Muscle
Congenital myopathies
Centronuclear myopathy

Author: Wesley Hiser, M.D. (see Authors page)
Editor: Jesse L. Kresak, M.D.

Revised: 30 October 2017, last major update October 2017

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

PubMed Search: Centronuclear myopathy [title] muscle "loattrfree full text"[sb]

Cite this page: Hiser W. Centronuclear myopathy. PathologyOutlines.com website. http://pathologyoutlines.com/topic/musclecentronuclearmyopathy.html. Accessed November 23rd, 2017.
Definition / general
  • Genetically heterogeneous group of myopathies defined by the presence of multiple centrally placed nuclei on histologic sections
Essential features
  • Diagnosis requires the clinical features of a congenital myopathy in combination with histologic finding of multiple centrally placed nuclei on muscle biopsy
  • Most frequent mutations include MTM1, DNM2 and BIN1
Terminology
  • X linked form is often referred to as myotubular myopathy
ICD-10 coding
Epidemiology
  • Uncertain incidence and prevalence but less frequent than central core and nemaline myopathies
  • X linked myotubular myopathy estimated at 1 per 100,000 male births per year (Brain Behav 2013;3:476)
Sites
  • Predominantly involves proximal musculature but may extend distally
  • Ocular muscles are typically involved
  • Autosomal recessive form more frequently involves facial muscles of mastication (Orphanet J Rare Dis 2008;3:26)
Pathophysiology
  • Disease occurs as a result of varying mutations affecting different proteins involved with multiple cellular pathways
  • Most proteins affected are involved with various pathways of membrane trafficking and remodeling, including endocytosis and autophagy
Etiology
  • Multiple mutations with differing inheritance patterns have been implicated in CNM:
    • X linked: MTM1 (90% of affected men)
    • Autosomal dominant: DNM2 and CCDC78
    • Autosomal recessive: BIN1 and TTN
Clinical features
  • Clinical presentation is variable and partly based on mutation
  • Marked proximal muscle weakness but may also involve distal musculature, particularly on lower extremities
  • X linked form is severe and presents at birth with significant weakness, hypotonia, external ophthalmoplegia and respiratory distress
    • Fetal signs include polyhydramnios, reduced fetal movement and thinning of the ribs
    • Large head circumference and length > 90th percentile
    • Cryptorchidism, pyloric stenosis and hepatic cavernous hemangiomas may also be seen
    • Most carriers are asymptomatic but some may have mild muscle weakness
  • Autosomal dominant form tends to be the mildest and occur later than the X linked
    • Severity varies based on what part of the protein is affected
    • Presentation frequently in adolescence / early adulthood but some mutations present in neonatal period
    • Progressive and typically begins in adolescence but rarely results in loss of ambulation before the sixth decade
    • May present with exercise induced myalgias
    • Neonatal presentation is often more severe but symptoms typically improve over time
    • Ocular involvement with ptosis is almost always seen
  • Autosomal recessive form is characterized by facial muscle weakness, particularly those involved with mastication, in addition to ocular involvement with ptosis and external ophthalmoplegia
    • Intermediate severity between X linked and autosomal dominant
    • Skeletal abnormalities (scoliosis, high arched palate) often seen
    • Variable degrees of respiratory distress but may be severe
    • Associated cardiomyopathy has been reported (Orphanet J Rare Dis 2008;3:26)
Diagnosis
  • Must have characteristic histologic findings of centrally placed nuclei in addition to compatible clinical presentation
  • DNA sequencing is used for molecular confirmation of the diagnosis
  • Screening for MTM1 mutations should be performed in females with appropriate clinical or histologic findings
Laboratory
  • Creatinine kinase (CK) normal to slightly elevated
Radiology description
  • Muscle MRI of patients with DNM2 mutations shows a characteristic progressive pattern of early ankle plantarflexor involvement with later changes in hamstring muscles and ending with anterior thigh
  • Also shows adductor longus and rectus femoris involvement (Orphanet J Rare Dis 2008;3:26)
Radiology images

Images hosted on other servers:

Selective muscle involvement in a 59 year-old man

Prognostic factors
  • X linked: typically fatal within first few months of life, though a small portion may live into teenage years or beyond with significant medical intervention
  • Autosomal recessive: More favorable prognosis with the absence of cardiorespiratory involvement
Case reports
Treatment
  • No curative treatment
  • Supportive therapy
Clinical images

Images hosted on other servers:

Elongated face and inverted V shaped mouth

Microscopic (histologic) description
  • Small muscle fibers with centrally located nuclei, often with a peripheral halo
  • Halos lack mitochondria and are highlighted by oxidative stains (Neuropathol Appl Neurobiol 2017;43:5)
  • Type 1 myofiber predominance, myofiber size variation and fatty infiltration
  • Necklace fibers: basophilic ring along the periphery of the cell membrane visible with H&E, PAS, Gömöri trichrome and oxidative stains in patients with MTM1 mutation (Acta Neuropathol 2009;117:283)
  • Radial arrangement of sarcoplasmic strands, visible with NADH stain, seen with DNM2 mutation (Orphanet J Rare Dis 2008;3:26)
Microscopic (histologic) images

Images hosted on PathOut server:

Images contributed by Marie Rivera-Zengotita, M.D.

H&E

NADH

Positive stains
Electron microscopy description
  • X linked: prominent nucleoli and central region with mitochondrial aggregates, glycogen granules and reduced myofilaments; increased mitochondria, glycogen granules and sarcoplasmic reticulum within necklace fibers
  • Autosomal dominant: central region with radial sarcoplasmic strands, tapering toward the center
  • Autosomal recessive: central region with filamentous, amorphous material comprised of mitochondria, tubules and glycogen (Brain Pathol 2015;25:651)
Differential diagnosis
Board review question #1
Necklace fibers are seen in association with which mutation involved with centronuclear myopathy?

  1. BIN1
  2. DNM2
  3. MTM1
  4. MTMR14
  5. RYR1
Board review answer #1
C. MTM1