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A New Dominant Spinocerebellar Ataxia Linked to Chromosome 19q13.4-qter
Zoran Brkanac, MD;
Laura Bylenok;
Magali Fernandez, MD;
Mark Matsushita, BS;
Hillary Lipe, NP;
John Wolff, BS;
David Nochlin, MD;
Wendy H. Raskind, MD, PhD;
Thomas D. Bird, MD
Arch Neurol. 2002;59:1291-1295.
ABSTRACT
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Background The autosomal dominant spinocerebellar ataxias (SCAs) are a clinically
and genetically heterogeneous group of neurodegenerative disorders. Although
molecular genetic studies have so far implicated 16 loci in the etiology of
these diseases, approximately 30% of families with SCAs remain unlinked.
Objectives To report the location of a gene causing a "pure" autosomal dominant
cerebellar ataxia in one family and to describe the clinical phenotype.
Patients We have identified a 4-generation American family of English and Dutch
ethnicity with a pure cerebellar ataxia displaying an autosomal dominant pattern
of inheritance. The disease typically has its onset in the third and fourth
decades of life, shows no evidence of anticipation, progresses slowly, and
does not appear to decrease life expectancy. Clinical DNA testing excluded
SCA1, 2, 3, 6, 7, and 8.
Methods A genome-wide linkage analysis at a 10 centimorgan (cM) level was performed
with samples from 26 family members (11 affected, 10 clinically unaffected
at risk, and 5 spouses).
Results Assuming 90% penetrance, we found suggestive evidence of linkage to
chromosome 19, with a lod score of 2.49 for D19S571.
More detailed mapping in this region provided a maximum 2-point lod score
of 2.57 at  = 0 for D19S254 and a maximum
multipoint lod score of 4.72 at D19S926. By haplotype
construction a 22-cM critical region from D19S601
to the q telomere was defined.
Conclusions We have mapped a gene for an autosomal dominant SCA to chromosome 19q13.4-qter
in one family. The critical region overlaps with the locus for SCA14, a disease
described in a single Japanese family and characterized by axial myoclonus.
Myoclonus was not seen in the family we studied, but it remains possible that
the 2 disorders are allelic variants.
INTRODUCTION
THE HEREDITARY ataxias are a heterogeneous group of disorders characterized
by slowly progressive incoordination of gait and poor coordination of hand
and eye movements, associated with degeneration of the cerebellar cortex and
spinal pathways. The hereditary ataxias can be subdivided by inheritance pattern,
clinical differences, and pathologic findings.1-3
With increasing gene discovery, a molecular classification system has replaced
the clinical one.4 The descriptive term spinocerebellar ataxia (SCA) is used to denote the progressive
autosomal dominant entities, previously abbreviated ADCA. Molecular genetic
studies have so far identified the loci responsible for SCA1 to 8 and SCA10
to 17. The most common genetic mechanism implicated in the etiology of SCAs
is expansion of trinucleotide repeat sequences that leads to elongated polyglutamine
tracts in the respective proteins. The SCAs are distinguished from the dominantly
inherited episodic ataxias EA1 and EA2, which result from point mutations
in ion channels, and dentatorubral-pallidoluysian atrophy, a disorder with
a more complex phenotype. Two additional autosomal dominant complex disorders
involving cerebellar ataxia have been identified. One of these disorders,
sensory and motor neuropathy with ataxia, is characterized primarily by sensory
ataxia, but affected individuals also have evidence of a motor neuropathy.5 Sensory and motor neuropathy with ataxia maps to chromosome
7q22.32. The other disorder, ataxia/pancytopenia, has prominent hematologic
manifestations; this gene has not yet been localized.6
In North American populations the known ataxia loci are not responsible
for the disease in at least 30% of families with SCA.7
Identification of additional SCA loci will contribute to our understanding
of the neurodegenerative process. We have identified a 4-generation American
family of English and Dutch ethnicity with a "pure" cerebellar ataxia displaying
an autosomal dominant pattern of inheritance. We report evidence of linkage
of the disease phenotype to a locus on chromosome 19q, providing further evidence
of heterogeneity in this condition.
SUBJECTS AND METHODS
PEDIGREE AND CLINICAL FINDINGS
This is a 4-generation family of English and Dutch ethnic background
with 14 affected family members, including 10 women and 4 men (Figure 1). Under protocols approved by the institutional review
board of the University of Washington, Seattle, subjects were examined and
blood samples were obtained from 24 members in 2 generations of the family.
Ten subjects were affected. The pedigree demonstrates an autosomal dominant
pattern of inheritance with evidence of male-to-male transmission. The clinical
characteristics of this family are summarized in Table 1. Precise age at onset is difficult to estimate because of
the subtle and slowly progressive nature of the symptoms. However, affected
family members recalled the earliest symptoms of gait instability from ages
10 to 50 years, with a mean of 31 years. All affected persons had gait ataxia
of a mild to moderate degree. No one required a wheelchair, but several older
persons experienced frequent falls and used canes. Mild to moderate dysarthria
was common, as was hand dysmetria with clumsiness of fine motor movements.
Six persons had either horizontal jerk nystagmus or saccadic interruptions
during smooth pursuit. Several persons had hyperactive tendon reflexes with
one instance of Babinski response, but others had normal to hypoactive reflexes.
No person had sensory loss, mental retardation, cognitive decline, or axial
myoclonus. Life span did not appear to be decreased.
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Figure 1. Five-generation pedigree of a
family with a pure spinocerebellar ataxia. A diagonal line denotes individuals
who are deceased. Haplotypes are shown for all pedigree members from whom
DNA was obtained. Marker distances were taken from the Marshfield Web site.8 The haplotype that segregates with affected family
members is darkened. Markers that segregate with the disease-related haplotype
are shown in the black box.
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Table 1. Clinical Characteristics*
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A typical affected family member was individual III:16. This 71-year-old
man recalled clumsiness while running and frequent falls at approximately
age 13 years. This impairment did not prevent him from physical activity and
he became a lifelong golfer. He was a highly educated professional with a
graduate degree. In his 40s he fractured both wrists in a fall, and at age
50 years he fractured a vertebral body in a fall while climbing stairs. On
neurologic examination at age 65 years, his mental status was entirely normal.
His positive findings were moderate wide-based gait ataxia with inability
to tandem walk, moderate dysarthria, full eye movements with mild horizontal
jerk nystagmus, dysmetria on finger-to-nose testing, hyperactive ankle reflexes,
and a right Babinski reflex. Results of sensory testing were unremarkable,
and he had no parkinsonian features. A magnetic resonance image at age 66
years showed midline cerebellar atrophy (Figure 2). In the past 5 years his gait had deteriorated and he
often used a cane.
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Figure 2. Magnetic resonance image of individual
III:16 at age 66 years showing marked midline atrophy of the cerebellum.
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Family member II:7 (mother of III:16) died suddenly at age 66 years
of a ruptured left middle cerebral artery aneurysm. Microscopic slides from
her autopsy were available for review. The cerebellar cortex showed patchy
Purkinje cell loss with empty baskets but no proliferation of Bergmann astrocytes
(Figure 3). The granule cell layer
was unremarkable. The medulla showed mild gliosis in the inferior olives without
appreciable neuronal loss. The basis pontis, basal ganglia, and cerebral cortex
were unremarkable, other than the acute hemorrhage.
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Figure 3. Neuropathologic specimen from
individual II:7, who died at age 66 years. Cerebellar cortex shows empty baskets
without Purkinje cell in the Purkinje cell layer (Bielschowsky silver method,
original magnification x79.25).
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No asymptomatic obligate carriers were observed, nor was there evidence
of genetic anticipation. Clinical DNA testing in one affected family member
did not identify a trinucleotide expansion in the genes for SCA1, 2, 3, 6,
7, or 8.
DNA ANALYSIS
DNA was extracted from leukocytes or Epstein-Barr virus–transformed
B-lymphoblastoid cell lines as previously described.9
To identify the locus responsible for the phenotype in our family, we performed
a whole genome linkage analysis at the 10 centimorgan (cM) level, using the
same methodology as recently described.5 For
the region of interest, additional polymorphic markers were identified from
the Marshfield genetic map8 and obtained from
Research Genetics (Huntsville, Ala). One primer of each pair was end-labeled
with [ 32]phosphorus by a T4 kinase reaction. DNA amplification
and product scoring were performed as previously described.9
LINKAGE ANALYSIS AND HAPLOTYPE CONSTRUCTION
Power analysis and 2-point linkage analyses were performed with the
SLINK and the MLINK subprograms of the LINKAGE package version 5.110-11 as previously described.5 For regions with 2-point lod scores greater than 0.5,
multipoint analyses and haplotype reconstruction were performed with GENEHUNTER
(version 1.2).12 For the region of interest
not excluded by these analyses, VITESSE13 was
used to compute the maximum multipoint lod score. Haplotypes were also constructed
manually. Sex-averaged map distances used were described by Broman et al14 and are available from the Marshfield Web site.8
RESULTS
Assuming a disease frequency of 0.00001, 90% penetrance, and 4 alleles
of equal frequency, a simulation study using SLINK and 200 iterations suggested
that a maximum lod score of 5.06 at a recombination fraction, , of
0.00 could be obtained with the available samples. These conditions gave a
41.5% chance of obtaining a lod score greater than 3.0. Using the same penetrance
estimate, a whole genome scan across all 22 autosomes with 355 microsatellite
markers at a 10-cM level found suggestive evidence of linkage to chromosome
19, with a lod score of 2.49 for D19S571 at
= 0.00. In addition, there were 2 loci with lod score greater than 1.0 and
less than 2.0 and 8 loci with lod score greater than 0.5 and less than 1.0.
Multipoint and haplotype analyses indicated that these other signals were
false positives. More detailed mapping in the chromosome 19 region provided
a maximum 2-point lod score of 2.57 at = 0.00 for D19S254 (Table 2). Multipoint
analysis including all subjects and 10 markers yielded a maximum lod score
of 4.72 at D19S926 (Figure 4), corresponding to 100.01 KcM (Kosambi centimorgans) on
the Marshfield sex-averaged map. By haplotype construction, a 22-cM critical
region from D19S601, in band 19q13.4, to the q telomere
cosegregating with the disease was defined. All the affected individuals carried
the disease-associated haplotype (Figure 1).
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Table 2. Two-Point Linkage Analysis for Markers on Chromosome 19q
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Figure 4. Multipoint linkage analysis performed
with VITESSE using 10 markers on chromosome 19q. The maximum lod score, 4.72,
was obtained at D19S926. KcM indicates Kosambi centimorgans.
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COMMENT
We have described a family with SCA mapping to a locus in the telomeric
segment of the long arm of chromosome 19. Clinically the family displays a
pure form of cerebellar ataxia without any additional distinguishing features,
such as mental retardation, cognitive decline, visual loss, myoclonus, or
peripheral neuropathy. Of note, gene-rich chromosome 19 has already been implicated
in 3 SCAs and the dominantly inherited episodic ataxia EA2. Spinocerebellar
ataxia type 6 and EA2 are allelic variants resulting from a triplet repeat
expansion and point mutation of the  -1A voltage-dependent calcium channel
(CACNAIA) gene, respectively.15-16 CACNAIA maps to the p arm of the chromosome. Spinocerebellar
ataxia type 13 was described in a single large French family and is clinically
distinguished by the presence of mental retardation, not seen in our family.17 The SCA13 gene has not yet been identified, but according
to the consensus National Center for Biotechnology Information (NCBI) maps,
its location is centromeric to that found in our family. Spinocerebellar ataxia
type 14 was described in a single Japanese family.18
In addition to cerebellar ataxia, this family manifested the unusual presenting
finding of axial myoclonus. No gene is currently identified for SCA14, but
its chromosomal location overlaps that of our family. Although different SCAs
may be indistinguishable on the basis of clinical features, axial myoclonus
has not been described with any other SCA and has not been observed in our
family. No neuropathologic findings have been reported in many of the rare
SCAs, including SCA13 and SCA14. The fortuitous, but limited, pathologic specimens
in this family suggest a primary Purkinje cell defect.
Not surprisingly, given the large size of the critical region, query
of the NCBI database,19 based on sequence information
available on June 3, 2002, disclosed more than 250 genes mapped to the relevant
region on chromosome 19q. Additional families with ataxia linked to this region
and further recombination events are needed to narrow the critical region
to make positional cloning efforts more feasible. Identifying the gene will
facilitate our understanding of the neurodegenerative process and may lead
to further experimental, diagnostic, and therapeutic strategies in neurodegenerative
diseases.
AUTHOR INFORMATION
Accepted for publication April 18, 2002.
Author contributions: Study concept and design (Drs Brkanac, Raskind, and Bird and Ms Bylenok); acquisition
of data (Drs Brkanac, Fernandez, Nochlin, Raskind, and Bird;
Mss Bylenok and Lipe; and Mr Wolff); analysis and interpretation of
data (Drs Brkanac, Raskind, and Bird, Ms Bylenok, and Mr
Matsushita); drafting of the manuscript (Drs Brkanac,
Raskind, and Bird); critical revision of the manuscript for important
intellectual content (Mss Bylenok and Lipe; Drs Fernandez,
Nochlin, Raskind, and Bird; and Mr Matsushita); statistical expertise (Mr Matsushita and Dr Raskind); obtaining funding (Ms Bylenok and Dr Bird); administrative, technical, or
material support (Ms Lipe, Mr Wolff, and Dr Bird);
study supervision (Drs Brkanac, Raskind, and Bird);
and clinical evaluations (Dr Fernandez).
This study was supported in part by funds from the Department of Veterans
Affairs, Washington, DC (Ms Lipe, Mr Wolff, and Drs Raskind and Bird); the
Mary Gates Endowment for Students, Seattle, Wash; a grant from the National
Aeronautics and Space Administration to the Washington Space Grant program,
Seattle (Ms Bylenok); and the P. Clementz family.
We thank the many members of the family who participated in this research.
We appreciate the assistance of James Cook. We want to thank the University
of Washington Center for Human Development and Disability Genetics Core for
the use of facilities and Jeff Goldy for technical assistance.
Corresponding author and reprints: Wendy H. Raskind, MD, PhD, Department
of Medicine, Box 35-7720, University of Washington, Seattle, WA 98195-7720
(e-mail: wendyrun{at}u.washington.edu).
From the Departments of Psychiatry (Dr Brkanac), Medicine (Ms Bylenok,
Messrs Matsushita and Wolff, and Drs Raskind and Bird), Neurology (Ms Lipe
and Dr Bird), and Pathology (Dr Nochlin), University of Washington School
of Medicine, Seattle; Department of Medicine, Ohio State University, Columbus
(Dr Fernandez); and Geriatric (Ms Lipe and Dr Bird) and VISN 20 Mental Illness
(Dr Raskind) Research, Education, and Clinical Centers, Veterans Affairs Puget
Sound Health Care System, Seattle.
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