Paraparesia Espastica y Esclerosis Lateral Primaria

ORIGINAL CONTRIBUTIONDifferentiation of Hereditary Spastic Paraparesis From Primary Lateral Sclerosis in Sporadic Adult-Onset Upper Motor Neuron Syndromes Frans Brugman, MD; Jan H. Veldink, MD, PhD; Hessel Franssen, MD, PhD; Marianne de Visser, MD, PhD; J. M. B.Vianney de Jong, MD, PhD; Carin G. Faber, MD, PhD; Berry H. P. Kremer, MD, PhD; H. Jurgen Schelhaas, MD, PhD; Pieter A. van Doorn, MD, PhD; Jan J. G. M. Verschuuren, MD, PhD; Richard P. M. Bruyn, MD, PhD; Jan B. M. Kuks, MD, PhD; Wim Robberecht, MD, PhD; John H. J. Wokke, MD, PhD; Leonard H. van den Berg, MD, PhD Objective: To study whether clinical characteristics can differentiate sporadic presentations of hereditary spastic paraparesis (HSP) from primary lateral sclerosis (PLS). Differentiation between these diseases is important for genetic counseling and prognostication. Design: Case series. Setting: Tertiary referral center. Patients: One hundred four Dutch patients with an adultonset, sporadic upper motor neuron syndrome of at least 3 years’ duration. Hereditary spastic paraparesis was genetically confirmed in 14 patients (7 with SPG4 and 7 with SPG7 mutations). Results: All 14 patients with the SPG4 or SPG7 mutation had symptom onset in the legs, and 1 of the patients with the SPG7 mutation also developed symptoms in the arms. Of the other 90 patients, 78 (87%) had symptom onset in the legs. Thirty-six patients developed a PLS phenotype (bulbar region involvement), 15 had a phenotype that was difficult to classify as similar to HSP or PLS (involvement of legs and arms only), and 39 continued to have a phenotype similar to typical HSP (involvement of the legs only). Median age at onset was lower in patients with the SPG4 or SPG7 mutation (39 [range, 29-69] years), but there was considerable overlap with patients with the PLS phenotype (52 [range, 32-76] years). No differences were found in the features used by previous studies to distinguish HSP from PLS, including evidence of mild dorsal column impairment (decreased vibratory sense or abnormal leg somatosensory evoked potentials), symptoms of urinary urgency, or mild electromyographic abnormalities. Conclusions: In most patients with a sporadic adultonset upper motor neuron syndrome, differentiation of sporadic presentations of HSP from PLS based on clinical characteristics is unreliable and therefore depends on results of genetic testing. Arch Neurol. 2009;66(4):509-514 rence of HSP is not uncommon, and mutations of the spastin (SPG4) and paraplegin (SPG7) genes are a frequent cause.1,22,23 Differentiation between HSP and PLS is important for genetic counseling of family members and for the patients’ prognosis because HSP generally has a more favorable prognosis than PLS.1 Furthermore, progression to amyotrophic lateral sclerosis (ALS), as may occur in PLS,24 is not expected in HSP. Symptomatic UMN involvement of the arms and particularly of the bulbar region is unusual in pure HSP and would favor a diagnosis of PLS.1,25 However, PLS may present with a slowly progressive spastic paraparesis of the legs, similar to the typical HSP phenotype, for many years before the onset of arm or bulbar region symptoms.1,9 To separate apparently sporadic HSP from PLS, previous studies used several clinical features, Author Affiliations are listed at the end of this article. sporadic adult-onset upper motor neuron (UMN) syndrome, clinical differentiation between primary lateral sclerosis (PLS) and hereditary spastic paraparesis (HSP) can be problematic.1 Primary lateral sclerosis is a rare sporadic disorder of progressive spinobulbar spasticity with a mostly spinal and occasionally bulbar region onset.2-12 Hereditary spastic paraparesis is a clinically and genetically heterogeneous group of disorders characterized by a slowly progressive spastic paraparesis.1,13 To date, 15 genes and more than 20 additional loci have been identified for autosomal dominant, autosomal recessive, and X-linked forms of HSP.14-21 To exclude HSP, current diagnostic criteria for PLS require absence of a family history.5 However, researchers increasingly recognize that the apparently sporadic occur- I N PATIENTS WITH AN APPARENTLY (REPRINTED) ARCH NEUROL / VOL 66 (NO. 4), APR 2009 509 WWW.ARCHNEUROL.COM Downloaded from www.archneurol.com on May 4, 2010 ©2009 American Medical Association. All rights reserved. we performed a nationwide search for patients in the Netherlands. The presence of mild focal amyotrophy limited to 1 or 2 muscles in 1 region and the presence of fasciculation were allowed. we performed additional genetic tests using multiplex ligation-dependent probe amplification to identify SPG4 exonic microdeletions.com on May 4.archneurol. and human immunodeficiency virus infection. clinical evidence of generalized lower motor neuron involvement fulfilling the revised El Escorial criteria for clinically probable or clinically definite ALS. All rights reserved. and 1 patient with the SPG7 mutation also developed UMN symptoms of the arms (arm hyperreflexia associated with loss of dexterity) after 1 year. OMIM *602783). obvious loss of dexterity due to spasticity (evaluated at the examination).COM CLINICAL EVALUATION The bulbar region was considered affected if pseudobulbar dysarthria was present. 2010 ©2009 American Medical Association. 36 had bulbar region involvement suggestive of PLS. and magnetic resonance imaging (MRI) of the brain and the spinal cord. human T-lymphotropic virus 1. In addition.ARCHNEUROL. 1 large referral center for patients with motor neuron disease in Leuven. 4). a pathogenic mutation of the spastin (SPG4) or paraplegin (SPG7) gene was found (7 with SPG4 and 7 with SPG7 mutations). pathological hyperreflexia (defined as an Institute of Neurological Diseases and Stroke Myotatic Reflex Scale31 score of 4 or 5 or extensor plantar response). the presence of sensory signs other than decreased distal vibration sensation (absent at the ankles).23 In the 14 patients with the SPG4 or SPG7 mutation. through March 31. and 15 patients had a phenotype that was difficult to classify as being similar to HSP or suggestive of PLS (UMN involvement of arms and legs). Of the 36 patients with bulbar region involvement. METHODS PATIENTS From November 1. Additional laboratory investigations were performed to exclude other causes.22. or dexterity loss were only present unilaterally. spasticity (modified Ashworth Scale score of 2). All 14 patients with the SPG4 or SPG7 mutation and 78 of the other patients with sporadic UMN disease (87%) had symptom onset in the legs. 39 had a phenotype similar to typical pure HSP (involvement of the legs only). the most common cause of autosomal dominant pure HSP. and written informed consent was obtained from each patient.23 In approximately 75% of our patients. VALUE OF CLINICAL CHARACTERISTICS FOR IDENTIFICATION OF HSP The pattern of disease progression in the 14 patients with the SPG4 or SPG7 mutation and the other 90 patients with a sporadic UMN syndrome is shown in Table 2. and other causes of UMN loss that were investigated using a predefined series of laboratory tests.B. Exclusion criteria were a positive family history.33 At inclusion. To study whether clinical characteristics can be used to differentiate between sporadic presentations of HSP and PLS in patients with apparently sporadic adultonset UMN syndromes. 2002. OMIM *604277). STATISTICAL ANALYSIS Differences between groups were tested using the Pearson 2 and Fisher exact tests.5 but how appropriate these criteria are has yet to be validated. agreed to participate. The WWW. and the results were classified as normal or abnormal. with the findings interpreted according to the revised El Escorial criteria. 13 had a typical pure HSP phenotype with only leg involvement. . paresis (Medical Research Council paresis grade of 4). Functional impairment was assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale. Of these.22.such as an age at onset of younger than 40 years. and the presence of a thin corpus callosum were not allowed. The study protocol was approved by the medical ethics review board of the University Medical Center Utrecht. Inclusion criteria were a gradually progressive UMN syndrome with adult onset (age.29 but none were found.32 We classified patients as having asymmetry if. APR 2009 510 Downloaded from www. and 55 were excluded on the basis of inclusion and exclusion criteria. plasma levels of vitamins B12 and E. which causes a form of autosomal recessive HSP with pure or complicated phenotypes. serologic testing for syphilis. Diagnostic MRI white matter changes.1 and symptoms of urinary urgency. We required that appropriate needle electromyography (EMG) had been performed at least 3 years after disease onset to exclude (laboratory-supported) ALS. We used the Kruskal-Wallis and MannWhitney tests to evaluate differences in the case of nonnormal distribution of values. patients underwent standardized needle EMG of 3 muscles per limb and 2 thoracic and 3 bulbar muscles. and 2 in the arms. or a UMN paresis (Medical Research Council grade of no greater than 4).28 was performed in all patients. Of the 36 patients with bulbar region symptoms. and very-long-chain fatty acids.26 DNA analysis of the spastin gene (SPG4) (GenBank AJ246001. for example abnormalities suggestive of demyelinating disorders or leukodystrophy.). biliary alcohol levels in urine. 23 patients were unable or unwilling to participate. all Dutch neurologists were asked to enroll patients with an apparently sporadic adult-onset idiopathic UMN syndrome.27 and the paraplegin gene (SPG7) (GenBank Y16610. fied Ashworth Scale30 score of 2). for any affected body region. including serum biochemistry. Lyme disease. RESULTS PATIENT CHARACTERISTICS The medical files of 182 eligible patients were screened for this study. thyrotropin. Results of leg SSEP studies were available for 33 patients. Of the other 90 patients.1. Statistical analysis was performed by one of us (F. Belgium.26 the presence of cerebellar or extrapyramidal signs. Hereditary spastic paraparesis was genetically confirmed in 14 patients (7 with SPG4 and 7 with SPG7 mutations) as published previously. 2005. according to the revised El Escorial criteria. 28 also had symptoms in the arms and legs. In 14 of the remaining 104 patients. 25 had symptom onset in the legs.10 evidence of mild dorsal column impairment such as decreased vibratory sensation in the distal legs or abnormal leg somatosensory evoked potentials (SSEPs). The patients’ characteristics are presented in Table 1. 2 patients in the legs. The arms and legs were considered affected if there was at least 1 of the following findings on the neurological examination results: spasticity (defined as a modi- (REPRINTED) ARCH NEUROL / VOL 66 (NO. 18 years) and a disease duration of at least 3 years.26 Diagnosis of probable laboratory-supported ALS according to the revised El Escorial criteria requires that at least 2 regions fulfill the EMG criteria. The range of age at onset. There were no other significant differences in clinical features between patients with the SPG4 or SPG7 mutation and the patients with the PLS phenotype. asymmetry. median (range). COMMENT Differentiation between HSP and PLS is important for genetic counseling of family members and for the patients’ prognosis because HSP generally has a more favorable progWWW. needle electromyography. fulfilling our definition of asymmetry.ARCHNEUROL. even after a relatively long disease duration. somatosensory evoked potentials. and in patients with at least bulbar region involvement (32-76 years). and 1 patient even developed a PLS phenotype after 18 years. median (range) Abbreviations: ALSFRS. . with only 1 leg being affected before symptoms progressed to the arms or bulbar region. Because previous studies used clinical characteristics such as onset before age 40 years. More than half of these patients developed bulbar region symptoms within 5 years.1 and symptoms of urinary urgency1. SSEPs. 4). Evidence of mild dorsal column impairment (decreased vibratory sense or abnormal leg SSEP). UMN. d The percentage uses the number of studies as the denominator. of studies Normal d ALSFRS score. which may be an underestimation because disease duration for some patients was only 3 years. however. Four of the 25 patients with symptom onset in the legs who developed bulbar region symptoms showed an asymmetrical pattern of progression. APR 2009 511 Downloaded from www. but not in the 14 patients with the SPG4 or SPG7 mutation. 3 developed bulbar region symptoms (Table 2).Table 1.archneurol.01] and with the patients with bulbar region involvement [PLS phenotype] [P=. median (range). Comparison of Clinical Characteristics Between Patients With the SPG4 or SPG7 Mutation and the Remaining Patients With an Apparently Sporadic Adult-Onset UMN Syndrome a Patients Without SPG4 or SPG7 Mutation Patients With SPG4 or SPG7 Mutation All Patients Leg Involvement Only Arm and Leg Involvement Bulbar Region Involvement (N = 90) (n = 39) (n = 15) (n = 36) (n=14) 6 (43) 0 0 14 (100) 39 (29-69) 9 (3-30) 6 (43) 2 (14) 5 (36) 0 0 0 0 11 (78) 6 (55) 5 (36) 2 (40) 33 (27-37) 56 (62) 8 (9) 4 (4) 78 (87) 49 (18-76) b 6 (3-29) 33 (37) 8 (9) 48 (53) 19 (21) 5 (6) 8 (9) 8 (9) 72 (80) 36 (50) 28 (31) 16 (57) 32 (13-38) 24 (62) 0 0 39 (100) 48 (18-66) 7 (3-29) 10 (26) 6 (15) 18 (46) 7 (18) 2 (5) 1 (3) 3 (8) 31 (79) 13 (42) 14 (36) 9 (64) 34 (26-38) 9 (60) 0 1 (7) 14 (93) 42 (20-62) 6 (3-15) 4 (27) 1 (7) 11 (73) 8 (53) 3 (20) 1 (7) 0 11 (73) 7 (64) 3 (20) 3 (100) 31 (24-37) 23 (64) 8 (22) 3 (8) 25 (69) 52 (32-76) c 7 (3-24) 19 (53) 1 (3) 19 (53) 4 (11) 0 7 (19) 4 (11) 28 (78) 15 (54) 11 (31) 4 (36) 25 (13-36) Characteristic Male Site of onset Bulbar region Arm Leg Age at onset.com on May 4. symptoms of urinary urgency. A significant difference was found only for age at onset (younger in patients with the SPG4 or SPG7 mutation compared with all patients without the SPG4 or SPG7 mutation [P=.002]).10 evidence of mild dorsal column impairment. b Statistically significant compared with the patients with the SPG4 or SPG7 mutation (P= . Six of the 14 patients with the SPG4 or SPG7 mutation had symptoms at 40 years or older. we compared the frequency of these and other clinical characteristics in the 14 patients with the SPG4 or SPG7 mutation with those of the other 90 patients with UMN disease and with those of the 36 patients with at least bulbar region symptoms (Table 1). y Disease duration.01). This pattern of asymmetrical progression was also seen in 4 of the 16 patients with involvement of only the arms and legs. of studies Normal c Leg SSEPs No. Eight patients had onset in the bulbar region that progressed in various patterns to the arms or legs in 6.COM (REPRINTED) ARCH NEUROL / VOL 66 (NO. was similar in patients with the SPG4 or SPG7 mutation (29-69 years). It is therefore possible that the patients in our study with a sporadic UMN disease and only leg involvement may still develop bulbar region symptoms. a Unless otherwise indicated.5 to separate HSP from PLS. data are expressed as number percentage of patients. EMG. and mild EMG abnormalities were present in the patients with the SPG4 or SPG7 mutation and in the patients with the PLS phenotype. the time range was broad.002). Four patients had symptom onset in the arms. and 3 of the 36 patients with at least bulbar region symptoms had onset before age 40 years. 2010 ©2009 American Medical Association. in all other patients with UMN disease (18-76 years). y Symptoms of urinary urgency Decreased vibratory sense Unilateral symptom onset Asymmetry at examination Unilateral at examination Fasciculation Mild focal atrophy EMG No. c Statistically significant compared with the patients with the SPG4 or SPG7 mutation (P = . All rights reserved. Figure shows the time from onset of leg symptoms (HSP phenotype) to development of bulbar region symptoms (PLS phenotype) in these patients. However. of these. upper motor neuron. Amyotrophic Lateral Sclerosis Functional Rating Scale. 8.0 0 5 10 15 20 Time From Disease Onset. Hereditary spastic paraparesis was genetically confirmed in 14 of 104 patients (7 with the SPG4 mutation and 7 with the SPG7 mutation). of Patients) a Leg involvement only (n=52) 1 Leg or both legs only Arm and leg involvement (n=16) Legs→ arms Legs→ right arm Legs→ left arm Right leg → right arm→ left leg → left arm Right leg → right arm Left leg → left arm Right arm → legs→left arm Bulbar region involvement (n=36) Legs→ arms→ bulbar region Legs→ bulbar region →arms Legs→ bulbar region Legs→ left arm→ bulbar region→ right arm Left leg → left arm → right leg → right arm → bulbar region Right leg → bulbar region→ left leg → arms Right leg → bulbar region Right leg → right arm→ left leg→ bulbar region Arms→ bulbar region→ legs Arms→ bulbar region Left arm→ legs →right arm→ bulbar region Bulbar region →arms→ legs Bulbar region →left arm Bulbar region → legs→arms Bulbar region → legs Bulbar region → right arm and leg→ left arm and leg Bulbar region only Patients With SPG4 All Other or SPG7 Mutation Patients (n=14) (n = 90) 13 1 39 5 1 4 1 1 2 1 13 5 2 1 1 1 1 1 1 1 1 2 1 1 1 1 2 0. its appearance could be an important clinical clue for SPG7 mutation as a cause in apparently sporadic UMN syndromes. For that reason. a phenotype (involvement of the arms and legs) that was difficult to classify as being similar to HSP or suggestive of PLS (subtype 3). the appropriateness of these criteria has yet to be validated. we chose to use only those HSP patients with a sporadic presentation because patients with familial HSP may present with different clinical features. We tested only the SPG4 and SPG7 genes to identify patients with genetically proved HSP. . progression. Our results demonstrate that these features are not useful in clinical practice for distinguishing HSP from PLS in the individual patient. which confirms several previous PLS studies. the oldest onset was 69 years. such as onset before age 40 years.2 0. described in the following paragraphs. or bulbar region involvement suggestive of PLS (subtype 4).5 were even more frequent in our patients with bulbar region involvement (53%) compared with patients with the SPG4 and SPG7 mutations (43%) and were also reported in more recent PLS series. a The right and left limbs are shown separately only if the symptoms spread to Abbreviation: UMN. progression to ALS. we compared the presence of these features in a large cohort of patients with an apparently sporadic adult-onset UMN syndrome that consists of patients who had genetically proved (the SPG4 or SPG7 mutation) HSP (subtype 1). a more extensive screen for HSP genes would not have influenced our main conclusion that features that have been considered indicative of HSP (onset at 40 years.5.1 Furthermore.archneurol. APR 2009 512 Downloaded from www. and it was even younger (23 and 26 years) in other PLS studies. More importantly.24 is not to be expected in HSP. who have the most definite diagnosis of HSP or PLS.9 Signs of mild dorsal column impairment (decreased vibratory sensation in the distal legs or abnormal leg SSEPs). previously considered atypical for PLS. decreased vibratory sensation in the distal legs or abnormal leg SSEPs). There was substantial overlap in age at onset between phenotypes: the youngest onset in our study occurred in a patient with a PLS phenotype at 32 years.1 and symptoms of urinary urgency1. The main objective of our study was to investigate whether clinical or laboratory features are useful to differentiate between patients in subtypes 1 and 4.6 0.34 whereas 6 patients with the SPG4 or SPG7 mutation had onset at 40 years or older. y Figure. another body region first before the onset of symptoms in the contralateral limb.8. Previous studies used several clinical and laboratory features. however.Table 2.com on May 4. 2010 ©2009 American Medical Association. a phenotype similar to typical pure HSP (involvement of the legs only) (subtype 2). WWW.ARCHNEUROL.0 Progression (No. 4 years). nosis than PLS.COM (REPRINTED) ARCH NEUROL / VOL 66 (NO.8 0. as may occur in PLS. Kaplan-Meier curve illustrating that the 25 patients who had disease onset in the legs and who eventually developed bulbar region involvement had a phenotype consistent with hereditary spastic paraparesis (leg involvement only or. but more extensive testing would have identified only a relatively small number of additional patients from subgroups 2 and 3. Pattern of Disease Progression in 104 Patients With an Apparently Sporadic Adult-Onset UMN Syndrome Proportion of Patients With Bulbar Region Involvement 1.4 0.23 Although the number of patients with genetically confirmed HSP included in our study was relatively low. mild dorsal column involvement. also of the arms) for up to 18 years (median duration. considered indicative of a diagnosis of HSP instead of PLS in a previous study.1 were also found in patients with a phenotype suggestive of PLS (bulbar region involvement) in our study.34 Because 3 of our 7 patients with the SPG7 mutation (and none of the other patients) developed cerebellar involvement during follow-up. 4). →. and urinary urgency) appear not to exclude PLS and that onset at 40 years or older is not uncommon in apparently sporadic HSP. at most. upper motor neuron.8. All rights reserved. Symptoms of urinary urgency.10 evidence of mild dorsal column impairment (eg. including 2 of 119 patients with sporadic disease (1. Wokke. New and more widely available genetic testing possibilities for HSP would be beneficial for patients with apparently sporadic UMN syndromes because HSP generally has a more favorable prognosis than PLS.36 Mutations in the novel mitochondrial protein REEP1 (REEP1) accounted for 6. All rights reserved. if associated with lower motor neuron involvement. and X-linked forms of HSP. We considered the presence of bulbar region symptoms to be part of the PLS phenotype.43 Some features may support a diagnosis of PLS. 2008. Diakonessenhuis Utrecht. previously reported in 1.41. The atlastin gene (SPG3A) mutation is the second most common cause of autosomal dominant HSP (approximately 10%) but is mostly associated with infantile or childhood onset. 3508 GA Utrecht.25. Male patients with proteolipid protein mutations (SPG2) are excluded. Author Contributions: Dr van den Berg had full access WWW. or marked asymmetry during the disease course may support a diagnosis of PLS. the most common cause of autosomal dominant HSP (in approximately 40%). the Netherlands (Dr van Doorn). the Netherlands (l. differentiation of sporadic presentations of HSP from PLS based on clinical characteristics is unreliable and therefore depends on genetic test results.17 whereas another study37 detected REEP1 mutations in 3% of a clinically mixed sample of patients with pure and complicated HSP. Academic Medical Center. Rotterdam. MD. We showed that bulbar region UMN symptoms may start many years after symptom onset in the legs ( 18 years). the Netherlands (Drs de Visser and de Jong). University Medical Center Utrecht.23 The role of the other known HSP genes in patients with apparently sporadic disease is largely unknown. and van den Berg) and Clinical Neurophysiology (Dr Franssen).8. The ZFYVE27 gene (SPG33) was mutated in 1 of 43 patients with autosomal dominant HSP in 1 study. Rudolf Magnus Institute of Neuroscience. autosomal recessive. but these were not frequently found in our study. and Departments of Neurology. Leiden. such as an onset of disease in the arms or the bulbar region and development of bulbar region symptoms or marked asymmetry during the disease course.7%. PhD. Author Affiliations: Departments of Neurology (Drs Brugman. Belgium (Dr Robberecht). the Netherlands. University Medical Center Groningen. Although we cannot fully rule out the possibility that genes will be discovered in patients with an HSP phenotype who develop bulbar region symptoms. . Correspondence: Leonard H. Rudolf Magnus Institute of Neuroscience.18 Mutations in the NIPA1 gene (SPG6) are a rare cause of autosomal dominant HSP in Europe ( 1%). seem to be limited to the early-onset forms. and University Hospital Leuven and Flanders Institute for Biotechnology.ARCHNEUROL. are an additional frequent cause of sporadic HSP (13% in this series). Nijmegen (Drs Kremer and Schelhaas). 2010 ©2009 American Medical Association.COM (REPRINTED) ARCH NEUROL / VOL 66 (NO. Leiden University Medical Center.5% of an unselected HSP population in a study. Erasmus University Medical Center.40 The patients with the SPG4 or SPG7 mutation all presented with UMN symptoms in the legs and that progressed to the arms in only 1 patient. Utrecht. 4). is a frequent cause of apparently sporadic spastic paraparesis (12%-13%). the Netherlands (Dr Faber). development of bulbar region involvement. Disease onset in the arms or bulbar region.archneurol.nl).”5 we and others found that such asymmetry may indeed be indicative of PLS. Development of UMN symptoms in the arms after disease onset in the legs usually supports a diagnosis of PLS but does not exclude HSP. Radboud University Medical Center. and. juvenile ALS. More than 30 genetic loci and 15 of the responsible genes have been identified for autosomal dominant. Groningen. which typically progress to the arms and the bulbar region. Although current diagnostic criteria for PLS require “symmetrical distribution of symptoms. van den Berg. Only 1 family was reported to have an autosomal dominant adult-onset UMN disease resembling typical PLS associated with a locus on chromosome 4p (PLS1). Utrecht (Dr Bruyn).38 The remaining known HSP genes are associated with complicated forms of HSP or probably each account for less than 1% of HSP cases. at least for those who have symptom onset in the legs.44 Despite our finding that unilateral symptom onset was common in patients with (36%) and without (53%) the SPG4 or SPG7 mutation. only 1 patient with adult-onset HSP). Most patients (87%) without the SPG4 or SPG7 mutation initially presented with symptoms similar to the patients with the SPG4 or SPG7 mutation. Maastricht. but in addition on the basis of our age-at-onset criterion because the SPG2 mutation is associated with early onset. Amsterdam. Maastricht University Medical Center. the absence of bulbar region symptoms in adultonset familial HSP makes this unlikely. because arm involvement was seen in 1 of our patients with the SPG7 mutation and was also reported previously in other patients with genetically confirmed HSP.h. Department of Neurology.14-21 Mutation of SPG4. CONCLUSIONS In patients with an apparently sporadic adult-onset UMN syndrome and symptom onset in the legs.com on May 4.35 Mutations of SPG7. the Netherlands (Dr Verschuuren).42 The autosomal recessive UMN diseases associated with alsin (ALS2) mutations. although patients with adult onset have been reported. APR 2009 513 Downloaded from www. Leuven. so there can be a long period during which PLS and (apparently sporadic) HSP are clinically similar. marked asymmetry at clinical evaluation was not seen in our patients with the SPG4 or SPG7 mutation. the Netherlands (Dr Kuks).39 We believe that the SPG11 mutation is practically excluded in our patients because it seems to be rare in sporadic disease and is associated with a thin corpus callosum.9 This should be verified in large prospective studies.Genetic testing is the only reliable way to differentiate HSP from PLS in patients with apparently sporadic adultonset UMN syndromes.5% to 6% of autosomal recessive cases of HSP.vandenberg @umcutrecht. described as juvenile PLS.22. so this requires confirmation in future larger studies. which was not seen in our patients. infantile ascending HSP. University Medical Center Utrecht. in part on the basis of the MRI criteria because many SPG2 patients have MRI changes. Accepted for Publication: October 3. 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