J Korean Med Sci.  2008 Dec;23(6):959-963. 10.3346/jkms.2008.23.6.959.

Clinical and Genetic Analysis of Korean Patients with Facioscapulohumeral Muscular Dystrophy

• Ki CS
• Lee ST
• Kim KS
• Kim JW
• Hong YH
• Sung JJ
• Park KS
• Lee KW

• KMID: 1107517
• DOI: http://doi.org/10.3346/jkms.2008.23.6.959

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominantly inherited muscular disorder, which is characterized by weakness of facial, shoulder and hip girdle, humeral, and anterior distal leg muscles. The FSHD gene has been mapped to 4q35 and a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4 was known to be the genetic background of the disorder. Although FSHD is the second most common muscular dystrophy in adulthood, there were few reports on the genetically confirmed patients in Korea. Recently, we experienced four Korean patients with clinical features resembling FSHD. In order to confirm the diagnosis, conventional Southern blot (SB) analysis by using double digestion with EcoRI and BlnI and hybridization with p13E-11 probe was performed in three patients and newly developed long polymerase chain reaction (PCR) method was used for one patient because genomic DNA was not enough for conventional SB for this patient. All patients were demonstrated to have shortened D4Z4 repeats that were consistent with FSHD. Therefore, we could confirm the diagnosis of FSHD in four Korean patients and appropriate genetic counseling was done for the patients and their families. It is of note that long-PCR method could be a good alternative for conventional SB when D4Z4 repeats were less than 5.

Keyword

Facioscapulohumeral Muscular Dystrophy; FSHD; D4Z4; Korean

MeSH Terms

Adolescent
Adult
Blotting, Southern
Chromosomes, Human, Pair 4
Female
Genotype
Humans
Korea
Male
Muscular Dystrophy, Facioscapulohumeral/*diagnosis/genetics
Pedigree
Phenotype
*Sequence Deletion
Tandem Repeat Sequences

Figure

• 

  Fig. 1 Pedigrees of 4 patients with FSHD. Circle, female; square, male; black symbol, affected with shortened D4Z4 repeats; gray symbol, possibly affected by history; arrow, proband; N, tested for D4Z4 repeats and found normal.

• 

  Fig. 2 Representative results of Southern blot analysis. Convential electrophoresis and Southern blot analysis of EcoRI (E) and EcoRI/BlnI (E/B) digested DNA from patient 4 and his father revealed a 28-kb sized EcoRI fragment (*) resistant to BlnI digestion only in patient 4. Another EcoRI framgenet between 38 kb and 48 kb disappeared after BlnI digestion (#). M1, 1-kb size marker; M2, high molecular weight size marker.

• 

  Fig. 3 Result of long-PCR amplification in patient 2. A 18.4 kb PCR product (*) corresponding to 3 D4Z4 repeats was detected in patient 2 (lane 1) while a 11.8 kb sized band (#) was noticed in positive control (P) with 2 D4Z4 repeats. No band was observed in the patient's brother (lane 2) and in negative control (N). M, high molecular weight size marker.

Reference

1. Kissel JT. Facioscapulohumeral dystrophy. Semin Neurol. 1999. 19:35–43.

2. Wijmenga C, Hewitt JE, Sandkuijl LA, Clark LN, Wright TJ, Dauwerse HG, Gruter AM, Hofker MH, Moerer P, Williamson R, van Ommen GB, Padberg GW, Frants RR. Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy. Nat Genet. 1992. 2:26–30.

3. van Deutekom JC, Wijmenga C, van Tienhoven EA, Gruter AM, Hewitt JE, Padberg GW, van Ommen GJ, Hofker MH, Frants RR. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet. 1993. 2:2037–2042.

4. Lunt PW, Jardine PE, Koch MC, Maynard J, Osborn M, Williams M, Harper PS, Upadhyaya M. Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD). Hum Mol Genet. 1995. 4:951–958.

5. Tawil R, Forrester J, Griggs RC, Mendell J, Kissel J, McDermott M, King W, Weiffenbach B, Figlewicz D. The FSH-DY Group. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. Ann Neurol. 1996. 39:744–748.

6. Felice KJ, Moore SA. Unusual clinical presentations in patients harboring the facioscapulohumeral dystrophy 4q35 deletion. Muscle Nerve. 2001. 24:352–356.

7. Felice KJ, North WA, Moore SA, Mathews KD. FSH dystrophy 4q35 deletion in patients presenting with facial-sparing scapular myopathy. Neurology. 2000. 54:1927–1931.

8. Krasnianski M, Eger K, Neudecker S, Jakubiczka S, Zierz S. Atypical phenotypes in patients with facioscapulohumeral muscular dystrophy 4q35 deletion. Arch Neurol. 2003. 60:1421–1425.

9. Uncini A, Galluzzi G, Di Muzio A, De Angelis MV, Ricci E, Scoppetta C, Servidei S. Facioscapulohumeral muscular dystrophy presenting isolated monomelic lower limb atrophy. Report of two patients with and without 4q35 rearrangement. Neuromuscul Disord. 2002. 12:874–877.

10. van der Kooi AJ, Visser MC, Rosenberg N, van den Berg-Vos R, Wokke JH, Bakker E, de Visser M. Extension of the clinical range of facioscapulohumeral dystrophy: report of six cases. J Neurol Neurosurg Psychiatry. 2000. 69:114–116.

11. Yamanaka G, Goto K, Matsumura T, Funakoshi M, Komori T, Hayashi YK, Arahata K. Tongue atrophy in facioscapulohumeral muscular dystrophy. Neurology. 2001. 57:733–735.

12. Tawil R, Storvick D, Feasby TE, Weiffenbach B, Griggs RC. Extreme variability of expression in monozygotic twins with FSH muscular dystrophy. Neurology. 1993. 43:345–348.

13. Tawil R, Van Der Maarel SM. Facioscapulohumeral muscular dystrophy. Muscle Nerve. 2006. 34:1–15.

14. Choi CU, Kwon JU, Kwon H, Lee SH. Facioscapulohumeral muscular dystrophy: report of two cases. J Korean Orthop Assoc. 1991. 26:1354–1358.

15. Choi YH, Hwang YK, Seo YI, Kang MS, Kim HJ, Kim NS, Suh CK, Chi JG. A family of facioscapulohumeral muscular dystrophy. J Korean Neurol Assoc. 1993. 11:121–126.

16. Ricci E, Galluzzi G, Deidda G, Cacurri S, Colantoni L, Merico B, Piazzo N, Servidei S, Vigneti E, Pasceri V, Silvestri G, Mirabella M, Mangiola F, Tonali P, Felicetti L. Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann Neurol. 1999. 45:751–757.

17. Goto K, Nishino I, Hayashi YK. Very low penetrance in 85 Japanese families with facioscapulohumeral muscular dystrophy 1A. J Med Genet. 2004. 41:e12.

18. Kekou K, Fryssira H, Sophocleous C, Mavrou A, Manta P, Metaxotou C. Facioscapulohumeral muscular dystrophy molecular testing using a non radioactive protocol. Mol Cell Probes. 2005. 19:422–424.

19. Goto K, Nishino I, Hayashi YK. Rapid and accurate diagnosis of facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2006. 16:256–261.

20. Hewitt JE, Lyle R, Clark LN, Valleley EM, Wright TJ, Wijmenga C, van Deutekom JC, Francis F, Sharpe PT, Hofker M, Frants RR, Williamson R. Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum Mol Genet. 1994. 3:1287–1295.

21. Lemmers RJ, de Kievit P, Sandkuijl L, Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM. Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet. 2002. 32:235–236.

22. Lemmers RJ, Wohlgemuth M, Frants RR, Padberg GW, Morava E, van der Maarel SM. Contractions of D4Z4 on 4qB subtelomeres do not cause facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2004. 75:1124–1130.

23. Lemmers RJ, de Kievit P, van Geel M, van der Wielen MJ, Bakker E, Padberg GW, Frants RR, van der Maarel SM. Complete allele information in the diagnosis of facioscapulohumeral muscular dystrophy by triple DNA analysis. Ann Neurol. 2001. 50:816–819.

24. Lemmers RJ, van der Wielen MJ, Bakker E, Frants RR, van der Maarel SM. Rapid and accurate diagnosis of facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2006. 16:615–617.

25. Zatz M, Marie SK, Cerqueira A, Vainzof M, Pavanello RC, Passos-Bueno MR. The facioscapulohumeral muscular dystrophy (FSHD1) gene affects males more severely and more frequently than females. Am J Med Genet. 1998. 77:155–161.

26. Matsumura T, Goto K, Yamanaka G, Lee JH, Zhang C, Hayashi YK, Arahata K. Chromosome 4q;10q translocations; comparison with different ethnic populations and FSHD patients. BMC Neurol. 2002. 2:7.