Journal of Neurology, Neurosurgery, and Psychiatry 1993;56:175-181 Hereditary "pure" spastic paraplegia: a study of nine families J M Polo, J Calleja, 0 Combarros, J Berciano Abstract The genetic and clinical features of 46 patients in nine families with "pure" hereditary spastic paraplegia are des- cribed. Inheritance was autosomal domi- nant in seven families and autosomal recessive in two. In dominant kinships, five families corresponded to type I with onset below 35 years, and two to type II with onset over 35 years. In early onset dominant families, in spite of apparent complete penetrance before 20, variable expression and incomplete penetrance occurred. Irrespective of genetic type, serial evaluation revealed that the main symptom consisted of slowly progressive spastic gait, extremely variable in sever- ity, associated in some patients with decreased vibratory sense and micturition disorders generally as late features. In dominant families, the disease tended to be more severe in late onset cases. No patient had symptoms in the upper limbs and plantar responses were flexor in six symptomatic patients. Central motor con- duction time studied by transcranial mag- netic stimulation was always normal in the upper limbs and increased in the lower limbs in five of the eight patients on whom it was performed. Monomorphic and ster- eotyped clinical pattern in this series does not support the concept of multisystem involvement of the central nervous system as a haflmark of the disease. (7 Neurol Neurosurg Psychiatry 1993;56:175-18 1) University Hospital "Marques de Valdecilla", University of Cantabria, Santander, Spain. Neurology Service J M Polo O Combarros J Berciano Department of Clinical Neurophysiology J Calleja Correspondence to: Dr Polo, Servicio de Neurologia, Hospital Universitario Marques de Valdecilla, E-39008 Santander, Spain Received 18 March 1992 Accepted 29 April 1992 Since the original descriptions more than 100 years ago,' 2 the nosology of hereditary spastic paraplegia (HSP) has been a matter of some controversy. As stated by Appel3: "Lorsqu'on parcourt l'abondante litterature de la para- plegie spasmodique familiale, on constate que jamais deux cas ne sont semblables". Indeed the history of HSP appears as if it were two different disorders. One is the so-called "pure" form, with clinical manifestations restricted to corticospinal system degeneration.4 The other is made up of a hotchpotch of "complicated" forms where spastic paraplegia coexists with some of the following: amyotrophy, mental retardation, pigmentary retinal degeneration, optic atrophy, extrapyramidal features, cere- bellar ataxia, sensory neuropathy or cutaneous lesions.5 It remains to be established whether both HSPs are pathogenetically related dis- orders. The "pure" form of HSP was first reported by Strumpell in 1880,2 who shortly afterwards also described the first neuropathological study.6 In 1981, Harding4 rechecked this "Striimpell's disease" by analysing 22 families from the London area. This wide experience, with 56 patients examined personally, enabled her to establish consistent diagnostic criteria and to determine genetic heterogeneity in the autosomal dominant families. Harding identi- fied two forms of dominant "pure" HSP: type I with an age of onset mostly below 35 years, and type II with onset usually over 35 years. To date no specific biochemical or genetic marker of "pure" HSP has been found, and diagnosis should be based on clinical findings and positive family history. Most ancilliary diagnostic tests show non-specific results in "pure" HSP, and are only useful for the differential diagnosis of every new case.7 " As "pure" HSP is an infrequent disease,9 personal series are scant. Most investigations are carried out with a small number of patients and any attempt to analyse reported studies comes up against their lack of comparability if minimal diagnostic criteria do not coincide or are simply not mentioned. In this paper we describe the genetic and clinical features of nine families with "pure" HSP. The study is part of a genetic and clinical investigation on hereditary ataxias, paraplegias and neuropathies, carried out in Cantabria, Spain, from 1974. Geographical and popula- tion data as well as epidemiological results have been detailed in previous reports.9 Patients and methods Patients Proband patients were initially evaluated at the hospital and thereafter systematic family research was carried out. All cooperative at- risk family members, parents, siblings and children of patients were visited in hospital or at home. In most of the affected members and in selected at-risk individuals, serial clinical examinations, yearly or less frequently, were performed. Diagnostic criteria were those of Harding,4 that is, progressive spastic paraplegia with pyramidal signs in lower limbs, patients not being excluded if they had minimal ataxia in the upper limbs or distal wasting of moderate degree if symptoms had been present for more than 10 years. In this study, an asymptomatic patient was defined as an at-risk relative in whom knee and ankle hyperreflexia and exten- sor plantar responses were present, as verified by two independent examiners (JMP and JB). No single cases were included here unless objective evidence of disease in at least one 175 on 27 May 2018 by guest. Protected by copyright. http://jnnp.bmj.com/ J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.2.175 on 1 February 1993. Downloaded from
Transcript
Journal of Neurology, Neurosurgery, and Psychiatry 1993;56:175-181
Hereditary "pure" spastic paraplegia: a study ofnine families
J M Polo, J Calleja, 0 Combarros, J Berciano
AbstractThe genetic and clinical features of 46patients in nine families with "pure"hereditary spastic paraplegia are des-cribed. Inheritance was autosomal domi-nant in seven families and autosomalrecessive in two. In dominant kinships,five families corresponded to type I withonset below 35 years, and two to type IIwith onset over 35 years. In early onsetdominant families, in spite of apparentcomplete penetrance before 20, variableexpression and incomplete penetranceoccurred. Irrespective of genetic type,serial evaluation revealed that the mainsymptom consisted of slowly progressivespastic gait, extremely variable in sever-
ity, associated in some patients withdecreased vibratory sense and micturitiondisorders generally as late features. Indominant families, the disease tended tobe more severe in late onset cases. Nopatient had symptoms in the upper limbsand plantar responses were flexor in sixsymptomatic patients. Central motor con-duction time studied by transcranial mag-netic stimulation was always normal inthe upper limbs and increased in the lowerlimbs in five ofthe eight patients on whomit was performed. Monomorphic and ster-eotyped clinical pattern in this series doesnot support the concept of multisysteminvolvement ofthe central nervous systemas a haflmark of the disease.
(7 Neurol Neurosurg Psychiatry 1993;56:175-18 1)
University Hospital"Marques deValdecilla", Universityof Cantabria,Santander, Spain.Neurology ServiceJ M PoloO CombarrosJ BercianoDepartment ofClinicalNeurophysiologyJ CallejaCorrespondence to:Dr Polo, Servicio deNeurologia, HospitalUniversitario Marques deValdecilla, E-39008Santander, SpainReceived 18 March 1992Accepted 29 April 1992
Since the original descriptions more than 100years ago,' 2 the nosology of hereditary spasticparaplegia (HSP) has been a matter of some
controversy. As stated by Appel3: "Lorsqu'onparcourt l'abondante litterature de la para-plegie spasmodique familiale, on constate quejamais deux cas ne sont semblables". Indeedthe history of HSP appears as if it were twodifferent disorders. One is the so-called "pure"form, with clinical manifestations restricted tocorticospinal system degeneration.4 The otheris made up of a hotchpotch of "complicated"forms where spastic paraplegia coexists withsome of the following: amyotrophy, mentalretardation, pigmentary retinal degeneration,optic atrophy, extrapyramidal features, cere-bellar ataxia, sensory neuropathy or cutaneouslesions.5 It remains to be established whetherboth HSPs are pathogenetically related dis-orders.The "pure" form of HSP was first reported
by Strumpell in 1880,2 who shortly afterwardsalso described the first neuropathologicalstudy.6 In 1981, Harding4 rechecked this"Striimpell's disease" by analysing 22 familiesfrom the London area. This wide experience,with 56 patients examined personally, enabledher to establish consistent diagnostic criteriaand to determine genetic heterogeneity in theautosomal dominant families. Harding identi-fied two forms of dominant "pure" HSP: typeI with an age of onset mostly below 35 years,and type II with onset usually over 35 years.To date no specific biochemical or genetic
marker of "pure" HSP has been found, anddiagnosis should be based on clinical findingsand positive family history. Most ancilliarydiagnostic tests show non-specific results in"pure" HSP, and are only useful for thedifferential diagnosis of every new case.7" As"pure" HSP is an infrequent disease,9 personalseries are scant. Most investigations are carriedout with a small number of patients and anyattempt to analyse reported studies comes upagainst their lack of comparability if minimaldiagnostic criteria do not coincide or aresimply not mentioned.
In this paper we describe the genetic andclinical features of nine families with "pure"HSP. The study is part of a genetic and clinicalinvestigation on hereditary ataxias, paraplegiasand neuropathies, carried out in Cantabria,Spain, from 1974. Geographical and popula-tion data as well as epidemiological results havebeen detailed in previous reports.9
Patients and methodsPatientsProband patients were initially evaluated at thehospital and thereafter systematic familyresearch was carried out. All cooperative at-risk family members, parents, siblings andchildren of patients were visited in hospital orat home. In most of the affected members andin selected at-risk individuals, serial clinicalexaminations, yearly or less frequently, wereperformed.
Diagnostic criteria were those of Harding,4that is, progressive spastic paraplegia withpyramidal signs in lower limbs, patients notbeing excluded if they had minimal ataxia inthe upper limbs or distal wasting of moderatedegree if symptoms had been present for morethan 10 years. In this study, an asymptomaticpatient was defined as an at-risk relative inwhom knee and ankle hyperreflexia and exten-sor plantar responses were present, as verifiedby two independent examiners (JMP and JB).No single cases were included here unlessobjective evidence of disease in at least one
175 on 27 M
ay 2018 by guest. Protected by copyright.
http://jnnp.bmj.com
/J N
eurol Neurosurg P
sychiatry: first published as 10.1136/jnnp.56.2.175 on 1 February 1993. D
additional family member had been found.In addition to the nine index patients, 109
relatives were examined of whom 37 werefound to be affected. Thus a total of46 affectedmembers were personally examined. A further10 living relatives were affected as a result oftheir history at the beginning of the study.Patients I-I and 1-2 in family E were examinedin 1929 by Dr Jose M AldamaTruchuelo in theformer "Casa de SaludValdecilla", and clinicaldata were obtained from medical records.A three point functional grading scale,
modified from Behan and Maia,'0 was adoptedfor the study. Grade 1 corresponds to anasymptomatic patient who had pyramidal signsin the lower limbs with normal or only slightlyspastic gait; grade 2 refers to a patient withspastic gait, able to walk independently with orwithout support; and grade 3 if the patient waschairbound or bedridden.
Electrophysiological techniquesWe concentrated here on patients in whomcentral motor conduction time (CMCT) wasstudied. Other electrophysiological features,including motor and sensory nerve conductionstudies and somatosensory and brainstemauditory evoked potentials, will be publishedlater.Nerve conduction velocity and electromyog-
raphy were performed according to the methoddescribed in an earlier study.11 Transcranialstimulation was carried out with a Magstim200 (Novametrix) magnetic stimulator follow-ing the technique described by Claus.'2 Mus-cle recordings were made on anelectromyograph (Medelec MS20) from theabductor pollicis brevis in the hand and exten-sor digitorum brevis in the foot. CMCT wascalculated on F-wave latency. Results werecompared with those from 15 subjects with nohistory of neurological disorders (6 men, 9woman; 27-40 years, mean (SD) 30 7(4-9);height 150-192 cm). The normal limits weretaken as mean (SD) 2-5. The purpose andmethodology of the studies were explained toeach patient and were performed with theirexplicit permission.
ResultsGENETIc FEATURESAutosomal dominant familiesIn seven families (fig 1) the disease occurred inseveral members of consecutive generations,and an autosomal dominant inheritance maybe deduced from pedigrees. Male-to-maletransmission was present in six, and in the last,family F, the symptoms were equally severe inboth sexes. No significant difference in dis-tribution between sexes was observed if allthose affected, examined or not, were con-sidered; there was, however, a predominanceof men, 45 as opposed to 29 women (Chisquare = 1-75; p > 0 05). The mean (SD) ageof onset established from the 33 patients aboutwhom information was available was 29-97(17-47) (range 3-63) years. Inspection of themean age of onset in each family (table 1)
suggests that two different diseases may bepresent. Comparison of these figures by theKruskal-Wallis test,'3 infers that the autosomaldominant "pure" HSP is caused by more thanone gene (S = 20-823; p < 0-005). The sevenfamilies could be assigned to one of the twogroups proposed by Harding,4 five belongingto type I and two to type II. Patient B-IV-12was an obvious exception. This man from anearly-onset family was found to be normalbetween 28 and 41 years, but after the age of42 developed increased running difficulties.Two years later he showed an unequivocalzlinical picture, very similar to that of hissiblings. Ancillary studies in this patient,including CSF examination and MRI provednegative.As an approximation to genetic counselling
in early-onset families, we have analysed thesiblings at-risk in which all siblings wereexamined, divided in two groups depending onwhether the examination took place before orafter the age of 20 (table 2). This limit waschosen provided that mean and median age ofonset in type I were between 15-20 years. Theproportion of affected to unaffected cases didnot differ from the expected 50%. Five of the13 affected were asymptomatic, four ofthem inthe younger group.
Incomplete penetrance based on history wasdetermined in the early-onset family B, inwhich three apparently unaffected men hadtransmitted the disease. None of them couldbe examined as they had died at 78, 53 and 34years, respectively, before the start of thisstudy. But in family D, patients D-III-12 andD-III-19, two women both daughter andmother of affected and examined women, wereasymptomatic and had a normal neurologicalexamination at the ages of 52 and 53.Although homozygosity could be invoked for
members in the second generation in family E(fig 1), none of the three affected subjects ofthe sibship had by history unusual clinicalfeatures that would not have been expected inheterozygotes.
AUTOSOMAL RECESSIVE FAMILIESIn two families the disease was confined to onegeneration (fig 2). In family H a man and twowomen were affected. Two siblings were still-born and two others had died during the firstyear of life, and no further information aboutthem was available. The father had died at theage of 80, before the start of the study, but hedid not show any symptoms to suggest HSPbefore his death. The mother was neuro-logically normal when examined at the age of81. Because the parents were first cousins andno other case was known in the family, it wasthought that recessive inheritance was verylikely. In family I, where three out of eightsiblings were found to be affected, no othercase was known among the ancestors and theparents, who were consanguineous, had anormal neurological examination at the age of75 and 74 years.There were three men and three women
affected in both families and the onset occur-red in the first decade of life in all of them
176 on 27 M
ay 2018 by guest. Protected by copyright.
http://jnnp.bmj.com
/J N
eurol Neurosurg P
sychiatry: first published as 10.1136/jnnp.56.2.175 on 1 February 1993. D
Figure 1 Pedigrees ofseven families (A to G)with "pure" HSP andautosomal dominantinheritance. Symbols withhorizontal markscorrespond to examinedindividuals.
11 *A kIII
IV
FAMILY A
11
III
IV
V
FAMILY B
11 * X iIII t)-4IV ,
FAMILY C
11
III
IV
VFAMILY D
Ie
III E
FAMILY E
[mean (SD) 6 67(0 52) years; range 6-7]. Allsix were unmarried and had no descendants.
Presenting symptomsIn the 31 symptomatic patients, both domi-nant and recessive, the first manifestation ofthe disease was insidious and concerned thelower limbs. It was described in a diversemanner by patients as abnormality of gait,running or jumping difficulties, clumsiness ingoing up and down slopes, or stiffness of thelegs. In 11 patients the disorder was first
noticed by their relatives. Seven patients had
prematurely worn out shoes and this seeminglyminor complaint was characteristically inter-preted by the patients themselves and theirrelatives as the first indication of the familydisease. Motor delay occurred in none of the30 patients for whom information was avail-able.
Fifteen patients of the dominant families, 12
in type I and three in type II, were asympto-matic at first examination. All were unaware of
a gait problem and came to us to complete the
11
III
11
III
IVFAMILY F FAMILY G
177
6 6 6 .i-.
on 27 May 2018 by guest. P
rotected by copyright.http://jnnp.bm
j.com/
J Neurol N
eurosurg Psychiatry: first published as 10.1136/jnnp.56.2.175 on 1 F
AD: autosomal dominant; NS: not signficantly different from the expected 50% by Chi-squaretest; *three individuals under ten years.
study of the families. After direct questioning,seven shared vague complaints in the lowerlimbs such as running or jumping difficulties orill-defined discomfort in the feet. Follow up ofthese asyptomatic patients enabled us to bepresent in five cases as their symptoms devel-oped.
CLINICAL FINDINGSAutosomal dominant patientsTable 3 summarises the occurrence of someselected clinical features. Spastic gait was theprominent sign in all symptomatic patients,with an exceedingly variable degree of severity.Twenty six early-onset patients had normal gaitor walked independently as opposed to 25%who were chair-bound in the late-onset group.Characteristically this dynamic hypertonia wasassociated with scant motor deficit and moder-ate spasticity when the.tonus was examined atrest. Both resting hypertonia and pyramidalweakness were more frequent in type IIalthough only the former shows a statisticallysignificant difference. Foot deformity predom-inated in type I, consisting of pes planus inone. These differences occurred when theclinical course in early-onset patients waslonger (table 3). Six symptomatic patients inboth types had flexor plantar responses. Super-
Figure 2 Pedigrees of twofamilies (H and I) with"pure" HSP andautosomal recessiveinheritance. Broken anddouble lines indicateconsanguinity.
11
IIL
FAMILY H
III
FAMILY I
ficial abdominal reflexes were unobtainable in10 out of 28 patients who had such anexamination.
Reduction of vibration sense in the feet,found in 10 patients, was the only sensationabnormality. It was more frequent in type II,but the difference was not significant. In early-onset patients, the mean (SD) duration ofdisease was longer in those with sensory loss,37 (29 93) years, than in those with normalsensory examination, 9-69 (14-49) years(p < 0 005). In late-onset patients the differ-ence was not significant, 14-4 (11 08) years asopposed to 6-71 (5 22) years (p > 0 05). Jointposition sense was normal in all patients as wassuperficial sensation. With the upper limbfindings, amyotrophy, pyramidal weakness andataxia were absent in all patients, and althoughmyothatic hyperreflexia; was more frequent intype II (table 3), the difference was notsignificant. Seven patients had urinary symp-toms, which consisted of permanent incon-tinence in one and urgent micturition in theother six. Anal control was normal in allpatients. Sexual involvement was not analysedbecause it was not assessed in most cases.The size of samples precludes any compar-
ison between the presence and duration ofdiverse symptoms and the duration ofdisease ifsubtypes were to be considered. Two patientsin type I and three in type II were chair-bound,having reached this level of severity betweenthe ages of 50 and 75. But in the late-onsetpatients the duration of the disease was 9, 20and 24 years, whereas in the early-onset it was40 and 60. Similarly, comparison of severitybetween sexes was not feasible; the onlyremarkable difference was the higher numberof asymptomatic women in type I, 9 asopposed to 3 men. Nine patients had diedsince the start of the study. Unfortunately postmortem examination was unavailable in any ofthe cases.
AUTOSOMAL RECESSIVE PATIENTS
The six patients in the recessive familiesexperienced a gradual deterioration of thelower extremities that had stabilised after10-20 years, but no major clinical differenceswere found in relation to dominant cases (table3). Gait disorder was severe in all, and at-rest-hypertonia and weakness predominated inthose with a longer duration of symptoms. Allhad pes cavus, whereas reduction of vibratorysensation occurred only in two patients infamily I. The three siblings in family H had hadunmodified urinary urgency and frequency formore than 20 years. All showed asymptomatichyperreflexia in upper limbs.
Electrophysiological studiesEight dominant patients (six men, two women)had motor conduction studies (table 4). All butone belonged to early-onset families. PatientG-IV-2 was the only asymptomatic one in thisgroup. Only two patients had brisk upper limbreflexes. Electromyography of abductor pollicisbrevis and extensor digitorum brevis musclesdid not reveal any relevant abnormalities.Motor nerve conduction studies ofmedian and
178 on 27 M
ay 2018 by guest. Protected by copyright.
http://jnnp.bmj.com
/J N
eurol Neurosurg P
sychiatry: first published as 10.1136/jnnp.56.2.175 on 1 February 1993. D
AR: autosomal recessive; AD: autosomal dominant; Only symptomatic paLtients when firstexamined; 'comparisons by Fisher's exact test or *Student's t test; NS: not significant.
Table 4 Autosomal dominant "Pure" HSP: central motor conduction times
peroneal nerves were normal. The results ofcentral conduction times appear in table 4.CMCT in the upper limbs was always withinthe normal range; bilateral examinations wereonly done in the four patients who were firstexamined. Responses evoked in the lowerlimbs were recorded on both sides in all eightpatients; CMCT was increased bilaterally inthree cases and unilaterally in two, and normalin the remainder.
DiscussionIn this series, "pure" HSP was transmitted asan autosomal dominant gene in seven out ofnine families, a proportion close to that repor-ted by other authors.4 "4 Bell and Carmichael"5found 49 probable recessively inherited pedi-grees among 74 published families, but it isclear that their material was clinically heteroge-neous. X-linked inherited "pure" HSP isexceedingly rare5 and only one family withapparent certainty has been described.'6
Genetic heterogeneity regarding age of onsetseems a well established fact in autosomaldominant "pure" HSP.4 Most of the patients inthis series conform to the cut-off point at 35years proposed by Harding.4 Schady andSheard"7 recently found that 20 years might bea better limit to avoid overlap between earlyand late-onset types. This lack of concensusmay in part be explained by the difficulty inestablishing the precise time of onset in adisease with insidious beginning of symp-toms.'8 In fact, the age at which the degen-erative process becomes apparent is rarely ornever the true age of onset of the disease.'5 In
our early-onset dominant patients, penetrancewas apparently complete before the age of 20,and therefore it seems possible to recognise thedisease even when patients are still asympto-matic. Because some exceptions may occur, asthis study indicates, it should be borne in mindthat the absence of signs in an individual at-riskdoes not rule out the likelihood of becomingill, irrespective of the age at which examinationis performed. This variable expression in rela-tion to age of onset, not uncommon indominantly inherited disorders, may be com-plicated still further due to the incompletepenetrance of the gene. Such a possibility in"pure" HSP was suggested by Burdick et al,'9based on the fact that some children becamesymptomatic before their parents, who lateralso became affected. But in the family thatBurdick studied the disparity of age of onsetlay on the earliness of the disease in theyoungest generation, giving the impressionthat genetic anteposition and variable expres-sion were perhaps confused with incompletepenetrance. In autosomal dominant disordersan incomplete penetrance occurs when a car-rier of the specific gene shows no clinical signof it,20 but is able to transmit it. Generationleaps based on family history that occurred inour family B, have occasionally been repor-ted.'0 21-24 But the high proportion of asymp-tomatic patients in "pure" HSP make it riskyto consider as unaffected an ancestor who hasnot been examined. Bickerstaff 2' and Bone etal5 reported objective instances of incompletepenetrance, but we agree with Harding5 thatthe clinical picture in affected descendantswas, to say the least, atypical. On the otherhand, we have found in an early-onset familytwo healthy women, descendants and mothersof examined patients. Provided that maternityis always confirmed, we conclude that, from apractical point of view, they constitute twocases of incomplete penetrance. Genetic coun-selling in "pure" HSP therefore sometimesbecomes a difficult task. A specific geneticmarker is a pressing need.Apart from the variability in age of onset, the
clinical features of "pure" HSP are quitestereotyped.4 But some aspects deserve com-ment. We were surprised by the high number ofasymptomatic, but clinically affected, patientswhen a systematic study of the families wascarried out. Already present in earlier descrip-tions,26 the existence of asymptomatic patientsin "pure" HSP was specifically mentioned byBickerstaff2" and Ozsvath.27 Harding4 foundthat 23% of her early-onset dominant patientswere asymptomatic; intriguingly, in our seriesthere were some even in late-onset families.The inclusion of those probable affected28 asaffected cases implies the risk of an exag-gerated diagnostic enthusiasm,2 1 but serialexaminations eventually lead to an unequivocaldiagnosis. We come to the conclusion thatmyotatic hyperreflexia and extensor plantarresponses, if consistenly assessed, are enoughto assure the presence of the gene in an at-riskperson. This fact also emphasises the need andusefulness of examining the greatest number ofindividuals in every new family.
179 on 27 M
ay 2018 by guest. Protected by copyright.
http://jnnp.bmj.com
/J N
eurol Neurosurg P
sychiatry: first published as 10.1136/jnnp.56.2.175 on 1 February 1993. D
Once started, the gait disorder increasesslowly to a variable severity level. There is acharacteristic predominance of dynamic spas-ticity over pyramidal weakness and at-resthypertonia. This spasmodic pseudoparalysis,already recognised in early studies,2 is asso-ciated with flexor plantar responses in somepatients with an important handicap. Appel3interpreted this particular combination of signsas the result of an area 6 syndrome, anattractive hypothesis not demonstrated for themoment. As occurred in six -patients of ourseries, flexor plantar responses have beenreported in some patients with an otherwisedefinite clinical picture;' 23 29-31 this fact mili-tates against including Babinski's sign as anobligatory criterion of the disease.8
In spite of the fact that degeneration of theGoll columns is a constant pathological findingin "pure" HSP,'° only a quarter of our patientsshowed involvement of propioceptive sensa-tion, a proportion which coincides with thatfound by Harding.4 Such clinico-pathological-dissociation has also been described in olivo-pontocerebellar atrophy.32 In "pure" HSP itcharacteristically consists of a loss of vibratoryperception in the legs and feet with an almostalways normal position sense, and is usually alate clinical feature.A more or less marked pes cavus was a sign
present in more than half of the patients, andin dominant families it was more frequent inthose with an earlier onset. It has been statedthat foot deformity in HSP may be differentfrom other neurological conditions in that thearching disappears on standing.2' 33 Most ofthe patients in this series had slight deform-ities, but ifpronounced it was indistinguishablefrom that found in other spinocerebellar syn-dromes. Incidentally, one patient had pesplanus.2934 Late involvement of the upperlimbs has been considered as an infrequent butcharacteristic feature in "pure" HSP.4 10Increased upper limb reflexes may be present,as in a third of our patients, even in the earlystages.24 But none of them had pyramidalweakness and in Harding's series4 only twopatients showed symptoms in the upper limbs.Even though pyramidal signs can be detectedin some, it therefore seems clear that brachialmanifestations are exceptional. Philip35 repor-ted for the first time urinary symptoms in"pure" HSP. Although these symptoms hadbeen considered infrequent,36 nearly half of thepatients in Harding's series4 had urinaryurgency or urinary frequency. In our series 10patients had impaired urinary function, gen-erally as a late clinical feature.4The impression, mentioned by Bickerstaff,2'
that the earlier the onset the faster its evolu-tion, was not borne out by Harding.4 Compar-ing type I with type II patients she found thatthe clinical picture is more serious if symptomsbegin after 35 years. We found a similartendency, even if statistical comparison wasnot significant, considering the larger durationof symptoms in our early-onset patients. Thiswas supported by the additional evidence thattype II patients become chair-bound earlier,4in spite of the fact that here again the small size
of our sample hindered a statistical analysis.Reports on transcranial stimulation of the
motor cortex in "pure" HSP are scarce. Usingelectrical stimulation, Thompson et al37 foundmild prolongation of latencies to the electro-myographic responses, only in one leg, in twomen with a static spastic paraparesis. Also withelectrical stimulation, Pelosi et ar38 foundabnormalities consisting of absent responses,reduced amplitude, slowed central conductionvelocity or prolonged central conduction timein the legs, in all 10 patients they studied. Byusing transcranial magnetic brain stimulation,Claus et al39 found that CMCT was normalwith upper limb recordings in eight out of 10patients, whereas it was abnormal in all fourpatients in whom it was recorded from thetibialis anterior muscle. The study by Schady etal' in a larger group of patients, failed toestablish a consistent pattern of changes usingmagnetic brain stimulation, in spite of the highnumber of abnormalities they found. In thesame way, our results indicate that even ifCMCT in "pure" HSP is increased in aproportion of patients, central motor conduc-tion studies lack value in detecting subclinicallesions in most patients with HSP.7The term "pure" when applied to "pure"
HSP is more than semantic because it refers toa clinical reality. As this series shows, thepatients develop a stereotyped clinical picture,exclusively made up of increasing spastic gait.This clinical picture has nothing to do with thereported "complicated" forms of HSP.5 8 It isclear from the published neuropathologicalstudies carried out in "pure" HSP8 '0 that thisentity is far from being the model of a solecorticospinal tract degeneration. The enigmanow is whether a subclinical involvement existsaffecting all the many neuronal systems aselectrophysiological investigations seem to sug-gest. In addition to corticospinal path-;vays7 37-39 and dorsal columns,38 40-43 bothknown to be affected in "pure" HSP, there isevidence of involvement of afferent pathwaysnediating pain and thermal sensibility," vis-ual4' 44-46 and auditory4l 46 pathways, cere-bellar control systems46 and evenneuropsychological function-maintainingstructures.46 It may be that a greater part of thenervous system is involved in the pathologicalprocess. Further investigations, includingmolecular genetic studies, will be required toprovide a definite answer to this still puzzlingdisease.
We are very grateful to Dr B Ruiz Blanco for translation ofGerman papers and to John Hawkins for stylistic revision of themanuscript. The study was supported in part by Fondo deInvestigaciones Sanitarias, grant 88/1502.
1 Seeligmuller A. Sklerose der Seitenstrange des Rucken-marks bei vier Kindern derselben Familie. Dtsch MedWochenschr 1876;2:185-6.
2 Strumpell A. Beitrage zur Pathologie des Ruckenmarks.Arch Psychiatr Nervenkr 1 880;10:676-7 17.
3 Appel L. Etudes sur la paraplegie spasmodique familiale.Analogie avec le syndrome de l'area 6. Acta Neurol Belg195 1;49:415-32.
4 Harding AE. Hereditary "pure" spastic paraplegia: a clinicaland genetic study of 22 families. Y Neurol NeurosurgPsychiatry 1981;44:871-83.
5 Harding AE. The hereditary ataxias and related disorders.Edinburgh: Churchill Livingstone, 1984.
180 on 27 M
ay 2018 by guest. Protected by copyright.
http://jnnp.bmj.com
/J N
eurol Neurosurg P
sychiatry: first published as 10.1136/jnnp.56.2.175 on 1 February 1993. D
(Strumpell-Lorrain). In: de Jong JMBV, ed. Handbook ofclinical neurology, vol. 15 (59). Amsterdam: Elsevier,1991:301-18.
9 Polo JM, Calleja J, Combarros 0, Berciano J. Hereditaryataxias and paraplegias in Cantabria, Spain. An epide-miological and clinical study. Brain 1991;114:855-66.
10 Behan WMH, Maia M. Striimpell's familial spastic para-plegia: genetics and neuropathology. .7 Neurol NeurosurgPsychiatry 1974;37:8-20.
11 Berciano J, Combarros 0, Figols J, et al. Hereditary motorand sensory neuropathy type II. Clinicopathological studyof a family. Brain 1986;109:897-914.
12 Claus D. Central motor conduction: method and normalresults. Muscle Nerve 1990;13:1125-32.
13 Emery AEH. Methodology in medical genetics. An introductionto statistical methods. 2nd ed. Edinburgh: Churchill Living-stone, 1986.
14 Holmes GL, Shaywitz BA. Strumpell's pure familial spasticparaplegia: case study and review of the literature.Neurol Neurosurg Psychiatry 1977;40: 1003-8.
15 Bell J, Carmichael EA. On hereditary ataxia and spasticparaplegia. Treasury of human inheritance 1939;4:141-281.
16 Keppen LD, Leppert MF, O'Connell P, et al. Etiologicalheterogeneity in X-linked spastic paraplegia. Am .7 HumGenet 1987;41:933-43.
17 Schady W, Sheard A. A quantitative study of sensoryfunction in hereditary spastic paraplegia. Brain1990;113:709-20.
18 Schoenberg BS. Epidemiology of the inherited ataxias. AdvNeurol 1978;21:15-32.
19 Burdick AB, Owens LA, Peterson CR. Slowly progressiveautosomal dominant spastic paraplegia with late onset,variable expression and reduced penetrance: a basis fordiagnosis and counselling. Clin Gent 1981;19:1-7.
20 Michels VV, Dvck PJ. Mendelian inheritance and basis ofclassification of hereditary neuropathy with neuronalatrophy and degeneration. In: Dyck PJ, Thomas PK,Lambert EH, Bunge R, eds. Peripheral neuropathy, vol II,2nd ed. Philadelphia: Saunders 1984:1512-24.
22 Thurmon TF, Walker BA. Two distinct types of autosomaldominant spastic paraplegia. Birth Defects OriginalArticleSeries 1971;7:216-18.
23 Sack GH, Huether CA, Garg N. Familial spastic paraplegia.Clinical and pathologic studies in a large kindred. JohnsHopkins MedJ7 1978;143:117-21.
24 Grassin D-Y La paraplegie spasmodiquefamiliale (Maladie deStrumpell-Lorrain). A propos de 11 genealogies (MDthesis). University Claude-Bemard of Lyon, 1975.
25 Bone I, Johnson RH, Ferguson-Smith MA. Occurrence offamilial spastic paraplegia in only one of monozygoustwins. Neurol Neurosurg Psychiatry 1976;39:1 129-33.
26 Newmark L. A contribution to the study of the family formof spastic paraplegia. Am _7 Med Sci 1893;55:432-40.
27 Ozsvath K. Paralysis spinalis spastica familiaris. Dtsch ZNervenheilk 1968;193:287-323.
28 Boustany R-MN, Fleischnick E, Alper CA, et al. Theautosomal dominant form of "pure" familial spasticparaplegia: clinical findings and linkage analysis of a largepedigree. Neurology 1987;37:910-15.
29 Kuhn H. Klinische Beitrage zur Kenntniss der hereditarenund familiaren spastischen Spinalparalyse. Dtsch Z Ner-venheilk 1902;22: 132-52.
30 Punton J. Hereditary spastic paraplegia. Report of sevencases in two families. J Nerv Ment Dis 1909;36:588-600.
34 Kraft-Ebbing R. Ueber infantile familiare spastische Spi-nalparalyse. Dtsch Z Nervenheilk 1900;17:87-98.
35 Philip RW. Primary spastic paralysis and pseudo-hyper-trophic paralysis in different members of the same familywith probable heredity in both. Brain 1886;8:520-7.
36 Sutherland JM. Familial spastic paraplegia. In: Vinken PJ,Bruyn GW, ed. Handbook of clinical neurology, vol 22.Amsterdam: North-Holland, 1975:421-31.
37 Thompson PD, Day JC, Rothwell JPR, et al. The inter-pretation of electromyographic responses to electricalstimulation of the motor cortex in diseases of the uppermotor neurone. _J Neurol Sci 1987;80:91-1 10.
38 Pelosi L, Lanzillo B, Perretti A, Santoro L, Blumhardt L,Caruso G. Motor and somatosensory evoked potentials inhereditary spastic paraplegia. J Neurol Neurosurg Psy-chiatry 1991;54;1099-102.
39 Claus D, Waddy HM, Harding AE, Murray NMF, ThomasPK. Hereditary motor and sensory neuropathies andhereditary spastic paraplegia: a magnetic stimulationstudy. Ann Neurol 1990;28:43-49.
40 Thomas PK, Jefferys JGR, Smith IS, Loulakakis D. Spinalsomatosensory evoked potentials in hereditary spasticparaplegia. J Neurol Neurosurg Psychiatry 1981 ;44:243-6.
41 Pedersen L, TrojaborgW Visual, auditory and somatosen-sory pathway involvement in hereditary cerebellar ataxia,Friedreich's ataxia and familial spastic paraplegia. Electro-encephalogr Clin Neurophysiol 1981 ;52:283-97.
42 Dimitrijevic MR, Lenman JAR, Prevec T Wheatly K. Astudy of posterior column function in familial spasticparaplegia. . Neurol Neurosurg Psychiatry 1982;45:46-9.
43 Uncini A, Treviso M, Basciani M, Gambi D. Striumpell'sfamilial spastic paraplegia: an electrophysiological dem-onstration of selective central distal axonopathy. Electro-encephalogr Clin Neurophysiol 1987;66: 132-6.
44 Happel LT, Rothschild H, Garcia C. Visual evoked poten-tials in two forms of hereditary spastic paraplegia.Electroencephalogr Clin Neurophysiol 1980;48:233-6.
46 Tedeschi G, Allocca SD, DiCostanzo A, et al. Multisysteminvolvement of the central nervous system in Striimpell'sdisease. A neurophysiological and neuropsychologicalstudy. . Neurol Sci 199 1;103:55-60.
181 on 27 M
ay 2018 by guest. Protected by copyright.
http://jnnp.bmj.com
/J N
eurol Neurosurg P
sychiatry: first published as 10.1136/jnnp.56.2.175 on 1 February 1993. D
