gene respectively. In none of these patients a SPG4 mutation was found.

Sensory pathways

SSEPs were available for median (n=47) and tibial (n=86) nerve stimulation. As peripheral stimulation at Erb and L1 was not available in several patients due to spastic reactions to repetitive stimulation, we included only cortical latencies in the analysis. Cortical latencies (N20) of median nerve SSEPs were prolonged in 9% and missing in 9%. Cortical latencies (P40) of tibial nerve SSEPs were delayed in 7% and missing in 29%. P40 latencies correlated with clinical sensory deficit (r = 0.314; p < 0.001), whereas for N20 latency significance was missed (r = 0.264; p < 0.063). Sensory nerve conduction velocities (SNCVs) correlated with cortical SSEP latencies in upper and lower limbs: Radial NCV correlated with N20 latency (r = 0.521; p < 0.003) and sural NCV with P40 latency (r = 0.326; p < 0.001). The validity of the correlation of SNCV and SSEP is limited as cortical latencies of SSEP also include peripheral nerve conduction time.

Peripheral nerve involvement

NCS were abnormal in 75 patients (59%). In 17% of patients only sensory nerves, in 16% only motor nerves and in 25% both sensory and motor nerves were affected. In 15% of patients only legs were affected, in 14% only arms, and in 30% of patients both legs and arms were involved. Details of nerve conduction abnormalities are given in Table 1.

Table 1 Peripheral nerve involvement assessed by nerve conduction studies (NCS) in HSP patients
Full size table

Abnormal distal motor latency (DML), NCV or F wave latency in combination with normal amplitudes were regarded as hint for demyelinating affection, whereas amplitude reduction and normal conduction parameters were interpreted as axonal involvement. According to this classification, 24% of patients presented with demyelinating, 5% with axonal and 6% with mixed neuropathy of tibial nerves, whereas in 66% neurography of tibial nerve was normal. In ulnar nerve 23% of patients showed a demyelinating and 1% a mixed pattern. In sural nerves, type of damage was demyelinating in 9% of patients, axonal in 9%, and mixed in 6%. In radial nerves 5% of patients presented with demyelinating and 18% with axonal type of damage, and 12% a mixed affection.

Amplitudes of CMAPs and SNAPs were inversely correlated with age, so the correlations of NCS were analysed with age as confounding factor. Central and peripheral conduction velocities correlated both in upper and lower limbs (Figure 3): NCV and F wave latency of the ulnar nerve correlated with CMCT to the arm (r = 0.249; p < 0.004 and r = −0.280; p < 0.002, respectively). Accordingly, NCV and F wave latency of the tibial nerve correlated with CMCT to the leg (r = 0.463; p < 0.0001 and r = −0.270; p < 0.09, respectively).

Figure 3
figure 3

Correlation of central and peripheral motor damage. (A and B) Nerve conduction velocity (NCV) and F wave latency of the ulnar nerve correlated with central motor conduction time (CMCT) to the abductor digiti minimi muscle (ADM) (r = 0.249; p < 0.004 and r = −0.280; p < 0.002, respectively). (C and D) Accordingly, NCV and F wave latency of tibial the nerve correlated with CMCT to abductor hallucis muscle (AH) (r = 0.463; p < 0.0001 and r = −0.270; p < 0.09, respectively). Patients with SPG4 mutations are indicated by red triangles, other patients by black squares.

Full size image

Clinical signs of peripheral nerve involvement correlated with electrophysiological peripheral neuropathy (r = 0.362; p < 0.0001). Clinical sensory deficits correlated with pathologic NCS of the sural nerve (r = 0.291; p < 0.004).

Subgroup analysis of genetically confirmed HSP patients

SPG4 patients

A clinically “pure” HSP form was found more often in SPG4 patients in comparison to patients with SPG4 excluded (non-SPG4 patients) (60% vs. 36%, p = 0.052). Nystagmus, limb ataxia, gait ataxia, impaired pinprick sensation, impaired joint position sense, and clinical signs for spasticity of the arms were significantly rarer in SPG4 patients (p < 0.05, respectively).

In most SPG4 patients CMCT was normal both to arms (mean 5.1 ± 1.5 ms) and legs (14.1 ± 3.9 ms). In contrast, non-SPG4 patients presented with significantly longer CMCT to arms (mean 6.9 ± 2.6 ms, p < 0.001) and legs (mean 18.2 ± 7.3 ms, p < 0.016; see also Figures 1 and 2). Within the group of SPG4 patients, CMCT depended on the type of mutation. Patients with SPG4 missense mutations had significantly shorter CMCTs to legs in comparison to patients with SPG4 splice site mutations, premature stop codon or in-frame exon deletions (10.5 ± 1.3 ms vs. 13.9 ± 3.7 ms, p < 0.013). In SPG4 patients nerve conduction abnormalities of tibial and ulnar motor nerves were present in 20.0% and 8.8% respectively. Sensory sural and radial nerves were pathologic in 20.0% and 24.1% respectively.

Other genetically defined HSP forms

Genetic testing revealed 19 patients with mutations in HSP genes other than SPG4 (see Methods section). In the majority of these patients CMCT to the legs was prolonged. Details of motor evoked potentials in different genotypes are given in Table 2. Nerve conduction studies were normal in the single SPG3 patient whereas SPG5, SPG8 and SPG10 patients presented with mild motor neuropathy and patients with SPG11 and SPG15 had sensory-motor neuropathy. In SPG7 patients sensory tracts were affected. Detailed results of electrophysiological testing are presented in Table 3.

Table 2 Transcranial magnetic stimulation and sensory evoked potentials in genetically defined subtypes of HSP
Full size table
Table 3 Nerve conduction studies in genetically defined subtypes of HSP
Full size table

Discussion

Comprehensive electrophysiological analyses in this up to date largest cohort of HSP patients revealed not only prominent affection of corticospinal tracts to the legs but also in many cases to the arms as well as affection of sensory systems and peripheral nerves. This affirms that HSP is not a pure upper motoneuron disease but frequently affects other long fibre tracts.

Some authors regard spread of corticospinal tract affection to the arms as an indicator of primary lateral sclerosis rather than HSP [18]. Here we show that according to MEP criteria arms are involved in about one third of HSP patients including many patients with genetically confirmed diagnosis carrying mutations in well-established HSP genes. Our results are in accordance with smaller studies finding prolonged CMCT to legs in the majority of cases and affection of arms in up to 32% [8–10]. The results are consistent with a length-dependent neurodegenerative process.

Conversely, CMCT to legs was normal in about 27% of HSP patients despite unequivocal clinical signs of corticospinal tract affection. This may be explained by a primarily axonal type of damage seen in several subtypes of HSP or alternatively by a selective affection of thinner motoneurons and other motor pathways (i.e. reticulo-spinal or vestibulo-spinal tracts) that spares the fastest conducting thick fibres investigated by transcranial magnetic stimulation.

Additionally, we show that HSP in many cases is not restricted to the motor system but affects the sensory system as well. Abnormal cortical potentials in 38% of tibial nerve SSEPs prove sensory system involvement in a substantial portion of HSP patients. Similarly, sensory NCS were abnormal in about one third of HSP patients. Previous studies included only small numbers of patients and led to variable results [9, 12–14].

Here we screened a large HSP cohort that was not selected for clinical signs of peripheral neuropathy and found involvement of peripheral motor nerves in 44% of patients. Tibial nerves were more frequently impaired than ulnar nerves reflecting the more severe affection of longer motor axons to the legs. The affection of upper and lower motoneurons may be of special importance in the differential diagnosis between HSP and amyotrophic lateral sclerosis (ALS). Although we did not perform electromyography (EMG) and cannot differentiate between neuronal and axonal damage, it becomes clear that the combination of upper and lower motor tract affection per se is not indicating ALS but is a rather frequent constellation in HSP as well. Recent data suggest a continuum in motoneuron disorders; several genes can underlie different phenotypes, resembling ALS, HSP and HM(SA)N respectively (reviewed in [19]), e.g. Alsin (ALS2) [20–22], Senataxin (ALS4) [23, 24], NIPA1 (SPG6, NIPA1 repeat expansions associated with ALS) [25, 26], BSCL2 (SPG17, HMSN V) [27–29], Atlastin-1 (SPG3, HSN-I) [30–32], KIF1A (SPG 30, HSAN-II) [33, 34], and REEP1 (SPG31, dHMN-V) [35, 36].

Electrophysiologically, there is an interrelation between central and peripheral damage. This could indicate a common length-dependent disease mechanism in several long fibre tracts. Hereby, electrophysiological analyses may provide a window into pathomechanisms that alter conduction parameters in long fibre tracts in a genotype specific manner.

The affection of long fibre tracts is also seen in neuropathological examinations. In pure HSP forms degeneration of the corticospinal tract and the posterior column was compatible with a dying-back axonopathy [37–39]. This result was also confirmed in genetically proven cases of SPG4[40, 41]. In complicated forms pathology shows more widespread neurodegeneration also affecting the thalamus, brainstem nuclei and the cerebellum [42].

Disturbance of axonal transport as in SPG4 and SPG10 with mutations in Spastin affecting microtubule severing and in KIF5A affecting the motor of anterograde axonal transport may go along with an axonal type of conduction disturbance [41, 43, 44]. In accordance with this pathophysiological assumption and previous studies [11, 15], in our cohort of SPG4 patients MEPs to the arms were normal. As a rule of thumb, massively elongated CMCT (arms ≥ 15.0 ms, legs ≥ 25.0 ms) argue against a SPG4 genotype. But even within the group of SPG4 patients a considerable variability of CMCTs with reduced amplitudes and prolonged latencies were reported [45]. On the basis of the results in two SPG4 families a role of the mutation type was proposed [16]. In our large cohort of 35 SPG4 patients MEP latencies in patients with SPG4 missense mutations were significantly shorter in comparison to SPG4 splice site mutations, premature stop codons or in-frame exon deletions.

Our data represent a cross-sectional analysis. It will be interesting to learn about the dynamics of electrophysiological abnormalities in HSP. At present, it remains open to speculation whether motor and sensory, central and peripheral systems are affected at the same time and whether there is a linear or a non-linear progression of electrophysiological abnormalities. Longitudinal studies will help to assess electrophysiological parameters as potential biomarkers of the neurodegenerative process. Given the clinical variability of spasticity with temperature and seasons as well as symptomatic treatment, and given the correlation of disease severity and MEP abnormalities demonstrated in this study, electrophysiological parameters may become important progression markers in upcoming interventional trials.

Conclusions

HSP is considered an upper motoneuron disease primarily affecting the longest fibres to the legs. Our clinical and electrophysiological analysis suggests a more widespread involvement of motor and sensory tracts in the central and peripheral nervous system. Pronounced elongation of MEPs favours against the most common form of HSP, SPG4. As electrophysiological measures are independent of symptomatic treatment they might become important progression markers in upcoming HSP trials.

Availability of supporting data

The data sets supporting the results of this article are included within the article.

Abbreviations

ADM:

Abductor digiti minimi

AH:

Abductor hallucis

ALS:

Amyotrophic lateral sclerosis

CMAP:

Compound motor action potential

CMCT:

Central motor conduction time

DML:

Distal motor latency

EMG:

Electromyography

HSP:

Hereditary spastic paraplegia

MEP:

Motor evoked potential

ms:

Millisecond

NCS:

Nerve conduction study

NCV:

Nerve conduction velocity

PMCT:

Peripheral motor conduction time

SNAP:

Sensory nerve action potential

SNCV:

Sensory nerve conduction velocity

SPRS:

Spastic Paraplegia Rating Scale

SSEP:

Somato-sensory evoked potential

TMCT:

Total motor conduction time

VLCFA:

Very long chain fatty acids.

References

  1. Strümpell A: Beiträge zur Pathologie des Rückenmarks I. Spastische Spinalparalysen. Arch Psychiatr Nervenkr. 1880, 10: 676-717. 10.1007/BF02224539.

    Article  Google Scholar 

  2. Harding AE: Hereditary "pure" spastic paraplegia: a clinical and genetic study of 22 families. J Neurol Neurosurg Psychiatry. 1981, 44: 871-883. 10.1136/jnnp.44.10.871.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Blackstone C, O'Kane CJ, Reid E: Hereditary spastic paraplegias: membrane traffic and the motor pathway. Nat Rev Neurosci. 2011, 12: 31-42.

    Article  CAS  PubMed  Google Scholar 

  4. Schule R, Schols L: Genetics of hereditary spastic paraplegias. Semin Neurol. 2011, 31: 484-493. 10.1055/s-0031-1299787.

    Article  PubMed  Google Scholar 

  5. Brignolio F, Leone M, Tribolo A, Rosso MG, Meineri P, Schiffer D: Prevalence of hereditary ataxias and paraplegias in the province of Torino, Italy. Ital J Neurol Sci. 1986, 7: 431-435. 10.1007/BF02283021.

    Article  CAS  PubMed  Google Scholar 

  6. Polo JM, Calleja J, Combarros O, Berciano J: Hereditary ataxias and paraplegias in Cantabria Spain. An epidemiological and clinical study. Brain. 1991, 114 (Pt 2): 855-866.

    Article  PubMed  Google Scholar 

  7. Fujigasaki H, Martin JJ, De Deyn PP, Camuzat A, Deffond D, Stevanin G, Dermaut B, Van Broeckhoven C, Durr A, Brice A: CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia. Brain. 2001, 124: 1939-1947. 10.1093/brain/124.10.1939.

    Article  CAS  PubMed  Google Scholar 

  8. Claus D, Waddy HM, Harding AE, Murray NM, Thomas PK: Hereditary motor and sensory neuropathies and hereditary spastic paraplegia: a magnetic stimulation study. Ann Neurol. 1990, 28: 43-49. 10.1002/ana.410280109.

    Article  CAS  PubMed  Google Scholar 

  9. Pelosi L, Lanzillo B, Perretti A, Santoro L, Blumhardt L, Caruso G: Motor and somatosensory evoked potentials in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry. 1991, 54: 1099-1102. 10.1136/jnnp.54.12.1099.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Schady W, Dick JP, Sheard A, Crampton S: Central motor conduction studies in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry. 1991, 54: 775-779. 10.1136/jnnp.54.9.775.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Lang N, Optenhoefel T, Deuschl G, Klebe S: Axonal integrity of corticospinal projections to the upper limbs in patients with pure hereditary spastic paraplegia. Clin Neurophysiol. 2011, 122: 1417-1420. 10.1016/j.clinph.2010.12.033.

    Article  PubMed  Google Scholar 

  12. McLeod JG, Morgan JA, Reye C: Electrophysiological studies in familial spastic paraplegia. J Neurol Neurosurg Psychiatry. 1977, 40: 611-615. 10.1136/jnnp.40.6.611.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Schady W, Sheard A: A quantitative study of sensory function in hereditary spastic paraplegia. Brain. 1990, 113 (Pt 3): 709-720.

    Article  PubMed  Google Scholar 

  14. Thomas PK, Jefferys JG, Smith IS, Loulakakis D: Spinal somatosensory evoked potentials in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry. 1981, 44: 243-246. 10.1136/jnnp.44.3.243.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Schulte T, Miterski B, Bornke C, Przuntek H, Epplen JT, Schols L: Neurophysiological findings in SPG4 patients differ from other types of spastic paraplegia. Neurology. 2003, 60: 1529-1532. 10.1212/01.WNL.0000058769.75218.69.

    Article  CAS  PubMed  Google Scholar 

  16. Bonsch D, Schwindt A, Navratil P, Palm D, Neumann C, Klimpe S, Schickel J, Hazan J, Weiller C, Deufel T, Liepert J: Motor system abnormalities in hereditary spastic paraparesis type 4 (SPG4) depend on the type of mutation in the spastin gene. J Neurol Neurosurg Psychiatry. 2003, 74: 1109-1112. 10.1136/jnnp.74.8.1109.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Schule R, Holland-Letz T, Klimpe S, Kassubek J, Klopstock T, Mall V, Otto S, Winner B, Schols L: The Spastic Paraplegia Rating Scale (SPRS): a reliable and valid measure of disease severity. Neurology. 2006, 67: 430-434. 10.1212/01.wnl.0000228242.53336.90.

    Article  CAS  PubMed  Google Scholar 

  18. Fink JK: Hereditary spastic paraplegia. Curr Neurol Neurosci Rep. 2006, 6: 65-76. 10.1007/s11910-996-0011-1.

    Article  CAS  PubMed  Google Scholar 

  19. Timmerman V, Clowes VE, Reid E: Overlapping molecular pathological themes link Charcot-Marie-Tooth neuropathies and hereditary spastic paraplegias. Exp Neurol. 2013, 246: 14-25.

    Article  CAS  PubMed  Google Scholar 

  20. Rowland LP: Primary lateral sclerosis, hereditary spastic paraplegia, and mutations in the alsin gene: historical background for the first International Conference. Amyotroph Lateral Scler Other Motor Neuron Disord. 2005, 6: 67-76.

    Article  PubMed  Google Scholar 

  21. Eymard-Pierre E, Lesca G, Dollet S, Santorelli FM, di Capua M, Bertini E, Boespflug-Tanguy O: Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet. 2002, 71: 518-527. 10.1086/342359.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, et al: The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001, 29: 160-165. 10.1038/ng1001-160.

    Article  CAS  PubMed  Google Scholar 

  23. De Jonghe P, Auer-Grumbach M, Irobi J, Wagner K, Plecko B, Kennerson M, Zhu D, De Vriendt E, Van Gerwen V, Nicholson G, et al: Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder?. Brain. 2002, 125: 1320-1325. 10.1093/brain/awf127.

    Article  CAS  PubMed  Google Scholar 

  24. Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, et al: DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004, 74: 1128-1135. 10.1086/421054.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Blauw HM, van Rheenen W, Koppers M, Van Damme P, Waibel S, Lemmens R, van Vught PW, Meyer T, Schulte C, Gasser T, et al: NIPA1 polyalanine repeat expansions are associated with amyotrophic lateral sclerosis. Hum Mol Genet. 2012, 21: 2497-2502. 10.1093/hmg/dds064.

    Article  CAS  PubMed  Google Scholar 

  26. Rainier S, Chai JH, Tokarz D, Nicholls RD, Fink JK: NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet. 2003, 73: 967-971. 10.1086/378817.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Magre J, Delepine M, Khallouf E, Gedde-Dahl T, Van Maldergem L, Sobel E, Papp J, Meier M, Megarbane A, Bachy A, et al: Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001, 28: 365-370. 10.1038/ng585.

    Article  CAS  PubMed  Google Scholar 

  28. Windpassinger C, Auer-Grumbach M, Irobi J, Patel H, Petek E, Horl G, Malli R, Reed JA, Dierick I, Verpoorten N, et al: Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004, 36: 271-276. 10.1038/ng1313.

    Article  CAS  PubMed  Google Scholar 

  29. Irobi J, Van den Bergh P, Merlini L, Verellen C, Van Maldergem L, Dierick I, Verpoorten N, Jordanova A, Windpassinger C, De Vriendt E, et al: The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain. 2004, 127: 2124-2130. 10.1093/brain/awh232.

    Article  PubMed  Google Scholar 

  30. Guelly C, Zhu PP, Leonardis L, Papic L, Zidar J, Schabhuttl M, Strohmaier H, Weis J, Strom TM, Baets J, et al: Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. Am J Hum Genet. 2011, 88: 99-105. 10.1016/j.ajhg.2010.12.003.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Leonardis L, Auer-Grumbach M, Papic L, Zidar J: The N355K atlastin 1 mutation is associated with hereditary sensory neuropathy and pyramidal tract features. Eur J Neurol. 2012, 19: 992-998. 10.1111/j.1468-1331.2012.03665.x.

    Article  CAS  PubMed  Google Scholar 

  32. Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber CH, Tukel T, Apak M, Heiman-Patterson T, Ming L, et al: Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia. Nat Genet. 2001, 29: 326-331. 10.1038/ng758.

    Article  CAS  PubMed  Google Scholar 

  33. Klebe S, Azzedine H, Durr A, Bastien P, Bouslam N, Elleuch N, Forlani S, Charon C, Koenig M, Melki J, et al: Autosomal recessive spastic paraplegia (SPG30) with mild ataxia and sensory neuropathy maps to chromosome 2q37.3. Brain. 2006, 129: 1456-1462. 10.1093/brain/awl012.

    Article  PubMed  Google Scholar 

  34. Riviere JB, Ramalingam S, Lavastre V, Shekarabi M, Holbert S, Lafontaine J, Srour M, Merner N, Rochefort D, Hince P, et al: KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. Am J Hum Genet. 2011, 89: 219-230. 10.1016/j.ajhg.2011.06.013.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Beetz C, Pieber TR, Hertel N, Schabhuttl M, Fischer C, Trajanoski S, Graf E, Keiner S, Kurth I, Wieland T, et al: Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. Am J Hum Genet. 2012, 91: 139-145. 10.1016/j.ajhg.2012.05.007.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Zuchner S, Wang G, Tran-Viet KN, Nance MA, Gaskell PC, Vance JM, Ashley-Koch AE, Pericak-Vance MA: Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet. 2006, 79: 365-369. 10.1086/505361.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Behan WM, Maia M: Strumpell's familial spastic paraplegia: genetics and neuropathology. J Neurol Neurosurg Psychiatry. 1974, 37: 8-20. 10.1136/jnnp.37.1.8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Bruyn RP: The neuropathology of hereditary spastic paraparesis. Clin Neurol Neurosurg. 1992, 94 (Suppl): S16-18.

    Article  PubMed  Google Scholar 

  39. Deluca GC, Ebers GC, Esiri MM: The extent of axonal loss in the long tracts in hereditary spastic paraplegia. Neuropathol Appl Neurobiol. 2004, 30: 576-584. 10.1111/j.1365-2990.2004.00587.x.

    Article  CAS  PubMed  Google Scholar 

  40. Wharton SB, McDermott CJ, Grierson AJ, Wood JD, Gelsthorpe C, Ince PG, Shaw PJ: The cellular and molecular pathology of the motor system in hereditary spastic paraparesis due to mutation of the spastin gene. J Neuropathol Exp Neurol. 2003, 62: 1166-1177.

    CAS  PubMed  Google Scholar 

  41. Kasher PR, De Vos KJ, Wharton SB, Manser C, Bennett EJ, Bingley M, Wood JD, Milner R, McDermott CJ, Miller CC, et al: Direct evidence for axonal transport defects in a novel mouse model of mutant spastin-induced hereditary spastic paraplegia (HSP) and human HSP patients. J Neurochem. 2009, 110: 34-44. 10.1111/j.1471-4159.2009.06104.x.

    Article  CAS  PubMed  Google Scholar 

  42. Seidel K, De Vos R, Derksen L, Bauer P, Riess O, den Dunnen W, Deller T, Hageman G, Rub U: Widespread thalamic and cerebellar degeneration in a patient with a complicated hereditary spastic paraplegia (HSP). Ann Anat. 2009, 191: 203-211. 10.1016/j.aanat.2008.11.003.

    Article  CAS  PubMed  Google Scholar 

  43. Karle KN, Mockel D, Reid E, Schols L: Axonal transport deficit in a KIF5A (−/−) mouse model. Neurogenetics. 2012, 13: 169-179. 10.1007/s10048-012-0324-y.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Fuger P, Sreekumar V, Schule R, Kern JV, Stanchev DT, Schneider CD, Karle KN, Daub KJ, Siegert VK, Flotenmeyer M, et al: Spastic Paraplegia Mutation N256S in the Neuronal Microtubule Motor KIF5A Disrupts Axonal Transport in a Drosophila HSP Model. PLoS Genet. 2012, 8: e1003066. 10.1371/journal.pgen.1003066.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Sartucci F, Tovani S, Murri L, Sagliocco L: Motor and somatosensory evoked potentials in Autosomal Dominant Hereditary Spastic Paraparesis (ADHSP) linked to chromosome 2p, SPG4. Brain Res Bull. 2007, 74: 243-249. 10.1016/j.brainresbull.2007.06.018.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors wish to thank the patients for participating in this study. We are grateful to Jutta Grimm and Anke Deutsch (Department of Neurology, University of Tübingen) for skilful technical assistance. This study has been funded by a grant of the German Ministry of Education and Research to GeNeMove (01GM0603).

Author information

Authors and Affiliations

  1. Department of Neurology, Eberhard Karls-University Tübingen, Tübingen, 72076, Germany

    Kathrin N Karle, Rebecca Schüle, Christian Frischholz & Ludger Schöls

  2. Hertie Institute for Clinical Brain Research, Eberhard Karls-University Tübingen, Tübingen, Germany

    Kathrin N Karle, Rebecca Schüle, Inga Liepelt-Scarfone & Ludger Schöls

  3. German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany

    Kathrin N Karle, Inga Liepelt-Scarfone & Ludger Schöls

  4. Department of Neurology, Christian-Albrechts-University Kiel, Kiel 24105, Germany

    Stephan Klebe

  5. Department of Neurology, Julius-Maximilians-University, Würzburg, 97080, Germany

    Stephan Klebe

  6. Department of Neurology, St. Josef Hospital, Ruhr University, Bochum, 44791, Germany

    Susanne Otto

Authors
  1. Kathrin N Karle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rebecca Schüle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephan Klebe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susanne Otto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christian Frischholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Inga Liepelt-Scarfone
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ludger Schöls
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ludger Schöls.

Additional information

Competing interests

LS received research grants of the Deutsche Forschungsgemeinschaft (SCHO754/4-1 and SCHO754/5-1), grants of the German Research Council (BMBF) to Leukonet (01GM0644) and mitoNET (01GM0864), an E-RARE grant to EUROSCAR (01GM1206) and an FP7 grant to NeurOmics (305121). He further received funding from the HSP-Selbsthilfegruppe Deutschland eV.

Authors’ contributions

RS and LS designed the study. KNK, RS, SK, SO, CF and LS acquired, analysed and interpreted the data. KNK and IL-S performed the statistical analysis. KNK and LS drafted the manuscript. RS, SK, OK, CK an IL-S revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Authors’ original file for figure 3

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Karle, K.N., Schüle, R., Klebe, S. et al. Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP). Orphanet J Rare Dis 8, 158 (2013). https://doi.org/10.1186/1750-1172-8-158

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/1750-1172-8-158

Keywords

Orphanet Journal of Rare Diseases

ISSN: 1750-1172