P.182Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: the clinical and molecular spectrum of 244 patients

In this retrospective study, we conducted a clinico‐genetic analysis of patients with autosomal recessive limb‐girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand‐dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3‐5/LGMD2C‐E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR‐LGMD and MMD in the Netherlands amounted to 14.4 × 10−6. Thirty‐three novel mutations were identified. A wide range in age of onset (0‐72 years) and loss of ambulation (5‐74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non‐invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes.

[1]  L. ten Dam,et al.  Author response for "Autosomal recessive limb‐girdle and Miyoshi muscular dystrophies in the Netherlands: the clinical and molecular spectrum of 244 patients." , 2019 .

[2]  A. Sahebkar,et al.  Prevalence, pathological mechanisms, and genetic basis of limb‐girdle muscular dystrophies: A review , 2018, Journal of cellular physiology.

[3]  Bjarne Udd,et al.  229th ENMC international workshop: Limb girdle muscular dystrophies – Nomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017 , 2018, Neuromuscular Disorders.

[4]  I. Nonaka,et al.  Cardiopulmonary dysfunction in patients with limb‐girdle muscular dystrophy 2A , 2016, Muscle & nerve.

[5]  C. Angelini,et al.  Progress and challenges in diagnosis of dysferlinopathy , 2016, Muscle & nerve.

[6]  G. Comi,et al.  The genetic basis of undiagnosed muscular dystrophies and myopathies , 2016, Neurology.

[7]  John K. Hall,et al.  Progress and prospects of gene therapy clinical trials for the muscular dystrophies. , 2016, Human molecular genetics.

[8]  N. Yonemoto,et al.  Respiratory and cardiac function in japanese patients with dysferlinopathy , 2016, Muscle & nerve.

[9]  D. MacArthur,et al.  Use of Whole-Exome Sequencing for Diagnosis of Limb-Girdle Muscular Dystrophy: Outcomes and Lessons Learned. , 2015, JAMA neurology.

[10]  Haluk Topaloglu,et al.  Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine , 2015, Neurology.

[11]  I. Nelson,et al.  Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing , 2014, European Journal of Human Genetics.

[12]  A. Wilde,et al.  Cardiac involvement in Dutch patients with sarcoglycanopathy: A cross‐sectional cohort and follow‐up study , 2014, Muscle & nerve.

[13]  W. Linssen,et al.  Comparing clinical data and muscle imaging of DYSF and ANO5 related muscular dystrophies , 2014, Neuromuscular Disorders.

[14]  R. Griggs,et al.  Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies , 2014, Neurology.

[15]  M. Hermanová,et al.  Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic , 2014, BMC Neurology.

[16]  P. Cluzel,et al.  Dilated cardiomyopathy in patients with mutations in anoctamin 5. , 2013, International journal of cardiology.

[17]  K. Bushby,et al.  ANO5 Gene Analysis in a Large Cohort of Patients with Anoctaminopathy: Confirmation of Male Prevalence and High Occurrence of the Common Exon 5 Gene Mutation , 2013, Human mutation.

[18]  N. Lévy,et al.  Long‐term follow‐up study on patients with Miyoshi phenotype of distal muscular dystrophy , 2013, European journal of neurology.

[19]  L. Køber,et al.  Anoctamin 5 muscular dystrophy in Denmark: prevalence, genotypes, phenotypes, cardiac findings, and muscle protein expression , 2013, Journal of Neurology.

[20]  C. Straathof,et al.  ANO5 mutations in the Dutch limb girdle muscular dystrophy population , 2011, Neuromuscular Disorders.

[21]  N. Bresolin,et al.  Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients , 2012, Neuromuscular Disorders.

[22]  K. Bushby,et al.  A founder mutation in Anoctamin 5 is a major cause of limb-girdle muscular dystrophy. , 2011, Brain : a journal of neurology.

[23]  F. Baas,et al.  Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. , 2010, American journal of human genetics.

[24]  K. Bushby,et al.  Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. , 2009, Brain : a journal of neurology.

[25]  C. Angelini,et al.  Frequency of LGMD gene mutations in Italian patients with distinct clinical phenotypes , 2009, Neurology.

[26]  P. Laforêt,et al.  Cardiac assessment of limb–girdle muscular dystrophy 2I patients: An echography, Holter ECG and magnetic resonance imaging study , 2008, Neuromuscular Disorders.

[27]  S. Salani,et al.  Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients , 2008, Human mutation.

[28]  G. Meroni,et al.  Mutations that impair interaction properties of TRIM32 associated with limb‐girdle muscular dystrophy 2H , 2008, Human mutation.

[29]  K. Bushby,et al.  EFNS guideline on diagnosis and management of limb girdle muscular dystrophies , 2007, European journal of neurology.

[30]  F. Spaans,et al.  Limb-girdle muscular dystrophy in the Netherlands: Gene defect identified in half the families , 2007, Neurology.

[31]  M. Schwartz,et al.  High prevalence and phenotype–genotype correlations of limb girdle muscular dystrophy type 2I in Denmark , 2006, Annals of neurology.

[32]  J. D. den Dunnen,et al.  Sarcoglycanopathies and the risk of undetected deletion alleles in diagnosis , 2005, Human mutation.

[33]  L. Anderson,et al.  Multiplex Western blotting system for the analysis of muscular dystrophy proteins. , 1999, The American journal of pathology.

[34]  A. Moorman,et al.  Sarcoglycanopathies in Dutch patients with autosomal recessive limb girdle muscular dystrophy , 1997, Neuromuscular Disorders.