Post by skyship on Aug 31, 2015 23:52:10 GMT -5
This gene location is what NIH had labeled as Morgellons rare disease.
here are examples of what this mutation can cause. Now the origin of this may be deletion of merosin or partial deletin of merosin.
-----------------------------------------------------------
Congenital muscular dystrophy with respiratory failure & muscle hypertrophy (CMD1B; MDC1B) 7
● Chromosome 1q42; Recessive
Epidemiology: Arab & German families
Clinical
Severe diaphragm involvement: Respiratory failure
Weakness
Neck
Proximal > Distal
Arms & Legs
Face: Mild
Walking: Onset at 1.5 to 2.5 years
No clear progression of weakness
Muscle hypertrophy: Generalized
Contractures
Ankles
Spine rigidity (50%)
Intellect: Normal
Laboratory
Serum CK: Very high; 1,700 to 7,600
Brain: Normal MRI
Muscle
Dystrophic changes
Connective tissue proteins: Reduced on some fibers
Merosin: Reduced; No mutations in Merosin gene
Integrins α-7 & β1D: Reduced
Heparan sulfate proteoglycans: Normal
neuromuscular.wustl.edu/syncm.html#cmddiaph
--------------------------------------------This is on 13 but is close to 11 and 12
Congenital myopathy with excess of thin filaments 5
● α-Actin (ACTA1; Skeletal muscle) ; Chromosome 1q42.13; Sporadic
Genetics
Actin (ACTA1) gene mutations
Gly15Arg: Surface exposed residue
Val163Leu: Hydrophobic core
Allelic syndromes
Clinical
Hypotonia
Respiratory insufficiency
Cardiomyopathy
Course: Variable with same actin mutation
Death in 1st months: 2 patients
Survival to childhood: 1 patient
Serum CK: Normal
Muscle
Masses of thin filaments (Actin)
Nuclear ± cytoplasmic rods
Fiber size variation
neuromuscular.wustl.edu/syncm.html#thin
-----------------------------------------------------------some of our filaments and symptoms may be
involved in this mutation.
NEM3 Rod myopathy
● α-Actin (ACTA1; Skeletal muscle) ; Chromosome 1q42.13; Dominant or Sporadic, Recessive
Genetics
Mutations
~15 Missense mutations identified
Distributed in all 6 coding exons
Some involve known functional domains of actin
Allelic syndromes
Actin (ACTA1) protein
α-Skeletal muscle actin
Normal adults: Present in muscle but not heart
Development: Becomes predominant isoform in muscle at 3rd trimester of gestation
Dominant syndromes: Mutant ACTA1 exerts dominant negative effect
Aggregation may be caused by
Heat shock
Leptomycin B (a specific inhibitor of nuclear export mediated by leucine-rich nuclear export signals)
Mutation in leucine-rich nuclear export signals
Clinical
Dominant inheritance
Clinical: Variable phenotypes
General
Onset age: Variable within families
Cardiac function: Normal
Mild
ACTA1 Mutations: Asn115Ser; Gly268Cys; Ile136Met
Clinical
Onset: Age 12
Weakness: Trunk & Proximal; Mild facial
Respiratory failure: 5th decade
Progression: Slow over decades
Laboratory
Serum CK: Normal
MRI: Gluteal & Anterolateral thigh involvement
Muscle morphology
Rods, especially in small fibers; Core-like structures
Muscle fiber hypertrophy: Ile136Met
Scapuloperoneal 120
Genetics: Glu197Asp ACTA1 mutation
Clinical
Onset age: Infancy to 3rd decade
Weakness: Scapuloperoneal & Distal
Wrist extensor
Finger drop
Foot drop
Quadriceps (50%)
Scapular winging
Face: Mild
Contractures: Ankle; Elbow; Shoulder
Tendon reflexes: Reduced or Absent
Laboratory
Muscle pathology: Type I fiber atrophy; Internal architecure irregular; Internal nuclei
Serum CK: Normal to Slightly high
Severe 85
ACTA1 genetics
New dominant mutations
N94K; L144F; Arg183Gly; G270R; Ile357Leu
Phenotypes
Lethal; Congenital
Congenital weakness
CNS involvement: Some patients
Developmental delay
Frontal lobe hypoplasia
Lateral ventricle dilation
Other organs: Few patients
Skeletal dysplasia
Hepatomegaly
Urinary tract stenosis
Muscle pathology
Fiber size: Varied; Small fibers in clusters
Nemaline rods: Cytoplasmic & Intranuclear
Thin filament aggregates
Endomysial fibrosis
Nemaline myopathy with intranuclear rods
Cap myopathy
Other mutations: Met132Val; Val163Met; Met269Arg
Pathology
Fiber types
Abnormal differentiation
Type I: Small
Glycogen accumulation
Rods
No relation between abundance & disease severity
More in small muscle fibers
Stain for α-actinin 2
Rods tend to be in type 1 muscle fibers
May be present in some muscles but not others
Some syndromes with no rods
Fiber morphology
Myofibrillar disruption
Whorling of actin thin filaments
Recessive inheritance 66
ACTA1 Genetics
Truncation mutations identified; ? Missense
Truncation: Arg41X (French), Tyr364fsX (Spanish), Asp181fsX10 (British)
Clinical
Weakness
Severe in most: Diffuse; Hypotonia
Respiratory failure
Feeding difficulties
Death in 1st year: Most
Contractures (30%)
Course: Survival through childhood in some
Laboratory
Serum CK: Mildly elevated or normal
Muscle
Morphology: Nemaline rods & Zebra bodies
Actin: Skeletal α-actin absent; Cardiac α-actin increased
Lipid: Increased
Sporadic patients: Often de novo mutations
ACTA1 variant: Nemaline myopathy with intranuclear rods 62
All mutations involve ACTA1
Inheritance
Sporadic (Most) or Dominant
Marked phenotypic variation in family
Onset: Birth (Most) to 55 years
Clinical
Narrow face
Thin musculature
Hypotonia
Weakness: Diffuse
Laboratory
Serum CK: Normal or Mildly elevated
EMG: Myopathic
Muscle: Intranuclear rods
Probably formed within nucleus
Larger than sarcoplasmic rods: Up to length of several sarcomeres
One or multiple per nucleus
Frequency: 2% to 80% of nuclei
Number of fibers with intranuclear rods correlates with disease severity
Course
Death in 1st year in 40% due to respiratory insufficiency
Similar to ACTA1 mutations without intranuclear rods
ACTA1 variant: Cap myopathy with ACTA1 mutation 82
Epidemiology: 1 patient
Mutation: Met47Val, Dominant
Clinical
Decreased fetal movements
Birth: Poor respiration
Motor
Hypotonia: Axial & Peripheral
Weakness: Severe
Minimal spontaneous movements
Generalized atrophy
Deep tendon reflexes: Absent
General
Low hairline
Micrognathia
High arched palate
Single palmar crease
Long fingers
Undescended testes
Death: 5 years
Laboratory
Serum CK: Normal
Head MRI: Normal
Muscle biopsies
5 weeks: Type 1 smallness; No caps
4 years
Caps: Contain thin filaments, α-Actinin, Actin & Desmin; NADH+
Internal nuclei
Expanded Z-bands
ACTA1 variant: Myofibrillar myopathy, congenital 121
Epidemiology: 1 patient
Genetics
Inheritance: Sporadic, Dominant
Mutation: In-frame 2-amino-acid insertion; c.437_442dupCCTCCG; p.146_147dupAlaSer
Clinical
Onset age: Congenital
Hypotonia
Motor delay
Weakness
Arms > Legs
Face: Diplegia
Tendon reflexes: Reduced
Dysmorphic features
Ears: Low-set
Contractures: Metacarpophalangeal & proximal interphalangeal joints involving most fingers
High arched palate
Death: 3 years
Laboratory
Brain MRI: Normal
Serum CK: Normal
EMG: Fibrillations; Motor units small
Muscle biopsy
Fiber morphology: Varied size; Splitting; Internal nuclei
Fiber architecture: Vacuoles; Myofibrillar disorganization; Hyline structures
Fiber aggregates: Desmin; αB-crystallin, Myotilin, Dystrophin, NCAM
Fiber damage: Necrosis & Regeneration
Endomysial connective tissue: Increased
Perimysium: Widened
Childhood-onset myofibrillar myopathies
BAG3
CRYAB, Recessive
ACTA1
Muscle MRI
Involved muscle signal: Increased T1
Involved muscles: Diffuse involvement of thigh and leg
Relative sparing: Gastrocnemius
neuromuscular.wustl.edu/syncm.html#aactin
Notice that connective tissue is very involved.
Fiber morphology: Varied size; Splitting; Internal nuclei
Fiber architecture: Vacuoles; Myofibrillar disorganization; Hyline structures
Fiber aggregates: Desmin; αB-crystallin, Myotilin, Dystrophin, NCAM
Fiber damage: Necrosis & Regeneration
Endomysial connective tissue: Increased
--------------------------------------------------------------
these are "pure congenital myopathic dystrophies" or hypertrophy....deletion due to mutation into gene.
What caused this mutation?
---------------------------------------------
here are examples of what this mutation can cause. Now the origin of this may be deletion of merosin or partial deletin of merosin.
-----------------------------------------------------------
Congenital muscular dystrophy with respiratory failure & muscle hypertrophy (CMD1B; MDC1B) 7
● Chromosome 1q42; Recessive
Epidemiology: Arab & German families
Clinical
Severe diaphragm involvement: Respiratory failure
Weakness
Neck
Proximal > Distal
Arms & Legs
Face: Mild
Walking: Onset at 1.5 to 2.5 years
No clear progression of weakness
Muscle hypertrophy: Generalized
Contractures
Ankles
Spine rigidity (50%)
Intellect: Normal
Laboratory
Serum CK: Very high; 1,700 to 7,600
Brain: Normal MRI
Muscle
Dystrophic changes
Connective tissue proteins: Reduced on some fibers
Merosin: Reduced; No mutations in Merosin gene
Integrins α-7 & β1D: Reduced
Heparan sulfate proteoglycans: Normal
neuromuscular.wustl.edu/syncm.html#cmddiaph
--------------------------------------------This is on 13 but is close to 11 and 12
Congenital myopathy with excess of thin filaments 5
● α-Actin (ACTA1; Skeletal muscle) ; Chromosome 1q42.13; Sporadic
Genetics
Actin (ACTA1) gene mutations
Gly15Arg: Surface exposed residue
Val163Leu: Hydrophobic core
Allelic syndromes
Clinical
Hypotonia
Respiratory insufficiency
Cardiomyopathy
Course: Variable with same actin mutation
Death in 1st months: 2 patients
Survival to childhood: 1 patient
Serum CK: Normal
Muscle
Masses of thin filaments (Actin)
Nuclear ± cytoplasmic rods
Fiber size variation
neuromuscular.wustl.edu/syncm.html#thin
-----------------------------------------------------------some of our filaments and symptoms may be
involved in this mutation.
NEM3 Rod myopathy
● α-Actin (ACTA1; Skeletal muscle) ; Chromosome 1q42.13; Dominant or Sporadic, Recessive
Genetics
Mutations
~15 Missense mutations identified
Distributed in all 6 coding exons
Some involve known functional domains of actin
Allelic syndromes
Actin (ACTA1) protein
α-Skeletal muscle actin
Normal adults: Present in muscle but not heart
Development: Becomes predominant isoform in muscle at 3rd trimester of gestation
Dominant syndromes: Mutant ACTA1 exerts dominant negative effect
Aggregation may be caused by
Heat shock
Leptomycin B (a specific inhibitor of nuclear export mediated by leucine-rich nuclear export signals)
Mutation in leucine-rich nuclear export signals
Clinical
Dominant inheritance
Clinical: Variable phenotypes
General
Onset age: Variable within families
Cardiac function: Normal
Mild
ACTA1 Mutations: Asn115Ser; Gly268Cys; Ile136Met
Clinical
Onset: Age 12
Weakness: Trunk & Proximal; Mild facial
Respiratory failure: 5th decade
Progression: Slow over decades
Laboratory
Serum CK: Normal
MRI: Gluteal & Anterolateral thigh involvement
Muscle morphology
Rods, especially in small fibers; Core-like structures
Muscle fiber hypertrophy: Ile136Met
Scapuloperoneal 120
Genetics: Glu197Asp ACTA1 mutation
Clinical
Onset age: Infancy to 3rd decade
Weakness: Scapuloperoneal & Distal
Wrist extensor
Finger drop
Foot drop
Quadriceps (50%)
Scapular winging
Face: Mild
Contractures: Ankle; Elbow; Shoulder
Tendon reflexes: Reduced or Absent
Laboratory
Muscle pathology: Type I fiber atrophy; Internal architecure irregular; Internal nuclei
Serum CK: Normal to Slightly high
Severe 85
ACTA1 genetics
New dominant mutations
N94K; L144F; Arg183Gly; G270R; Ile357Leu
Phenotypes
Lethal; Congenital
Congenital weakness
CNS involvement: Some patients
Developmental delay
Frontal lobe hypoplasia
Lateral ventricle dilation
Other organs: Few patients
Skeletal dysplasia
Hepatomegaly
Urinary tract stenosis
Muscle pathology
Fiber size: Varied; Small fibers in clusters
Nemaline rods: Cytoplasmic & Intranuclear
Thin filament aggregates
Endomysial fibrosis
Nemaline myopathy with intranuclear rods
Cap myopathy
Other mutations: Met132Val; Val163Met; Met269Arg
Pathology
Fiber types
Abnormal differentiation
Type I: Small
Glycogen accumulation
Rods
No relation between abundance & disease severity
More in small muscle fibers
Stain for α-actinin 2
Rods tend to be in type 1 muscle fibers
May be present in some muscles but not others
Some syndromes with no rods
Fiber morphology
Myofibrillar disruption
Whorling of actin thin filaments
Recessive inheritance 66
ACTA1 Genetics
Truncation mutations identified; ? Missense
Truncation: Arg41X (French), Tyr364fsX (Spanish), Asp181fsX10 (British)
Clinical
Weakness
Severe in most: Diffuse; Hypotonia
Respiratory failure
Feeding difficulties
Death in 1st year: Most
Contractures (30%)
Course: Survival through childhood in some
Laboratory
Serum CK: Mildly elevated or normal
Muscle
Morphology: Nemaline rods & Zebra bodies
Actin: Skeletal α-actin absent; Cardiac α-actin increased
Lipid: Increased
Sporadic patients: Often de novo mutations
ACTA1 variant: Nemaline myopathy with intranuclear rods 62
All mutations involve ACTA1
Inheritance
Sporadic (Most) or Dominant
Marked phenotypic variation in family
Onset: Birth (Most) to 55 years
Clinical
Narrow face
Thin musculature
Hypotonia
Weakness: Diffuse
Laboratory
Serum CK: Normal or Mildly elevated
EMG: Myopathic
Muscle: Intranuclear rods
Probably formed within nucleus
Larger than sarcoplasmic rods: Up to length of several sarcomeres
One or multiple per nucleus
Frequency: 2% to 80% of nuclei
Number of fibers with intranuclear rods correlates with disease severity
Course
Death in 1st year in 40% due to respiratory insufficiency
Similar to ACTA1 mutations without intranuclear rods
ACTA1 variant: Cap myopathy with ACTA1 mutation 82
Epidemiology: 1 patient
Mutation: Met47Val, Dominant
Clinical
Decreased fetal movements
Birth: Poor respiration
Motor
Hypotonia: Axial & Peripheral
Weakness: Severe
Minimal spontaneous movements
Generalized atrophy
Deep tendon reflexes: Absent
General
Low hairline
Micrognathia
High arched palate
Single palmar crease
Long fingers
Undescended testes
Death: 5 years
Laboratory
Serum CK: Normal
Head MRI: Normal
Muscle biopsies
5 weeks: Type 1 smallness; No caps
4 years
Caps: Contain thin filaments, α-Actinin, Actin & Desmin; NADH+
Internal nuclei
Expanded Z-bands
ACTA1 variant: Myofibrillar myopathy, congenital 121
Epidemiology: 1 patient
Genetics
Inheritance: Sporadic, Dominant
Mutation: In-frame 2-amino-acid insertion; c.437_442dupCCTCCG; p.146_147dupAlaSer
Clinical
Onset age: Congenital
Hypotonia
Motor delay
Weakness
Arms > Legs
Face: Diplegia
Tendon reflexes: Reduced
Dysmorphic features
Ears: Low-set
Contractures: Metacarpophalangeal & proximal interphalangeal joints involving most fingers
High arched palate
Death: 3 years
Laboratory
Brain MRI: Normal
Serum CK: Normal
EMG: Fibrillations; Motor units small
Muscle biopsy
Fiber morphology: Varied size; Splitting; Internal nuclei
Fiber architecture: Vacuoles; Myofibrillar disorganization; Hyline structures
Fiber aggregates: Desmin; αB-crystallin, Myotilin, Dystrophin, NCAM
Fiber damage: Necrosis & Regeneration
Endomysial connective tissue: Increased
Perimysium: Widened
Childhood-onset myofibrillar myopathies
BAG3
CRYAB, Recessive
ACTA1
Muscle MRI
Involved muscle signal: Increased T1
Involved muscles: Diffuse involvement of thigh and leg
Relative sparing: Gastrocnemius
neuromuscular.wustl.edu/syncm.html#aactin
Notice that connective tissue is very involved.
Fiber morphology: Varied size; Splitting; Internal nuclei
Fiber architecture: Vacuoles; Myofibrillar disorganization; Hyline structures
Fiber aggregates: Desmin; αB-crystallin, Myotilin, Dystrophin, NCAM
Fiber damage: Necrosis & Regeneration
Endomysial connective tissue: Increased
--------------------------------------------------------------
these are "pure congenital myopathic dystrophies" or hypertrophy....deletion due to mutation into gene.
What caused this mutation?
---------------------------------------------