Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E

Claudio Semplicini; John Vissing; Julia R Dahlqvist; Tanya Stojkovic; Luca Bello; Nanna Witting; Morten Duno; France Leturcq; Cinzia Bertolin; Paola D'Ambrosio; Bruno Eymard; Corrado Angelini; Luisa Politano; Pascal Laforêt; Elena Pegoraro

doi:10.1212/WNL.0000000000001519

Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E

Claudio Semplicini, John Vissing, Julia R Dahlqvist, Tanya Stojkovic, Luca Bello, Nanna Witting, Morten Duno, France Leturcq, Cinzia Bertolin, Paola D'Ambrosio, Bruno Eymard, Corrado Angelini, Luisa Politano, Pascal Laforêt, Elena Pegoraro

30 Citations (Scopus)

Abstract

OBJECTIVE: To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease.

METHODS: All LGMD2E patients followed in participating centers were included. A specific clinical protocol was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed.

RESULTS: Thirty-two patients were included (16 male, 16 female; age 7-67 years; 15 severe, 12 mild, and 5 unknown). Neurologic examination showed proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). Seventeen different mutations were identified, and 3 were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation.

CONCLUSIONS: This study expands the spectrum of phenotype in β-sarcoglycanopathy and provides strong evidence that severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan protein expression.

Original language	English
Journal	Neurology
Volume	84
Issue number	17
Pages (from-to)	1772-81
Number of pages	10
ISSN	0028-3878
DOIs	https://doi.org/10.1212/WNL.0000000000001519
Publication status	Published - 28 Apr 2015

Keywords

Adolescent
Adult
Age Factors
Aged
Child
Consanguinity
Female
Humans
Male
Middle Aged
Mutation
Phenotype
Prognosis
Sarcoglycanopathies
Sarcoglycans
Severity of Illness Index
Young Adult

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10.1212/WNL.0000000000001519

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title = "Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E",

abstract = "OBJECTIVE: To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease.METHODS: All LGMD2E patients followed in participating centers were included. A specific clinical protocol was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed.RESULTS: Thirty-two patients were included (16 male, 16 female; age 7-67 years; 15 severe, 12 mild, and 5 unknown). Neurologic examination showed proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). Seventeen different mutations were identified, and 3 were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation.CONCLUSIONS: This study expands the spectrum of phenotype in β-sarcoglycanopathy and provides strong evidence that severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan protein expression.",

keywords = "Adolescent, Adult, Age Factors, Aged, Child, Consanguinity, Female, Humans, Male, Middle Aged, Mutation, Phenotype, Prognosis, Sarcoglycanopathies, Sarcoglycans, Severity of Illness Index, Young Adult",

author = "Claudio Semplicini and John Vissing and Dahlqvist, {Julia R} and Tanya Stojkovic and Luca Bello and Nanna Witting and Morten Duno and France Leturcq and Cinzia Bertolin and Paola D'Ambrosio and Bruno Eymard and Corrado Angelini and Luisa Politano and Pascal Lafor{\^e}t and Elena Pegoraro",

note = "{\textcopyright} 2015 American Academy of Neurology.",

year = "2015",

month = apr,

day = "28",

doi = "10.1212/WNL.0000000000001519",

language = "English",

volume = "84",

pages = "1772--81",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams & Wilkins",

number = "17",

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TY - JOUR

T1 - Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E

AU - Semplicini, Claudio

AU - Vissing, John

AU - Dahlqvist, Julia R

AU - Stojkovic, Tanya

AU - Bello, Luca

AU - Witting, Nanna

AU - Duno, Morten

AU - Leturcq, France

AU - Bertolin, Cinzia

AU - D'Ambrosio, Paola

AU - Eymard, Bruno

AU - Angelini, Corrado

AU - Politano, Luisa

AU - Laforêt, Pascal

AU - Pegoraro, Elena

PY - 2015/4/28

Y1 - 2015/4/28

N2 - OBJECTIVE: To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease.METHODS: All LGMD2E patients followed in participating centers were included. A specific clinical protocol was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed.RESULTS: Thirty-two patients were included (16 male, 16 female; age 7-67 years; 15 severe, 12 mild, and 5 unknown). Neurologic examination showed proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). Seventeen different mutations were identified, and 3 were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation.CONCLUSIONS: This study expands the spectrum of phenotype in β-sarcoglycanopathy and provides strong evidence that severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan protein expression.

AB - OBJECTIVE: To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease.METHODS: All LGMD2E patients followed in participating centers were included. A specific clinical protocol was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed.RESULTS: Thirty-two patients were included (16 male, 16 female; age 7-67 years; 15 severe, 12 mild, and 5 unknown). Neurologic examination showed proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). Seventeen different mutations were identified, and 3 were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation.CONCLUSIONS: This study expands the spectrum of phenotype in β-sarcoglycanopathy and provides strong evidence that severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan protein expression.

KW - Adolescent

KW - Adult

KW - Age Factors

KW - Aged

KW - Child

KW - Consanguinity

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Phenotype

KW - Prognosis

KW - Sarcoglycanopathies

KW - Sarcoglycans

KW - Severity of Illness Index

KW - Young Adult

U2 - 10.1212/WNL.0000000000001519

DO - 10.1212/WNL.0000000000001519

M3 - Journal article

C2 - 25862795

SN - 0028-3878

VL - 84

SP - 1772

EP - 1781

JO - Neurology

JF - Neurology

IS - 17

ER -

Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E

Abstract

Keywords

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