LETTER TO THE EDITORS

A novel mutation of the SGCE-gene in a German familywith myoclonus-dystonia syndrome

Christian Johannes Hartmann • Barbara Leube •

Lars Wojtecki • Beate Betz • Stefan Jun Groiss •

Peter Bauer • Alfons Schnitzler • Martin Sudmeyer

Received: 6 December 2010 / Revised: 9 January 2011 / Accepted: 10 January 2011 / Published online: 26 January 2011

� Springer-Verlag 2011

Dear Sirs,

Here we describe the clinical and genetic findings of a

40 year old female patient and her 2-years-younger sister

(Fig. 1, probands III:1 and III:2) suffering from myoclo-

nus-dystonia syndrome (MDS) with a novel missense

mutation in the gene encoding e-sarcoglycan (SGCE),

which inhibits the expression of exon 4 and leads to a

truncated and, therefore, inactive protein. MDS is an

autosomal-dominant inherited disease characterized by

a combination of dystonia and myoclonic jerks that

frequently respond to ethanol ingestion [1]. Additional

non-motor symptoms like anxiety and panic attacks,

obsessive–compulsive symptoms, or addiction may coexist.

In many cases, mutations in the SGCE-gene have been

proven to cause the disease [2].

The two sisters experienced progressive symptoms of

dystonia combined with myoclonic features in both lower

extremities since the age of 1 year. While the older patient

developed additional myoclonic jerks of the head as well as

of both arms, particularly during action, the symptoms of

her sister were less severe and limited to the lower

extremities and the trunk (online resource 1 and 2). No

other member of the family was affected (Fig. 1). The

patients never suffered from seizures or psychiatric dis-

eases. Cranial MRI, MEP, SSEP, and EEG were normal.

Laboratory testing of spinal fluid, urine, and blood did not

provide any hints for immunological or metabolic diseases.

After extraction and sequencing of the patients’ and

their father’s (Fig. 1, proband II:1) DNA, a novel hetero-

zygote point mutation with a substitution of guanosine

against adenosine at the last position of exon 4 (c.463G[A)

was detected in both patients and their father (Fig. 2a).

Different software algorithms suggested a high chance for

an aberrant splicing, and thus, the presence of a transla-

tionally relevant mutation. This prediction was confirmed

with the electrophoresis of the probands’ RT–PCR prod-

ucts on an agarose gel, which revealed a shortened RT–

PCR product for both sisters, but not for the father.

Sequencing of the short RT–PCR fragment confirmed that

the sequence of exon 3 was followed by the sequence of

exon 5 (Fig. 2b). The phenomenon of the missing exon 4 in

the cDNA had to be due to aberrant splicing, because the

coding strand of the sisters’ DNA contained the nucleotide

sequence of all exons. As the DNA sequence of exon 4

consists of 73 nucleotides, this aberrant splicing did not

only cause a deletion of relevant nucleotides [3, 4], but also

predicted to result in an inactive protein due to a frame

shift and a stop after 14 amino acids (p.I131TfsX15). In

contrast to the findings in both sisters, the RT–PCR product

of the father had a regular sequence.

Electronic supplementary material The online version of thisarticle (doi:10.1007/s00415-011-5911-6) contains supplementarymaterial, which is available to authorized users.

C. J. Hartmann (&) � L. Wojtecki � S. J. Groiss �A. Schnitzler � M. Sudmeyer

Institute of Clinical Neuroscience and Medical Psychology,

Department of Neurology, Heinrich-Heine University

Dusseldorf, Moorenstrasse 5, 40225 Dusseldorf, Germany

e-mail: christian-hartmann@uni-duesseldorf.de

B. Leube � B. Betz

Department of Human Genetics,

Heinrich-Heine University Dusseldorf,

Dusseldorf, Germany

P. Bauer

Department of Human Genetics,

Eberhard Karls University Tubingen,

Tubingen, Germany

123

J Neurol (2011) 258:1186–1188

DOI 10.1007/s00415-011-5911-6

Both sisters can be considered to have inherited this

mutation from their father, as he also is carrier of the

mutation and a maternal inheritance is generally unlikely

due to imprinting [5]. As the penetrance in paternal

inheritance is more than 90%, the manifestation of symp-

toms in both daughters is not astonishing [6]. The fact that

the father was not clinically affected and that he did not

present the aberrant splicing of exon 4, though being a

mutation carrier, can be explained by an inactivation of the

mutated gene by imprinting of the maternal allele. As

neither he nor anyone else of the family members in former

generations developed any symptoms, it is most likely that

he either inherited the gene from his mother or developed a

spontaneous mutation in SGCE-gene on the maternal

allele. We underline the importance to register novel

mutations and to add them to the preexisting list of known

mutations [7] in order to ensure an as fast and cost-effec-

tive diagnostic procedure as possible.

Fig. 2 Sequencing analysis of the probands’ nucleic acids. Because

of the fluorescent staining of dedeoxy nucleotides, different colors

represent the four nucleotides: green adenosine, blue cytosine, blackguanosine, red thymidine. a Sequencing pattern of PCR products

obtained from DNA of a control (first line), proband II:1 (secondline), and proband III:1 (third line) by use of forward primer in intron

3 and reverse primer in intron 4 of the SGCE-gene, revealing the

heterozygous substitution of adenosine against guanosine at the last

position of exon 4 in the sequence of both probands (arrows).

b Sequencing pattern of the RT–PCR fragments (exon 3 to exon 5 of

the SGCE-gene) of a control and proband II:1 reveal the regular exon

3/exon 4 and exon 4/exon 5 junctions. Sequencing of the shorter

RT–PCR fragment of proband III:1 reveals a deletion of exon 4

Fig. 1 Pedigree of the female patient (proband III:1) and her sister

(proband III:2) suffering from myoclonus-dystonia syndrome (black-colored symbols). Their father (proband II:1) is also a mutation carrier

(dotted symbol), but neither expresses a defective RNA-transcript nor

presents any symptoms. No other family member of the non-

consanguineous family presented any symptoms. Symbols marked

with a diagonal line represent deceased family members

J Neurol (2011) 258:1186–1188 1187

123

Acknowledgments Dr. Hartmann received—unrelated to the cur-

rent project—a research grant by the German Academic Exchange

Service. Dr. Leube, Stefen Groiss, Dr. Betz: declares no financial

disclosure. Dr. Wojtecki received—unrelated to the current project—

travel grants and honoraria for lectures from Meda Pharma, Boeh-

ringer, Cephalon Pharma, TEVA Pharma, Desitin, St. Jude Medical,

and Medtronic. Dr. Bauer received honoraria from Roche Diag-

nostics (Mannheim, Germany) and Actelion Pharmaceuticals (Basel,

Switzerland). He is a consultant for CENTOGENE (Rostock,

Germany) and furthermore received research grants of the German

Research Council (BMBF) to GeNeMove (01GM0603), EUROSPA

(01GM0807), and RISCA (09GM0820) as well as from the EU for

EUROSCA (LSHM-CT-2004-503304), MarkMD (FP7-People PIAP-

2008-230596), and TECHGENE (FP7-Health 2007-B 223143). A

further project received funding from the HSP-Selbsthilfegruppe

Deutschland e.V. Prof. Schnitzler declares research support by the

DFG, BMBF, Helmholtz Society, and Volkswagen Foundation. He

served—unrelated to the current project—on scientific advisory

boards of Novartis, UCB, and Cephalon. He received—unrelated to

the current project—honoraria for lectures from Boehringer

Ingelheim, Novartis, UCB, Meda Pharma, and TEVA Pharma. Dr.

Sudmeyer declares research support by the Helmholtz Society, the

‘‘Stiftung fur Altersforschung’’, and the ‘‘Forschungskommission’’,

Heinrich-Heine-University, Dusseldorf (Germany). He received—

unrelated to the current project—honoraria for lectures from Solvay,

Meda Pharma, and TEVA Pharma.

Conflict of interest None.

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