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

Article (PDF Available)inThe American Journal of Human Genetics 64(2):586-93 · March 1999with29 Reads
DOI: 10.1086/302241 · Source: PubMed
We have recently observed a large pedigree with a new rare autosomal dominant spastic paraparesis. In three subsequent generations, 13 affected individuals presented with bilateral cataracts, gastroesophageal reflux with persistent vomiting, and spastic paraparesis with amyotrophy. Bilateral cataracts occurred in all affected individuals, with the exception of one patient who presented with a chorioretinal dystrophy, whereas clinical signs of spastic paraparesis showed a variable expressivity. Using a genomewide mapping approach, we mapped the disorder to the long arm of chromosome 10 on band q23.3-q24.2, in a 12-cM chromosomal region where additional neurologic disorders have been localized. The spectrum of phenotypic manifestations in this family is reminiscent of a smaller pedigree, reported recently, confirming the possibility of a new syndrome. Finally, the anticipation of symptoms suggests that an unstable trinucleotide repeat may be responsible for the condition.
Am. J. Hum. Genet. 64:586–593, 1999
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
Marco Seri,
Roberto Cusano,
Paola Forabosco,
Roberta Cinti,
Francesco Caroli,
Paolo Picco,
Rita Bini,
Vincenzo Brescia Morra,
Giuseppe De Michele,
Margherita Lerone,
Margherita Silengo,
Ivana Pela,
Carla Borrone,
Giovanni Romeo,
and Marcella Devoto
Laboratorio Genetica Molecolare and
II Divisione Pediatrica, Istituto G. Gaslini, Genoa;
Dipartimento di Oncologia, Biologia e Genetica,
Universita` di Genova, Genoa, Italy;
Universita` di Firenze, Ospedale Pediatrico Meyer, Florence, Italy;
Dipartimento di Scienze
Neurologiche, Universita` Federico II di Napoli, Naples, Italy;
Istituto di Discipline Pediatriche, Universita` di Torino, Turin, Italy; and
Lyon, France
We have recently observed a large pedigree with a new
rare autosomal dominant spastic paraparesis. In three
subsequent generations, 13 affected individuals pre-
sented with bilateral cataracts, gastroesophageal reflux
with persistent vomiting, and spastic paraparesis with
amyotrophy. Bilateral cataracts occurred in all affected
individuals, with the exception of one patient who pre-
sented with a chorioretinal dystrophy, whereas clinical
signs of spastic paraparesis showed a variable expres-
sivity. Using a genomewide mapping approach, we
mapped the disorder to the long arm of chromosome
10 on band q23.3-q24.2, in a 12-cM chromosomal re-
gion where additional neurologic disorders have been
localized. The spectrum of phenotypic manifestations in
this family is reminiscent of a smaller pedigree, reported
recently, confirming the possibility of a new syndrome.
Finally, the anticipation of symptoms suggests that an
unstable trinucleotide repeat may be responsible for the
An interesting pedigree showing a genetic disorder in-
herited in an autosomal dominant fashion, and probably
representing a rare syndrome, has recently been ob-
served. The affected members of this large, three-gen-
eration family (fig. 1) show bilateral cataracts, gastro-
Received July 6, 1998; accepted for publication December 17, 1998;
electronically published February 2, 1999.
Address for correspondence and reprints: Dr. Marco Seri, Labora-
torio di Genetica Molecolare, Istituto G. Gaslini, Largo G. Gaslini n.
5, 16148 Genova Quarto, Italy. E-mail:
q 1999 by The American Society of Human Genetics. All rights reserved.
esophageal reflux with persistent vomiting, and spastic
paraparesis with amyotrophy.
Congenital cataracts account for 10%–30% of blind-
ness in children, and the phenotype is clinically heter-
ogeneous. Although X-linked and autosomal recessive
transmission of hereditary cataracts have been observed,
the most frequent mode of inheritance is autosomal
dominant (Merin 1991). In addition, cases of congenital
cataracts may have a genetic cause, either as part of a
systemic disease or as a nonsyndromic Mendelian trait.
Eleven distinct dominant loci of congenital cataracts
have been mapped so far (Hejtmancik 1998): the Volk-
mann “zonular progressive” cataract (MIM 115665; Ei-
berg et al. 1995) and a “posterior polar” cataract (MIM
116600; Ionides et al. 1997) to 1p; the Coppock type
“zonular pulverulent” cataract (MIM 116200; Renwick
and Lawler 1963) to the chromosomal region 1q21-q25;
the Coppock-like “nuclear pulverulent” cataract (MIM
123660; Brakenhoff et al. 1994) to 2q33-q36; and two
different forms, the Marner zonular progressive cataract
(MIM 116800; Eiberg et al. 1988) and the posterior
polar cataract (Maumenee 1979), to 16q22.1. Two ad-
ditional types, the “cerulean” (MIM 115660; Armitage
et al. 1995) and the “zonular sutural” cataract (MIM
600881; Padma et al. 1995), have been mapped to the
long arm of chromosome 17 in the q24 and q11-12
regions, respectively. A second locus for the cerulean type
has been mapped to 22q (MIM 601547; Kramer et al.
1996). Recently, a locus for the “anterior polar” cataract
has been localized to 17p (MIM 601202; Berry et al.
1996), whereas a second locus for the zonular pulver-
ulent cataract has been mapped to 13q (MIM 601885;
Mackay et al. 1997).
Spastic paraplegia is also a genetically heterogeneous
disease. Indeed, autosomal dominant, autosomal reces-
sive, and X-linked recessive varieties of spastic paraple-
gia have been recognized, and
11 recessive or dominant
forms exist. The majority of the reported families
Seri et al.: Genetic Mapping of a Rare Spastic Paraparesis 587
Figure 1 The pedigree of the family with haplotype reconstruction for informative markers on 10q23.3-q24.2. The “at-risk” haplotype
is boxed. Arrows indicate the boundaries of the critical interval identified. The LOD score values at for the different markers are reported.v 5 0
(70%–80%) display autosomal dominant inheritance,
with autosomal recessive inheritance being responsible
for most of the remaining cases (Reid 1997).
Three autosomal dominant and two recessive forms
of pure spastic paraplegia have already been mapped to
the chromosomal regions 2p24-p21 (MIM 182601),
14q12-q21 (MIM 182600), 15q11.2-q12 (MIM
600363), 8p11-q13 (MIM 270800), and 16q24.3 (MIM
602783) (Hazan et al. 1993, 1994; Hentati et al. 1994a,
1994b; Fink et al. 1995; De Michele et al. 1998). Spastic
paraplegia can be complicated by the presence of ad-
ditional neurologic or nonneurologic features. In partic-
ular, optic nerve involvement, pigmentary retinopathy,
extrapyramidal signs, distal amyotrophy, dementia,
ataxia, skin lesions, oligophrenia, neuropathy, deafness,
and cone-shaped epiphyses have been reported to be
associated with spastic paraplegia. The complicated
forms of spastic paraplegia consist of a large number of
rare conditions and have already been reviewed by Bun-
dey (1992) and Harding (1993).
Recently, Slavotinek et al. (1996) reported a pedigree
with recurrence of congenital cataracts, motor system
disorder, short stature, learning difficulties, and skeletal
abnormalities (MIM 601162). The spectrum of phe-
notypic manifestations segregating in the pedigree we
collected is reminiscent of those segregating in the
smaller pedigree reported by Slavotinek et al. (1996),
suggesting the possibility of a new syndrome.
A simulated linkage analysis of the whole pedigree
here reported yielded a maximum LOD score of 3.2 at
recombination fraction (v) 5 .01 and of 3.02 at v 5
under an affected-only model, and of 6.22 and 5.81,.05
respectively, under a complete penetrance model. Since
the family is highly informative, DNA samples and lym-
phoblastoid cell lines were collected from 24 (12 affected
and 12 unaffected) members of this pedigree, to perform
genomewide mapping.
Subjects and Methods
Clinical Report
The spectrum of phenotypic manifestations segregat-
ing in the collected pedigree probably represents a new,
588 Am. J. Hum. Genet. 64:586–593, 1999
Table 1
Clinical Features of the Affected Individuals from the Family
Gait Brisk Reflexes Hypertone
Sign Other
II-3 1 1 1 1 LL 1
II-7 1 1 1 1 LL
II-11 1 1 1 1 LL LL GER
III-16 1 1 Developed
1 1 UL 1 1 1
III-18 1 1 Developed
1 1 1 1 1 1
III-20 1 1 1 1 LL 1 1 1
III-21 Chorioretinal
with myopia
1 1 1 1 1 1 1
III-33 1 1 1 1
III-38 1 1 1 1 1 LL
III-39 1 1 1 1 1 LL
III-40 Zonular
1 1 1 GI, GER
IV-4 1 1 1 1 1 GI, IVD
.—A plus sign (1) indicates presence of characteristic; LL 5 lower limbs; UL 5 upper limbs; GER 5 gastroesophageal reflux; GI 5
growth impairment; and IVD 5 interventricular defect.
rare, and complicated form of spastic paraparesis. Table
1 summarizes the clinical features of the affected family
Ocular abnormalities occur with complete penetrance.
All of the affected individuals presented with bilateral
cataracts, with the exception of patient III-21, who pre-
sented with myopia and a chorioretinal dystrophy. An
ophthalmologic evaluation of patient III-40 disclosed
lens opacities in the zonular area, without anomalies of
the anterior/posterior segment. Furthermore, all subjects
presented with persistent vomiting, and in two of them,
gastroesophageal reflux was diagnosed. The presence of
a hiatus hernia was ascertained by an esophageal en-
doscopy in subjects II-11, III-38, III-39, and III-40.
Spastic paraparesis shows incomplete penetrance and/
or variable expressivity. Pes cavus and the Babinski sign,
along with different degrees of muscle wasting localized
in the hands and forelegs, are present in some subjects.
Electrophysiologic studies confirmed involvement of the
central motor pathways and revealed a peripheral neu-
ropathy that mainly involved the motor axons. In par-
ticular, somatosensory and central motor–evoked po-
tentials were abnormal in subjects III-16, III-18, and
III-21, indicating involvement of the central motor and
sensory pathways. An electromyogram in the same sub-
jects revealed a neurogenic pattern, although the nerve
conduction velocities were normal, suggesting an axonal
motor neuropathy. Brainstem-evoked potentials showed
delayed bilateral I–III latency in subjects III-16 and III-
18, whereas these potentials were normal in patient III-
21. Magnetic resonance imaging showed spinal cord at-
rophy in patient III-18. With regard to the age at onset,
spastic paraparesis appeared in the first and in the third
decade of life in different members of the family, with
some indications of anticipation. For example, patient
II-3 presented with difficulties during ambulation only
in later adulthood. The daughter, patient III-16, mani-
fested muscle weakness and difficulties in ambulation
Seri et al.: Genetic Mapping of a Rare Spastic Paraparesis 589
Table 2
LOD Score Values of the Markers Present in the ABI PRISM
Linkage Mapping Set Spanning Chromosome 10
v 5
.0 .01 .05 .1 .2 .3 .4
D10S249 23.75 2.79 2.1 .15 .27 .21 .1
D10S591 24.49 24.14 22.89 21.93 2.83 2.29 2.06
D10S189 22.56 22.12 21.01 2.56 2.22 2.10 2.04
D10S547 23.90 23.74 22.31 21.37 2.50 2.12 .02
D10S191 24.46 23.34 21.82 21.09 2.39 2.07 .03
D10S548 24.21 22.94 21.51 2.88 2.32 2.07 .02
D10S197 27.87 24.38 22.14 21.15 2.29 .03 .08
D10S208 21.23 21.16 2.91 2.64 2.25 2.04 .04
D10S220 23.47 23.14 21.32 2.48 .16 .27 .16
D10S561 .00 .00 .00 .00 .00 .00 .00
D10S537 25.17 21.22 .59 1.13 1.26 .93 .39
D10S201 2.17 .81 1.87 2.08 1.86 1.30 .56
D10S583 4.83 4.75 4.42 3.99 3.06 2.02 .86
D10S192 22.88 1.04 1.55 1.61 1.37 .95 .41
D10S597 23.66 21.84 21.03 2.63 2.26 2.10 2.03
D10S190 23.85 23.06 21.05 2.23 .32 .34 .11
D10S587 22.16 2.21 .39 .55 .51 .29 .05
D10S217 24.99 24.51 22.67 21.59 2.60 2.22 2.09
D10S212 28.57 24.62 22.52 21.60 2.72 2.30 2.10
.—All of these markers were used to type the 24 available
family members.
during pregnancy, at age 25 years. At present, she is aged
35 years and has a severe impairment of ambulation.
Her son, patient IV-4, has shown gait disturbances and
the presence of pes cavus at the age of 4 years. Finally,
growth impairment was ascertained in patients III-40
(height and weight both below 3d percentile) and IV-4
(height and weight both at the 25th percentile).
Large-Scale Mapping
We performed large-scale genetic mapping, using a
DNA sequencer apparatus (ABI 373A) and the ABI
PRISM Linkage Mapping Set (Perkin-Elmer). This set
comprises 360 markers that define a 10-cM–resolution
human map, with an average heterozygosity of 0.81. The
markers are organized into 28 panels. Each panel con-
tains 7–16 fluorescent dye–labeled primer pairs that gen-
erate PCR products, which can be pooled and detected
in a single gel lane. PCR conditions were the same as
those specified in the manufacturer’s instructions. PCR
products were pooled, combined in a tube with a size
standard, and loaded onto the gel in the automated se-
quencer ABI 373A. We performed DNA fragment sizing
analysis using GENESCAN, whereas we used GENO-
TYPER to perform semiautomatic “allele-calling.”
Linkage Analysis
Classic two-point LOD score analysis was done in this
pedigree under the assumption of autosomal dominant
inheritance, with 90% penetrance of the segregating trait
and an estimated disease-allele frequency of .001. All of
the individuals showing at least bilateral cataracts and
persistent vomiting were included as “affected” in the
linkage analysis. We used the MLINK program included
in the LINKAGE package (Lathrop et al. 1984) to per-
form linkage analysis.
Haplotype Reconstruction
Haplotype analysis was performed, to better charac-
terize the possible meiotic recombinants and to define
the critical region of the disease gene. Seven microsa-
tellites (D10S1644, D10S1765, D10S1739, D10S1753,
D10S536, D10S564, and D10S1755 [Ge´ne´thon])
known to map between D10S201 and D10S583, the two
markers present in the ABI-PRISM Linkage Mapping
Set, and nine microsatellites (D10S1736, D10S1680,
D10S574, D10S1758, D10S577, D10S1709, D10S-
1726, D10S198, and D10S603 [Ge´ne´thon]), which span
the interval between D10S583 and D10S192 in the ABI-
PRISM Linkage Mapping Set, were synthesized by an
Oligo 1000 M DNA Synthetizer (Beckmann). All mark-
ers, with the exception of D10S564 and D10S574, were
synthesized by labeling the forward primers with 6-FAM
or TET fluorescent amidites and were purified with OPC
columns (ABI, Perkin-Elmer), according to the manu-
facturer’s conditions. PCR was performed under stan-
dard conditions, and amplification products were loaded
onto an automated sequencer ABI 373A to define allele
size, by use of GENESCAN. The dinucleotide repeats
D10S564 and D10S574 were amplified under standard
conditions, electrophoresed in an 8% polyacrilamyde/6
M urea gel, and revealed by silver staining (Budowle et
al. 1991).
Large-Scale Mapping
To map the disease gene, we used the 360 fluorescent
markers in the ABI PRISM Linkage Mapping panels
spanning the entire genome to type the 24 family mem-
bers. First, we studied those chromosomes in which can-
didate regions containing genes responsible for different
forms of congenital cataracts and spastic paraparesis had
been identified. Two-point LOD score linkage analysis
was performed on this pedigree, under the assumption
of autosomal dominant inheritance of the segregating
A LOD score of 4.83 at was obtained forv 5 .0
marker D10S583 (table 2). Thus, the gene responsible
for the disease was mapped to the long arm of chro-
mosome 10 on band q23.3-q24.2. Since D10S201 and
D10S192, the two markers flanking D10S583 in the ABI
590 Am. J. Hum. Genet. 64:586–593, 1999
PRISM Linkage Mapping Set, showed recombination
events in some family members, additional markers were
used for haplotype analysis in this region, to better char-
acterize the possible meiotic recombinants and to define
the critical region for the disease gene.
Haplotype Analysis
All family members were typed for seven microsatel-
lites (D10S1644, D10S1765, D10S1739, D10S1753,
D10S536, D10S564, and D10S1755), mapping between
markers D10S201 and D10S583, and for nine micro-
satellites (D10S1736, D10S1680, D10S574, D10S1758,
D10S577, D10S1709, D10S1726, D10S198, and D10-
S603), mapping between D10S583 and D10S192.
Markers D10S1739, D10S1758, D10S577, D10S1709,
D10S1726, and D10S198 were determined to be not
informative and were excluded from haplotype recon-
struction (fig. 1).
A recombination event in patient II-7 positioned the
gene telomeric to D10S1765. Her affected daughter, pa-
tient III-33, inherited the same at-risk haplotype,
whereas the unaffected son, subject III-34, received only
part of this at-risk haplotype, from D10S1753 to
D10S564. This additional recombination event allowed
us to define the centromeric boundary of the critical
region as between markers D10S564 and D10S1755.
Furthermore, a recombination event in patient III-18 re-
fined the distal limit of the critical interval to between
markers D10S574 and D10S603. Thus, the haplotype
reconstruction reduced the critical region to a 12-cM
interval, flanked by markers D10S564 and D10S603.
The present study reports the genetic mapping of a
new rare spastic paraparesis, segregating in a large,
three-generation family. The affected members show bi-
lateral cataracts, gastroesophageal reflux with persistent
vomiting, and spastic paraparesis with amyotrophy.
From a clinical point of view, the spectrum of symptoms
present in this family is reminiscent of that in a previous
disorder, reported elsewhere by Slavotinek et al. (1996).
In particular, the spastic paraparesis and the bilateral
cataract represent the major characteristics of this new
syndrome, although some other minor features are pre-
sent in the affected individuals of both pedigrees. These
features include persistent vomiting associated with hi-
atus hernia; weakness and wasting of the muscles; pres-
ence of associated motor polyneuropathy with axonal
degeneration, onset of the symptoms, in some women,
during pregnancy; as well as presence of anticipation.
To our knowledge, this association represents a new rare
form of complicated spastic paraparesis (Bundey 1992;
Harding 1993). Since anticipation of symptoms, caused
by an abnormal expansion of trinucleotide repeats (Ab-
bott and Chambers 1994; Neri et al. 1996), is a char-
acteristic of single-gene disorders, a similar pathogenetic
mechanism could also be supposed for this syndrome.
The expansion of trinucleotide repeats normally causes
neurodegenerative disorders. Besides, an autosomal
dominant pure spastic paraplegia, already mapped to
2p21-24, has recently been shown, by a repeat expan-
sion-detection experiment (Schalling et al. 1993), to be
caused by a CAG-repeat expansion (Nielsen et al. 1997).
Using genomewide screening, we mapped this com-
plicated form of spastic paraparesis to the long arm of
chromosome 10 on band q23.3–q24.2. The gene re-
sponsible is located in an interval spanning 12 cM of
genomic DNA, between markers D10S564 and
This interval is physically covered by the YAC contig
WC10.7, available at the Whitehead Institute/MIT web-
site. Furthermore, an integrated physical and genetic
map, spanning chromosome band 10q24 (Gray et al.
1997), allows us to better characterize this critical in-
terval. On the basis of this map, we estimated the size
of the interval between markers D10S564 and D10S603
to be 6–7 Mb. This integrated physical and genetic map
contains 10 known gene loci and 11 additional ex-
pressed sequences (Gray et al. 1997). Seven of the 10
genes, as well as 8 of the 11 expressed sequence tags
(ESTs), map inside of the D10S564/D10S603 interval.
Some of these could represent, on the basis of their lo-
cation, function, and expression, candidate genes. Fur-
thermore, a search of the Human Genome Map database
(Schuler et al. 1996), for expressed sequences in the ge-
nomic region between markers D10S564 and D10S603,
results in >119 ESTs that are included within this in-
terval, representing additional potential candidate genes.
Different neurologic disorders, as well as other diseases,
already have been mapped to this region (fig. 2).The
critical intervals of some of these disorders overlap, for
a large portion, the region defined in the present study.
A corneal dystrophy, the Thiel-Behnke type (MIM
602082; Behnke and Thiel 1965), has been mapped to
a 12-cM region, between markers D10S677 and
D10S1671 (Yee et al. 1997), overlapping 6 cM of the
critical interval here reported. Furthermore, a gene for
partial epilepsy (MIM 600512) has been assigned to
10q24, located in a 10-cM interval between markers
D10S185 and D10S566 (Ottman et al. 1995). This re-
gion overlaps, for 7 cM, the critical interval defined in
the present study. Since families with recurrence of spas-
tic paraparesis and epilepsy are reported (Gigli et al.
1993), it would be interesting to test whether they rep-
resent a new contiguous-gene syndrome.
The Hermansky-Pudlak syndrome (HPS; MIM
203300) has also been mapped to this region, in a 14-
cM interval that contains the markers D10S198 and
Seri et al.: Genetic Mapping of a Rare Spastic Paraparesis 591
Figure 2 Schematic representation of the chromosomal region 10q23.3-q24.2, to which the syndrome described in the present study has
been assigned. The overlapping of the critical interval with the regions to which other disorders have been mapped is reported. Cen 5 centromere;
Tel 5 telomere; IOSCA 5 infantile-onset spinocerebellar ataxia; EPT 5 partial epilepsy; UFS 5 urofacial syndrome; and CDTB 5 corneal
dystrophy, Thiel-Behnke type.
D10S1239 (Wildenberg et al. 1995). By positional clon-
ing, the HPS gene has been identified (Oh et al. 1996),
and recently mutation in the homologous murine Hps
gene has been identified, in the “pale ear” mouse (Feng
et al. 1997), mapping to murine chromosome 19. These
results establish a murine region of interest, to identify
additional mutant mice as animal models for the new
syndrome here described.
By homozygosity mapping, the urofacial syndrome or
“Ochoa syndrome” (MIM 236730; Elejalde 1979) has
been assigned to a 1-cM interval, containing markers
D10S1726/D10S198 (Wang et al. 1997) and overlap-
ping the telomeric side of the critical region defined in
the present study. Furthermore, an infantile-onset form
of spinocerebellar ataxia (MIM 271245) with sensory
neuropathy has been assigned, by homozygosity map-
ping, to the 10q23.3–q24.1 locus (Nikali et al. 1995).
This locus, designated “SCA8,” has been restricted to a
region between two adjacent microsatellites, D10S192
and D10S1265 (Nikali et al. 1997). This neurologic dis-
order maps telomeric to the region defined in the new
syndrome, described in the present paper, but the two
critical intervals are closely located.
Finally, an interesting disorder has been mapped in
close proximity to the syndrome reported in the present
study. This disorder (MIM 157640) shows progressive
external ophthalmoplegia (PEO), mitochondrial myopa-
thy, and other abnormalities, such as progressive prox-
imal muscle weakness and bilateral cataracts (Zeviani
et al. 1989, 1990; Cormier et al. 1991; Suomalainen et
al. 1992). This disorder, inherited as an autosomal dom-
inant trait, is associated with multiple different deletions
of mtDNA, suggesting the presence of a nuclear-encoded
factor responsible for mitochondrial deletions (Zeviani
et al. 1989; Cormier et al. 1991), and has been mapped
to chromosome 10 in a 20-cM region between D10S198
and D10S562 (Suomalainen et al. 1995), which is close
to the critical interval identified in the present study. The
presence of genetic heterogeneity in PEO syndrome sug-
gests that another nuclear gene, or genes, is involved in
the pathogenesis of this disorder. There may be other
examples of human pathologic disorders caused by mu-
tations involved in the “cross-talk” between the nuclear
and the mtDNA. Pure and complicated forms of hered-
itary spastic paraplegia have been demonstrated to be
caused by mutations in a nuclear gene coding for a mi-
tochondrial ATPase (Casari et al. 1998), suggesting the
presence of an impairment of mitochondrial functions
in this class of progressive neurodegenerative disorders.
We report here the genetic mapping of a new rare
autosomal dominant spastic paraparesis, which proba-
bly represents the disorder already investigated by Sla-
votinek et al. (1996). Haplotype reconstruction in this
second pedigree would be important, to confirm that the
disorder represents a new homogeneous syndrome and
to possibly reduce the critical interval. This syndrome is
localized in 10q23.3–q24.1, a chromosomal region con-
taining different genes, and one to which several neu-
rologic disorders have been mapped. The search for the
disease gene through the candidate-gene approach could
add clues to the understanding, at a functional level, of
the molecular defects causing important types of path-
592 Am. J. Hum. Genet. 64:586–593, 1999
ologic entities, such as congenital cataract and spastic
The Telethon grant E.440 is gratefully acknowledged. This
work was supported by the Italian Ministry of Health. We
thank Dr. G. Casari and the Telethon Institute of Genetics and
Medicine for providing fluorescent markers.
Electronic- Database Information
Accession numbers and urls for data in this article are as
Ge´ne´thon, (for markers used)
Human Genome Map,
/Science96/ (for expressed sequences)
Online Mendelian Inheritence in Man (OMIM), http:// (for congenital cataracts
[MIM 115665, 116600, 116200, 123660, 116800, 115660,
600881, 601547, 601202, 601885], spastic paraplegia
[MIM 182601,182600, 600363, 270800, 602783, 601162],
corneal dystrophy [MIM 602082], partial epilepsy [MIM
600512], Hermansky-Pudlak syndrome [MIM 203300],
Ochoa syndrome [MIM 236730], SCA8 [MIM 271245] and
PEO syndrome [MIM 157640]
Whitehead Institute/MIT, (for
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    • "HSP forms and putative protein function of each HSP gene product are summarized inTable 1. Inheritance and clinical features of each HSP form are described inTable 2. ADHSP To date, 20 genetic SPG loci for ADHSP have been identified, but only 12 genes are known. There are at least eight identified ADHSP loci with an uncloned gene associated with the disease in both pure and complicated forms (Tables 1 and 2): SPG9 (Panza et al., 2008; Seri et al., 1999), SPG19 (Valente et al., 2002), SPG29 (Orlacchio et al., 2005a), SPG36 (Schüle et al., 2009a), SPG37 (Hanein et al., 2007), SPG38 (Orlacchio et al., 2008b), SPG40 (Subramony et al., 2009), and SPG41 (Zhao et al., 2008). SPG3A SPG3A/ATL1 mutations represent approximately 10% of ADHSP patients and are the most frequent cause of HSP with onset before age 10 years (Namekawa et al., 2006). "
    [Show abstract] [Hide abstract] ABSTRACT: Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurological disorders characterized by pathophysiologic hallmark of length-dependent distal axonal degeneration of the corticospinal tracts. The prominent features of this pathological condition are progressive spasticity and weakness of the lower limbs. To date, 71 spastic gait disease-loci and 54 spastic paraplegia genes (SPGs) have been identified. All modes of inheritance (autosomal dominant, autosomal recessive, and X-linked) have been described. Recently, a late onset spastic gait disorder with maternal trait of inheritance has been reported, as well as mutations in genes not yet classified as spastic gait disease. Several cellular processes are involved in its pathogenesis, such as membrane and axonal transport, endoplasmic reticulum membrane modelling and shaping, mitochondrial function, DNA repair, autophagy, and abnormalities in lipid metabolism and myelination processes. Moreover, recent evidences have been found about the impairment of endosome membrane trafficking in vesicle formation and about the involvement of oxidative stress and mtDNA polymorphisms in the onset of the disease. Interactome networks have been postulated by bioinformatics and biological analyses of spastic paraplegia genes, which would contribute to the development of new therapeutic approaches.
    Full-text · Article · Jun 2014
    • "As a result, genetic analysis of families with suspected hereditary GOR has been difficult (Katz, 1998). As yet, two forms of dominantly inherited GOR have been identified: GOR with spastic paraparesis, amyotrophy and cataracts linked to chromosome 10q23–q24 (Seri et al., 1999), and a severe paediatric form linked to chromosome 13q14 (Hu et al., 2000). However, none of the previously published GOR families has had sensory neuropathy or cough. "
    [Show abstract] [Hide abstract] ABSTRACT: Autosomal dominant hereditary sensory neuropathy (HSN I) is a clinically and genetically heterogeneous group of disorders, and in some families it is due to mutations in the serine palmitoyltransferase (SPTLC1) gene. We have characterized two families with HSN I associated with cough and gastro-oesophageal reflux (GOR). From a large Australian family, 27 individuals and from a smaller family, 11 individuals provided clinical information and blood for genetic analysis. Affected individuals had an adult onset of paroxysmal cough, GOR and distal sensory loss. Cough could be triggered by noxious odours or by pressure in the external auditory canal (Arnold's ear-cough reflex). Other features included throat clearing, hoarse voice, cough syncope and sensorineural hearing loss. Neurophysiological and pathological studies demonstrated a sensory axonal neuropathy. Gastric emptying studies were normal, and autonomic function and sweat tests were either normal or showed distal hypohidrosis. Cough was likely to be due to a combination of denervation hypersensitivity of the upper airways and oesophagus, and prominent GOR. Most affected individuals were shown on 24 h ambulatory oesophageal pH monitoring to have multiple episodes of GOR, closely temporally associated with coughing. Hoarse voice was probably attributable to acid-induced laryngeal damage, and there was no evidence of vocal cord palsy. No other cause for cough was found on most respiratory or otorhinological studies. Linkage to chromosome 3p22-p24 has been found in both families, with no evidence of linkage to loci for known HSN I, autosomal dominant hereditary motor and sensory neuropathy, hereditary GOR or triple A syndrome. These families represent a genetically novel variant of HSN I, with a distinctive cough owing to involvement of the upper aerodigestive tract.
    Full-text · Article · Jan 2006
    • "We also directly sequenced the HSPB1 gene for 7q11 and the HSPB8 for 12q24 loci. Moreover, since it has been reported that families with complicated autosomal dominant hereditary spastic paraplegia (ADHSP) may present with upper and lower motor neuron dysfunction [5] [10] [11], we performed the linkage analysis to all the known loci for ADHSP to rule out the possibility that our family was affected by ADHSP complicated by peroneal muscular atrophy. Finally a molecular analysis for mutations in Super Oxide Dismutase (SOD1) gene was also performed. "
    [Show abstract] [Hide abstract] ABSTRACT: Distal hereditary motor neuronopathy is a genetically and clinically heterogeneous disorder. To date, five loci, and their relative genes, have been mapped on chromosomes 7p14, 7q11, 9q34, 11q12 and 12q24, respectively. We describe an Italian family with autosomal dominant distal HMN starting at around 30 years of age with weakness and atrophy of distal leg muscles and pyramidal features. We performed genetic linkage analysis on chromosomes 7p14, 9q34, 11q12 and 12q24. Moreover we sequenced the genes mapped to 7q11 and 12q24. Negative LOD scores excluded linkage to 7p14, 9q34, and 11q12 chromosomes in our family. No mutations were found in genes mapped to 7q11 and 12q24. In addition, because of pyramidal features, we performed the linkage analysis to all the known loci for autosomal dominant hereditary spastic paraparesis. The analysis was negative thus excluding a complicated form of autosomal dominant hereditary spastic paraparesis. These data further confirm a genetic heterogeneity within inherited motor neuronopathy.
    Full-text · Article · Dec 2004
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