HUMAN MUTATION Mutation in Brief #992 (2007) Online

MUTATION IN BRIEF

2007 WILEY-LISS, INC.

Received 7 May 2007; accepted revised manuscript 5 October 2007.

Myoclonus-dystonia: Significance of Large SGCE Deletions A. Grnewald1,2, A. Djarmati1,2, K. Lohmann-Hedrich1,2, K. Farrell3, J.A. Zeller4, N. Allert5, F. Papengut4, B. Petersen6, V. Fung7, C.M. Sue7,8,9, D. O'Sullivan10, N. Mahant7, A. Kupsch11, R.S. Chuang12, K. Wiegers1,2, H. Pawlack1,2, J. Hagenah1,2, L.J. Ozelius13, U. Stephani6, R. Schuit14, A.E. Lang12, J. Volkmann4, A. Mnchau15, and C. Klein1,2*

Departments of 1Neurology and, 2Human Genetics, Lbeck University, Lbeck, Germany; 3Department of Pediatrics, University of British Columbia, Vancouver, Canada; 4Department of Neurology, Christian Albrechts University, Kiel, Germany; 5Neurological Rehabilitation Centre Godeshhe, Bonn, Germany; 6Department of Neuropediatrics, Christian Albrechts University, Kiel, Germany; 7Department of Neurology, Westmead Hospital, Westmead, Australia; 8Department of Neurology and, 9Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, Australia; 10St. Vincent's Hospital, Darlinghurst, Australia; 11Charit Hospital, Humboldt University, Berlin, Germany; 12Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, Toronto, Canada; 13Department of Genetics, Albert Einstein College of Medicine, New York; 14MRC-Holland, Amsterdam, The Netherlands; 15Department of Neurology, University of Hamburg, Hamburg, Germany

*Correspondence to: Christine Klein, MD, Dept. of Neurology, University of Lbeck, Ratzeburger Allee 160, 23538 Lbeck, Germany; Tel.: +49-451-2903353; Fax: +49-451-2903355; E-mail: christine.klein@neuro.uni-luebeck.de

Grant sponsor: Volkswagen Foundation, Fritz Thyssen Foundation. Communicated by Andreas Gal

Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotypephenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing. 2007 Wiley-Liss, Inc.

KEY WORDS: COL1A2; deletion; myoclonus-dystonia; MLPA; SGCE

DOI: 10.1002/humu.9521

2 Grnewald et al.

INTRODUCTION

Myoclonus-dystonia (M-D) is a rare autosomal dominant movement disorder characterized by a combination of rapid, brief muscle contractions and/or sustained twisting and repetitive movements that result in abnormal postures. While myoclonic jerks most often affect neck, trunk, and upper limbs, involvement of the legs is less common. Age of onset is usually in childhood or early adolescence. Alcohol ingestion is reported to ameliorate these signs in most cases [Gasser, 1998; Klein and Ozelius, 2002; Nemeth, 2002; Klein, 2003].

Epsilon-sarcoglycan (SGCE; MIM# 604149) is the sole gene that is unequivocally associated with M-D. However, mutations are only found in a minority of screened cases (Table 1). Until the end of 2006, 38 sequence changes were identified in SGCE by sequence analysis, including nine recurrent mutations (Fig. 1).

Moreover, an interstitial deletion of chromosome 7q encompassing the entire SGCE gene has been reported in one patient with a phenotype combining a variety of dysmorphic features and language delay with myoclonus [DeBerardinis et al., 2003]. Recently, deletions of single exons have been described in two patients [Asmus et al., 2005]. Exon rearrangements are not detectable with qualitative screening methods and may explain at least part of the mutation-negative cases with a typical M-D phenotype.

We systematically evaluated the role of exon rearrangements in a group of 35 M-D index patients and available family members and compared the genotype and phenotype within the study sample and patients published in the literature. Figure 1. Schematic representation of the SGCE gene and identified mutations. Point mutations are indicated above the gene, and small deletions and exon rearrangements are shown below the gene. Mutations detected in the current study are emphasized by bold characters. The number of published reports of each mutation is given in parentheses, and the respective references are given in the legend. Numbering of the mutation according to the translation start as +1; GenBank reference sequence: NM_001099401.1. The sequence encoding the transmembrane domain of SGCE is highlighted in gray. * mutation also includes 82bp of the adjacent intron. Letter-key: A Asmus et al., 2002 J Hedrich et al., 2004a

B Asmus et al., 2005 K Hjermind et al., 2003 C Cif et al., 2004 L Klein et al., 2002a D DeBerardinis et al., 2003 M Marechal et al., 2003 E Doheny et al., 2002b N Muller et al., 2002 F du Montcel et al., 2006 O ORiordan et al., 2004 G Foncke et al., 2003 P Schule et al., 2004 H Gerrits et al., 2006 Q Valente et al., 2005 I Han et al., 2003 R Zimprich et al., 2001

Significance of Large SGCE Deletions 3

Table 1A. Review of recent case reports on screening for SGCE mutations in M-D patients

No. Case report reference (original clinical description)

No. of patients (all M-D)

No. of mut. carriers

Pos. family history of mut. carriers

No. of mut.-pos. families with exceptions from imprint

Atypical features in mut. carriers

Psychiatric tures Comments

index (add. aff. FMs)

index (add. aff. FMs avail. for testing)

(family code) (No. of Cases) (No. of Cas

1/2 Zimprich et al. , 2001; Grabowski et al. , 2003 (Scheidtmann et al. , 2000; Asmus et al ., 2001)

6 (31) 6 (22) 6/6 1/6 (MD7); aff. daughter inherited mut. from mother

none alcohol abu ), panic attacks (1) all families previously known to be linked to the SGCE region

3 Asmus et al. , 2002 9 (15) 9 (15) 7/9 0/1 none alcohol abu ), panic attacks (2) in 3 families linkage previously known

4 Klein et al. 002 (Dohney et al. , 2002a)

2 (10) 2 (9) 2/2 n/a; gender disguised

none depression nxiety (5), , 2

panic attack ), OCD (3), alcohol/dru use (2), attention de disorder (1), personality rder (1)

the 1 non-mut. carrier had possible dystonia only; several members of both families carry add. mut. in other genes (DRD2 or DYT1 )

5 Dohney et al. , 2002b 2 (14) 2 (12) 2/2 n/a; gender disguised

none alcohol/dru use (4), depression schizophrenia (2), anxiety (3), ic attacks (3), phobic diso (2), OCD (3), nonspecific chotic disorder (1)

Family F3 included in Foncke et al. , 2003

6 Muller et al , 2002 (Kock et al. , 2004)

1 (0) 1 (0) 0/1 n/a none n.r. first evidence of maternal imprinting of SGCE ; Family V include in Schule et al. , 2004

7 Marecha et al. , 2003 1 (5) 1 (3) 1/1 0/1 no response to alcohol (3) OCD; depre n none

8 Hjermind al. , 2003 1 (8) 1 (8) 1/1 0/1 positive response to L-dopa (1); prominent lower limb involvement

n/a n/a

9 Foncke et al , 2003 1 (9) 1 (3) 1/1 1/1 (F3); aff. son inherited disease from mother

epilepsy and EEG changes depression none

10 DeBerardinis et al. , 2003 1 (0) 1 (0) 0/1 n/a microcephaly, short stature, dysmorphic face, language delay

n.r. interstitial deletion affecting chromosome 7q21

11 Hedrich et . , 2004b 2 (4) 2 (2) 1/2 0/1 none n.r. report of de novo mut.; Families A and C included in Gerrits et al. , 2006

12 O'Riordan et al. , 2004 1 (3) 1 (3) 1/1 0/1 epilepsy (3) n.r. 2 mutation carriers without any myoclonus

13 Cif et al. , 2004 1 (7) 1 (0) 1/1 1/1; aff. son inherited disease from mother

none none treatment of an M-D patient with deep brain stimulation

14 Asmus et al , 2005 2 (7) 2 (5) 2/2 0/2 none none first report of single exonic deletion in SGCE

Total 30 (113) 30 (82) 25/30 3/15

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Abbreviations: add. additional; aff. affected; D-M dystonia-myoclonus [Lang, 1997]; FM family member; mut. mutation; n/a not available; neg. negative; not reported; OCD obsessive compulsive disorder; pos. positive

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4 Grnewald et al.

Table 1B. Review of recent studies on screening for SGCE mutations in