Myotubular myopathy

  • misnomer
  • no arrest of muscle in myotubular stage during fetal development

pathogenesis

  • loss of myotubularin protein due to structural and functional anomalies

clinical features

  • decreased fetal movement in late gestation
  • polyhydramnios
  • thin muscle mass at birth
  • severe generalised hypotonia
  • poor respiratory efforts
  • undescended testis
  • ophthalmoplegia
  • weak deep tendon reflexes
  • X-linked form can be associated with cardiomyopathy

Lab findings

  • CKMB - normal
  • EMG - Normal
  • NCV - slow or normal
  • ECG - normal
  • CXR - thin ribs

diagnosis

  • mostly clinical
  • muscle biopsy - large vesicular and centrally placed nuclei
  • Histochemical stains - central distribution of myotubules
  • positive of vimentin and desmin
  • mature structure with Adenosine Triphosphate stains
  • myotubularins can be detected in serum

Genetics

5 varients

  • Myotubularin MTM1 - X-linked
    • most common
    • Xp28
  • Dynamin 2 DNM2 - AD or sporadic
  • Amphibysin 2 BIN1 - AR
  • Titin TTN - AR
  • Ryanodine receptor 1 RYR1 AR or sporadic

Treatment

  • currently - only palliative
  • Gene therapy for XL type in research

prognosis

  • 75% die in first week
  • rarely walk
  • AD types - better prognisis

Congenital myofiber type disproportion

  • a syndrome
  • associated with
    • nemaline rod disease
    • krabbe diseae
    • congenital muscular dystophy

pathogenesis

  • abnormal suprasegmental influence on motor unit between 20 and 28 weeks of gestation
  • embryological distrubance of fiber-type growth and differentitaion

Clinical manifestation

  • muscular weakness - not severe
  • contracture at birth (25%)
  • Poor head control, Gross motor developmental delay - but milestones acheived
  • dolichocephalic with facial weakness present
  • thin wasted appearance
  • cardiomyopathy is rare
  • mild respiratory weakness +
  • cerebellar hypoplasia can be present (due to epigenetic effect)

labs

  • CKMB - normal
  • EMG - Normal
  • NCV - normal
  • ECG - normal
  • CXR - thin ribs

diagnosis - muscle biopsy

  • Type 1 fibres
    • uniformly small
    • more than type 2
  • Type 2 fibres
    • hypertropic

Genetics

  • TMP2
  • TMP2
  • MYH7
  • RYR1
  • skeletal muscle α-actin gene 1 ACTA1
  • LMNA

treatment

  • physiotherapy

Nemaline Rod myopathy

  • abnormal rod shaped inclusion like structures within muslce fibres (nemaline rods)
  • not seen with H&E stain but seen with special stains
  • composition of nemaline rods
    • not inclusion bodies
    • excessive Z band material
      • actin
      • α-actinin
      • trophomyosin 3
      • protein nebulin

Pathogenesis

  • unusual response of the muscle fibre to injury

clinical manifestations

  • highly variable
  • both proximal and distal muscle involved
  • fetal akinesia to mildly affected till adulthood
  • prenatal and natal subtypes
    • fatal due to respiratory failure
  • infantile
    • generalised hypotonia
    • weakness
    • thin muscle mass
    • dolichocephalic
    • high arched / cleft palate
    • hypoxia, dysphagia and arthogryoposis
    • facies similar to neonatal muslce dystrophy
  • juvenile
    • mildest
    • not associated with respiratory failure
    • facial involvement +
  • adult
    • slow progressive proximal weakness with axial involvement
  • Sporadic late onset nemaline myopathy
    • associated with
      • monoclonal gammapathy
      • HIV infectionn
      • various autoimmune disorders
    • treatable cause

labs

  • CKMB - normal or mildly elevated
  • muscle biopsy diagnostic
    • nemaline rods (not pathognomonic - can occur in other diseases)
    • CMFTD phenotype
    • focal myofibrillar degeneration

genetics

  • atleast 10 genes
    • ACTA1 (skeletal muscle α-actin) 25%, NEB (nebulin) 50%, TPM3 (slow muscle αα-tropomyosin), TPM2 (ββ-tropomyosin), CFL2 (skeletal muscle cofilin), TNNT1 (slow mus cle troponin-T), LMOD3 (leiomodin 3), KBTBD13 (Kelch- repeat and BTB domain containing 13), KLHL40, and KLHL41 (Kelch- like 40 and 41)
    • NEB related nemaline myopathy
      • most common
      • usually present in childhood or infancy
      • disproportionate axial and bulbar involvement
      • ambulatory but scoliosis and respiratory involvement +
      • no cardiomyopathy
  • ACTA1 related nemaline myopathy
    • severe
    • cardiomyopathy +
      • progressive scapuloperoneal and distal weakness - AD
      • Limb gridle muscle dystrophy
      • severe congenital presentation with myofibrilar features
      • rigid spine - AR
      • zebra body myopathy

treatment

  • no cure
  • management of symptoms
    • gastrostomy - for dysphagia
  • nocturnal hypoventilation syndrome
  • L-tyrosine - reduced fatigue and improvement in drooling
  • KLHL40 type - acetylcholine esterase inhibitor - pyridostigmine

core myopathies

  • 3 subtypes
    • central core
    • mutlimini core
    • atypical core
  • cores are areas in myofibrils that are devoid of myofibrils and organelles
  • contain amorphous granular cytoplasm

Clinical features

  • variable spectrum
  • hypotonia, joint laxity, motor developmental delay, hip girdle and axial muscle weakness, recurrent shoulder and patellar disloaction, dysplasia of foot congenital hip dislocation
  • older children - thoraco lumbar scoliosis

Central core myopathy

  • longitudinal extensive areas in the central area of myofiber devoid of oxidative enzyme activity
  • associated with RYR1
    • external opthalmoplegia, congential myopathy, ptosis, predominant internal ptosis - potential candidates
  • AD
  • mild to moderate muscle weakness in infancy and childhood
  • wide variation in symptoms
  • hip girdle and axial involvement
  • respiratory and cardaic involvement - uncommon
  • associated with malignant hypothermia susceptibility trait
  • 30% shows exertional rahbdomyolysis
  • cardiac involvement if present - sudden cardiac death and dialated cardiomyopathy

Multimini core disease

  • AR
  • SEPN1 gene
    • axial weakness
    • early spinal ridigity
    • scoliosis
    • respiratory involvement +
  • unable to hold neck despite able to walk (isolated neck myopathy)
  • myopathic face +
  • proximal shoulder gridle involvement (rigid spine deformity)
  • by 2nd decade scoliosis and rigid spine
  • some varients can show cardiomyopathy
  • external ophthalmoplegia
  • recurrent episodes of periodic paralysis
  • distal weakness
  • wasting

labs

  • CK - normal except during time of MHS
  • muscle biopsy - core formation

genetics

  • RYR1
  • SEPN1
  • slow β myosin gene (MYH7)
  • autorecessive titin (TTN)
  • MEGF10
    • EMARRD
      • early onset myopathy
      • areflexia
      • respiratory distress
      • dysphagia

treatment

  • orthopedic care
    • scoliosis and other skeletal problems can develop quickly
  • watch for Malignant Hyperthermia
  • respiratory funtion tests for nocturnal hypoventilation syndrome