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Mesial Temporal Lobe Abnormalities in a Family With 15q26qter Trisomy
Eliane Kobayashi, MD;
Daniela Facchin, MD;
Carlos E. Steiner, MD, MSc;
Andrea A. A. Leone, MSc;
Nilma L. V. Campos, PhD;
Fernando Cendes, MD, PhD;
Iscia Lopes-Cendes, MD, PhD
Arch Neurol. 2002;59:1476-1479.
ABSTRACT
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Background The association of chromosomal imbalances and neurologic abnormalities
is well known.
Objective To describe a family with 2 brothers presenting with 15q trisomy due
to a maternal equilibrated translocation involving chromosomes 12 and 15.
Design, Setting, and Patients Among patients with epilepsy followed up in our hospital, we identified
2 brothers with epilepsy and mental retardation who presented dysmorphic features.
Detailed clinical, electroencephalographic, and magnetic resonance imaging
investigation was performed. In addition, we collected blood samples for karyotyping.
Results Clinical findings included minor dysmorphic features, mental retardation,
abnormal behavior, and secondary generalized epilepsy. Electroencephalography
showed left temporal slow waves in the older brother and background abnormality
associated with generalized and multifocal epileptiform discharges in the
other. Their magnetic resonance images showed mesial temporal lobe malformation,
including the hippocampus and parahippocampal and fusiform gyri, with abnormal
shape and axis.
Conclusions To our knowledge, this is the first report of mesial temporal lobe malformation
associated with chromosomal abnormalities. Our finding may contribute to the
understanding of the genetic mechanisms involved in central nervous system
malformations, especially in the mesial temporal lobe structures.
INTRODUCTION
THE NEUROBIOLOGICAL aspects of abnormal cortical development and epilepsy
have been poorly understood and represent a high priority in clinical neuroscience.
Identifiable harmful events that may lead to these disorders include prenatal
infections, vascular failure, and genetic factors such as single gene mutations,
polygenic or multifactorial influences, and chromosome imbalances.
Since the development of new cytogenetic techniques, many partial trisomies
and monosomies have been described in malformative syndromes, allowing a better
definition of these disorders. The distal 15q trisomy is associated with a
clinical picture characterized mainly by mental retardation, postnatal growth
retardation, epilepsy (usually generalized seizures), and additional malformations.
To date, no magnetic resonance (MR) imaging studies in patients with 15q trisomy
have been reported, and computed tomographic scans detected only cranial abnormalities
such as microcephaly or craniosynostosis.1
We describe herein the clinical presentation, MR imaging findings, and cytogenetic
findings in 2 brothers with 15q trisomy due to a maternal equilibrated translocation
involving chromosomes 12 and 15. In addition, we present data on the extended
family.
PATIENTS AND METHODS
Among patients with epilepsy followed up in our hospital, we identified
2 brothers (Figure 1) with epilepsy
and mental retardation who presented dysmorphic features. The seizures and
epilepsy syndrome, as well as the development milestones, were characterized
by clinical history. In addition, we performed detailed neurologic and dysmorphologic
examinations, including cognitive evaluation with estimated IQ (Wechsler Adult
Intelligence Scale–Revised and Wechsler Intelligence Scale for Children–Revised)
in both patients and all available relatives.
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Figure 1. Pedigree of the family studied.
Proband is indicated by an arrow (IV:10). Squares indicate males; circles,
females; triangles in generation III, spontaneous abortions; half-filled symbols,
individuals with the balanced translocation, ie, 46,X_,t(12;15)(p13.3;q26.2);
symbols filled with dark gray shading, individuals with partial trisomy of
chromosome 15, 46,X_,der(12)t(12;15)(p13.3;q26.2); and double line, consanguineous
marriage. Individual IV:7 was referred as having a normal karyotype (46,XY?);
however, it was performed almost 20 years ago with no banding.
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After obtaining informed consent, we collected blood samples for cytogenetic
studies on short-term culture of peripheric blood lymphocytes by means of
standard G-banding technique. In addition, we performed routine interictal
electroencephalograms using the international 10-20 system for electrode placement
and MR images. Imaging studies were conducted in a 2-T scanner (Elscint-Prestige;
Elscint Ltd, Haifa, Israel) including T1- and T2-weighted images in 3 orthogonal
planes with 3- to 6-mm slices. We also performed a T1 volumetric acquisition
with 1-mm thickness. The MR imaging analyses included detailed visual evaluation
and multiplanar reconstruction using a workstation for 3-dimensional image
reformatting.
RESULTS
Individual III:8 was a 42-year-old woman who was asymptomatic and had
a normal IQ. Cytogenetic evaluation identified a chromosomal translocation,
with 46,XX,t(12:15)(p13.3;q26.2) constitution. Her MR image showed only diffuse
subcortical T2 hyperintense lines, with temporal predominance and small temporal
pole arachnoid cysts.
Individual IV:7 was a male, born at term with a birth weight of 2260
g and length of 44 cm. He had died at 6 months of age. We assessed his medical
records, including pictures, and determined that he had had multiple malformations
detected at birth. These included severe microcephaly, low frontal hairline,
arched eyebrows, left microphthalmos, right anophthalmos, prominent upper
lip with thin lips, micrognathia, malformed external ears, umbilical hernia,
ectopic testes, and balanoprepucial hypospadia (Figure 2A). A low-resolution cytogenetic evaluation performed at
the time of death, 20 years earlier, was considered normal; however, his clinical
features suggest that he had a 15q monosomy.
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Figure 2. A, Individual IV:7, showing severe
microcephaly, low frontal hairline, arched eyebrows, left microphthalmos,
right anophthalmos, prominent upper lip with thin lips, micrognathia, and
malformed external ears, suggestive of 15q monosomy. B, Individual IV:8, showing
dysmorphic ears and broad nasal bridge. C, Patient IV:10, with dysmorphic
ears, broad nasal bridge, hypertelorism, and long nasolabial philtrum.
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Individual IV:8 (Figure 2B),
a 19-year-old man, had been born at term after an uncomplicated pregnancy
and delivery; birth weight was 3110 g and length was 47 cm. Neuropsychomotor
milestones showed no abnormalities, but a borderline IQ (70) was identified.
He developed generalized tonic-clonic seizures at age 3 years, with satisfactory
control on medication. In addition, he showed abnormal behavior with heteroaggressivity,
controlled with medication. Dysmorphologic evaluation showed short stature,
dysmorphic ears, broad nasal bridge, and scoliosis. His electroencephalogram
showed left temporal slow waves. The MR image showed mesial temporal region
malformation (more evident on the left side), with altered axis and shape
of the hippocampus and fusiform and parahippocampal gyri (Figure 3). An additional imaging finding was corpus callosum malformation
(not shown). Cytogenetic evaluation showed a 46,XY,der(12)t(12;15)(p13.3;
q26.2) constitution resulting in a partial 15q trisomy.
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Figure 3. Magnetic resonance imaging findings
in individuals IV:8 (A) and IV:10 (B), showing the mesial temporal malformation
pattern (arrows), with abnormal axis and shape including the hippocampus and
parahippocampal and fusiform giri.
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Individual IV:10 (Figure 2C),
an 18-year-old man, had been born at term after an uncomplicated pregnancy
and delivery; birth weight was 3530 g and length was 49 cm. He had an abnormal
neuropsychomotor development with severe mental retardation and abnormal behavior.
Estimated IQ could not be determined because he was not able to perform the
requested tests. At age 8 years he began to have generalized seizures with
poor control despite medication. Dysmorphologic evaluation showed short stature,
dysmorphic ears, broad nasal bridge, hypertelorism, long nasolabial philtrum,
high arched palate, scoliosis, and short fingers. His electroencephalogram
showed abnormal background activity with generalized and multifocal epileptiform
activity. The MR image showed mesial temporal region malformation (more evident
on the left side), with altered axis and shape of the hippocampus and fusiform
and parahippocampal gyri (Figure 3),
as well as corpus callosum malformation. Additional findings were bilateral
temporal pole arachnoid cysts and diffuse subcortical T2 hyperintense lines,
perpendicular to the gyri. Cytogenetic evaluation showed a 46,XY,der(12)t(12;15)(p13.3;q26.2)
constitution resulting in a partial 15q trisomy. This patient died suddenly
while sleeping at age 18 years, but autopsy was not performed.
Individual IV:11 16-year-old girl, had been born after an uncomplicated
pregnancy and delivery; she had normal neuropsychomotor development. She had
never had seizures but showed facial dysmorphism similar to her 2 brothers
(individuals IV:8 and IV:10). She had an estimated IQ of 86 but had important
learning difficulties; her karyotype showed an 46,XX,t(12:15)(p13.3;q26.2)
constitution, which was the same chromosomal translocation seen in her mother
(III:8). The MR image showed the same abnormalities observed in individuals
IV:8 and IV:10.
Individual IV:12 was a 15-year-old boy who had a normal phenotype and
karyotype. His MR image showed only diffuse hyperintense T2 lines.
Individual III:6, a 46-year-old woman, had been born at home and had
been very small according to information obtained from her sister (III:8).
During her first year of life she had a febrile convulsion and delayed neuropsychomotor
development. She started having tonic-clonic seizures in adulthood, partially
controlled by medication. She presented with a clear cognitive deficit; however,
we were unable to perform IQ testing because of her severe mental retardation
and abnormal behavior. On physical examination we observed short stature,
long face, high forehead, telecanthus, prognathism, flat philtrum, thin lips,
and short fifth finger with camptodactyly. Neurologic examination showed no
focal signs. Her interictal electroencephalogram was considered normal, and
the MR image showed multiple areas of gliosis attributed to head trauma, but
no identifiable hippocampal abnormalities. The cytogenetic evaluation showed
a 46,XX,der(12)t(12;15)(p13.3;q26.2) constitution (partial 15q trisomy).
Individual III:9, a 42-year-old man, showed no abnormalities on clinical
examination, with a normal IQ. The MR image was normal and his karyotype showed
the same balanced translocation (46,XY,t[12;15][p13.3;q26.2]) seen in his
sister (individual III:8). His children, aged 7 and 18 years, who were not
examined, had normal development and no seizures.
COMMENT
Cytogenetic abnormalities on chromosome 15 have been associated with
epilepsy and mental retardation with a wide range of clinical presentations.
Partial trisomy for this chromosome has been reported more often than for
any other chromosome of the D-group.2 Duplications
of the short arm and proximal segment of the long arm of chromosome 15 are
among the most common rearrangements involving this chromosome, whereas duplications
involving the distal long arm are less frequent and complete trisomy 15 is
very rare in liveborn infants.3
The clinical picture of duplication of the distal half of the long arm
of chromosome 15 is quite variable, including developmental delay, growth
retardation, dysmorphic craniofacial appearance, skeletal abnormalities, and
hand abnormalities. Some patients exhibit only a few dysmorphic features.1 Mental retardation is the most common finding,1, 3-4 and the performance
seems to depend directly on the size of the duplication.3
Growth retardation of postnatal onset is also a frequent sign, and seizures
occur in at least 30% of these patients.1, 3-4
There is a male-to-female preponderance of 1.6:1.1
After the first report of partial trisomy of the long arm of chromosome
15,5 many other patients were identified, with
the proximal break point ranging from 15q21 to 15q26. The more proximal breakpoints
(15q21 to 15q23) were more likely to be found.1
Most cases are due to an unbalanced segregation of a familial translocation,1, 3, 6 and most of these abnormalities
are maternally inherited.3, 7
One of the first reports of abnormal central nervous system structures
in vivo was the description of a girl with partial trisomy 15.2
In this report, a pneumoencephalogram showed reduced lateral ventricules combined
with an enlarged left temporal horn and some enlarged sulci in the right frontotemporal
cortex. A few reports of MR images in patients with abnormalities on chromosome
15 have been published. Leonard et al8 found
a significantly larger proportion of anomalous fissures among children with
Angelman syndrome than in children with Prader-Willi syndrome. Battaglia et
al7 described 4 patients with the inv dup(15)
syndrome, which results in 15p tetrasomy and 15q partial tetrasomy including
the Prader-Willi/Angelman critical region, 3 of them with normal MR images.
We observed different MR imaging findings in patients with the same
karyotype in 2 different generations: patients III:8, III:9, and IV:11 had
the balanced translocation 46,X_,t(12;15)(p13.3;q26.2), but different MR imaging
findings: individuals III:8 and III:9 showed no mesial temporal lobe abnormalities,
whereas patient IV:11 had hippocampal malformation. Individuals III:6, IV:8,
and IV:10, all with partial 15q trisomy, also had different MR imaging findings:
individual III:6 presented with no mesial temporal lobe malformation, as opposed
to patients IV:8 and IV:10, who had clear-cut hippocampal abnormalities. One
possible explanation for this finding is the phenomenon of imprinting, in
which clinical manifestation depends on the parental origin of the abnormal
chromosome. In generation IV, the chromosomal abnormality was maternally inherited.
However, the parental origin of the abnormal chromosome in generation III
could not be determined, since none of the parents were available for testing.
There is strong clinical and experimental evidence of maternal and paternal
imprinted genes on chromosome 15q.9 Thus, if
in generation III the chromosomal abnormality was transmitted through the
paternal line, critical genes for mesial temporal structures development could
be silenced and only the normal maternally transmitting genes would be active,
leading to normal hippocampal structures in individuals III:6, III:8, and
III:9. By contrast, the maternally inherited abnormality would have full clinical
expression in individuals in the fourth generation, leading to malformations
of mesial temporal structures in patients IV:8, IV:10, and IV:11. That the
offspring of individual III:9 (male with balanced translocation) were asymptomatic
corroborates our theory, although they have not been karyotyped. Alternatively,
one should be aware of the usual clinical variability seen in patients with
chromosomal syndromes, as well as a maternal effect, with possible duplication
or deficiency of genes expressed in the oocyte, when there is maternal transmission
of the translocation.
Our finding of clear-cut hippocampal abnormalities in patients with
partial 15q trisomy and a family member with a translocation involving chromosomes
12 and 15 suggests that this chromosomal region may contain genes that are
important for the development of mesial temporal lobe structures. A more comprehensive
understanding of the role of this chromosomal region in central nervous system
development will depend on the description of additional patients with chromosomal
15q abnormalities. Human chromosomal abnormalities have been critical to localize
genes involved in many disorders, including other types of central nervous
system malformations.10-11 Thus,
we strongly recommend that detailed neuroimaging studies should be performed
in patients with such chromosomal imbalances.
AUTHOR INFORMATION
Accepted for publication December 27, 2001.
Author contributions: Study
concept and design (Drs Kobayashi, Facchin, Steiner, Cendes, and Lopes-Cendes); acquisition of data (Drs Kobayashi, Facchin, Cendes, and
Lopes-Cendes and Ms Leone); analysis and interpretation
of data and critical revision of the manuscript for important intellectual
content (Drs Kobayashi, Facchin, Steiner, Campos, Cendes, and Lopes-Cendes
and Ms Leone); drafting of the manuscript (Drs Kobayashi,
Facchin, Steiner, and Lopes-Cendes); obtained funding
(Dr Lopes-Cendes); administrative, technical, or material
support (Drs Kobayashi, Facchin, Steiner, and Campos and Ms Leone); and study supervision (Drs Cendes and Lopes-Cendes).
Dr Kobayashi is the recipient of a scholarship from Fundação
de Amparo à Pesquisa do Estado de São Paulo (FAPESP), São
Paulo, Brazil, and Dr Facchin is the recipient of a scholarship from Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brasília,
Brazil. Drs Cendes and Lopes-Cendes are supported by Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq), Brasília,
Brazil. This study was supported by grants from FAPESP (Drs Cendes and Lopes-Cendes).
Corresponding author and reprints: Iscia Lopes-Cendes, MD, PhD, Departamento
de Genética Médica, Faculdade de Ciências Médicas—UNICAMP,
Caixa Postal 6111, Cidade Universitária Zeferino Vaz, Campinas SP,
Brazil, CEP 13083-970 (e-mail: icendes{at}unicamp.br).
From the Departamento de Neurologia (Drs Kobayashi and Cendes and Ms
Leone) and Departamento de Genética Médica (Drs Facchin, Steiner,
Campos, and Lopes-Cendes), Faculdade de Ciências Médicas, Universidade
de Campinas, Campinas, Brazil.
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