hereditary spastic paraplegia

Hereditary spastic paraplegia

John K. Fink, MDThe Department of Neurology, University of Michigan and Geriatric Research

Education and Care Center, Ann Arbor Veterans Affairs Medical Center,

Ann Arbor, MI

Hereditary spastic paraplegia (HSP; also known as familial spastic para-plegia [FSP] and Strumpell-Lorrain syndrome) [1] is a syndromic designationfor inherited disorders in which the primary symptoms are progressivebilateral lower extremity spastic weakness. This article summarizes theauthor’s knowledge of the clinical, pathologic, and genetic features of thisgroup of disorders. For previous reviews of HSP, see [2–4] and websiteshttp://www.geneclinics.org/profiles/hsp/ and http://www.med.umich.edu/hsp.

Classification

HSP is classified according to the mode of inheritance (autosomal dom-inant, autosomal recessive, and X-linked); clinically (‘‘uncomplicated’’ and‘‘complicated’’); and according to the specific genetic locus (‘‘SPG1’’through ‘‘SPG17’’, discussed below). The syndrome of ‘‘uncomplicatedHSP’’ consists of insidiously progressive spastic leg weakness, frequentlyaccompanied by urinary urgency and mildly impaired vibration sensationin the distal lower extremities. ‘‘Complicated HSP’’ refers to inherited dis-orders in which the principle symptoms of ‘‘uncomplicated HSP’’ are accom-panied by additional neurologic abnormalities such as seizures, dementia,cataracts, amyotrophy, extrapyramidal disturbance, cutaneous abnormal-ities, or peripheral neuropathy [2]. Although the term ‘‘pure’’ is used inter-changeably with ‘‘uncomplicated’’ HSP, it is important to note that‘‘uncomplicated HSP’’ typically is not a ‘‘purely motor’’ disorder. Many ifnot most subjects with ‘‘uncomplicated HSP’’ have both motor (cortico-spinal tract) and subtle sensory (dorsal column) impairment.

Neurol Clin N Am 20 (2002) 711–726

E-mail address: [email protected] (J.K. Fink).

This research is supported by grants from the Veterans Affairs Merit Review and the

National Institutes of Health (NINDS R01NS33645, R01NS36177 and R01NS38713) to J.K.F.

We gratefully acknowledge the expert secretarial assistance of Ms. Lynette Girbach.

0733-8619/02/$ - see front matter � 2002, Elsevier Science (USA). All rights reserved.

PII: S 0 7 3 3 - 8 6 1 9 ( 0 2 ) 0 0 0 0 7 - 5

Clinical features of HSP

Gait disturbance, because of bilateral lower extremity spasticity and/orweakness, is the primary symptom of uncomplicated HSP. Leg muscle stiff-ness and spasm, particularly at night, following exertion, or in cold weather,are common early symptoms. Gait disturbance may begin at any age, fromearly childhood through senescence. For most individuals, particularly thosewith onset after adolescence, gait disturbance progresses insidiously overdecades. It is noteworthy, however, that many individuals with early child-hood onset of symptoms have very little progressive worsening.

Symmetry

HSP affects both lower extremities, typically at approximately the sametime and to approximately the same degree. It is very unusual for uncompli-cated HSP to exhibit unilateral involvement or marked asymmetry or forone leg to become affected many years before the other. Such findingsshould prompt further search for alternate disorders particularly multiplesclerosis.

Additional symptoms

Urinary urgency is a frequent symptom of HSP. Although usually expe-rienced later in the course of the disorder, urinary urgency is occasionally anearly symptom of HSP.

Many subjects with uncomplicated HSP experience lower extremity par-esthesiae. A spinal sensory level or loss of light touch or pinprick sensationare not features of uncomplicated HSP, however.

Subclinical cognitive disturbance and late-onset dementia have been de-scribed in some families with the most common form of dominantly inheritedHSP (due to SPG4 mutations, described below) [5–10]. The frequency ofcognitive impairment in this and other forms of HSP is not known.

Neurologic examination of subjects with uncomplicated HSP reveals low-er extremity weakness, spasticity, hyperreflexia, extensor plantar responses,and often mildly diminished distal vibratory sensation.

Weakness and spasticity occur in variable proportions. Some patientshave increased lower extremity tone but normal strength. Weakness is mostevident in tibialis anterior, hamstring, and iliopsoas muscles. Pes cavus isoften present.

Upper extremity deep tendon reflexes may be mildly brisk; however,upper extremity muscle tone, strength, and dexterity are normal in uncom-plicated HSP.

When not attributable to co-existing peripheral neuropathy or other dis-orders, decreased vibratory sensation in the toes is a helpful diagnostic sign.

712 J.K. Fink / Neurol Clin N Am 20 (2002) 711–726

Involvement of both motor (corticospinal tract) and sensory (dorsalcolumn) fibers helps distinguish HSP from pure motor syndromes such asamyotrophic lateral sclerosis and primary lateral sclerosis, disorders whoseprognosis differs significantly from that of HSP [11].

The severity of gait impairment in uncomplicated HSP ranges from subtledisturbance that is of no functional consequence; to frank spastic diplegiarequiring use of a wheelchair. Affected subjects who are ambulatory exhibitshort strides due to limited flexion of the thigh and difficulty fully dorsiflex-ing the feet; circumduction; and a tendency to maintain the legs partiallyflexed (knees bent) due to hamstring muscle spasticity. Hyperlordosis iscommon.

Muscle bulk is usually preserved in uncomplicated HSP although somesubjects have mildly decreased muscle bulk in their shins. Troyer syndromeand Silver syndrome are autosomal recessive and dominant forms (respec-tively) of complicated HSP in which lower extremity spasticity is associatedwith distal atrophy in the hands and feet [12–14]. The presence of significantmuscle wasting should prompt electrophysiologic analysis and considerationof motor neuron disease (such as amyotrophic lateral sclerosis); complicatedHSP syndromes associated with peripheral neuropathy or motor neuronop-athy [15–23], or co-existing disorders affecting the lower motor neuron.

Subjects with uncomplicated HSP do not demonstrate cranial nerve dis-turbance, bulbar muscle weakness, upper extremity weakness, significantmuscle wasting, fasciculations, peripheral neuropathy, or spinal sensorylevel. The presence of these signs should prompt careful search for alternatediagnoses or co-existing disorders. It would be appropriate to classify a sub-ject as having a ‘‘complicated’’ form of HSP if (a) additional neurologicsigns were present; (b) these signs were part of the inherited syndrome; and(c) no other cause for these signs could be found.

Prognosis

Although uncomplicated HSP does not shorten life span, most individ-uals experience insidiously progressive gait disturbance. Nonetheless, manyindividuals, particularly those for whom symptoms begin in childhood, donot appear to significantly worsen. For such individuals, spastic gait is a rela-tively nonprogressive disorder.

The age of symptom onset and degree of severity may vary widely withina given family; between families with the same genetic type of HSP; andbetween different genetic types of HSP. The occurrence of both mildlyaffected and more severely affected individuals within the same family mustbe considered when providing genetic counseling and when offering a prog-nosis at the time of diagnosis. A cautious wait-and-see approach is recom-mended, rather than assuming that an individual will have the samedegree of symptoms as his immediate relatives.

713J.K. Fink / Neurol Clin N Am 20 (2002) 711–726

Implications of diagnosing HSP

The diagnosis of HSP has important implications for the patient andtheir family. First, diagnosis of HSP indicates that the disorder is inherited.Depending on the mode of inheritance, siblings, children, and potentiallyparents would be considered at risk. The authors have observed a numberof families in which a child developed symptoms before their parents. It isimportant to use the term ‘‘hereditary’’ (rather than ‘‘presumed hereditary’’)only when there is clear family history of similarly affected relatives; or whena mutation in an HSP gene has been identified. Second, the diagnosis of‘‘uncomplicated’’ HSP carries the prognosis that although lower extremityspastic gait may worsen, there will be no involvement of upper extremities,speech, or swallowing. Third, the diagnosis of HSP indicates that there is nocurrent treatment to reverse, prevent, or retard the underlying diseaseprocess.

Laboratory evaluation

Routine laboratory studies including vitamin B12, serum long chain fattyacids, lactate, pyruvate, and routine cerebrospinal fluid examination arenormal in uncomplicated HSP.

Neuroimaging

Magnetic resonance imaging (MRI) of the spinal cord may be normal orshow atrophy particularly in thoracolumbar segments [24–27]. MRI of thebrain is usually normal in uncomplicated HSP. Some subjects with auto-somal recessive HSP linked to chromosome 15q have thin corpus callosum[28]. An estimated 50% of autosomal recessive HSP subjects have this ge-netic type of HSP.

Neurophysiologic evaluation

Electromyography and nerve conduction studies are usually normal inuncomplicated HSP [29–31]. Subclinical sensory neuropathy in otherwiseuncomplicated HSP has been described [32,33].

Somatosensory evoked potentials recorded from lower extremities oftenshow delayed conduction while those from the upper extremities are usuallynormal [31,34–37].

Cortical evoked potentials recorded from the lower extremities oftenshow reduced conduction velocity and amplitude of the evoked potential.Cortical evoked potentials recorded from cervical spinal segments are usu-ally normal or show only mildly reduced conduction velocity [34,38–41].


Muscle biopsy

Some subjects with autosomal recessive HSP due to paraplegin gene muta-tions (discussed below) showed ragged red fibers and cytochrome oxidase Cnegative fibers [42]. Muscle biopsies in autosomal dominant HSP linked tochromosomes 2p, 8q, 14q, and 15q have been normal [43].

Differential diagnosis

For most subjects, HSP is a diagnosis of exclusion. The differential diag-nosis of HSP [2,3] includes treatable disorders (including dopa-responsivedystonia [44,45], B12 deficiency, tethered cord syndrome, spinal cord com-pression, multiple sclerosis and tertiary syphilis). The differential diagnosisalso includes disorders whose prognosis is substantially different from un-complicated HSP. Such disorders include amyotrophic lateral sclerosis, pri-mary lateral sclerosis [46], spinal cord arteriovenous malformation, steadilyprogressive multiple sclerosis; leukodystrophies including Pelizaeus-Merz-bacher disease (X-linked), Krabbe disease (autosomal recessive), metachro-matic leukodystrophy (autosomal recessive), and adrenomyeloneuropathy(X-linked) [47–49]; and other degenerative neurologic disorders includingtropical spastic paraparesis [50,51], Machado-Joseph disease (spinocerebel-lar ataxia type 3) Friedreich’s ataxia [50], and lathryrism.

Neuropathology

Neuropathologic examination of HSP reveals axonal degeneration inthe spinal cord that is maximal in the terminal portions of the cortico-spinal tracts (in thoracolumbar region) and dorsal column fibers (in cervico-medullary region). Spinocerebellar fibers are involved to a lesser extent. Thedegree of myelin loss is consistent with primary axonal degeneration [52]rather than a primary demyelinating disease. Although usually normal,decreased numbers of cortical motor neurons and anterior horn cells havebeen reported [52,53]. Dorsal root ganglia, posterior roots and peripheralnerves are normal in uncomplicated HSP [53].

Genetic analysis

HSP shows extreme genetic heterogenity. Thus far, nine autosomal dom-inant, four autosomal recessive, and three X-linked HSP loci have been dis-covered. HSP loci (designated spastic paraplegia [SPG] loci) are numbered1 through 17 in order of their discovery (Table 1).

Various genetic forms of uncomplicated HSP are clinically very similarand cannot be distinguished reliably by clinical parameters alone. Genetictypes of uncomplicated HSP vary, however, in the average age at whichsymptoms begin. Gait disturbance for autosomal dominant uncomplicatedHSP linked to chromosomes 2p (SPG4), 2q (SPG13) 8 (SPG8), and 15 (SPG6)


Table

1

Her

edity

spast

icpara

ple

gia

(HSP)

loci

Spast

icgait

(SPG

)lo

cus

Chro

moso

me

HSP

syndro

me

Ref

eren

ces

Auto

som

aldom

inantH

SP

SPG

4(s

past

in)

2p22

Unco

mplica

ted

[54–56]

SPG

13

2q24-3

4U

nco

mplica

ted

[57]

SPG

88q23-q

24

Unco

mplica

ted

[58,5

9]

SPG

910q23.3

-q24.2

Com

plica

ted:sp

ast

icpara

ple

gia

ass

oci

ate

dw

ith

cata

ract

s

and

gast

roes

ophagea

lre

flux,and

moto

rneu

ronopath

y

[60]

SPG

17

11q12-q

14

Com

plica

ted:sp

ast

icpara

ple

gia

ass

oci

ate

dw

ith

am

yotr

ophy

ofhand

musc

les

(Silver

Syndro

me)

[61]

SPG

10

12q13

Unco

mplica

ted

[62]

SPG

3A

(atlast

in)

14q11-q

21

Unco

mplica

ted

[63–65]

SPG

615q11.1

Unco

mplica

ted

[66]

SPG

12

19q13

Unco

mplica

ted

[59]

Auto

som

alre

cess

ive

HSP

SPG

14

3q27-2

8C

om

plica

ted:sp

ast

icpara

ple

gia

ass

oci

ate

dw

ith

men

tal

reta

rdation

and

dista

lm

oto

rneu

ropath

y

[21]

SPG

58q

Unco

mplica

ted

[67]

SPG

11

15q

Unco

mplica

ted

or

com

plica

ted:variably

ass

oci

ate

dw

ith

HSP

ass

oci

ate

dw

ith

thin

corp

us

callosu

m,m

enta

lre

tard

ation,

upper

extr

emity

wea

knes

s,dysa

rthria,and

nyst

agm

us

[68]


SPG

7(p

ara

ple

gin

)16q

Unco

mplica

ted

or

com

plica

ted:variably

ass

oci

ate

dw

ith

mitoch

ondrialabnorm

alities

on

skel

etalm

usc

lebio

psy

and

dysa

rthria,dysp

hagia

,optic

disc

pallor,

axonalneu

ropath

y,

and

evid

ence

of‘‘vasc

ula

rle

sions’’,

cere

bel

lar

atr

ophy,or

cere

bra

latr

ophy

on

crania

lM

RI

[42,6

9]

SPG

15

14q

Com

plica

ted:sp

ast

icpara

ple

gia

ass

oci

ate

dw

ith

pig

men

ted

macu

lopath

y,dista

lam

yotr

ophy,dysa

rthria,m

enta

l

reta

rdation,and

furt

her

inte

llec

tualdet

erio

ration.

[70]

X-lin

ked

HSP

SPG

1(L

1C

AM

)X

q28

Com

plica

ted:ass

oci

ate

dw

ith

men

talre

tard

ation,and

variably

,

hydro

cephalu

s,aphasia,and

adduct

edth

um

bs

[71]

SPG

2

(Pro

teolipopro

tein

)

Xq28

Com

plica

ted:variably

ass

oci

ate

dw

ith

MR

Iev

iden

ce

ofC

NS

white

matt

erabnorm

ality

[72–74]

SPG

16

Xq11.2

Unco

mplica

ted

[75]

Com

plica

ted:ass

oci

ate

dw

ith

moto

raphasia,re

duce

dvisio

n,

mild

men

talre

tard

ation,and

dysf

unct

ion

ofth

ebow

el

and

bla

dder

[76]


begins on average after age 20. In contrast, symptoms begin on averagebefore age 11 in subjects with HSP linked to chromosomes 12 (SPG10),14 (SPG3), and 19 (SPG12) [4]. It is important to note, however that there isoverlap in the age of symptom onset in different genetic forms of HSP. Thisis particularly true for the most common forms of dominantly inherited HSP(linked to chromosome 2p locus (due to spastin mutations) in which diseaseonset occurs in early childhood or late adulthood). This overlap limits theability to predict the genetic type of uncomplicated HSP by knowing the ageof symptom onset in only several affected individuals within a given family.

The most common types of dominantly inherited uncomplicated HSP arethose linked to the SPG4 locus on chromosome 2p (approximately 45%) andthose linked to the SP3A locus on chromosome 14q (approximately 10%)[3,77,78]. Each of the other types of autosomal dominant HSP have beenreported in only one to several kindreds. Approximately 50% of autosomalrecessive HSP kindreds are linked to the SPG11 locus on chromosome15q13-q15 [28]. Each of the other types of autosomal recessive HSP (linkedto the SPG5 locus on chromosome 8p11-q13 and the SPG7 locus on chro-mosome 16q24.3) have been described in only a few kindreds.

Genes have been identified for the most common forms of autosomaldominant HSP (linked to chromosome 2p and chromosome 14q), a rare auto-somal recessive form (linked to chromosome 16q); and two forms of X-linkedcomplicated HSP.SPG4 (which codes for ‘‘spastin’’) gene mutations cause the most common

form (approximately 45%) of autosomal dominant HSP (linked to the SPG4locus on chromosome 2p) [54]. Spastin’s function is unknown, althoughpredicted to be involved assembly or function of nuclear protein complexes[54]. Spastin may also interact with a and b tubulin [79]. More than 40 SPG4mutations have been identified [54,55,80–86] and are predicted cause loss ofspastin function (haploinsufficiency) rather than act through a gain of‘‘dominant negative’’ function. Nearly all mutations are uniquely present inthe family in which they are discovered, making genetic testing very difficult.

Zhao et al [63] identified mutations in a novel GTPase (designated ‘‘atlas-tin’’) as the cause of autosomal dominant HSP linked to the SPG3A locuson chromosome 14q. Alvarado et al [87] observed mutations in this genein 25% of childhood onset, dominantly inherited uncomplicated HSP. Nei-ther the true function of atlastin nor the mechanisms by which mutations inthis gene cause HSP are known at this time.

SPG7 gene mutations cause a rare form of autosomal recessive HSP(linked to chromosome 16q). (DeMichele et al, 1998) [88] SPG7 encodesparaplegin, a nuclear-encoded mitochondrial protein highly homologousto several yeast metalloproteases which have both proteolytic and chaper-one activities [88,89]. Some but not all subjects with autosomal recessiveHSP due to SPG7 gene mutations have abnormal mitochondria (raggedred fibers and cytochrome C oxidase negative fibers) on skeletal musclebiopsy. While some SPG7 autosomal recessive HSP subjects had an


‘‘uncomplicated’’ HSP syndrome, others also had dysarthria, dysphagia,optic disc pallor, axonal neuropathy, and evidence of ‘‘vascular lesions’’,cerebellar atrophy, or cerebral atrophy on cranial MRI [42].

Proteolipid protein is an intrinsic myelin protein. PLP gene mutationscause both Pelizaeus-Merzbacher disease [90], an x-linked infantile-onsetdysmyelinating disorder; and a childhood onset slowly progressive spasticgait disorder (X-linked HSP) [91]. The basis for this phenotypic variationis not fully understood [90]. Both early-onset severe, and more slowly pro-gressive phenotypes have occurred in the same family as well as in unrelatedindividuals with the same PLP mutation (F. Cambi, JK Fink, unpublishedobservation). Subjects with X-linked HSP due to PLP mutation may haveMRI evidence of abnormal white matter in the brain or spinal cord [26,92,93].

Neural cell adhesion molecule (L1CAM) gene mutations cause severaldevelopmental neurologic disorders including X-linked spastic paraplegia[94], X-linked hydrocephalus; and mental retardation, aphasia, shufflinggait, adducted thumbs (MASA) syndrome; and CRASH syndrome (corpuscallosum hypoplasia, retardation, adducted thumbs, spastic paraparesis andhydrocephalus) [94–96].

Laboratory testing for mutations in known HSP genes

Laboratory testing for spastin gene mutations, the cause of approxi-mately 45% of dominantly inherited uncomplicated HSP is available throughcommercial laboratories. This information can be used to confirm the clinicaldiagnosis of HSP and for genetic counseling for this form of HSP. PLP geneanalysis is available commercially although is usually limited to detection ofPLP gene duplication (the common cause of Pelizaeus-Merzbacher disease)and thus may not detect all disease-causing PLP gene mutations. Testing formutations in the SPG3A (Atlastin), SPG7 (paraplegin) and L1CAM genes isperformed only in research laboratories and is not yet available for routineclinical diagnostic purposes.

Genetic counseling

Autosomal dominant HSP is transmitted as a single-gene disorder withvery high, age-dependent penetrance (70–85%) [78]. Genetic counseling mustconsider that there may be significant variability in the age at which symp-toms begin and the extent to which symptoms are disabling [77]. Individualswith steadily progressive, severe paraplegia and those with mild non-dis-abling gait disturbance may co-exist in the same families. A comprehensive,detailed family history is crucial to providing the best genetic counselingto affected families. For many HSP families, however, there may be too fewaffected subjects to determine the range of ages at which symptoms begin,the range of severity of symptoms and the age above which a subject canbe considered at low risk of developing HSP.


Caution must be observed when providing genetic counseling to smallfamilies in which young children are affected with HSP but the parents arenot affected. The disorder in such families could be recessively inherited(with 25% chance that subsequent progeny will be affected). It is also possi-ble that the disorder is dominantly inherited but exhibits extremely variableseverity or wide range of age of symptom onset. We have encountered anumber of families in which children were affected before their parents. Suchgenetic anticipation has been reported for chromosome 2q-linked HSP [97],but was not related to trinucleotide repeat expansion.

Very little reliable genetic counseling can be provided to individuals whohave all signs and symptoms of uncomplicated HSP and for whom otherdisorders have been excluded but who do not have family history of the dis-order. We classify such subjects as having ‘‘apparently sporadic’’ spasticparaplegia. The empiric risk of disease occurrence in first-degree relativesof such subjects is not known. Some of these subjects could have recessivelyinherited HSP. Their siblings would be at 25% risk of developing similarsymptoms [51,98]. Autosomal dominant HSP could also be ascertained asan apparently sporadic disorder, with the absence of other affected relativesdue to incomplete family ascertainment, variable age of symptom onset(including very late onset in which mild gait disturbance was unrecognizedor attributed to other causes), mistaken paternity, or new mutation. Thepossibility that some subjects with apparently sporadic spastic paraplegiacould have autosomal recessive disease and others with autosomal dominantdisease limits the ability to provide accurate prediction about the risk oftransmitting the disorder to progeny. Evaluation of the spastin gene (andatlastin, paraplegin, proteolipid protein genes and other HSP genes as theybecome available) will help diagnose the disorder and provide genetic coun-seling to subjects with apparently sporadic spastic paraplegia and others forwhom the mode of inheritance is unclear.

Treatment

At present, only symptomatic treatments are available. Muscle spas-ticity may be reduced with physical therapy and medications such asLioresal, (Norvartis Pharmaceuticals, East Hanover, NJ) (oral or intra-thecal), Dantrolene, (Procter & Gamble Pharmaceuticals, Cincinnati, OH)or Tizanidine, (Elan Pharmaceuticals, South San Francisco, CA) [99–101].Oxybutynin, (Alza Corp., Mountain View, CA) chloride is useful to reduceurinary urgency. The author advocates regular physical exercise directedtoward lower extremity muscle stretching and strengthening and to im-proved cardiovascular fitness. Individuals who participate regularly in theseactivities consistently report increased strength, increased endurance, anddecreased fatigue.


Summary

The hereditary spastic paraplegias are a large group of clinically similardisorders. Seventeen different HSP loci have been discovered thus far.Different genetic forms of uncomplicated HSP are clinically very similar.Except for the average age at which symptoms appear, different genetictypes of uncomplicated HSP cannot be distinguished reliably by clinicalparameters alone.

For most subjects, HSP is a diagnosis of exclusion. The differential diag-nosis includes treatable disorders as well as those for which the prognosis isquite different from HSP. Even with the emerging availability of laboratorytesting for HSP gene mutations, it is still essential that alternative disordersbe excluded by careful history, examination, laboratory studies, neuroimag-ing, and neurophysiologic evaluation. Uncomplicated HSP is due to axonaldegeneration at the ends of the longest motor (corticospinal tract) and sen-sory (dorsal column fibers) in the spinal cord. The observation that someforms begin in childhood and are essentially nonprogressive while otherforms begin in adulthood and are slowly progressive raises the possibilitythat some forms of HSP (eg; those associated with LICAM gene mutationsand possibly those due to SPG3A mutations) are neurodevelopmental dis-orders; and other forms are truly neurodegenerative disorders. The mecha-nisms by which spastin, atlastin, and paraplegin mutations cause axonaldegeneration that results in clinically similar forms of HSP are not known.Nonetheless, the identification of these genes and the ability to generate ani-mal models of these forms of HSP will permit direct exploration of themolecular basis of HSP.

References

[1] Strumpell A. Die primaere Seitenstrangsklerose (spastischeSpinalparalyse). Dtsch Z

Nervenheilk 1904;27:291–339.

[2] Fink JK. Hereditary spastic paraplegia, Emery & Rimoin’s Principles and Practice of

Medical Genetics. In: Rimoin D, Pyeritz R, Connor J, Korf B, editors. London: Harcourt

Publishers Limited, UK; 2001.

[3] Fink JK, Heiman-Patterson T, Bird T, Cambi F, Dube M-P, Figlewicz DA, et al. Heredi-

tary spastic paraplegia: advances in genetic research. Neurology 1996;46:1507–14.

[4] Fink JK, Hedera P. Hereditary spastic paraplegia: Genetic heterogeneity and genotype-

phenotype correlation. Semin Neurol 1999;19:301–10.

[5] Heinzlef O, Paternotte C, Mahieux F, Prud’homme JF, Madigand M, Pouget J, et al.

Mapping of a complicated familial spastic paraplegia to locus SPG4 on chromosome 2p.

J Med Genet 1998;35:89–93.

[6] Lizcano-Gil LA, Garcia-Cruz D, Bernal-Beltran MdP, Hernandez A: Association of late

onset spastic paraparesis and dementia: Probably an autosomal dominant form of compli-

cated paraplegia. Am J Med Genet 1997;68:1–6.

[7] Webb S, Coleman D, Byrne P, Parfrey N, Burke T, Hutchinson J, et al. Autosomal

dominant hereditary spastic paraparesis with cognitive loss linked to chromosome 2p.

Brain 1998;121:601–9.


[8] Byrne PC, Webb S, McSweeney F, Burke T, Hutchinson M, Parfrey N. Linkage of AD HSP

and cognitive impairment to chromosome 2p: haplotype and phenotype analysis indicates

variable expression and low or delayed penetrance. Eur J Human Genet 1998;6:275–82.

[9] Reid E, Grayson C, Rubinsztein DC, Rogers MT, Rubinsztein JS. Subclinical cognitive

impairment in autosomal dominant �pure� hereditary spastic paraplegia. J Med Genet

1999;36:797–8.

[10] Tedeschi G, Allocca S, DiCostanzo A, Carlomagno S, Merla F, Petretta V, et al. Multi-

system involvement of the central nervous system in Strumpell’s disease. A neurophysio-

logical and neuropsychological study. J Neurol Sci 1991;103:55–60.

[11] Fink JK. Progressive spastic paraparesis: hereditary spastic paraplegia and it’s relation to

primary and amyotrophic lateral sclerosis. Semin Neurol 2001;21:199–208.

[12] Cross HE, McKusick VA. The Troyer syndrome. A recessive form of spastic paraplegia

with distal muscle wasting. Arch Neurol 1967;16:473–85.

[13] Farag TI, El-badramany MH, Al-Sharkawy S. Troyer Syndrome: report of the first ‘‘non-

Amish’’ sibship and review. Am J Med Genet 1994;52:383–5.

[14] Silver JR. Familial spastic paraplegia with amyotrophy of the hands. Ann Hum Genet.

London 1966;30:69–73.

[15] Antinolo G, Nieto M, Borrego S, Sierra J, Rufo M, Siljestrom ML. Familial spastic para-

plegia with neuropathy and poikiloderma. A new syndrome? Clin Genet 1992;41:281–4.

[16] Matthys JH. De la -araplegie spasmodique de strumpell-lorrain a l’amyotrophie de

Charcot-Marie-Tooth. J Genet Hum 2000;10:326–37.

[17] McKusick VA. Catalogs of Autosomal Dominant, Autosomal Recessive, and X–Linked

Phenotypes, Anonymous, 1994.

[18] Thomas PK, Misra VP, King RHM, Muddle JR, Wroe S, Bhatia KP, et al. Autosomal

recessive hereditary sensory neuropathy with spastic paraplegia. Brain 1994;117:651–9.

[19] Cavanagh NPC, Eames RA, Galvin RJ, Brett EM, Kelly RE. Hereditary sensory

neuropathy with spastic paraplegia. Brain 1979;102:79–84.

[20] Stewart RM, Tunell G, Ehle A. Familial spastic paraplegia, peroneal neuropathy, and

crural hypopigmentation: A new neurocutaneous syndrome. Neurology 1981;31:754–7.

[21] Vazza GZM, Boaretto F, Micaglio GF, Sartori V, Mostacciuolo ML. A New Locus for

Autosomal Recessive Spastic Paraplegia Associated with Mental Retardation and Distal

Motor Neuropathy SPG14, Maps to Chromosome 3q27-q28. Am J Hum Genet 2000;

67:504–9.

[22] Serena M, Rizzuto N, Moretto G, Arrigoni G. Familial spastic paraplegia with peroneal

amyotrophy. A family with hypersensitivity to pyrexia. Ital J Neurol Sci 1989;11:583–8.

[23] Neuhauser G, Wiffler C, Opitz JM. Familial spastic paraplegia with distal muscle wasting

in the Old Order Amish; atypical Troyer syndrome or ‘‘new’’ syndrome. Clin Genet 1976;

9:315–23.

[24] Durr A, Brice A, Serdaru M, Rancurel G, Derouesne C, Lyon-Caen O, et al. The

phenotype of ‘‘pure’’ autosomal dominant spastic paraplegia. Neurology 1994;44:1274–7.

[25] Krabbe K, Nielsen JE, Fallentin E, Fenger K, Herning M. MRI of autosomal dominant

pure spastic paraplegia. Neuroradiology 1997;39:724–7.

[26] Cambi F, Tartaglino L, Lublin FD, McCarren D. X-linked pure familial spastic para-

paresis: characterization of a large kindred with magnetic resonance imaging studies.

Arch Neurol 1995;52:665–9.

[27] Hedera P, Rainier S, Zhao X, Trobe J, Wald J, Eldevik OP, Kluin K, Fink JK. Spastic

paraplegia, ataxia, mental regardation (SPAR): a novel genetic disorder. (Abstract). Am

J Hum Genet 1999;65:(suppl):A7.

[28] Martinez-Murillo FM, Kobayashi H, Pegoraro E, Galluzzi G, Creel G, Mariani C, et al.

Genetic localization of a new locus for recessive familial spastic paraparesis to 15q13–15.

Neurology 1999;53:50–6.

[29] Mcleod JG, Morgan JA, Reye C. Electrophysiological studies in familial spastic para-

plegia. Neurol Neurosurg Psychiatry 1993;40:611–5.


[30] Owens LA, Peterson CR. Familial spastic paraplegia: A clinical and electrodiagnostic

evaluation. Arch Phys Med Rehabil 1982;63:357–61.

[31] Dimitrijevic MR, Lenman JAR, Prevec T, Wheatly K. A study of posterior column

function in familial spastic paraplegia. J Neurol, Neurosurg. Psych 1982;45:46–9.

[32] Schady W, Scheard A. A qualitative study of sensory functions in hereditary spastic

paraplegia. Brain 1990;113:709–20.

[33] Schady W, Smith DI. Sensory neuropathy in hereditary spastic paraplegia. J Neurol

Neurosurg Psychiatr 1994;57:693–8.

[34] Pelosi L, Lanzillo B, Perretti A. Motor and somatosensory evoked potentials in hereditary

spastic paraplegia. J Neurol Neurosurg Psychiatry 1991;54:1099–102.

[35] Pedersen L, Trojaborg W. Visual, auditory and somatosensory pathway involvement in

hereditary cerebellar ataxia, Friedreich’s ataxia and familial spastic paraplegia. Electro-

encephalogr Clin Neurophys 1981;52:283–97.

[36] Uncini A, Treviso M, Basciani M, Gambi D. Strumpell’s familial spastic paraplegia:

an electrophysiological demonstration of selective central distal axonopathy. Electro-

encephalogr Clin Neurophys 1987;66:132–6.

[37] Battistella PA, Suppiej A, Mandara V. Evoked potentials in familial spastic paraplegia:

description of three brothers and review of the literature. Giorn Neuropsi Evol 1997;

17:201–12.

[38] Claus D, Waddy HM, Harding AE. Hereditary motor and sensory neuropathies and

hereditary spastic paraplegia: a magnetic stimulation study. Ann Neurol 1990;28:43–9.

[39] Claus D, Jaspert A. Central motor conduction in hereditary spastic paraparesis

(Strumpell’s disease) and tropical spastic paraparesis. Neurol Croatica 1995;44:23–31.

[40] Polo JM, Calleja J, Combarris O, Berciano J. Hereditary ‘‘pure’’ spastic paraplegia:

a study of nine families. J Neurol Neurosurg Psychiatry 1993;56:175–81.

[41] Schady W, Dick JP, Sheard A, Crampton S. Central motor conduction studies in

hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 1991;54:775–9.

[42] DeMichele G, DeFusco M, Cavalcanti F, Filla A, Marconi R, Volpe G, et al. A new locus

for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3. Am

J Hum Genet 1998;63:135–9.

[43] Hedera P, DiMauro S, Bonilla E, Wald J, Eldevik OP, Fink JK. Phenotypic analysis of

autosomal dominant hereditary spastic paraplegia linked to chromosome 8q. Neurology

1999;53:44–50.

[44] Nygaard TG. Dopa-responsive dystonia: clinicala, pathological, and genetic distinction

from juvenile parkinsonism. In: Segawa M, Nomura Y, Basel, Karger, editors. Monogr

Neural Sci. vol 14. Age-related dopamine-dependent disorders 1995. p. 109–19.

[45] Fink JK, Barton N, Cohen W, Lovenberg W, Burns RS, Hallett M. Dystonia with

marked diurnal variation associated with biopterin deficiency. Neurology 1988;38:707–11.

[46] Rabin BA, Griffin JW, Crain BJ, Scavina M, Chance PF, Cornblath DR. Autosomal

dominant juvenile amyotrophic lateral sclerosis. Brain 1999;122:1539–50.

[47] O’Neill BP, Swanson JW, Brown IFR, Griffin JW, Moser HW. Familial spastic para-

paresis: An adrenoleukodystrophy phenotype? Neurology 1985;35:1233–5.

[48] Maris T, Androulidakis EJ, Tzagournissakis M, Papavassilious S, Moser H, Plaitakis A.

X-linked adrenoleukodystrophy presenting as neurologically pure familial spastic para-

paresis. Neurology 1994;45:1101–4.

[49] Gudesblatt M, Moser H, Plaitakis A: Dominantly inherited familial spastic paraplegia

through 3 generations as a manifestation due to adrenoleukodystrophy, (Abstract).

Neurology 1995;45:A440.

[50] Matsumura R, Takayanagi T, Fujimoto Y, Murata K, Mano Y, Horikawa H, et al. The

relationship between trinucleotide repeat length and phenotypic variation in Machado-

Joseph disease. J Neurol Sci 1996;139:52–7.

[51] Salazar-Grueso EF, Roos RP, Wollmann R, Gutierrez R, Dawson G: HTLV-I Infection

AssociatedwithaFamilial SpasticParaparesis Syndrome.AnnNeurol 26:1521989 (Abstract).


[52] Behan W, Maia M. Strumpell’s familial spastic paraplegia: genetics and neuropathology.

J Neurol Neurosurg Psychiatry 1974;37:8–20.

[53] Harding AE. Hereditary spastic paraplegias. Semin Neurol 1993;13:333–6.

[54] Hazan J, Fonknechten N, Mavel D, Paternotte C, Samson D, Artiguenave F, et al.

Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant

spastic paraplegia. Nat Genet 1999;23:296–303.

[55] Hazan J, Fontaine B, Bruyn RPM, Lamy C, Van deutekom JCT, Rime CS, Durr A,

Melki J, Lyoncaen O, Agid Y, Munnich A, Padberg GW, Derecondo J, Frants RR,

Brice A, Weissenbach J. Linkage of a new locus for autosomal dominant familial

spastic paraplegia to chromosome 2p. Hum Mol Genet 1994;3:1569–73.

[56] Hentati A, Pericak-Vance MA, Lennon F, Wasserman B, Hentati F, Juneja T, et al.

Linkage of the late onset autosomal dominant familial spastic paraplegia to chromosome

2p markers. Hum Molec Genet 1994;3:1867–71.

[57] Fontaine B, Davoine C-S, Durr A, Paternotte C, Feki I, Weissenbach J, et al. A new locus

for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34. Am J Hum

Genet 2000;66:702–7.

[58] Hedera P, Rainier S, Alvarado D, Zhao X, Williamson J, Otterud BE, et al. Novel locus

for autosomal dominant hereditary spastic paraplegia on chromosome 8q. Am J Hum

Genet 1999;64:563–9.

[59] Reid E, Dearlove AM, Osborn M, Rogers T, Rubinsztein DC. A Locus for Autosomal

Dominant ‘‘Pure’’ Hereditary Spastic Paraplegia Maps to Chromosome 19q13. Am J

Hum Genet 2000;66:728–32.

[60] Seri M, Cusano R, Forabosco P, Cinti R, Caroli F, Picco P, et al. Genetic mapping to

10q23.3-q24.2, in a large Italian pedigree, of a new syndrome showing bilateral cataracts,

gastroesophageal reflux, and spastic paraparesis with amyotrophy. Am J Hum Genet

1999;64:586–93.

[61] Patel H, Hart PE, Warner TT, Houlston RS, Patton MA, Jeffery S, et al. The silver

syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12-q14, with

evidence for genetic heterogeneity within this subtype. Am J Hum Genet 2001;69:209–15.

[62] Reid E, Dearlove AM, Rhodes M, Rubinsztein DC. A new locus for autosomal dominant

�pure� hereditary spastic paraplegia mapping to chromosome 12q13 and evidence for

further genetic heterogeneity. Am J Hum Genet 1999;65:757–63.

[63] Zhao X, Alvarado D, Rainier S, Lemons R, Hedera P, Weber C, et al. Mutations in a novel

GTPase cause autosomaldominanthereditary spastic paraplegia.NatGenet 2001;29:326–31.

[64] Hazan J, Lamy C, Melki J, Munnich A, de Recondo J, Weissenbach J. Autosomal

dominant familial spastic paraplegia is genetically heterogeneous and one locus maps to

chromosome 14q. Nat Genet 1993;5:163–7.

[65] Paternotte C, Rudnicki D, Fizames C, Davoine C-S, Mavel D, Durr A, et al. Quality

assessment of whole genome mapping data in the refined familial spastic paraplegia

interval on chromosome 14q. Genome Res 1998;8:1216–27.

[66] Fink JK, Wu C-TB, Jones SM, Sharp GB, Lange BM, Lesicki A, et al. Autosomal

dominant familial spastic paraplegia: tight linkage to chromosome 15q. Am J Hum Genet

1995;56:188–92.

[67] Hentati A, Pericack-Vance MA, Hung W-Y, Belal S, Laing N, Boustani RM, et al.

Linkage of the ‘‘pure’’ recessive familial spastic paraplegia to chromosome 8 markers and

evidence of genetic locus heterogeneity, (Abstract). Hum Genet 1993;53:1013.

[68] Martinez-Murillo F, Kobayashi H, Pegoraro E, Galluzzi G, Cree G, Mariani C, Farina E,

Marks H, Ricci E, Alfonso G, Pauli R, Hoffman EP. Genetic localization of a new locus

for recessive spastic paraplegia to 15q13-15. Am J Hum Genet 1998;(Suppl).

[69] Garner CC, Garner A, Huber G, Kozak C, Matus A. Molecular cloning of micro-

tubule-associated protein 1 (MAP1A) and microtubule-associated protein 5 (MAP1B):

identification of distinct genes and their differential expression in developing brain.

J Neurochem 1990;55:146–54.


[70] Hughes CA, Byrne PC, Webb S, McMonagle P, Patterson V, Hutchinson M, et al.

SPG15, a new locus for autosomal recessive complicated HSP on chromosome 14q.

Neurology 2001;56:1230–3.

[71] Jouet M, Rosenthal A, Armstrong G, MacFarlane J, Stevenson R, Paterson J, et al.

X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result

from mutations in the L1 gene. Nat Genet 1994;7:402–7.

[72] Kobayashi H, Hoffman EP, Marks HG. The rumpshaker mutation in spastic paraplegia.

Nat Genet 1994;7:351–2.

[73] Saugier-Veber P, Munnich A, Bonneau D, Rozet J-M, LeMerrer M, Gil R, et al. X-linked

spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid

protein locus. Nat Genet 1994;6:257–62.

[74] Cambi F, Tang XM, Cordray P, Fain PR, Keppen LD, Barker DF. Refined genetic

mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic

paraplegia. Neurology 1996;46:1112–7.

[75] Steinmuller R, Lantingua-Cruz A, Carcia-Garcia R, Kostrzewa M, Steinberger D,

Muller U. Evidence of a third locus in X-linked recessive spastic paraplegia. [letter] Hum

Genet 1997;100:287–9.

[76] Tamagaki A, Shima M, Tomita R, Okumura M, Shibata M, Morichika S, et al. Segre-

gation of a pure form of spastic paraplegia and NOR insertion into Xq11.2. Am J Med

Genet 2000;94:5–8.

[77] Fonknecten J, Mavel D, Byrne P, Davoine CS, Cruaud C, Boentsch D, et al. Spectrum

of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet 2000;9:

637–44.

[78] Durr A, Davoine C-S, Paternotte C, von Fellenberg J, Cogilnicean S, Coutinho P, et al.

Phenotype of autosomal dominant spastic paraplegia linked to chromosome 2. Brain

1996;119:1487–96.

[79] Azim AC, Hentati A, Haque MFU, Hirano M, Ouachi K, Siddique T. Spastin, a new

AAA protein, binds to a and b tubulins. Am J Hum Genet 2000;67:(suppl):197.

[80] White KD, Ince PG, Lusher M, Lindsey J, Cookson M, Bashir R, et al. Clinical and

pathologic findings in hereditary spastic paraparesis with spastin mutation. Neurology

2000;55:89–94.

[81] Santorelli FM, Patrono C, Fortini D, Tessa A, Comanducci G, Bertini E, et al.

Intrafamilial variability in hereditary spastic paraplegia associated with an SPG4 gene

mutation. Neurology 2000;55:702–5.

[82] Hentati A, Deng H-X, Zhai BA, Chen W, Yang Y, Hung W-Y, et al. Novel mutations in

spastin gene and absence of correlation with age at onset of symptoms. Neurology 2000;

55:1388–90.

[83] Svenson IK, Ashley-Koch AE, Gaskell PC, Riney TJ, Warner C, et al. Mutation analysis

of the spastin gene in hereditary spastic paraplegia s type 4–evidence of aberrant transcript

splicing caused by mutations in concanionical splice site sequences. Am J Hum Genet

2000;67(suppl 2):375.

[84] Martinez-Murillo F, Choudhn A, Devaney J, Marino M, Hoffman EP. Genotype/

Phenotype correlations in 60 spastic paraparesis families, (Abstract). Am J Hum Genet

2000;67(suppl 2):351.

[85] Lindsey JC, Lusher ME, McDermott CJ, White KD, Reid E, Rubinzstein DC, et al.

Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic para-

paresis. J Med Genet 2000;37:759–65.

[86] Burger JJ, Fonknechten N, Hoeltzenbein M, Neumann L, Hazan J, Reis A: Hereditary

Spastic Paraplegia caused by mutations in the SPG4 gene, (Abstract). Am J Hum

2000;67:372.

[87] Alvarado DM, Ming L, Hedera P, Rainier S, Zhao X, Raskind W, Bird T, Fink JK:

Atlastin gene analysis in early onset hereditary spastic paraplegia, (Abstract). Am J Hum

Genet 2001;69:597.


[88] Casari G, Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, et al. Spastic

paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-

encoded mitochondrial metalloprotease. Cell 1998;93:973–83.

[89] Settasatian C, Whitmore SA, Crawford J, Bilton RL, Cleton-Jansen AM, Sutherland GR,

et al. Genomic structure and expression analysis of the spastic paraplegia gene, SPG7.

Hum Genet 2000;105:139–44.

[90] Hodes ME, Zimmerman AW, Aydanian A, Naidu S, Miller NR, Garcia Oller JL, et al.

Different mutations in the same codon of the proteolipidprotein gene, PLP, may help in

correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic

paraplegia (PMD/SPG2). Am J Med Genet 1999;82:132–9.

[91] Willard HF, Riordan JR. Assignment of the gene for myelin proteolipid protein to the X

chromosome: implications for X-linked myelin disorders. Science 1985;230:940–2.

[92] Woodward K, Kendall E, Vetrie D, Malcolm S. Pelizaeus-Merzbacher disease: identi-

fication of Xq22 proteolipid-protein duplications and characterization of breakpoints

by interphase FISH. Am J Hum Genet 1998;63:207–17.

[93] Hentati A. Contribution a’ le’tude des paraplegies spasmodiques et familiales pures

(Strumpell-Lorrain) et associ’ed en Tunisie. Thesis for doctorate in Medicine. Faculte’ de

Medicine de sfax (Tunisia) 1989.

[94] Jouet M, Rosenthal A, Armstrong G, MacFarlane J, Stevenson R, Patterson J, et al.

X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result

from mutations in the L1 gene. Nat Genet 1994;7:402–7.

[95] Fryns JP, Spaepen A, Cassiman JJ, van den Boorn N. X-linked complicated spastic

paraplegia, MASA syndrome, and X-linked hydrocephaly due to congenital stenosis of

the aqueduct of Sylvius: a variable expression of the same mutation at Xq28. J Med Genet

1991;28:429–31.

[96] Fransen E, Lemmon V, Van Camp G, Vits L, Coucke P, Willems PJ. Crash syndrome:

clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic

paraparesis and hydrocephalus due to mutations in one singe gene, L1. Eur J Human

Genet 1995;3:273–84.

[97] Nielsen JE, Koefoed P, Abell K, Hasholt L, Eiberg H, Fenger K, et al. CAG repeat

expansion in autosomal dominant pure spastic paraplegia linked to chromosome 2p21-

p24. Hum Molec Genet 1997;6:1811–6.

[98] Salazar-Grueso EF, Holzer TJ, Gutierrez RA, Casey JM, Desai SM, Devare SG, et al.

Familial spastic paraparesis syndrome associated wity HTLV-I infection. New Engl J

Med 1990;323:732–7.

[99] Dan B, Bouillot E, Bengoetxea A, Cheron G. Effect of intrathecal baclofen on gait control

in human hereditary spastic paraparesis. Neuro Lett 2000;280:176–8.

[100] Meythaler JM, Steers WD, Tuel SM, Cross LL, Sesco DC, Haworth CS. Intrathecal

Baclofen in hereditary spastic paraparesis. Arc Phys Med Rehabil 1992;73:794–7.

[101] Van Schaeybroeck P, Nuttin B, Lagae L, Schrijvers E, Borghgraef C, Feys P. Intrathecal

Baclofen for intractable cerebral spasticity: A prospective placebo-controlled, double-

blind study. Neurosurgery 2000;46:603–12.


hereditary spastic paraplegia

Documents