familial spastic paraplegia- evidence for a fourth locus

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Clinical Neurology

and Neurosurgery

ELSEVIER Clinical Neurology and Neurosurgery 99 (1997) 87-90

Familial spastic paraplegia: evidence for a fourth locus

R.P.M. Bruyn a,*, M.M.M. van Veen b, H. Kremer b, P.H. Scheltens ‘, G.W. Padberg d

aDepartment of Neurology, O udenryn Hospit al, Vtrecht,The N etherlands

b Department of Human Genetics, Univ ersity Hospit al, Nij megen, The Netherlands

c Department of Neurology, Free Univ ersity Am sterdam, Am sterdam, The Netherlands

d Department of Neurology, Universit y Hospit al, Nijm egen, The Netherlands

Accepted 18 December 1996

Abstract

Autosomal dominant familial spastic paraparesis (AD-FSP) is a genetically heterogeneous disorder of the central nervous

system characterized by a progressive spasticity of the legs. One gene causing AD-FSP (FSPl) has recently been mapped to

chromosome 14q, another gene (FSP2) to chromosome 2p, and a third gene (FSP3) to chromosome 15q. We now report a large

Dutch family with AD-FSP without linkage to any of these chromosomes, providing evidence for a fourth locus (FSP4). 0 1997

Elsevier Science B.V.

Keywords: Familial spastic paraplegia; Genetic linkage; Heterogeneity

1. Introduction

Hereditary or familial spastic paraparesis (FSP) is a

neuro-degenerative disorder, in which slowly progres-

sive spasticity of the legs is the most prominent sign [l].

Harding [2] classified FSP according to whether spastic-

ity of the legs is the only neurological sign (pure or

uncomplicated form), or associated with other (non)-

neurological features, such as dementia, amyotrophy,

ataxia, retinal abnormalities, extrapyramidal signs, op-

tic atrophy and skin abnormalities (complicated form).

Furthermore, she distinguished two clinical types in the

autosomal dominant mode of inheritance; type 1 with

an onset younger than 35 years, and type 2 with an

onset after the age of 35 .

The major neuropathological abnormalities in auto-

somal dominant pure FSP include degeneration of the

spinal pyramidal tracts, decreasing from lower lumbar

to upper cervical level, and an increasing degeneration

*Corresponding author. Present address: Department of Neurol-

ogy, Oudenryn Hospital Utrecht, 1 van Heuven Goedhartlaan, 3527

CE Utrecht, The Netherlands. Tel.: + 31 30 2953953; fax: + 31 30

2953 901.

0303-8467/97/$17.00 0 1997 Elsevier Science B.V. All rights reserved.

PII SO303-8467(97)00602-l

of the dorsal columns, and in a lesser degree of the

spinocerebellar tracts, ascending the spinal cord, being

maximal at cervical level [4,5].

Neither clinical, nor neuropathological descriptions

provide an unequivocal classification, and therefore a

decisive role for molecular genetics seems obvious.

More than a century after the first description of the

clinical picture [6], molecular-biological techniques will

finally provide in a more secure nosology.

Autosomal dominant pure FSP is genetically hetero-

geneous. Three different loci have been described: link-

age to chromosome 14q (FSPI) [7,8], 2p (FSP2) [9-111and recently 15q (FSP3) [12]. We now report a large

Dutch family showing linkage to none of the above

mentioned loci, providing evidence for a fourth locus.

2. Material and methods

2.1. Family analysis

We examined 30 members of a nonconsanguineous

Dutch family with autosomal dominant pure FSP



88 R.P.M. Bruyn et al. /Clinical Neurology and Neurosurgery 99 (1997) 87-90

II

Fig. 1. Pedigree of family V. Clinical details were given in Scheltens et al. [13] Filled symbols indicate affected cases (examined); symbols with

vertical l ine indicate probably affected (not examined). Numbered cases were included in the linkage analysis.

(Fig. 1). Twelve subjects were affected, and four other

siblings, who could not be examined, are affected ac-

cording to family-members (probably affected). Onset

was usually in the fourth or fifth decade, the mean ageat onset being 38 years and severity was usually mild to

moderate, only three patients became wheelchair

bound. The 12 affected members, i.e. progressive leg

spasticity, hyperreflexia of the legs, and usually a

Babinski sign, and no other (non)neurological signs,

three probably affected, 10 unaffected members, and

five healthy spouses were included in the linkage study.

Clinical details have been described elsewhere [13].

2.2. Genetic analysis

Blood samples were obtained from 30 subjects. DNA

was isolated according to standard methods [14]. Thefollowing microsatellite markers were used: D2S 144,

D2S170, D2S177, D14S288, D14S52, D148274,

chr. 2 chr. 14 chr. 15

I4

FSPP

FSPl

D14S63, D15S122, GABRB3 and D15S156 (Fig. 2);

primer sequences are available through the human

Genome Data Base (GDB). The number and frequen-

cies of alleles were estimated from the spouses of thepedigree.

The PCR reactions were performed according to

standard procedures [15] in a 15-ul volume, using 30 ng

of each oligonucleotide, 1xSuperTaq buffer (HT Bio-

technology), 200 uM dTTP, dGTP and dATP, 2,uM

dCTP, and 0.7 uCi [a-32P]-dCTP (3000 Ci/mmol; Amer-

sham) and 0.06 U SuperTaq (HT Biotechnology); 50 ng

genomic DNA was subjected to 26 cycles of amplifica-

tion (30 s 94°C 2 min 55°C and 1 min 72°C). The PCR

products were separated through 6% polyacrylamide

gels containing 7 M urea (Severn Biotech). After elec-

trophoresis, the gels were dried and exposed overnight

to X-ray films (Kodak X-AR). In the linkage analysisFSP is regarded as an autosomal dominant disorder

with an age dependent penetrance and a gene frequency

FSP3

562

I 7

Fig. 2. Sex-average genetic map of chromosome 14qFSP1, 2pFSP2 and 15qFSP3 region based on data of Gyapay et al. [18]; distances are given

in centi Morgans.



R.P.M. Bruyn et al. /Clinical Neurology and Neurosurgery 99 (1997) 87-90 89

Table 1

Pairwise lod scores were calculated at various recombination fractions using the liability classes described in the Materials and Methods section.

Recombination fraction

Locus 0.00 0.01 0.05 0.10 0.20 0.30 0.40

D2S144 -8.77 -5.00 -3.06 - 1.73 0.51 -0.12 - 0.07

D2S170 - 10.45 -6.32 -4.12 -2.80 -1.43 - 0.69 -0.25

D2S177 -7.53 -5.77 -2.90 -1.53 -0.41 - 0.05 0.01

D14S288 -9.96 -7.97 -5.79 -3.95 -1.79 -0.71 -0.16

D14S52 -9.60 -5.50 -2.90 -1.70 -0.63 -0.17 0.01

D14S274 -6.52 -4.26 -2.16 -1.19 -0.45 -0.17 -0.04

D14S63 -6.80 -4.76 -3.93 -2.76 -1.15 -0.40 -0.08

D15S122 -5.50 -3.73 -2.49 - 1.62 -0.71 -0.26 -0.04

GABRB3 -6.55 -6.42 -4.94 - 3.39 - 1.65 -0.72 -0.22

D15S156 -4.01 - 3.34 -1.88 -1.17 -0.50 -0.20 -0.05

Exclusion is lod score -2.0.

of 0.001. According to Boustany et al [16], eight differ-

ent liability classes were constructed (class 1: O-20

years, 5%; class 2: 20-25 years, 13%; class 3: 25-30years, 25%; class 4: 30-35 years, 40%; class 5: 35-40,

57%; class 6: 40-45 years, 73%; class 7: 45-50 years,

86%; class 8: greater than 50 years, 90%). Pairwise lod

scores were calculated using the LINKAGE program

package version 5. 10 [17].

3. Results

Two-point linkage analysis for the three 2p markers

D2S144, D2S170, D2S177, four 14q markers D148288,

D14S52, D148274, D14S63 and three 15q markers

D15S122, GABRB3 and D15S156 in respectively theFSPl, FSP2 and the FSP3 candidate region gave all

convincingly negative lod scores (Table 1).

4. Discussion

Since this family had been described [13], more fam-

ily-members have been examined, leading to the present

pedigree (Fig. 1). The family was clinically homoge-

neous with a late onset in all family members (type 2

according to Harding’s criteria [3]).

In contrast to the clinical homogeneity, the disorder

is genetically heterogeneous, and there are no clear-cut

correlations between clinical features and different loci;

the severity varied from mild in the early-onset family

with the FSPl locus, mapped to chromosome 14q [7],

to mild, moderate or severe in five French families and

one Dutch family earlier reported on [lo]- all late onset

families- harboring the FSP2 locus, mapped to chromo-

some 2p [9]. Hentati et al. [l l] described three late-onset

families and one early-onset family with linkage to the

FSP2 locus; a fifth, early-onset family, showed linkage

to FSPl locus, however, no data were given concerning

severity of the affected members. Gispert et al. [8]

described one early-onset family with the FSPl locus,

in which severity varied markably, and anticipationseemed likely, while the age at onset was before the age

of 13 in all patients. Two other families, with ages at

onset of 22 years in the one and of 30 years in the

other, were not linked to this locus. The mean age at

onset of the family in which linkage was found on

chromosome 15q [12] was 22 years, and severity was

severe (at least nine of 31 patients became wheelchair

bound).

The linkage analysis in this study using microsatellite

DNA markers excluded the FSPl, FSP2 and FSP3

locus, therefore this family provides evidence for an

additional (FSP4) locus. Further search for this locus is

in progress.

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familial spastic paraplegia- evidence for a fourth locus

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