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Three cases of manifesting female carriers in patients with Duchenne muscular dystrophy.
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PMID:  21155054     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Duchenne muscular dystrophy usually affects males. However, females are also affected in rare instances. Approximately 8% of female Duchenne muscular dystrophy (DMD) carriers are manifesting carriers and have muscle weakness to some extent. We investigated the clinical features of 3 female patients with dystrophinopathy diagnosed by clinical, pathological, and genetic studies at our neuromuscular disease clinic. The onset age of manifesting symptoms varied (8-28 years). Muscle weakness grade varied as follows: patient 1 showed asymmetrical bilateral proximal upper and lower extremities weakness, patient 2 showed asymmetrical bilateral upper extremities weakness similar to scapulohumoral muscular dystrophy, and patient 3 had only bilateral asymmetric proximal lower extremities weakness. Two patients had familial histories of DMD (their sons were diagnosed with DMD), but the 1 remaining patient had no familial history of DMD. The serum creatine kinase level was elevated in all patients, but it was not correlated with muscular weakness. An electromyography study showed findings of myopathy in all patients. One patient was diagnosed with a DMD carrier by a muscle biopsy with an immunohistochemical stain (dystrophin). The remaining 2 patients with familial history of DMD were diagnosed by multiplex ligation-dependent probe amplification (MLPA). There were inconsistent clinical features in the female carriers. An immunohistochemical analysis of dystrophin could be useful for female carrier patients. Also, multiplex ligation-dependent probe amplification is essential for the diagnosis of a manifesting female carrier DMD in female myopathic patients because conventional multiplex PCR could not detect the duplication and is less accurate compared to MLPA.
Authors:
Tae-Jin Song; Kyung-A Lee; Seong-Woong Kang; Hanna Cho; Young-Chul Choi
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Publication Detail:
Type:  Case Reports; Journal Article    
Journal Detail:
Title:  Yonsei medical journal     Volume:  52     ISSN:  1976-2437     ISO Abbreviation:  Yonsei Med. J.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-14     Completed Date:  2011-05-03     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0414003     Medline TA:  Yonsei Med J     Country:  Korea (South)    
Other Details:
Languages:  eng     Pagination:  192-5     Citation Subset:  IM    
Affiliation:
Departments of 1Neurology and 2Laboratory Medicine, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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MeSH Terms
Descriptor/Qualifier:
Adult
Child
Female
Humans
Muscular Dystrophy, Duchenne / diagnosis*
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Journal Information
Journal ID (nlm-ta): Yonsei Med J
Journal ID (publisher-id): YMJ
ISSN: 0513-5796
ISSN: 1976-2437
Publisher: Yonsei University College of Medicine
Article Information
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© Copyright: Yonsei University College of Medicine 2011
open-access:
Received Day: 02 Month: 3 Year: 2009
Revision Received Day: 01 Month: 5 Year: 2009
Accepted Day: 15 Month: 5 Year: 2009
Print publication date: Day: 01 Month: 1 Year: 2011
Electronic publication date: Day: 30 Month: 11 Year: 2010
Volume: 52 Issue: 1
First Page: 192 Last Page: 195
ID: 3017697
PubMed Id: 21155054
DOI: 10.3349/ymj.2011.52.1.192

Three Cases of Manifesting Female Carriers in Patients with Duchenne Muscular Dystrophy
Tae-Jin Song1
Kyung-A Lee2
Seong-Woong Kang3
Hanna Cho1
Young-Chul Choi1
1Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.
2Department of Laboratory Medicine, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
3Department of Rehabilitation Medicine and Rehabilitation Institute of Muscular Disease, Yonsei University College of Medicine, Seoul, Korea.
Correspondence: Corresponding author: Dr. Young-Chul Choi, Department of Neurology, Yonsei University College of Medicine, Gangnam Severance Hospital, 712 Eonju-ro, Gangnam-gu, Seoul 135-720, Korea. Tel: 82-2-2019-3323, Fax: 82-2-3462-5904, ycchoi@yuhs.ac

INTRODUCTION

Two-thirds of mothers of affected males are thought to be Duchenne muscular dystrophy (DMD) gene carriers and approximately 8% of female DMD carriers have muscle weakness to some extent and are designated as manifesting DMD carriers.1-3 We investigated the clinical features of 3 female myopathic carrier patients with DMD.


CASE REPORT
Case 1

A 9 year-old girl was admitted with complaints of slow, progressive proximal limb weakness that started 1 year prior. Until the age of 8, she had grown up without abnormality, developed a normal walking course, and normal cognitive function. There was no familial history of neuromuscular disease, including her elder brother. Upon neurological examination, she showed normal intelligence and no cranial nerve abnormality. However, her bilateral limb-girdle muscular power decreased (right arm abductor, arm elevator, arm adductor, forearm flexor, forearm extensor G4+/left arm abductor, arm elevator, arm adductor, forearm flexor, forearm extensor G4°/right hip flexor, hip extensor, knee flexor, knee extensor G4°/left hip flexor, hip extensor, knee flexor, knee extensor G4+). Gower signs and bilateral calf muscle pseudohypertrophy were also observed. Liver enzymes, serum CK, lactate dehydrogenase, and aldolase were elevated (AST: 97 IU/L; ALT: 225 IU/L; and CK: 456 1 U/L, CK-MB 225 U/L, LDH 1714 IU/L, and Aldolase 16.4 U/mL). The patient also showed normal findings for viral hepatitis markers and arterial blood gas analysis. Electrocardiography and cardiac echocardiography showed no abnormal findings. An electromyography study revealed spontaneous activity (positive sharp waves) and short duration polyphasic potentials in voluntary contraction. We carried out a muscle biopsy on the left vastus lateralis muscle because limb-girdle muscular dystrophy was suspected as the patient was female and did not have a familial history of DMD. The expression of dystrophin protein showed mosaic patterns on a dystrophin immunohistochemical stain from a muscle biopsy (Fig. 1). The other immunohistochemical stain for detecting limb girdle muscular dystrophy and congenital myopathy revealed no abnormality. Accordingly, she was diagnosed as a DMD carrier.

Case 2

A 32 year-old woman was admitted with complaints of progressive limb weakness that started 9 years prior. She had 2 sons who were diagnosed by exon duplication (exon 52, 53, 56-61) with DMD. On a neurological examination, she showed intellectual disability (IQ = 70) and her bilateral upper extremities, especially scapulohumoral lesion, showed muscular weakness (right arm abductor, elevator, adductor G4°/left arm abductor, elevator, adductor G4+). The power of other muscles was within a relatively normal range. Gower signs and bilateral calf pseudohypertrophy were not observed. Serum CK was mildly elevated (CK: 3708 U/L). Cardiac echocardiography showed normal findings, but ECG findings revealed the R/S > 1 in Vl, 2 leads, and deep Q wave in I, V4-6 leads. An electromyography study revealed spontaneous activity (fibrillation and positive sharp waves) and short duration polyphasic potentials in voluntary contraction. A conventional multiplex polymerase chain reaction (PCR) had negative findings, but a multiplex ligation-dependent probe amplification (MLPA) revealed exon duplication at exon 52, 53, 56-61.

Case 3

A 34 year-old woman was admitted with complaints of progressive weakness in both legs that started 6 years prior. She had 2 sons, who were diagnosed by exon deletion (exon 43, 44 and 45) with DMD. On a neurological examination, she showed intellectual disability (IQ = 78) and her bilateral lower extremities showed muscular weakness (right hip flexor, hip extensor, knee flexor, knee extensor G3°/left hip flexor, hip extensor, knee flexor, knee extensor G4-). The power of the other muscles was within a relatively normal range. Gower signs and bilateral calf pseudohypertrophy were not observed. Serum CK was mildly elevated (CK: 1289 U/L). Electrocardiography and cardiac echocardiography showed no abnormal findings. An electromyography study revealed spontaneous activity (fibrillation and positive sharp waves) and short duration polyphasic potentials in voluntary contraction. A conventional multiplex PCR had negative findings but a MLPA revealed exon deletion at 43, 44 and 45.


DISCUSSION

The clinical features of female carriers in this study were inconsistent. In Duchenne and Becker dystrophinopathic carriers, muscular weakness is predominantly asymmetric (81.8%). 41% of dystrophinopathic carriers have weakness limited to the upper extremities, 23% of carriers have weakness of the lower extremities, and 36% of carriers have muscular weakness of the upper and lower extremities.4 In this study, the patients revealed asymmetrical muscular weakness in different lesion.

Serum CK levels are elevated in approximately 45-70% of carriers and the measurement of serum CK is the most commonly used method for detecting carriers.5 In our cases, serum CK levels were elevated in all patients. But, although muscular weakness was more severe in the third case, the serum CK level was lowest. The CK level is usually due to the progressive involvement of muscle function. Further study regarding the correlation between the serum CK level and muscular weakness is requested in female carriers. In DMD carriers, incidences of cardiac involvement progresses with age. Researchers reported latent and clinical cardiac involvement in 55% of carriers under the age of 16 and in 90% of carriers after the age of 16, especially dilated cardiomyopathy.6 Abnormal ECG patterns were reported (R/S > 1 in Vl, 2: deep Q wave in I, V4-6) in 6.6-16.44% of female carriers of DMD.7 In this case, ECG findings of the second case were compatible with the previous report. However, ECG and echocardiographs of the other patients showed whole normal findings.

The dystrophin is localized on the cytoplasmic surface of the plasma membrane of skeletal and cardiac muscle cells.8 The mosaic distribution of dystrophin-positive and -negative fibers in the skeletal and cardiac muscles of biopsy is the characteristic finding of a DMD carrier.9 The surface membranes of muscles in DMD patients do not react with anti-dystrophin antiserum, while those from carriers show a mosaic pattern.9 In the first case, we could diagnosis the DMD manifesting carrier because the patient's biopsy revealed a typical mosaic pattern in immunohistochemical stains. Therefore, the dystrophin immunohistochemistry could be useful to diagnosis what type of myopathy is present and whether mosaicism is present in female myopathic patients.

The multiplex PCR have traditionally been used in a clinical diagnostic set up and allow a detection of 90-95% of the deletions in male patients, but duplications are not identified in DMD.10-12 However, the MLPA method has turned out to be reliable and accurate for identifying duplications and deletions in DMD.13,14 The MLPA technique could increase mutation pick-up rate by 33% rather than PCR.14 Moreover, the technique could confidently identify carrier individuals.14 In our cases, exon duplication detected in case 2, on the other hand, exon deletion also detected in case 3 but the PCR could not detect genetic abnormality. These results support that MLPA is essential for diagnosis of manifesting female carrier DMD in female myopathic patients because conventional multiplex PCR could not detect the duplication and is less accurate compared to MLPA.


Notes

The authors have no financial conflicts of interest.

References
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2. Ceulemans BP,Storm K,Reyniers E Jr,Callewaert L,Martin JJ. Muscle pain as the only presenting symptom in a girl with dystrophinopathyPediatr NeurolYear: 200838646618054699
3. Hoffman EP,Arahata K,Minetti C,Bonilla E,Rowland LP. Dystrophinopathy in isolated cases of myopathy in femalesNeurologyYear: 1992429679751579251
4. Hoogerwaard EM,Bakker E,Ippel PF,Oosterwijk JC,Majoor-Krakauer DF,Leschot NJ,et al. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in The Netherlands: a cohort studyLancetYear: 19993532116211910382696
5. Griggs RC,Mendell JR,Brooke MH,Fenichel GM,Miller JP,Province M,et al. Clinical investigation in Duchenne dystrophy: V. Use of creatine kinase and pyruvate kinase in carrier detectionMuscle NerveYear: 1985860674058458
6. Politano L,Nigro V,Nigro G,Petretta VR,Passamano L,Papparella S,et al. Development of cardiomyopathy in female carriers of Duchenne and Becker muscular dystrophiesJAMAYear: 1996275133513388614119
7. Lukasik E. Electrocardiographic studies in female carriers of Duchenne muscular dystrophyJ NeurolYear: 197520927928551911
8. Hoffman EP,Brown RH Jr,Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locusCellYear: 1987519199283319190
9. Arahata K,Ishihara T,Kamakura K,Tsukahara T,Ishiura S,Baba C,et al. Mosaic expression of dystrophin in symptomatic carriers of Duchenne's muscular dystrophyN Engl J MedYear: 19893201381422643040
10. Chamberlain JS,Gibbs RA,Ranier JE,Nguyen PN,Caskey CT. Deletion screening of the Duchenne muscular dystrophy locus via multiplex DNA amplificationNucleic Acids ResYear: 19881611141111563205741
11. Beggs AH,Koenig M,Boyce FM,Kunkel LM. Detection of 98% of DMD/BMD gene deletions by polymerase chain reactionHum GenetYear: 19908645482253937
12. Kunkel LM,Snyder JR,Beggs AH,Boyce FM,Feener CA. Lindsten J,Petterson USearching for dystrophin gene deletions in patients with atypical presentationsEtiology of Human Diseases at the DNA LevelYear: 1991New YorkRaven Press5160
13. Schouten JP,McElgunn CJ,Waaijer R,Zwijnenburg D,Diepvens F,Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplificationNucleic Acids ResYear: 200230e5712060695
14. Schwartz M,Dunø M. Multiplex ligation-dependent probe amplification is superior for detecting deletions/duplications in Duchenne muscular dystrophyClin GenetYear: 20056718919115679833

Article Categories:
  • Case Report
    • Neurology & Neurosciences

Keywords: Dystrophinopathy, female carrier, multiplex ligation-dependent probe amplification.

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