Congential Myopathies

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

RYR1 related MmD spectrum

• 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