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LETTER TO THE EDITORS
Cerebellar ataxia, mental retardation and dysequilibriumsyndrome 1 (CAMRQ1) caused by an unusual constellationof VLDLR mutation
Lars Schlotawa • Alrun Hotz •
Christine Zeschnigk • Britta Hartmann •
Jutta Gartner • Deborah Morris-Rosendahl
Received: 24 February 2013 / Revised: 23 April 2013 / Accepted: 25 April 2013 / Published online: 14 May 2013
� Springer-Verlag Berlin Heidelberg 2013
Dear Sirs,
Cerebellar ataxia, mental retardation, and dysequilibrium
syndrome 1 (CAMRQ1 or DES, OMIM 224050) is a rare,
autosomal recessively inherited disorder characterized by
nonprogressive cerebellar ataxia, intellectual disability and
cerebellar hypoplasia [3, 10]. Additional clinical symptoms
comprise microcephaly, delayed ambulation, strabism,
short stature, and seizures [3, 7, 8]. In some patients qua-
drupedal walking has been observed [9, 11]. Brain MRI of
patients shows cerebellar vermis hypoplasia and missing
foliation of the hemispheres. Cerebral gyration may be
simplified with cortical thickening [5, 7–9, 11]. DES is
caused by mutations in the VLDLR gene (OMIM 192977)
on chromosome 9p24, encoding the VLDL receptor [2, 3,
7–9]. This receptor is part of the reelin (RELN) pathway in
neurons responsible for neuronal migration in the cerebral
cortex and cerebellum [4, 6]. Eight different VLDLR
mutations have been reported (see Table 1) [2, 3, 7–9]. A
comprehensive picture of the phenotypic spectrum of the
disease and correlation of genotype and phenotype is
lacking due to a limited number of patients.
We report a male patient born to German parents who
were closely related (degree of relatedness undisclosed). At
birth the head circumference measured 29 cm (\-3 SD).
Failure to thrive was observed during the first weeks of life.
Psychomotor development was delayed. At 2 years of age
the patient began to sit unaided and speech developed but
never exceeded two combined words. Generalized seizures
appeared at this time; at age 6 years absence-like episodes
appeared frequently. At age 9 years the patient still showed
microcephaly with a head circumference of 49 cm (\3rd
centile), length between the 3rd and 10th percentile, and
body weight between the 25th and 50th percentile. He was
able to combine two words, but articulation was severely
compromised due to dysarthria. Severe cerebellar ataxia
affected his arms and legs. The patient has never achieved
free ambulation, walking is only possible by pushing a
wheelchair with an unstable gait and frequent falls.
Reflexes were not altered, but muscle tone was reduced.
Visual as well as hearing abilities were not compromised.
The patient has no control over bowel or bladder function.
Cranial MRI showed mildly simplified cerebral gyral pat-
tern with cortical thickening (Fig. 1a, b); a normal corpus
callosum (Fig. 1c) and severe cerebellar hypoplasia with
hypoplasia of the cerebellar vermis (Fig. 1c, d). Mesen-
cephalon, pons and medulla oblongata were slightly
hypoplastic (Fig. 1d). EEG displayed generalized spike-
wave discharges. Complete metabolic testing in blood,
urine, and CSF did not show any abnormalities.
Sequence analysis in the VLDLR gene showed that the
patient was homozygous for each of two mutations:
c.820C [ T and c.820 ? 1G [ C affecting neighbouring
nucleotides at the exon 5/intron 5 splice junction. The
Electronic supplementary material The online version of thisarticle (doi:10.1007/s00415-013-6941-z) contains supplementarymaterial, which is available to authorized users.
L. Schlotawa (&) � J. Gartner
Department of Pediatrics, University Medical Center Gottingen,
Robert-Koch-Str. 40, 37075 Gottingen, Germany
e-mail: [email protected]
A. Hotz � C. Zeschnigk � B. Hartmann � D. Morris-Rosendahl
Institute of Human Genetics, Albert-Ludwigs University
Medical Center Freiburg, Breisacher Str. 33,
79106 Freiburg, Germany
D. Morris-Rosendahl (&)
Molecular Genetics and Genomics, National Heart and Lung
Institute, Imperial College London, SW3 6LY London, UK
e-mail: [email protected]
123
J Neurol (2013) 260:1678–1680
DOI 10.1007/s00415-013-6941-z
Table 1 Mutations in the VLDLR gene including those found in this study
Position in
gene
Type of
mutation
Mutation at cDNA level Mutation at protein
level
Inheritance Ethnic back-ground of
patients
Reference
Exon 1–5 21,190 kb
deletion
chr 9p24.2: 2.612148-
2.633.338
Homozygous Turkish Kolb et al. [7]
Exon 5 Nonsense c.769C [ T p.R257X Homozygous Turkish Ozcelik et al. [9]
Exon 5 Splice site c.820C [ T p.P274SfsX2 Homozygous German This study
Intron 5 Splice site c.820 ? 1G [ C Homozygous
Exon 10 Nonsense c.1342C [ T p.R448X Homozygous Iranian Moheb et al. [8]
Exon 11 Missense c.1561G [ C p.D521H Compound
heterozygous
Scottish-German Boycott et al. [3]
Exon 12 Frameshift c.1711_1712dupT p.Y571LfsX7 Irish-German
Exon 15 Missense c.2240G [ T p.R747L Homozygous Omani Al-Gazali
et al. [1]
Exon 17 Frameshift c.2339delT p.I780TfsX3 Homozygous Turkish Turkmen et al. [11]
Exon 1–19 199,163 kb
deletion
Entire coding region Homozygous Hutterite Boycott et al. [3]
B
DC
A
A A C T G T C G T A A G T A
Mother
Patient
Control
CT
GCCT
E
C C C T T T G T GA
Intron5 CC C T C T C G T T
Exon6C A G T G A GAGT
Exon6
G
FVLDLR Ex 3-7 Control amplicon
Marker (bp)
Fig. 1 Cranial MRI pictures and molecular analysis of the VLDLRgene of a patient with DES a, b Mildly simplified cerebral gyral
pattern with cortical thickening. c, d Severe cerebellar hypoplasia
with hypoplasia of the cerebellar vermis, normal corpus callosum and
slightly hypoplastic mesencephalon, pons and medulla oblongata.
e DNA analysis of the VLDLR gene in the patient, his mother and a
healthy control. The patient is homozygous for two mutations:
c.820C [ T and c.820 ? 1G [ C, the mother heterozygous for both
changes. f Fragment analysis of the patient’s cDNA revealed weak
transcripts, with an additional slightly larger transcript in the patient
due to the retention of intron 5. g Reverse-strand sequencing of
patient cDNA derived from transformed lymphocytes showing the
retention of intron 5 in one transcript
J Neurol (2013) 260:1678–1680 1679
123
patient’s mother was heterozygous for both these changes
(Fig. 1e). She showed no neurological and neuropsycho-
logical symptoms which indicated further testing. Since no
material from the father was available, the possibility of a
deletion of one VLDLR allele or maternal uniparental dis-
omy in the patient was eliminated using quantitative PCR
and microsatellite analysis, respectively (Supplementary
material and Supplementary Table 1). Fragment analysis of
cDNA products in lymphocytes from the patient revealed
two alternate transcripts: one in which intron 5 (96 bp) was
retained, and the other in which an earlier potential splice
donor site at position c.809_812 (AGGT) in exon 5 was
used, thus eliminating the last 10 nucleotides of exon 5
(Fig. 1f, g). Both transcripts are predicted to lead to
frameshift mutations, ending with stop codons. The latter,
shorter transcript would also involve the deletion of the
amino acids V271, N272 and C273 at the end of exon 5.
Although the patient presents with this unusual con-
stellation of VLDLR mutations, the clinical and brain MRI
findings reported are in line with previously described
cases of DES [2, 3, 7–9]. Despite the growing diversity of
VLDLR mutations, the clinical as well as neuroradiological
presentation of patients is relatively constant. Our data
confirm and expand the phenotype of this rare disorder.
Furthermore, they emphasize that there does not appear to
be a genotype-phenotype correlation in DES caused by
VLDLR mutations.
Acknowledgments We are grateful to the patient and his mother for
their cooperation, and to Elke Jantz-Schuble, Angela Steiert and
Christine Hodler for technical assistance.
Conflicts of interest The authors declare that they have no conflict
of interest.
Ethical standard Informed consent was obtained from the patient
and his mother.
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