spastic - Journal of Neurology, Neurosurgery, and …Described in a doctor's letter as having 'spastic paraplegia without sensory loss' 1I Said to have been affected similarly to other

Journal of Neurology, Neurosurgery, and Psychiatry, 1974, 37, 8-20

Strumpell's familial spastic paraplegia:genetics and neuropathology

WILHELMINA M. H. BEHAN1 AND MARIA MAIA2

From the Department of Neuropathology, Radeliffe Infirmary,and the M.R.C. Population Genetics Unit, Oxford

SUMMARY Uncomplicated Striimpell's disease (Striimpell's familial spastic paraplegia) with a

dominant mode of inheritance is recorded in six families. The neuropathological findings in twocases from these families are given, bringing the total of similar histologically documented reports inthe literature to 11. It is concluded that, although exact classification and identification of the manydifferent hereditary neurological degenerative diseases is not yet practicable, cases conforming to thepicture described by Striimpell can be separated from the larger general group of familial spasticparaplegias, show a consistent clinical picture, and have a standard pathology. It is suggested that,since the lesions are confined to the longest fibre tracts in the central nervous system, the patho-logical process may be different from that found in the 'system' degenerations.

Striimpell's familial spastic paraplegia (SFSP) isa rare hereditary disorder, characterized by pro-gressive weakness and spasticity affecting pre-dominantly the lower limbs. Although mostneurologists in large centres have seen one ortwo cases, the life span of the patients tends notto be shortened, nor do they usually die inhospital, thus neuropathological reports are veryfew. The lack of detailed pathological knowledgehas created many difficulties in classification,particularly in establishing the relationship ofthis disease to other familial degenerative dis-orders. We were able to study six families withuncomplicated familial spastic paraplegia (FSP)to determine their phenotypic relationship, andto examine neuropathological material fromsingle patients from two of these families. Thisreport is concerned mainly with the neuro-pathological findings, with a brief description ofthe clinical findings, and a note on the genetics.From our studies it is concluded that SFSPshould be regarded as a circumscribed clinicaland pathological entity, characterized by distal

1 Present address: 6 Ledlameroch Crescent, Bearsden, Glasgow.G614AA.2 Present address: Department of Neurology, Sto. Antonio Hospital,Oporto, Portugal.

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axonal degeneration of the long ascending anddescending tracts in the spinal cord.

METHODS

GENETIC STUDIES The six families studied consistedof four families with members who had been referredto the Population Genetics Unit in Oxford forgenetic advice, and two additional families, in eachof which one affected member had died and been thesubject of a neuropathological examination at theNeuropathology Department, Radcliffe Infirmary,Oxford. With two exceptions (noted below) allliving affected members of these families were visited,as were family members suspected of having a dis-ability, and as far as possible those apparently at riskby reason of age or relationship to known affected.individuals. A detailed history was taken and clinicalexaminations carried out on all the individuals byone of us (M.M.).The findings are recorded as diagrammatic pedi-

grees (Figs 1-6) and all clinical data are summarizedin the Table. It was decided to classify the disorderinto stages I-IV, with subgroups (a) and (b), on thefollowing basis:

I Pyramidal tract signs in the legs, but nocomplaints of symptoms.

II Spastic gait, but the patients could walkunaided.

III Patients could walk with the aid of sticks.

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Striimpell's familial spastic paraplegia: genetics and neuropathology

tE24a

Family BI

IN&+$iAin

IV.

FIG. 1.

FI.2o

Family DI

mIV

vFIG. 4.

Family FI

II

IV

IvV

FIG. 5. FIG. 6.

FIGS 1 to 6. Family trees of six families. Key: Dmales, 0 females, K sex unknown, 7f propositus,

IV Patients were, for practical purposes, confinedto a chair or bed.

Each group is subclassified as (a) when deepsensation is normal, and (b) when deep sensation isimpaired.

* examined and affected, [Il said to be afjected,m doubtful, * neuropathological report, 0 still born.

NEUROPATHOLOGICAL STUDIES Detailed macroscopicand microscopic examinations were made of thebrain and spinal cord in both cases, and of peri-pheral nerves and muscles in case 1.

Family AI

mGIV

Family CI

II

mIVv

FIG. 3.

Family EI

m 6+UrVU

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Wilhelmni)ia M. H. Behaln anid Alaria Maia

CASE 1

Family E (1112). Age at death, 62 years. Generalnecropsy: no significant findings.

CENTRAL NERVOUS SYSTEM Macroscopic The brain(1,650 g) was swollen. There was a small recenthaemorrhage in the corpus callosum. The cause ofdeath was a haemorrhage in the right cerebellarhemisphere, which had ruptured into the fourthventricle. The spinal cord, roots, and meningesappeared normal apart from some greyness of theposterolateral columns in transverse sections. Thefixed spine revealed a small, midline protrusion

associated with C 4-5 intervertebral disc. The pro-trusion was 0 5 cm laterally, 0 5 cm from abovedownwards, and projected 0 3 cm anteriorly. Smallerlateral protrusions were associated with this disc andthe two below. This degree of cervical spondylosiswas not considered significant.

Microscopic Blocks were taken from the corpuscallosum, Rolandic cortex, cerebellum, three levelsof brain-stem, and all segments of the spinal cord;cervical and lumbar nerve roots; and nerves andmuscles from all four limbs. Customary staining wascarried out for nerve cells, axons, myelin, andneuroglia.

TABLECLINICAL DETAILS OF FAMILIES A TO F

Pedigree Age itt Age at Pyramidal signs Impairment ClinicalNo. 1970 onset of cleep stage

(yr) (yr) legs arnis sensation

Additional infMormiiation

Family A

I1I 54 7 + + + lVb Condition said not to have progressed since first recognized at 7 yruntil about 29 yr of age. Confined to a chair for 14 years

II11, 41 31 + + + Illb Sensory disturbance to touch and pin prick on R arm below elbowand in leg below the middle of thighs. EMG showed normal sensoryevoked potentials in the median nerve proximal to the wrist. Reflexactivity (stretch reflex, H reflex and C reflex) was similar to thatfound in other spastic patients

IV, 13 12 + - - I First noticed to swing L leg outwards when walking at about 12 yr ol'age. Obvious spasticity of L leg. R flexor plantar response but leftneutral response

117 Refused to be visited. Is confined to a chair. Her sister, lIif, says that her trouble with walkinig started at age 171ll Died in 1917 in New Zealand. Described in a doctor's letter as having 'spastic paraplegia without sensory loss'1I Said to have been affected similarly to other members of the family from the age of about 30 yr

Family B

ItIl 45 30 + + - Ilia Leg weakness first noticed after her first clhild. Stationary until secondchild was born 5 yr later when her condition deteriorated. Slightimpairment to touch and pin prick in the outer aspects of the L leg

ll4 ~ 41 24 + + _ Ila Weakness began after first child-cleared in a few weeks. Weaknessrecurred after successive pregnancies but from age 35 conditiolndeteriorated. Left pupil larger than right but consensual andaccommodation reflexes present

5lls 37 21 + + IlIb Used caliper on R leg after fracture of the femur and pelvic girdle at7 yr but unable to play games in 'teens. Slow progression of weak-ness, now walking only on crutches. Bilateral slight rotatoryniystagmus. No ataxia

IV3 23 3 + + - lila First walked at 3 yr-on toes. Several orthopaedic operationis inchildhood. Attended school for physically handicapped

IV, 21 2 + + + llb Walked at 18 mth but always dragged herlegs; at school for physicallyhandicapped

IV,, 17 1 + - - Ila Walked on toes from infancy. Marked spasticity of legs: clonus of Rankle and bilaterally extensor plantar responses

Ill Not examined as in extremiiis in hospital with pelvic sarcoma. Hospital notes say onset at 25 yr. Spasticity of legs with exaggeratedreflexes

It Was said to use sticks in old age after being injured by bull113 Also used sticks, but probably due to accident

III,

Illl.12 and 112lifa

Famoily C

64 44 + + - Ila Myelogram in 1967 showed free flow. Relatively slow progression;can still drive car

62 48 + + - Ila Similar to her brotherSaid to have been affected like rest of tamily but no details availableHospital records confirmed spastic paraplegia with no impairment of sensation. L pupillary reaction was said to be brisker than

R. Beginning of weakness about 40. Died age 60 (cause unknown)

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Striirnpell's familial spastic paraplegia: genetics and neuropathology

The haemorrhages in the brain showed no peculiarfeatures, and were considered to be related to thepatient's arterial hypertension. No abnormality wasfound in motor cortex, internal capsule, thalamus,and upper brain-stem. Myelin pallor was justdetectable in the medullary pyramids; otherwisethere was no sign of tract degeneration in the brain-stem.

In the cord, there was degeneration of the cortico-spinal tracts at all levels, including the uncrossedtracts in the cervical and upper thoracic segments(Figs 7 and 8). Myelin and axon stains showed that

the degeneration involved mainly the thicker fibres,and became progressively more severe at lower levels.There was an associated astrocytic and fibroglialreaction. No lipid degeneration products or PAS-positive material, were seen. There was also degenera-tion of the posterior columns, mild at sacral levels,and becoming more severe on ascending the cord(Figs 7, 8, and 9). At lower cervical levels the cuneatefasciculi were only mildly affected, whereas the gracilefasciculi were grossly degenerate and reduced in size;while at C-I segment and in the lower medulla thecuneate fasciculi were severely affected. At all levels

TA B LE-continued

Pedigree Age in Age at Pyramidal signs Impairment ClinicalNo. 1970 onset . . -- of deep stage

(yr) (yr) legs arssss sensation

Additional information

Famytily D

llsf 68 35 + + + IVb Was able to work as radio mechanic until 45. Now repairs radio setsin bed. Very marked spasticity with knee clonus

I1II 65 40 + + + IVb Steady progression since onset1116 62 39 + + + IlIb Walking with a stick for 20 yr. Investigation in 1968 revealed no

spinal abnormality and normal CSF1117 60 50 + + - Ila Steady progression since onsetIf[, Died aged 49 of cancer. Only information available is that walked with stiff gait with great difficulty for 6 yr before deathll2 and l13 Both walked with sticks for many years12 Remembered by II6 wAlking with sticks

Famtiily E

1l2 died at 35 -4 ? + ? Neurological report (Dr. Worster-Drought) in 1943 when aged 4263 stated 'upper neurone paraplegia with impairment of deep forms of

sensation in lower limbs and retention of superficial sensation'.Neuropathology: case 1

Ili, 62 35 + + + lXlb Only had to use sticks for walking 3 yr before seen1117 64 35 + + + lilb Said never to have run as well as other boys because R side was always

weak. Very brisk and symmetrical tendon-jerks knee and ankleclonus

IV, 40 ? + - + Ilb Said he was perfectly normal but on questioning admitted some diffi-culty with cricket over the last year. Walks with circumduction ofhips and has brisk reflexes with extensor plantar responses

IV7 42 ? + - - I Not aware of his condition. Has difficulty in walking on heels andspasticity of legs with polyclonic reflexes and extensor plantarresponses. No neurological signs could be elicited in his children VBwho are respectively 17 and 9 yr old

if, Dr. Worster-Drought's report in 1944: 'straightforward spastic paraplegia which had been present for 30 yr'112 7Il remembers he had walked on sticks from age of 35 and committed suicide from depression due to his increasing disability. Died

about 59 yr of age12 Said to have been spastic and remembered by II7 'always to have walked with sticks'

Fanmily F

1111 died at 55 + ? ? ? Hospital notes say he began to have difficulty in walking at 55. One66 year before death, Dr. Samtain observed spastic paraplegia with

objectively little hypertony of the legs, brisk reflexes, extensorplantar responses and no impairment of sensation.' Died of embol-ism after prostatectomy operation. Neuropathology: case 2

II3 64 31 + - + IlIb Had Achilles tenotomies when aged 44. L pupil smaller than R butaccommodation and consensual responses normal. Not worked forlast 25 yr. It takes him several minutes to walk couple of feet

1114 61 1 + - - Illa Walked on toes since childhood but at only about aged 50 did walkingbegin to be difficult. Slow progression since

IV2 Died when age 39 in heart failure (mitral stenosis developed after rheumatic fever when he was 10 years old). Little information, asmother too ill in hospital to be questioned. Hospital notes about his motor condition said, 'severe spastic congenital diplegia'.Necropsy not done

ll1 and 1a2 Remembered by their sons and nephews to have walked with sticks for many yearsI1 Said to have been stiff and walked with two sticks for 'many years'

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Wilhelmina M. H. Behan and Maria Maia

FIG. 7. Case 1. C6 Letvel. Moder>ate,myelin pallor of lateral corticospinaltracts; severe pallor of gracile anldcuneate fasciculi. Weil, x 5...~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.........

there was relative sparing of the more lateral fibres inthe posterior columns-that is, those portionsclosest to their point of entry-and entering posteriorroot fibres appeared entirely normal. As in thecorticospinal tracts there was a fibrillar gliosis pro-portional to the degree of degeneration. No lipiddegeneration products were seen.

Anterior horn cells appeared intact and no fibre

FIG. 8. Case 1. Ti Level. More severe myelin pallorof lateral corticospinal tracts; severe degeneration ofgracile fasciculus, less involvement of cuneatefasciculus. Weil, x 5.

loss was detectable in anterior or posterior roots.Spinal arteries, veins, and meninges appearednormal throughout. There was no sign, in brain orcord, of any disease specifically affecting myelinsheaths.

Peripheral nerves (ulnar, median, femoral) andmuscles (diaphragm, deltoid, vastus, gastrocnemius)all appeared normal.

FIG. 9. Case 1. SI Level. Lateral corticospinial anidposterior columns just identifiable as areas of myelinpallor. Weil, x 5.

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Striimpell's familial spastic paraplegia: genietics and neuropathology

I FIG. 10. Case 2. Medulla.Mild myelin pallor ofpyra-mids. Weil, x 10.

,:.....

FIG. 11. Case 2. Medulla. Mildgliosis ofpyramids. Holzer, x 10.

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Wilhelininia M. H. Behan anid Maria Maia

*. FIG. 12. Case 2. C8 Level.Moderate myelin pallor oflateral and anterior cortico-spinal tracts, and offascicui-lus gracilis. Weil, x 5.

CASE 2

Family F (III1). Died of pulmonary embolism afterprostatectomy, aged 66 years.

CENTRAL NERVOUS SYSTEM Macroscopic The brain(1,250 g) was normal externally, with healthy vessels.On slicing, there was an infarct, 1 cm in diameter,involving the right lentiform and caudate nuclei, withpart of the anterior limb of the internal capsule. Therest of the brain, spinal cord, nerve roots, andmeninges appeared normal. Peripheral nerves andmuscles were not available.

Microscopic Blocks were taken from the right basalganglia, five levels of brain-stem, five levels of spinalcord, and anterior and posterior nerve roots. Cus-tomary stains were used.The striatal infarct was of several months' stand-

ing, and could be related to a clinical episode of lefthemiparesis a few months before death. It had notinterrupted fibres passing through the cerebralpeduncle, which appeared normal on both sides.Otherwise, no significant changes were seen in thebrain apart from the medullary pyramids, whichappeared somewhat pale in myelin stains (Figs 10and 11).

In the cord there was degeneration of the cortico-spinal tracts (including the uncrossed tracts) at alllevels. As in case 1, this became progressively more

severe at lower levels (Figs 12 and 14). Posteriorcolumn degeneration was less severe than in case 1

but showed the same pattern, being barely detectableat sacral level and in the cuneate fasciculi, but pro-

gressively worse in the gracile fasciculi on ascendingthe cord. As before, thick fibres appeared to be moreaffected than thin ones, and there was a fine fibrillargliosis in the degenerate tracts (Fig. 13) withoutvisible lipid breakdown products. In the upper levelsthere was also a mild diffuse myelin loss in thelateral columns, without specific involvement ofspinocerebellar tracts. Nerve cells in the anteriorhorns and thoracic nuclei (Clarke's columns) appearnormal. There was no detectable loss of fibres inposterior or anterior nerve roots.

There was no sign of specific myelin disease inbrain or cord.

DISCUSSION

Striimpell (1880) recorded the case histories oftwo brothers presenting in middle age with pro-gressive weakness and spasticity involving pre-dominantly the lower limbs. He was able toreport the pathological findings on one of thesecases later (Striumpell, 1886) and then the post-mortem findings in an unrelated but similar case(Striimpell, 1904). In both pathological speci-mens, the lesions were almost entirely confined tothe spinal cord and consisted of degeneration ofthe lateral pyramidal tracts, increasing fromcervical to lumbar region; there was less obviousinvolvement of the anterior corticospinal fibres.He noted slight degeneration of the lateralcerebellar tracts in the thoracic and cervicalregions with degeneration also of the tracts of

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Striiimpell's familial spastic paraplegia: gelnetics anid neur-opathology

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FIG. 13. Case 2. Upper thoracic level. Moderategliosis of lateral and anterior corticospinal tracts, andoffasciculus gracilis. Holzer, x 5.

FIG. 14. Case 2. Lower thoracic level. Severe myelinpallor of lateral corticospinal tracts. Weil, x 5.

Goll, present in one case (Strampell, 1886) fromlumbar region to medullary nuclei and in theother (Struimpell, 1904) from upper thoracicregion to the medulla. There was also marginaldegeneration of the cord, probably of no signifi-cance. The motor cortex, internal capsule, basal

ganglia, and medulla were not noted to beabnormal in either case.The disease is sometimes classed along with

the hereditary spinocerebellar degenerations(Greenfield, 1954). The pathogenesis in thesediseases is thought to be that of simple neuronalatrophy or 'abiotrophy' as defined by Gowers(Greenfield, 1954) namely, 'Slow decay of thenerve elements which have a common function,decay limited to these but extending throughouttheir entire extent'. Classification of the spino-cerebellar degenerations and their related dis-orders has proved very difficult for two reasons.First, there is the difficulty of correctly allocatingthe site of the lesion to spinal cord or brain-stemon clinical examination alone. It is interesting inthis context to note that several of the casesdescribed by Marie as suffering from hereditarycerebellar ataxia were shown at postmortemexamination to have lesions involving spinalcord alone (Greenfield, 1954). Secondly, patientsare reported with combined forms of the diseasessuch as both Friedreich's ataxia and peronealmuscular atrophy, or as having transitional typesof degeneration- for example, the Roussy-Levysyndrome (hereditary areflexic dystasia) (Green-field, 1954). Histological examinations, how-ever, have sometimes shown that very differentclinical pictures in the same family may be pro-duced by similar pathological lesions which havea different intensity of damage at various points(Schut and Haymaker, 1951).As first described, Struimpell's familial spastic

paraplegia (SFSP) seemed to be a relativelycircumscribed disease with a characteristicclinical and pathological picture, but since thattime there have been numerous reports of SFSPassociated in the same patient with spinocere-bellar atrophies such as Friedreich's ataxia(Schut, 1950), hereditary spastic ataxia (Green-field, 1963), or as in the Roussy-Levy syndrome.Rhein (1916) first drew attention to the remark-able heterogeneity of signs and symptomsassociated with the disease. Families are recordedin which spasticity is associated with dementia(Van Bogaert, 1952), mental deficiency (Johnstonand McKusick, 1962), retinal degeneration(Jequier and Streiff, 1947), retrobulbar neuritis(Bickerstaff, 1950), dysarthria, extrapyramidaldisturbances (Dick and Stevenson, 1953), or pescavus and amyotrophy (Garland and Astley,

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1950). Rarely, the illness has also been describedas occurring with the leucodystrophies, aninteresting association in view of the inheritedmetabolic defects known to produce the latter(Poser et al., 1957).

Striimpell's familial spastic paraplegia occursfar less frequently than spastic paraplegia associ-ated with other defects. Indeed, Bell (1939) couldfind only one such family, after searching therecords over 20 years in two London hospitalswith large neurological departments. They cited74 families published in the world literature upto 1939, but scrutiny of their clinical and familysummaries indicates that in only 28 of thesefamilies was pure SFSP segregating in themembers. Only one further family with SFSPhas been reported from Great Britain since 1949(Bickerstaff, 1950). Hlowever, Ozsvath (1968) wasable to derive, from the literature and his ownexperience, 142 families with the disease. SinceOzsvath's review, a family of nine cases has beenreported from Japan with members affected infour generations (Kirikae et al., 1968) andFontaine et al. (1969) have described anotherfamily with 10 cases in four generations.With regard to the mode of inheritance, there

appears to be general agreement that SFSP maybe inherited as an autosomal dominant (probablyin rather more than half of the families) or as anautosomal recessive gene. Two families withspastic paraplegia (Johnston and McKusick,1962; Baar and Gabriel, 1966) where the pedi-grees were compatible with X-linked recessiveinheritance were not of pure spastic paraplegia.In both families the affected members showedearly signs of brain-stem and cortical lesions.Autosomal recessive forms tend to have an

earlier onset and a more rapid progression, aspointed out by Bell (1939) and by subsequentreviewers. In almost all these cases the onset isunder the age of 10 years, although occasionalcases appearing up to 14 years of age have beenreported. In contrast, the age of onset of thoseaffected families where the inheritance appearedto be autosomal dominant is much higher-onthe average over 20 years of age, and often notuntil early middle age. There is, however, anoverlap between the ages of onset in the dominantand recessive forms, since in some cases with thedominant mode the onset may be in early child-hood: in these latter cases it is interesting to note

that progression is usually very slow. Bell (1939)points to the high sib/pair correlations of ages ofonset but low correlations between pairs derivedfrom different families. That this is in generaltrue seems clear from the published data but, aspointed out a long time ago (Rhein, 1916), insome families there is a very marked bimodaldistribution of ages of onset-some membersbeing affected much earlier than others.

Clinically, all the patients recorded here aresimilar to those described by other authors ashaving Striimpell's FSP. They presented withspastic paraplegia without any signs of ataxia,amyotrophy, extrapyramidal signs, or mentaldeterioration. All the affected patients examinedby us had positive Babinski signs and some hadabsent abdominal reflexes. As the duration ofthe symptoms increased, loss of deep sensationin the lower limbs and pyramidal tract signs inthe arms became increasingly common. All thepatients seen were able to work until middle age,and only seven of them had been admitted tohospital for investigation. This could explainwhy Bell (1939) found so few records of patientsin London hospitals and why only one family(Bickerstaff, 1950) has been reported from theUnited Kingdom in the last 20 years.

In most of our six families, the neurologicalsigns and the rates of progression varied verylittle in the members. Typically, the first symp-toms and signs were in the legs, spreading up-wards much later to the arms. In a considerableproportion there was an impairment of deepsensation after the disorder had persisted forsome time. Clinical findings suggested that some-times the posterior columns were first affectedand that in some cases the pathological processmost severely affected pyramidal tracts at thecervical level with involvement of both arms andlegs. It is noteworthy that in the two patientsworst disabled from childhood (BIV3 and BIV5),pyramidal tract signs in the upper limbs werepresent in both, by 23 and 21 years respectively,and that one of them (BIV5) already had im-paired deep sensation.With regard to the age of onset, two different

patterns of disease emerge. In families C, D, andE, the history suggests that no members wereaffected below the age of 30 years and that on thewhole the ages of onset, as judged by the accountof patients and relatives, are highly correlated

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within families. However, there is always con-siderable doubt as to the actual age of onset, sothat sib/pair correlations within and between thefamilies, or analysis of variance, hardly seemedjustified.

The picture is different in families A, B, and F.In family A, three affected members first hadtrouble after 30 years of age, but in the otherthree the onset seems to have been much earlier.Perhaps not much reliance can be placed on theage of 17 years given for 117, but both 119 andIV4 were seen and had obvious disabilities inwalking, as well as definite neurological signs. Infour of the affected members of family B, the agewhen symptoms were first noted ranged from 21to 30 years, but in the three others who wereaffected, and who were examined at 17, 21, and23 years, it is impossible not to conclude thatthey walked late as children, and that when theyfirst walked, they had talipes equinus and spasticparesis. Similarly, in family F, two members (II1and II13) had first symptoms at 55 and 30 yearsrespectively, but 1114 and IV2 both had obvioussigns when they first walked in childhood.

Thus, there seem to be two groups of familiesas regards onset: in the first group the diseaseprocess starts in middle life and has a slowlyprogressive course (families C, D, and E); andin the second group, there is bimodal distribu-tion: some members are affected in the seconddecade but others in childhood. The latter, how-ever, show no increase in severity of the diseaseuntil about 30 years of age. There does not seemto be an adequate hypothesis to explain thisbimodal distribution of age of onset.

Examination of the data in the Table does notsuggest a strong correlation between clinicalstage, age of onset, or duration of disability.However, no patients appeared to reach stage IVuntil at least 18 years after the symptoms hadappeared. No stage IV patients and only one ofthe stage III patients examined still had noneurological signs in their arms, or unimpaireddeep sensation.The most plausible explanation of the inherit-

ance of pure spastic paraplegia in all of thesefamilies, except family B, is that the trait is aregularly expressed autosomal dominant. FamilyB presents some problems. If I1 and '2 were in-deed affected, and I1 was not, then we have topostulate complete failure of penetrance in Il1,

who must have been heterozygous. It is, ofcourse, possible that 112 had minimal signs oreven symptoms but the history certainly didnot suggest that he had any symptoms. If noneof I1, '2, or I1 was affected, then we have anexample of a moderately common phenomenonwhereby the characteristic has appeared all in onesibship for the first time but the trait is thereaftertransmitted in a manner compatible with itsbeing an autosomal dominant. Various explana-tions have been offered for this phenomenon,but whatever the explanation, the basic mechan-ism appears to be autosomal dominance infamily B also.

It will be noted that of all those who areprobably affected, even ignoring B12 and B112,there is an excess of affected males. This seemsto be a common feature in reported families.However, in the pedigrees here presented, it canbe observed that there were, in fact, many fewerfemales 'at risk' than males, in the sense thatthey had a presumptive heterozygote parent. Itis therefore not surprising that more males thanfemales were affected in our six families.

In summary, the clinical picture of thesepatients is of a slowly progressive spastic para-plegia with impairment of deep sensation andspastic paresis of upper limbs in the late stages;there are no cerebellar signs, amyotrophy, ormental deterioration. Over the years, severehandicap develops.As to the pathology, Schwarz (1952) provided

an extensive review of the pathological literature(amounting to 24 cases), discarded severalreports as being not relevant or not informativeenough, and stated that he considered all neuro-pathological knowledge of the condition restedon the descriptions of seven cases-six describedbefore 1912 and one in 1937. The cases wereStriimpell's original two cases (Striimpell, 1886,1904), Newmark's three (1904, 1906, 191 1), andthe single reports of Jakob (1909) and Kahlstorf(1937). In addition, he thought that possiblyfour others-two cases of Bischoff (1902) and theone described by Raymond and Rose (1909) andthe case ofFarago (1947)-might have been ofthesame condition. Reducing the descriptions of thedisease to this small number, he found a uni-formity in the lesions noted (vide infra). He addedthe pathological description of a typical casefrom a family which had been studied by Bayley

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in 1897 and Spiller in 1902. Schwarz and Liu(1956) then reported the clinical findings in afurther family with the necropsy study from acase in a different family, thus bringing thenumber of necropsies on acceptable cases ofSFSP recorded in the literature to a total of nine.

In his first paper, Schwarz attempted to sum-marize the pathological features of all the sevenpreviously reported cases thus: first, in all therewas bilateral degeneration of the crossed cortico-spinal tracts, with involvement of the uncrossedtracts in four. The Betz cells were judged to beatrophic in three cases and the motor horn cellswere reduced in number in one of these threespecimens. With regard to the ascending fibres,there was invariably symmetrical degenerationof the fasciculus gracilis, visible at thoracic leveland increasing at cervical regions up to themedullary nuclei. The spinocerebellar tracts wereinvolved in four cases, with bilateral loss offibres. No lipid degeneration products werefound. Atrophy of the basal ganglia was men-tioned in one case.

Having reviewed the literature up to 1950,Schwarz and Liu (1956) went on to discuss the 16families which were reported between 1950 and1955, with five neuropathological reports. Mostof the reports dealt with patients showingStriumpell's FSP among other neurologicaldeficits. Of the cases that came to necropsy, thetwo described by Appel and Van Bogaert (1952)were most similar to those previously character-ized (the other three cases were of quadriplegicidiots). The first case was reasonably typicalclinically. Pathologically, there was degenerationand gliosis of crossed pyramidal tracts in thespinal cord, with minor involvement of the un-crossed tracts. In the cervical levels of cord onlythere was slight degeneration of the gracile andcuneate fasciculi. There was, however, degenera-tion throughout the cord of anterior horn cells:an atypical finding in SFSP. On clinical examina-tion the second case had a spastic quadriparesis,slight atrophy of the muscles of the calves,thighs, thenar eminences, and the backs of thehands, but the pathological examination wasmore characteristic of SFSP as previouslydescribed, with degeneration and gliosis ofpyramidal tracts extending from the cerebralpeduncle to the sacral levels, and similar changesin the posterior columns from the second thoracic

level to the medulla. There were no anterior horncell changes. It has to be admitted that neither ofthese cases is typical of uncomplicated SFSP.The two new cases that Schwarz reported

showed findings similar to those expected. In thefirst case (1952), the brain-stem and cord onlywere examined. The major findings were of bi-lateral fibre loss in both crossed and uncrossedcorticospinal tracts, worse at lower levels, withpossible thinning of the medullary pyramids. Thefasciculus gracilis showed slight loss of fibres atlower cervical level. Possible degeneration in thespinocerebellar tracts was commented on. Thesecond case (Schwarz and Liu, 1956) was interest-ing in that all changes were so much moresevere at thoracic level that the authors postulatedthat this was the original site of damage. Again,bilateral loss of fibres in the lateral corticospinaltracts was found, increasing caudally and mostsevere at thoracic level, and mild myelin pallorwas recorded at the level of the pyramidal tractdecussation. There was degeneration of thefasciculus gracilis from the lowest thoracic levelupwards with a loss of neurones from Clarke'scolumns, but no involvement of the fasciculuscuneatus. The dorsal spinocerebellar tractsshowed a fibre loss which could be traced intothe medulla. Schwarz and Liu concluded also inthis case, on the basis of counting procedures,that there was a reduction in the Betz cellpopulation, and a loss of fibres in the medullarypyramids.The two cases which we have examined histo-

logically show the same pattern, with clear-cutlesions: corticospinal tract degeneration fromthe medullary pyramids downwards, increasingcaudally, and posterior column degeneration,without loss of posterior root fibres, increasingrostrally. These findings are almost identical withthose in Striimpell's original descriptions andthose of Schwarz (1952) and Schwarz and Liu(1956). Thus a strong case can be made forregarding FSP, as originally described byStruimpell, as a well-defined clinical and patho-logical entity. Inheritance is autosomal, andusually dominant. It is rare, but not as un-common as the paucity of reports would suggest,since many affected patients do not attend hos-pital. For the same reason, neuropathologicalreports have been very few. Accepting, asSchwarz does, Newmark's three cases and the

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single cases of Jakob and Kahlstorf in additionto those of Striimpell, Schwarz, and Liu, the twocases reported here bring the total up to 11.The nature of the disease, as with other

primary neuronal degenerations, is obscure. Atfirst sight, it appears to show, in common withother degenerations, the phenomenon of 'dying-back'-that is, a progressive withering of axonsbeginning at their terminations and proceedingtowards the cell body, which eventually dis-appears. This 'dying-back' is a recognizedfeature of the corticospinal tracts in motorneurone disease, of the pontocerebellar fibres inolivopontocerebellar atrophy, and of the pos-terior spinocerebellar tracts in Friedreich'sataxia. On the other hand, there is no evidence,in SFSP, of the phenomenon of trans-synaptic,or ' chain' degeneration, seen in olivoponto-cerebellar degeneration and Friedreich's ataxia.It is worth noting, too, that the two tracts whichare constantly affected in SFSP contain thelongest fibres in the central nervous system: andthat, in spite of the long duration of the disease,the cells of origin of these tracts in the cerebralcortex and posterior root ganglia respectively-show little, if any, depletion at the time of death.It may well be that the mechanism of distal fibredegeneration in SFSP is different from that inthe so-called 'system' degenerations, in whichcollections of neurones are affected regardless ofthe length of their axons. The findings, in fact,could be explained as the result of a generalizedfailure of nerve cells to maintain the vitality ofaxons of more than a certain length, rather thanas a specific disease of particular types, or sys-tems, of neurones. This conjectured differencemay or may not be real; in any case, it cannot beassumed that the basic cause is the same in allkinds of primary neuronal degeneration.

Greenfield (1954) commented on Gower'sabiotrophy theory in the pathogenesis of thespinocerebellar degenerations and suggested thatthe lesion would ultimately be found to be anenzyme deficiency. It has been shown that acci-dental organic phosphate poisoning in man hasresulted in degeneration of long tract fibres-corticospinal and gracile-especially at the distalends (Aring, 1942); and experimentally Cavanagh(1954), using tri-ortho-cresyl phosphate, andFenton (1955) with di-iso-propyl-fluorophos-phonate, were able to reproduce similar but

more acute changes in chickens. The organicphosphates destroy pseudocholinesterase, anenzyme which has no known function in thecentral nervous system; but affection of otherenzymes as well is a possibility. A prematureageing process has been suggested as the patho-genesis of various spinocerebellar disorders, aconcept proposed by Raymond (1908) and thenexpanded to include a wide variety of familial orhereditary disorders which show distal axonalatrophy. In SFSP, no excess of the signs com-monly associated with ageing in the centralnervous system has been reported in theliterature, nor did we see any in our cases.One of the puzzling features of these disorders

is the age of onset. It is difficult to understandhow a system which has functioned well frombirth to 30 years should then fail. In the case ofmetachromatic leukodystrophy we can under-stand why the disorder is not seen in infantsbefore 2j or 3 years of age, because it is knownthat aryl sulphatase-A deficiency will not pro-duce an effect until myelin formation hasoccurred (Jatzkewitz, 1968). There is no explana-tion, however, for similar cases of this disorderstarting in adulthood. Whether or not what isinherited in SFSP is a tendency to 'switch-over'enzyme production from normal to abnormal ata certain age, cannot be determined. Since theflow of nutrients is from perikaryon to axonaltermination, it is understandable that the distalparts of the long axons would be affected first ifthere were any derangement in cell nourishment.

In conclusion, we consider that uncomplicatedFSP is a well-defined clinical and pathologicalentity, and recommend the use of the eponymicterm 'Striimpell's familial spastic paraplegia' todistinguish it from the bewildering array offamilial system degenerations in which spasticweakness of the legs is only one feature in acomplex or variable neurological picture.

ADDENDUM

Since the preparation of this paper, we havestudied an additional case, with necropsymaterial. The patient was a man with a strongfamily history (mother, brother, two sisters) ofdifficulty in walking, who died at age 74 years,having been weak in the legs for an unknown

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Wilhelmiina M. H. Behant anid Maria Maia

period. The findings in the brain and cord werealmost identical with those in case 2 (above).

Our thanks are due to Dr. D. R. Oppenheimer, Dr.J. Trevor Hughes, and Professor A. C. Stevenson fortheir encouragement and help and to Dr. G.Rushworth for the EMG study. Dr. Peter Andrewskindly provided pathological material. We wish toacknowledge also the interest of the late Dr. C.Worster-Drought, who looked after case 1 anddirected the material to us. M.M. is very thankful forthe help she received from the various families.W.M.B. gratefully records financial support fromthe United Oxford Hospitals.

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Aring, C. D. (1942). The systemic nervous affinity of tri-orthocresyl phosphate (Jamaica ginger palsy). Brain, 65,34-47.

Baar, H. S., and Gabriel, A. M. (1966). Sex-linked spasticparaplegia. American Journal of Mental Deficiency, 71,13-18.

Bell, J. (1939). On hereditary ataxia and spastic paraplegia.In Treasury of Human Inheritance. Vol. 4, pp. 141-281.Cambridge University Press: London.

Bickerstaff, E. R. (1950). Hereditary spastic paraplegia.Jouirnal of Neutrology, Neurosurgery, and Psychiatry, 13,134-145.

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Newmark, L. (1911). Klinischer Bericht iiber den siebentenFall von spastischer Paraplegie in einer Familie undErgebnis der dritten Autopsie aus derselben Familie.Deutsche Zeitschrift fur Nervenheilkunde, 42, 419-431.

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Poser, C. M., Dewulf, A., and Van Bogaert, L. (1957).Atypical cerebellar degeneration associated with leuco-dystrophy. Journal of Neuropathology and ExperimentalNeurology, 16, 209-237.

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