Genetic Anticipation in a Large Family With PureAutosomal Dominant Hereditary Spastic Paraplegia

T.F. Thurmon,1 Ching He,2 Carroll Haskell,2 Patricia Thorpe,2 S.G. Thurmon,1 and D.R. Rosen2*1Department of Pediatrics, Louisiana State University School of Medicine, Shreveport, Louisiana2Laboratory of Human Genetics, Wadsworth Center for Laboratories and Research, New York State Department ofHealth, Albany, New York

We have reinvestigated a large kindredidentified over 25 years ago segregating fora form of pure autosomal dominant heredi-tary spastic paraplegia (HSP). We have ex-amined additional relatives in order to re-fine the clinical and genetic characteristicsof this disorder, and performed an analysisto determine if anticipation is present inthis family. Analysis of onset ages in parent-to-child transmissions of HSP is consistentwith anticipation. These results providesupport for dynamic mutation as the under-lying mechanism of this form of HSP, andsuggest a trinucleotide repeat instability oc-curring primarily in the female germ line.Am. J. Med. Genet. 83:392–396, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: genetic anticipation; dy-namic mutation; trinucleo-tide repeat; spastic paraple-gia

INTRODUCTION

The hereditary spastic paraplegias (HSPs; Strumpelldisease) are a set of clinically similar disorders charac-terized by progressive weakness and spasticity of thelower limbs [Harding, 1990, 1993; Fink, 1997]. Thecommon pathogenesis of the spastic paraplegias is de-generation of corticospinal motor neurons. When lim-ited solely to motor neuron involvement, the spasticparaplegia is said to be “pure” or “uncomplicated” [Har-ding, 1993; Fink, 1997; Reid, 1997]. Clinical signs ofpure spastic paraplegia typically include spastic gait,

hyperreflexia, and a Babinski response. Proprioceptionimpairment and sphincter muscle dysfunction mayalso be present. When the spastic paraplegia is accom-panied by other neurological symptoms, such as reti-nopathy, deafness, or mental retardation, the disorderis classified as “complicated” [Harding, 1993; Fink,1997; Online Mendelian Inheritance in Man (OMIM),1996] (MIM number 312920). Age of onset, rate of pro-gression, and range of associated symptoms for theHSPs can be highly variable, even within a single fam-ily [Harding, 1993; Fink, 1997].

The HSPs are heterogeneous. X-linked recessive[Keppen et al., 1987], autosomal recessive [Hentati etal., 1994a], and autosomal dominant [Hentati et al.,1994b] forms have been described. Genes for two formsof X-linked spastic paraplegia have been identified:L1CAM, at Xq28 [Jouet et al., 1994], and myelin pro-teolipid protein (PLP), at Xq21 [Saugier-Veber et al.,1994]. In addition to causing spastic paraplegia, muta-tions in L1 CAM are also associated with MASA syn-drome (mental retardation, aphasia, shuffling gait, andadducted thumbs) [OMIM, 1996] (MIM numbers312920, 600146) [Hazan et al., 1993] and X-linked hy-drocephalus [Hentati et al., 1994b]. Similarly, muta-tions of PLP can cause spastic paraplegia and Peliza-eus-Merzbacher disease [OMIM, 1996] (MIM number312900). Both of the X-linked spastic paraplegia genesencode functions essential for the normal structure andfunction of neurons.

Genes that, when mutated, cause the autosomalforms of spastic paraplegia have been geneticallymapped, but not yet identified. A gene for autosomalrecessive spastic paraplegia has been mapped to chro-mosomal area 8q12-13 (SPG5) [Hentati et al., 1994a].Three genes underlying autosomal dominant HSP havebeen mapped to chromosomal locations 14q12-q21(SPG3) [Hazan et al., 1993], 2p21-p24 (SPG4) [Hentatiet al., 1994b], and 15q11.1 (SPG6) [Fink et al., 1995].There is at least one additional autosomal dominantgene that is unmapped [Kobayashi et al., 1996a,1996b]. Together, the three mapped autosomal domi-nant HSP genes account for approximately half of thetotal number of cases of this type, with the chromosome2 locus the cause of autosomal dominant HSP in mostfamilies [Fink, 1997; Reid, 1997].

Contract grant sponsor: National Institutes of Health; Contractgrant number: NS35932.

*Correspondence to: Dr. D.R. Rosen, Wadsworth Center, Em-pire State Plaza, Albany, NY, 12201-0509. E-mail: daniel.rosen@wadsworth.org

Received 25 September 1998; Accepted 10 December 1998

American Journal of Medical Genetics 83:392–396 (1999)

© 1999 Wiley-Liss, Inc.

Recently, it was proposed that dynamic mutationmay be the molecular basis of some forms of HSP [Ko-bayashi et al., 1996b; Raskind et al., 1997]. Geneticanticipation is the clinical observation of earlier andmore severe disease onset as a hereditary disorder istransmitted through a family [Howeler et al., 1989].The basis of genetic anticipation is “dynamic muta-tion,” typically an increase in the size of a trinucleotiderepeat associated with the disease-causing gene, as thegene is passed through the germ line of a parent tooffspring (reviewed by Willems [1994]). Dynamic mu-tations, especially expansions of CAG trinucleotide re-peats, are the cause of several neurological disorders,including X-linked spinal and bulbar muscular atrophy(Kennedy disease) [LaSpada et al., 1991], Huntingtondisease [Huntington Disease Collaborative Group,1993], and several forms of spinocerebellar ataxia (re-viewed by Raskind et al. [1997]). Some experimentalevidence has been collected to support a dynamic mu-tation basis for HSP [Nielson et al., 1997].

We have revisited a large family with autosomaldominant spastic paraplegia ascertained by Dr. VictorA. McKusick in 1966. Family studies were reported byone of us (T.F.T.) more than 25 years ago [Thurmonand Walker, 1971]. Our new data provide evidence forgenetic anticipation in this form of HSP.

RESULTSThe Family

A pedigree of the family was presented in a previousreport [Thurmon and Walker, 1971]. At that time, thesize of the pedigree was 121 individuals in six genera-tions. There were 28 documented cases of spasticparaplegia, and one case of spastic quadriplegia withmental retardation. Recently, the affected daughter(Fig. 1, Individual IV-17) of one of the original cases(Thurmon and Walker [1971], Case 9) contacted us re-garding a possible reinvestigation of her family. Start-ing with the original pedigree information, we havebeen able to increase the pedigree size to more than600 individuals in nine generations. An abridged pedi-gree including most of the known, spastic paraplegia-affected family members is shown in Figure 1. A thirdbranch of the family with affected members, originat-ing from Individual II-3, is newly recorded in the up-dated pedigree. In the enlarged pedigree, we haveadded 21 cases of spastic paraplegia, for a total of 49documented, affected members of this family.

Phenotype

Twelve relatives who do not appear to have clinicalsigns of spastic paraplegia were examined, and medical

Fig. 1. A six-generation condensed pedigree of the spastic paraplegia family, showing most known affected relatives. A third line of spastic paraplegiatransmission (Individual II-3) has been added to the pedigree as originally reported [Thurmon and Walker, 1971]. An arrow indicates the proposita of thisreport. Approximate age of onset of spastic paraplegia symptoms is shown above and to the left of each person for which it is known. Pedigree positionis indicated below selected individuals. Cases that were examined are indicated with a cross-bar. Double marriage line indicates a consanguineousmarriage.

Anticipation With Spastic Paraplegia 393

records of a thirteenth relative were reviewed (Fig. 1).Fifteen relatives who had clinical signs of spasticparaplegia were examined. Table I contains data oneach affected relative.

The previously reported [Thurmon and Walker,1971] manifestations of this form of HSP include purespastic paraplegia limited to legs; variable age of onset;slow progression; urgency of micturition at late stagesof the disorder; spasm and stiffening of legs, sometimesaccompanied by clonus, upon exertion; pedal edema;bilateral hyperreflexivity and Babinski sign. In somecases, pes cavus was present. The first symptoms of thedisorder typically involved clumsiness and/or a stiffgait. Our recent clinical assessment of HSP-affectedmembers of this family recapitulated the earlier find-ings. However, we noted two important variations fromgenerally described clinical signs of most other spasticparaplegias: variable spasticity and Babinski re-sponses. In this family, spasticity is not a prominentaspect of the disorder; most affected relatives exhibitleg paralysis, with little or no spasticity. Furthermore,not all individuals who exhibited hyperreflexia and/ora paraplegic gait exhibited a Babinski response. Onlyindividuals with long-duration (>22 years) HSP typi-cally manifested a combination of paraplegic gait, hy-perreflexia, and Babinski sign, although one individualwith HSP for as short as 3 years also had all of thesemanifestations.

During our examinations, we found additional evi-dence for a possible homozygote. This boy (Figure 1,Individual V-9) was the son of Case 4 in the previousreport [Thurmon and Walker, 1971]. At the time of theprevious report, he was affected with spastic quadriple-gia and mental retardation, and died at the age of 111/2 years of pneumonia. It was noted then that this boywas the product of a consanguineous marriage, andthat the father of the boy was affected with HSP. Sincethe time of that report, the boy’s mother has also be-come affected. These data suggest that this boy’s spas-tic quadriplegia and mental retardation were the resultof homozygosity of HSP.

Genetic AnticipationThe variable age of onset and the increased severity

of spastic paraplegia in some younger relatives sug-gested the possibility that anticipation may be present.Therefore, we attempted to determine if there is evi-dence of genetic anticipation for spastic paraplegia inthis family. Table II summarizes the age of onset of 18different parent-to-child transmissions of spasticparaplegia in this family.

We performed a statistical analysis of the data pre-sented in Table II. For each transmission mode (father-to-child, mother-to-child), we calculated the averageage of onset in parent and child, with standard devia-tions, and the difference. Using a two-tailed, paired,Student’s t-test, we compared the age of onset in par-ents with that in children for each instance of trans-mission. Probability (P) values indicated that the ob-served difference in age of onset of father-to-childtransmissions (+8.7 years) was not significant (P 40.123; n 4 9), while the difference in age of onset ofmother-to-child transmissions (−16.5 years) was sig-nificant (P 4 0.011; n 4 9). This analysis indicatesthat there is a nonrandom decrease in age of onset(−16.5 years; n 4 9) in mother-to-child transmissionsof HSP. Although caution must be used in acceptingthese results because of the small sample size, the dra-matic decrease in age of onset in mother-to-child trans-missions of HSP supports the possibility of anticipationin this family.

DISCUSSIONIn this report, we present the results of an analysis of

age of onset in parent-to-child transmissions in a largefamily segregating for autosomal dominant pure HSP.Our goal was to determine whether genetic anticipa-tion was present in this family.

Analysis of age of onset of symptoms in cases of ge-netic transmission of spastic paraplegia suggest thatanticipation exists in this family. Statistical analysisindicates that there is a substantial, nonrandom de-crease in age of onset in the children of affected moth-ers (−16.5 years; P 4 0.011). Caution must be used in

TABLE I. Summary of Manifestations

SubjectAge of onset

(years)Duration(years) Gait Spasticity Leg tendon reflexes Babinski sign

IV-17 43 24 Noneb Severe 4+ BilateralIV-19 35 19 Paraplegic Moderate 4+ NoV-14 18 29 Paraplegic Moderate 4+ BilateralIV-23 30 49 None No 4+ BilateralIV-15 55 21 None No 3+ NoV-12 28 22 Paraplegic No 4+ BilateralV-10 54 NDa Paraplegic ND ND NDV-21 40 2 Unsteady No 3+ NoIV-29 53 14 Unsteady No 4+ NoIV-9 45 32 Paraplegic No 2 BilateralIV-14 60 2 Paraplegic No 2 NoIV-13 60 8 Unsteady No 3+ BilateralIV-3 70 15 None No 3+ NoVI-6 17 19 Paraplegic No 4+ NoIV-20 57 3 Unsteady No 4+ Bilateral

aND, Not determined.bNone, not accomplished.

394 Thurmon et al.

interpreting these results, as we were able to statisti-cally analyze a total of only 18 examples of parent-to-child transmission of HSP for this family.

The large decrease in age of onset in cases of mother-to-child transmission suggests that there may be some-thing unique about the condition in this family. Wepropose that the basis of this disparity is the amplifi-cation of an HSP-associated trinucleotide repeat as it ispassed through the female germ line. Sex-specific tri-nucleotide expansion has been observed for most otherdynamic mutation diseases (reviewed by Caskey et al.[1992]).

The spastic paraplegia in this family is interestingbecause of the relative absence of spasticity until ad-vanced stages of the disorder, and because of the vari-able presence of a Babinski response in affected indi-viduals. The lack of spasticity suggests that, unlikemost other types of spastic paraplegia, in which unevenspinocerebellar neuron loss leads to loss of coordinationbetween inhibition and facilitation of nerve impulses,the disorder affecting members of this family results ina progressive unresponsiveness and heaviness of thelegs, suggestive of a more localized and a more evenloss of neuron function. As a result, relatives affectedwith this type of spastic paraplegia do not have thedeformities that result from the uneven, asymmetricpulling of spastic limb muscles. This hypothesis is sup-ported by the lack of an obvious Babinski sign in someclearly affected relatives (as judged by the presence ofa paraplegic gait and hyperreflexia), suggesting thatthere is a slow erosion of upper motor neuron function,rather than the apparent precipitous decline seen inother spastic paraplegias and other motor neuron dis-eases. Proprioception in affected members of this fam-ily appears to be normal, although sphincter musclefunction is compromised at later stages. The manifes-

tations of HSP in this family, while unusual, fall withinthe accepted spectrum of those described for HSP ingeneral, and do not represent a distinct subtype.

In this update, we have proposed that a member ofthis family afflicted with spastic quadriplegia and men-tal retardation may have been a genetic homozygote.The basis for this hypothesis is that both parents arenow known to have the HSP trait, and the boy’s con-genital quadriplegia suggests an extreme form of theparaplegia observed in other relatives. If this conjec-ture is correct, it is notable that the homozygous con-dition for this HSP is not an obligatory lethal event. Adynamic mutation is consistent with the possibility ofan HSP homozygote, as trinucleotide repeat expan-sions typically do not eliminate normal functioning ofthe disease-associated gene in which they occur [Cas-key et al., 1992], but rather cause disease through again-of-function mechanism. Further, mental retarda-tion is present in some forms of complicated spasticparaplegia [Harding, 1990, 1993; Fink, 1997] and, com-bined with quadriplegia, could represent an extreme inthe spectrum of severity of spastic paraplegia.

ACKNOWLEDGMENTS

We thank all members of this family for their coop-eration and extensive assistance with this study. Wethank Dr. Daniel Rissi for his generous provision offacilities for patient examination. We thank Drs. Gil-more, Garland, Babbitt, Brown, and Mossman for pro-vision of medical records. C. He was supported by NIHgrant NS35932. Travel expenses for clinical examina-tions were supported by funds generously provided bythe Wadsworth Center, a division of the New YorkState Department of Health.

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TABLE II. Age of Parent to Child HSP Transmissions,and Difference

Transmissionno.

Father to Mother to

Daughter Son Daughter Son

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10 40 → 1711 40 → 1712 40 → 113 17 → 4014 40 → 1715 50 → 7016 40 → 6017 40 → 6018 58 → 40Mean 37.4 → 46.1 46.3 → 29.8SD 8.8 15.7 8.8 19.8Difference (n) +8.7 (9) −16.5 (9)Paired t-value 1.73 −3.28Probability

(two-tail) 0.123 0.011

Anticipation With Spastic Paraplegia 395

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