Differentiation of Hereditary Spastic Paraparesis from Primary Lateral Sclerosis in Sporadic Adult-Onset Upper Motor Neuron Syndromes

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ORIGINAL CONTRIBUTION Differentiation 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 had a phenotype that was difficult to classify as similar differentiate sporadic presentations of hereditary spas- to HSP or PLS (involvement of legs and arms only), and tic paraparesis (HSP) from primary lateral sclerosis (PLS). 39 continued to have a phenotype similar to typical HSP Differentiation between these diseases is important for (involvement of the legs only). Median age at onset was genetic counseling and prognostication. lower in patients with the SPG4 or SPG7 mutation (39 [range, 29-69] years), but there was considerable over- Design: Case series. lap with patients with the PLS phenotype (52 [range, 32-76] years). No differences were found in the features Setting: Tertiary referral center. used by previous studies to distinguish HSP from PLS, including evidence of mild dorsal column impairment Patients: One hundred four Dutch patients with an adult- (decreased vibratory sense or abnormal leg somatosen- onset, sporadic upper motor neuron syndrome of at least sory evoked potentials), symptoms of urinary urgency, 3 years’ duration. Hereditary spastic paraparesis was genetically confirmed in 14 patients (7 with SPG4 and 7 or mild electromyographic abnormalities. with SPG7 mutations). Conclusions: In most patients with a sporadic adult- Results: All 14 patients with the SPG4 or SPG7 muta- onset upper motor neuron syndrome, differentiation of tion had symptom onset in the legs, and 1 of the pa- sporadic presentations of HSP from PLS based on clini- tients with the SPG7 mutation also developed symp- cal characteristics is unreliable and therefore depends on toms in the arms. Of the other 90 patients, 78 (87%) had results of genetic testing. symptom onset in the legs. Thirty-six patients developed a PLS phenotype (bulbar region involvement), 15 Arch Neurol. 2009;66(4):509-514

N PATIENTS WITH AN APPARENTLY rence of HSP is not uncommon, and mu- sporadic adult-onset upper motor tations of the spastin (SPG4) and paraplegin neuron (UMN) syndrome, clini- (SPG7) genes are a frequent cause.1,22,23 cal differentiation between pri- Differentiation between HSP and PLS mary lateral sclerosis (PLS) and he- is important for genetic counseling of fam- reditary spastic paraparesis (HSP) can be ily members and for the patients’ progno- I 1 problematic. Primary lateral sclerosis is a sis because HSP generally has a more fa- rare sporadic disorder of progressive spi- vorable prognosis than PLS.1 Furthermore, nobulbar spasticity with a mostly spinal and progression to amyotrophic lateral scle- occasionally bulbar region onset.2-12 Heredi- rosis (ALS), as may occur in PLS,24 is not tary spastic paraparesis is a clinically and ge- expected in HSP. Symptomatic UMN in- netically heterogeneous group of disor- volvement of the arms and particularly of ders characterized by a slowly progressive the bulbar region is unusual in pure HSP spastic paraparesis.1,13 To date, 15 genes and and would favor a diagnosis of PLS.1,25 more than 20 additional loci have been iden- However, PLS may present with a slowly tified for autosomal dominant, autosomal progressive spastic paraparesis of the legs, recessive, and X-linked forms of HSP.14-21 To similar to the typical HSP phenotype, for exclude HSP, current diagnostic criteria for many years before the onset of arm or bul- PLS require absence of a family history.5 bar region symptoms.1,9 To separate ap- Author Affiliations are listed at However, researchers increasingly recog- parently sporadic HSP from PLS, previ- the end of this article. nize that the apparently sporadic occur- ous studies used several clinical features,

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 such as an age at onset of younger than 40 years,10 evi- fied Ashworth Scale30 score of Ն2), obvious loss of dexterity dence of mild dorsal column impairment such as de- due to spasticity (evaluated at the examination), pathological creased vibratory sensation in the distal legs or abnor- hyperreflexia (defined as an Institute of Neurological Diseases 31 mal leg somatosensory evoked potentials (SSEPs),1 and and Stroke Myotatic Reflex Scale score of 4 or 5 or extensor symptoms of urinary urgency,1,5 but how appropriate these plantar response), or a UMN paresis (Medical Research Coun- cil grade of no greater than 4).32 We classified patients as hav- criteria are has yet to be validated. ing asymmetry if, for any affected body region, spasticity (modi- To study whether clinical characteristics can be used fied Ashworth Scale score of Ն2), paresis (Medical Research to differentiate between sporadic presentations of HSP Council paresis grade of Յ4), or dexterity loss were only pres- and PLS in patients with apparently sporadic adult- ent unilaterally. Functional impairment was assessed using the onset UMN syndromes, we performed a nationwide search Amyotrophic Lateral Sclerosis Functional Rating Scale.33 for patients in the Netherlands. At inclusion, patients underwent standardized needle EMG of 3 muscles per limb and 2 thoracic and 3 bulbar muscles, with the findings interpreted according to the revised El Escorial cri- METHODS teria.26 Diagnosis of probable laboratory-supported ALS according to the revised El Escorial criteria requires that at least PATIENTS 2 regions fulfill the EMG criteria. Results of leg SSEP studies were available for 33 patients, and the results were classified From November 1, 2002, through March 31, 2005, all Dutch as normal or abnormal. neurologists were asked to enroll patients with an apparently sporadic adult-onset idiopathic UMN syndrome. In addition, 1 large referral center for patients with motor neuron disease STATISTICAL ANALYSIS in Leuven, Belgium, agreed to participate. The study protocol was approved by the medical ethics review board of the Uni- Differences between groups were tested using the Pearson ␹2 versity Medical Center Utrecht, and written informed consent and Fisher exact tests. We used the Kruskal-Wallis and Mann- was obtained from each patient. Whitney tests to evaluate differences in the case of nonnormal Inclusion criteria were a gradually progressive UMN syn- distribution of values. Statistical analysis was performed by one drome with adult onset (age, Ն18 years) and a disease duration of us (F.B.). of at least 3 years. Exclusion criteria were a positive family history, clinical evidence of generalized lower motor neuron involvement fulfilling the revised El Escorial criteria for clinically RESULTS probable or clinically definite ALS,26 the presence of cerebellar or extrapyramidal signs, the presence of sensory signs other than PATIENT CHARACTERISTICS decreased distal vibration sensation (absent at the ankles), and other causes of UMN loss that were investigated using a pre- The medical files of 182 eligible patients were screened defined series of laboratory tests. The presence of mild focal amy- for this study. Of these, 23 patients were unable or un- otrophy limited to 1 or 2 muscles in 1 region and the presence of willing to participate, and 55 were excluded on the basis fasciculation were allowed. Additional laboratory investigations were performed to exclude other causes, including serum bio- of inclusion and exclusion criteria. In 14 of the remaining 104 patients, a pathogenic mutation of the spastin chemistry, plasma levels of vitamins B12 and E, thyrotropin, and very-long-chain fatty acids; biliary alcohol levels in urine; sero- (SPG4) or paraplegin (SPG7) gene was found (7 with SPG4 logic testing for syphilis, Lyme disease, human T-lymphotropic and 7 with SPG7 mutations).22,23 In the 14 patients with virus 1, and human immunodeficiency virus infection; and mag- the SPG4 or SPG7 mutation, 13 had a typical pure HSP netic resonance imaging (MRI) of the brain and the spinal cord. phenotype with only leg involvement, and 1 patient with Diagnostic MRI white matter changes, for example abnormali- the SPG7 mutation also developed UMN symptoms of the ties suggestive of demyelinating disorders or leukodystrophy, and arms (arm hyperreflexia associated with loss of dexter- the presence of a thin corpus callosum were not allowed. We ity) after 1 year. Of the other 90 patients, 39 had a phe- required that appropriate needle electromyography (EMG) had notype similar to typical pure HSP (involvement of the legs been performed at least 3 years after disease onset to exclude (laboratory-supported) ALS, according to the revised El Escorial cri- only), 36 had bulbar region involvement suggestive of PLS, teria.26 DNA analysis of the spastin gene (SPG4) (GenBank and 15 patients had a phenotype that was difficult to clas- AJ246001, OMIM *604277), the most common cause of auto- sify as being similar to HSP or suggestive of PLS (UMN somal dominant pure HSP,27 and the paraplegin gene (SPG7) involvement of arms and legs). Of the 36 patients with bul- (GenBank Y16610, OMIM *602783), which causes a form of au- bar region involvement, 28 also had symptoms in the arms tosomal recessive HSP with pure or complicated phenotypes,28 and legs, 2 patients in the legs, and 2 in the arms. The pa- was performed in all patients. Hereditary spastic paraparesis was tients’ characteristics are presented in Table 1. genetically confirmed in 14 patients (7 with SPG4 and 7 with 22,23 SPG7 mutations) as published previously. In approximately VALUE OF CLINICAL CHARACTERISTICS 75% of our patients, we performed additional genetic tests using FOR IDENTIFICATION OF HSP multiplex ligation-dependent probe amplification to identify SPG4 exonic microdeletions,29 but none were found. The pattern of disease progression in the 14 patients with CLINICAL EVALUATION the SPG4 or SPG7 mutation and the other 90 patients with a sporadic UMN syndrome is shown in Table 2. All 14 The bulbar region was considered affected if pseudobulbar dys- patients with the SPG4 or SPG7 mutation and 78 of the arthria was present. The arms and legs were considered af- other patients with sporadic UMN disease (87%) had symp- fected if there was at least 1 of the following findings on the tom onset in the legs. Of the 36 patients with bulbar re- neurological examination results: spasticity (defined as a modi- gion symptoms, 25 had symptom onset in the legs. The

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 1. Comparison of Clinical Characteristics Between Patients With the SPG4 or SPG7 Mutation and the Remaining Patients With an Apparently Sporadic Adult-Onset UMN Syndromea

Patients Without SPG4 or SPG7 Mutation Patients With SPG4 or SPG7 Mutation All Patients Leg Involvement Only Arm and Leg Involvement Bulbar Region Involvement Characteristic (n=14) (N=90) (n=39) (n=15) (n=36) Male 6 (43) 56 (62) 24 (62) 9 (60) 23 (64) Site of onset Bulbar region 0 8 (9) 0 0 8 (22) Arm 0 4 (4) 0 1 (7) 3 (8) Leg 14 (100) 78 (87) 39 (100) 14 (93) 25 (69) Age at onset, median (range), y 39 (29-69) 49 (18-76)b 48 (18-66) 42 (20-62) 52 (32-76)c Disease duration, median (range), y 9 (3-30) 6 (3-29) 7 (3-29) 6 (3-15) 7 (3-24) Symptoms of urinary urgency 6 (43) 33 (37) 10 (26) 4 (27) 19 (53) Decreased vibratory sense 2 (14) 8 (9) 6 (15) 1 (7) 1 (3) Unilateral symptom onset 5 (36) 48 (53) 18 (46) 11 (73) 19 (53) Asymmetry at examination 0 19 (21) 7 (18) 8 (53) 4 (11) Unilateral at examination 0 5 (6) 2 (5) 3 (20) 0 Fasciculation 0 8 (9) 1 (3) 1 (7) 7 (19) Mild focal atrophy 0 8 (9) 3 (8) 0 4 (11) EMG No. of studies 11 (78) 72 (80) 31 (79) 11 (73) 28 (78) Normalc 6 (55) 36 (50) 13 (42) 7 (64) 15 (54) Leg SSEPs No. of studies 5 (36) 28 (31) 14 (36) 3 (20) 11 (31) Normald 2 (40) 16 (57) 9 (64) 3 (100) 4 (36) ALSFRS score, median (range) 33 (27-37) 32 (13-38) 34 (26-38) 31 (24-37) 25 (13-36)

Abbreviations: ALSFRS, Amyotrophic Lateral Sclerosis Functional Rating Scale; asymmetry, fulfilling our definition of asymmetry; EMG, needle electromyography; SSEPs, somatosensory evoked potentials; UMN, upper motor neuron. a Unless otherwise indicated, data are expressed as number percentage of patients. b Statistically significant compared with the patients with the SPG4 or SPG7 mutation (P=.01). c Statistically significant compared with the patients with the SPG4 or SPG7 mutation (P=.002). d The percentage uses the number of studies as the denominator.

Figure shows the time from onset of leg symptoms (HSP disease (18-76 years), and in patients with at least bulbar phenotype) to development of bulbar region symptoms region involvement (32-76 years). Six of the 14 patients (PLS phenotype) in these patients. More than half of these with the SPG4 or SPG7 mutation had symptoms at 40 years patients developed bulbar region symptoms within 5 years, or older, and 3 of the 36 patients with at least bulbar re- which may be an underestimation because disease dura- gion symptoms had onset before age 40 years. Evidence tion for some patients was only 3 years. However, the time of mild dorsal column impairment (decreased vibratory range was broad, and 1 patient even developed a PLS phe- sense or abnormal leg SSEP), symptoms of urinary ur- notype after 18 years. It is therefore possible that the pa- gency, and mild EMG abnormalities were present in the tients in our study with a sporadic UMN disease and only patients with the SPG4 or SPG7 mutation and in the pa- leg involvement may still develop bulbar region symp- tients with the PLS phenotype. toms, even after a relatively long disease duration. Be- Four patients had symptom onset in the arms; of these, cause previous studies used clinical characteristics such 3 developed bulbar region symptoms (Table 2). Eight pa- as onset before age 40 years,10 evidence of mild dorsal col- tients had onset in the bulbar region that progressed in umn impairment,1 and symptoms of urinary urgency1,5 to various patterns to the arms or legs in 6. separate HSP from PLS, we compared the frequency of these Four of the 25 patients with symptom onset in the legs and other clinical characteristics in the 14 patients with who developed bulbar region symptoms showed an asym- the SPG4 or SPG7 mutation with those of the other 90 pa- metrical pattern of progression, with only 1 leg being af- tients with UMN disease and with those of the 36 pa- fected before symptoms progressed to the arms or bulbar tients with at least bulbar region symptoms (Table 1). A region. This pattern of asymmetrical progression was also significant difference was found only for age at onset seen in 4 of the 16 patients with involvement of only the (younger in patients with the SPG4 or SPG7 mutation com- arms and legs, but not in the 14 patients with the SPG4 or pared with all patients without the SPG4 or SPG7 muta- SPG7 mutation. tion [P=.01] and with the patients with bulbar region involvement [PLS phenotype] [P=.002]). There were no other significant differences in clinical features between COMMENT patients with the SPG4 or SPG7 mutation and the patients with the PLS phenotype. The range of age at onset, Differentiation between HSP and PLS is important for ge- however, was similar in patients with the SPG4 or SPG7 netic counseling of family members and for the patients’ mutation (29-69 years), in all other patients with UMN prognosis because HSP generally has a more favorable prog-

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 2. Pattern of Disease Progression in 104 Patients 1.0 With an Apparently Sporadic Adult-Onset UMN Syndrome

0.8 Patients With SPG4 All Other Progression or SPG7 Mutation Patients a (No. of Patients) (n=14) (n=90) 0.6 Leg involvement only (n=52) 1 Leg or both legs only 13 39 0.4 Arm and leg involvement (n=16)

Legs→arms 1 5 Proportion of Patients Legs→right arm 1 0.2 With Bulbar Region Involvement Legs→left arm 4 Right leg→right arm→left 1 → 0.0 leg left arm 0 5 10 15 20 → Right leg right arm 1 Time From Disease Onset, y Left leg→left arm 2 Right arm→legs→left arm 1 Bulbar region involvement (n=36) Figure. Kaplan-Meier curve illustrating that the 25 patients who had disease Legs→arms→bulbar region 13 onset in the legs and who eventually developed bulbar region involvement had a phenotype consistent with hereditary spastic paraparesis (leg Legs→bulbar region→arms 5 → involvement only or, at most, also of the arms) for up to 18 years (median Legs bulbar region 2 duration, 4 years). Legs→left arm→bulbar region→ 1 right arm Left leg→left arm→right 1 features are not useful in clinical practice for distinguish- leg→right arm→bulbar region ing HSP from PLS in the individual patient. There was sub- Right leg→bulbar region→left 1 stantial overlap in age at onset between phenotypes: the leg→arms Right leg→bulbar region 1 youngest onset in our study occurred in a patient with a Right leg→right arm→left 1 PLS phenotype at 32 years, and it was even younger (23 leg→bulbar region and 26 years) in other PLS studies,8,34 whereas 6 patients Arms→bulbar region→legs 1 with the SPG4 or SPG7 mutation had onset at 40 years or Arms→bulbar region 1 older; the oldest onset was 69 years. Symptoms of urinary Left arm→legs→right 1 urgency, previously considered atypical for PLS,5 were even arm→bulbar region Bulbar region→arms→legs 2 more frequent in our patients with bulbar region involve- Bulbar region→left arm 1 ment (53%) compared with patients with the SPG4 and Bulbar region→legs→arms 1 SPG7 mutations (43%) and were also reported in more re- Bulbar region→legs 1 cent PLS series.8,9 Signs of mild dorsal column impair- Bulbar region→right arm and 1 ment (decreased vibratory sensation in the distal legs or → leg left arm and leg abnormal leg SSEPs), considered indicative of a diagnosis Bulbar region only 2 of HSP instead of PLS in a previous study,1 were also found Abbreviation: UMN, upper motor neuron; →, progression. in patients with a phenotype suggestive of PLS (bulbar re- a The right and left limbs are shown separately only if the symptoms spread to gion involvement) in our study, which confirms several another body region first before the onset of symptoms in the contralateral limb. previous PLS studies.8,34 Because 3 of our 7 patients with the SPG7 mutation (and none of the other patients) de- nosis than PLS.1 Furthermore, progression to ALS, as may veloped cerebellar involvement during follow-up, its ap- occur in PLS,24 is not to be expected in HSP. Previous stud- pearance could be an important clinical clue for SPG7 mu- ies used several clinical and laboratory features, such as tation as a cause in apparently sporadic UMN syndromes.23 onset before age 40 years,10 evidence of mild dorsal col- Although the number of patients with genetically con- umn impairment (eg, decreased vibratory sensation in the firmed HSP included in our study was relatively low, we distal legs or abnormal leg SSEPs),1 and symptoms of uri- chose to use only those HSP patients with a sporadic pre- nary urgency1,5; however, the appropriateness of these cri- sentation because patients with familial HSP may present teria has yet to be validated. For that reason, we com- with different clinical features. Hereditary spastic parapa- pared the presence of these features in a large cohort of resis was genetically confirmed in 14 of 104 patients (7 patients with an apparently sporadic adult-onset UMN syn- with the SPG4 mutation and 7 with the SPG7 mutation). drome that consists of patients who had genetically proved We tested only the SPG4 and SPG7 genes to identify pa- (the SPG4 or SPG7 mutation) HSP (subtype 1), a pheno- tients with genetically proved HSP, but more extensive test- type similar to typical pure HSP (involvement of the legs ing would have identified only a relatively small number only) (subtype 2), a phenotype (involvement of the arms of additional patients from subgroups 2 and 3, described and legs) that was difficult to classify as being similar to in the following paragraphs. More importantly, a more ex- HSP or suggestive of PLS (subtype 3), or bulbar region in- tensive screen for HSP genes would not have influenced volvement suggestive of PLS (subtype 4). The main ob- our main conclusion that features that have been consid- jective of our study was to investigate whether clinical or ered indicative of HSP (onset at Ͻ40 years, mild dorsal laboratory features are useful to differentiate between pa- column involvement, and urinary urgency) appear not to tients in subtypes 1 and 4, who have the most definite di- exclude PLS and that onset at 40 years or older is not un- agnosis of HSP or PLS. Our results demonstrate that these common in apparently sporadic HSP.

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Genetic testing is the only reliable way to differentiate Some features may support a diagnosis of PLS, such HSP from PLS in patients with apparently sporadic adult- as an onset of disease in the arms or the bulbar region onset UMN syndromes, at least for those who have symp- and development of bulbar region symptoms or marked tom onset in the legs. More than 30 genetic loci and 15 of asymmetry during the disease course. The presence of the responsible genes have been identified for autosomal mild focal atrophy or fasciculation may also support a dominant, autosomal recessive, and X-linked forms of diagnosis of PLS, but these were not frequently found in HSP.14-21 Mutation of SPG4, the most common cause of au- our study, so this requires confirmation in future larger tosomal dominant HSP (in approximately 40%), is a fre- studies. Development of UMN symptoms in the arms af- quent cause of apparently sporadic spastic paraparesis ter disease onset in the legs usually supports a diagnosis (12%-13%).22,35 Mutations of SPG7, previously reported in of PLS but does not exclude HSP, because arm involve- 1.5% to 6% of autosomal recessive cases of HSP, are an ad- ment was seen in 1 of our patients with the SPG7 muta- ditional frequent cause of sporadic HSP (13% in this series).23 tion and was also reported previously in other patients The role of the other known HSP genes in patients with with genetically confirmed HSP.25,44 Despite our finding apparently sporadic disease is largely unknown. The at- that unilateral symptom onset was common in patients lastin gene (SPG3A) mutation is the second most com- with (36%) and without (53%) the SPG4 or SPG7 mu- mon cause of autosomal dominant HSP (approximately tation, marked asymmetry at clinical evaluation was not 10%) but is mostly associated with infantile or childhood seen in our patients with the SPG4 or SPG7 mutation. onset, although patients with adult onset have been re- Although current diagnostic criteria for PLS require “sym- ported.36 Mutations in the novel mitochondrial protein metrical distribution of symptoms,”5 we and others found REEP1 (REEP1) accounted for 6.5% of an unselected HSP that such asymmetry may indeed be indicative of PLS.8,9 population in a study,17 whereas another study37 detected This should be verified in large prospective studies. REEP1 mutations in 3% of a clinically mixed sample of patients with pure and complicated HSP, including 2 of 119 CONCLUSIONS patients with sporadic disease (1.7%; only 1 patient with adult-onset HSP). The ZFYVE27 gene (SPG33) was mu- In patients with an apparently sporadic adult-onset UMN tated in 1 of 43 patients with autosomal dominant HSP in syndrome and symptom onset in the legs, differentia- 18 Mutations in the NIPA1 gene (SPG6) are a rare 1 study. tion of sporadic presentations of HSP from PLS based on cause of autosomal dominant HSP in Europe (Ͻ1%).38 The clinical characteristics is unreliable and therefore de- remaining known HSP genes are associated with compli- pends on genetic test results. Disease onset in the arms cated forms of HSP or probably each account for less than or bulbar region, development of bulbar region involve- 1% of HSP cases. Male patients with proteolipid protein mu- ment, or marked asymmetry during the disease course tations (SPG2) are excluded, in part on the basis of the MRI may support a diagnosis of PLS. New and more widely criteria because many SPG2 patients have MRI changes, but available genetic testing possibilities for HSP would be in addition on the basis of our age-at-onset criterion be- beneficial for patients with apparently sporadic UMN syn- cause the SPG2 mutation is associated with early onset.39 dromes because HSP generally has a more favorable prog- We believe that the SPG11 mutation is practically ex- nosis than PLS. cluded in our patients because it seems to be rare in sporadic disease and is associated with a thin corpus callosum, which was not seen in our patients.40 Accepted for Publication: October 3, 2008. The patients with the SPG4 or SPG7 mutation all pre- Author Affiliations: Departments of Neurology (Drs Brug- sented with UMN symptoms in the legs and that pro- man, Veldink, Wokke, and van den Berg) and Clinical gressed to the arms in only 1 patient. Most patients (87%) Neurophysiology (Dr Franssen), Rudolf Magnus Insti- without the SPG4 or SPG7 mutation initially presented with tute of Neuroscience, University Medical Center Utrecht, symptoms similar to the patients with the SPG4 or SPG7 Utrecht, the Netherlands; and Departments of Neurol- mutation. We showed that bulbar region UMN symp- ogy, Academic Medical Center, Amsterdam, the Neth- toms may start many years after symptom onset in the legs erlands (Drs de Visser and de Jong), Maastricht Univer- (Յ18 years), so there can be a long period during which sity Medical Center, Maastricht, the Netherlands (Dr PLS and (apparently sporadic) HSP are clinically similar. Faber), Radboud University Medical Center, Nijmegen We considered the presence of bulbar region symptoms (Drs Kremer and Schelhaas), Erasmus University Medi- to be part of the PLS phenotype. Although we cannot fully cal Center, Rotterdam, the Netherlands (Dr van Doorn), rule out the possibility that genes will be discovered in pa- Leiden University Medical Center, Leiden, the Nether- tients with an HSP phenotype who develop bulbar region lands (Dr Verschuuren), Diakonessenhuis Utrecht, symptoms, the absence of bulbar region symptoms in adult- Utrecht (Dr Bruyn), University Medical Center Gronin- onset familial HSP makes this unlikely. Only 1 family was gen, Groningen, the Netherlands (Dr Kuks), and Uni- reported to have an autosomal dominant adult-onset UMN versity Hospital Leuven and Flanders Institute for Bio- disease resembling typical PLS associated with a locus on technology, Leuven, Belgium (Dr Robberecht). chromosome 4p (PLS1).41,42 The autosomal recessive UMN Correspondence: Leonard H. van den Berg, MD, PhD, diseases associated with alsin (ALS2) mutations, which typi- Department of Neurology, Rudolf Magnus Institute of cally progress to the arms and the bulbar region, seem to Neuroscience, University Medical Center Utrecht, PO Box be limited to the early-onset forms, described as juvenile 85500, 3508 GA Utrecht, the Netherlands (l.h.vandenberg PLS, infantile ascending HSP, and, if associated with lower @umcutrecht.nl). motor neuron involvement, juvenile ALS.43 Author Contributions: Dr van den Berg had full access

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©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 to all of the data in the study and takes responsibility for 16. Windpassinger C, Auer-Grumbach M, Irobi J, et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Sil- the integrity of the data and the accuracy of the data analy- ver syndrome. Nat Genet. 2004;36(3):271-276. sis. Study concept and design: Brugman, Wokke, and van 17. Züchner S, Wang G, Tran-Viet KN, et al. Mutations in the novel mitochondrial den Berg. Acquisition of data: Brugman, Franssen, de Vis- protein REEP1 cause hereditary spastic paraplegia type 31. Am J Hum Genet. ser, de Jong, Faber, Kremer, Schelhaas, Bruyn, Kuks, Rob- 2006;79(2):365-369. 18. Mannan AU, Krawen P, Sauter SM, et al. ZFYVE27 (SPG33), a novel spastin- berecht, and Wokke. Analysis and interpretation of data: binding protein, is mutated in hereditary spastic paraplegia. Am J Hum Genet. Brugman, Veldink, Franssen, de Jong, Kremer, van Doorn, 2006;79(2):351-357. Verschuuren, Robberecht, Wokke, and van den Berg. Draft- 19. Valdmanis PN, Meijer IA, Reynolds A, et al. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am J Hum Genet. 2007; ing of the manuscript: Brugman, Veldink, de Jong, Kuks, 80(1):152-161. and van den Berg. Critical revision of the manuscript for im- 20. Stevanin G, Santorelli FM, Azzedine H, et al. Mutations in SPG11, encoding spatac- portant intellectual content: Brugman, Veldink, Franssen, sin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007;39(3):366-372. de Visser, de Jong, Faber, Kremer, Schelhaas, van Doorn, 21. Hanein S, Durr A, Ribai P, et al. A novel locus for autosomal dominant “uncom- Verschuuren, Bruyn, Kuks, Robberecht, Wokke, and van plicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3. Hum den Berg. Statistical analysis: Brugman and Veldink. Ob- Genet. 2007;122(3-4):261-273. tained funding: van den Berg. Administrative, technical, and 22. Brugman F, Wokke JH, Scheffer H, Versteeg MH, Sistermans EA, van den Berg LH. Spastin mutations in sporadic adult-onset upper motor neuron syndromes. material support: Brugman, Franssen, and Schelhaas. Study Ann Neurol. 2005;58(6):865-869. supervision: de Jong, Wokke, and van den Berg. 23. Brugman F, Scheffer H, Wokke JHJ, et al. Paraplegin mutations in sporadic adult- Financial Disclosure: None reported. onset upper motor neuron syndromes. Neurology. 2008;71(19):1500-1505. 24. Bruyn RP, Koelman JH, Troost D, de Jong JM. Motor neuron disease (amyotro- Funding/Support: This study was supported by the Neth- phic lateral sclerosis) arising from longstanding primary lateral sclerosis. JNeu- erlandsOrganizationforScientificResearch(DrvandenBerg) rol Neurosurg Psychiatry. 1995;58(6):742-744. and the Interuniversity Attraction Poles program P6/43 of 25. Nielsen JE, Krabbe K, Jennum P, et al. Autosomal dominant pure spastic paraple- the Belgian Federal Science Policy Office (Dr Robberecht). gia: a clinical, paraclinical, and genetic study. J Neurol Neurosurg Psychiatry. 1998;64(1):61-66. Role of the Sponsor: The funding organizations had no role 26. Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Re- in the design and conduct of the study; the collection, man- search Group on Motor Neuron Diseases. El Escorial revisited: revised criteria agement, analysis, and interpretation of the data; or in the for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293-299. preparation, review, or approval of the manuscript. 27. Hazan J, Fonknechten N, Mavel D, et al. Spastin, a new AAA protein, is altered in Additional Contributions: We are grateful for the coop- the most frequent form of autosomal dominant spastic paraplegia. 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