title: Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene.
abstract: BACKGROUND
  Minicore myopathy (multi-minicore disease [MmD]) is a congenital myopathy characterized by multifocal areas with loss of oxidative activity on muscle biopsy. MmD is clinically heterogeneous and distinct phenotypes have been associated with recessive mutations in either the selenoprotein N (SEPN1) or the skeletal muscle ryanodine receptor (RYR1) gene, also implicated in central core disease and malignant hyperthermia. External ophthalmoplegia is an additional finding in a subset of patients with MmD.
  
  
  OBJECTIVE
  To clinically and genetically examine families with MmD and external ophthalmoplegia.
  
  
  METHODS
  The authors investigated 11 affected individuals from 5 unrelated families. Clinical, histopathologic, and imaging studies were performed and RYR1 haplotyping and mutational analysis were carried out.
  
  
  RESULTS
  All patients had multiple cores involving the entire fiber diameter on longitudinal sections. Weakness and wasting in the shoulder girdle, scoliosis, moderate respiratory impairment, and feeding difficulties were prominent. In contrast to SEPN1-related myopathies, soleus was more severely affected than gastrocnemius on muscle MRI. Haplotyping suggested linkage to the RYR1 locus in informative families and mutational screening revealed four novel RYR1 mutations in three unrelated families; in addition, functional haploinsufficiency was found in one allele of two recessive cases.
  
  
  CONCLUSIONS
  These findings expand the phenotypic spectrum associated with mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Recessive mutations of domains commonly affected in malignant hyperthermia appear to be particularly prevalent in multi-minicore disease with external ophthalmoplegia and might suggest a different pathomechanism from that involved in central core disease.
authors.affiliation: Dubowitz Neuromuscular Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, UK. h.jungbluth@imperial.ac.uk
authors.forename: H
authors.initials: H
authors.lastname: Jungbluth
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: L
authors.initials: L
authors.lastname: Hartley
authors.forename: B
authors.initials: B
authors.lastname: Halliger-Keller
authors.forename: S
authors.initials: S
authors.lastname: Messina
authors.forename: C
authors.initials: C
authors.lastname: Longman
authors.forename: M
authors.initials: M
authors.lastname: Brockington
authors.forename: S A
authors.initials: SA
authors.lastname: Robb
authors.forename: V
authors.initials: V
authors.lastname: Straub
authors.forename: T
authors.initials: T
authors.lastname: Voit
authors.forename: M
authors.initials: M
authors.lastname: Swash
authors.forename: A
authors.initials: A
authors.lastname: Ferreiro
authors.forename: G
authors.initials: G
authors.lastname: Bydder
authors.forename: C A
authors.initials: CA
authors.lastname: Sewry
authors.forename: C
authors.initials: C
authors.lastname: Müller
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D000293:Adolescent; D000328:Adult; D001706:Biopsy; D002648:Child; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D004252:DNA Mutational Analysis; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D008022:Ligaments / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018908:Muscle Weakness / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009133:Muscular Atrophy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D009801:Oculomotor Muscles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009886:Ophthalmoplegia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D013577:Syndrome
chemical_list: D005819:Genetic Markers; D019837:Ryanodine Receptor Calcium Release Channel