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: lars.schlotawa@med.uni-goettingen.de

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: d.morris-rosendahl@imperial.ac.uk

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

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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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