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CONTRACTURES & OTHER JOINT DISORDERS

Contractures + Neuromuscular disorders
Arthrogryposis
  Myopathy
  Distal
Bethlem Myopathy
Congenital MD
Dermatomyositis
Dystrophinopathies
Ehlers-Danlos: 1; 2
Emery-Dreifuss
Fasciitis
Hereditary IBM + Ophthalmoplegia 
IM drug injections
Lethal congenital (LCCS)
Nemaline (Rod) myopathy: Severe
Rigid spine syndromes
Scleroatonic muscular dystrophy (Ullrich)
Spinal Muscular Atrophy
  5q-linked Congenital
  X-linked Infantile
Tel Hashomer camptodactyly
Williams-Beuren syndrome
Joint Hyperlaxity
  Ullrich CMD
  CMD + Joint hyperlaxity
  Mental retardation

Contractures with myopathy or other neuromuscular disease



Joint Hypermobility 31

Genes Syndromes Inheritance NM features Hypermobility Other
COL5A1
COL5A2
Ehlers-Danlos (ED)
  I & II
Dominant Hypotonia
Fatigue
Generalized Skin: Hyperextensible
  Bruises; Scars
TNXB Hypermobility III
ED-like + Myopathy
Dominant
Recessive
Musculoskeletal pain
Weakness
Generalized Skin: Bruises; Velvety
  Hyperextensible; Scars
COL3A1 ED 4 Dominant Tendon & muscle
  rupture
Distal Skin, Vessel & Organ:
  Fragility
PLOD ED 6 Recessive Hypotonia
Motor delay
Distal Scoliosis
Sclera fragile
CHST14 EDSMC1 Recessive Hypotonia
Weakness
Distal Scoliosis
DSE EDSMC2 Recessive Motor delay
Weakness
Distal Dysmorphism
Sclera: Blue
COL1A1 Arthrochalasia
  (ED VII)
Dominant Hypotonia
Motor delay
Diffuse Arthrogryposis
Face dysmorphism
FKBP14 EDSKMH Recessive Weakness Distal Scoliosis
Deafness
FBN1 Marfan Dominant Muscle atrophy
Cramps; Fatigue
Distal Aorta dilatation
Arachnodactyly; Scoliosis
TGFBR1
TGFBR2
SMAD3
TGFB2
TGFB3
SMAD2
Loeys–Dietz 1
LDS2
LDS3
LDS4
LDS5
LDS6
Dominant Hypotonia General Hypertelorism
Aneurysm
Contractures
COL6A1/A2/A3 Ulrich
Bethlem
Recessive
Dominant
Weakness Distal Keratosis pilaris
COL12A1 Ullrich
Bethlem
Recessive
Dominant
Weakness Distal Kyphosis
Skin scarring
ITGA9 Ullrich, mild Recessive Weakness
Respiratory
Distal Scoliosis
SEPN1 Congenital MD Recessive Weakness
Respiratory
Distal Rigid spine
RYR1 Mini/Multicore Recessive Weakness Face dysmorphic
CUL4B Cabezas X
Recessive
Muscle wasting Short stature
Small testes
Mental retardation
MYH7
Titin
Multi/Mini-Core Dominant Weakness Distal
β-Sarcoglycan LGMD 2E Recessive Weakness Distal
ZAK Congenital
  myopathy
Recessive Weakness General Scoliosis
Type I fiber predominance
P4HA1 Congenital
  myopathy
Recessive Weakness Distal Contractures
Myopia

Emery-Dreifuss Muscular Dystrophy 2


EMD1: Emerin; Xq28; Recessive
EMD2: Lamin A/C; 1q21.2; Dominant
EMD3: Lamin A/C; 1q21.2; Recessive
EMD4: SYNE1; 6q25; Dominant
EMD5: SYNE2; 14q23; Dominant
EMD6: FHL1; Xq26; Recessive or Semi-Dominant
EMD7; TMEM43; 3p25; Dominant
EMD: Titin; 2q31; Recessive
EMD modifiers: SUN1; SUN2
Other: Sporadic & Dominant

from A Kornberg MD

Emery-Dreifuss MD 1 (EMD1; EDMD1)
  Emerin ; Chromosome Xq28; Recessive

Emery-Dreifuss MD 2 & 3
  Lamin A/C ; Chromosome 1q22; Dominant (EMD2) or Recessive (EMD3)
Genetics
Protein
Clinical
  Variant syndromes

Emery-Dreifuss MD 4 (EMD4; EDMD4) 20
  Synaptic nuclear envelope protein 1 (SYNE1; Nesprin-1) ; Chromosome 6q25.2; Dominant
Emery-Dreifuss MD 5 (EMD5; EDMD5) 20
  Synaptic nuclear envelope protein 2 (SYNE2; Nesprin-2) ; Chromosome 14q23.2; Dominant
Emery-Dreifuss MD 7 (EMD7; EDMD7) 24
  Transmembrane protein 43 (TMEM43; LUMA) ; Chromosome 3p25.1; Dominant
Contractures, Joint & Spine + Weakness 35
  Kyphoscoliosis peptidase (KY) ; Chromosome 3q22.2; Recessive
Skeletal dysplasia, Weakness, Intellectual Disability, Ovarian Dysfunction 53
  SRY-Box 8 (SOX8) ; Chromosome 16p13.3; Recessive

Nuclei: Muscle Fibers


Nuclear Protein Disorders: Envelope & Matrix 51



Arthrogryposis Multiplex Congenita (AMC) 29

General aspects
  Clinical features
  Associated disorders & syndromes
  Treatment & prognosis
    Neurogenic
Syndromes + Myopathy

Syndromes ± Myopathy
  Recessive
    Arthrogryposis Multiplex Congenita (AMC)
      1: LGI4
      2: ERGIC1
      3: SYNE1
      4: SCYL2 (Corpus callosum agenesis)
      5: TOR1A
      6: NEB
      AMC: CACNA1H
    Arthropathy-Camptodactyly: PRG4
    Cerebellar & Pancreatic Aplasia: PTF1A
    COFS: ERCC6
    Distal arthrogryposis
      5D: ECEL1; 2q37
      KFS4: MYO18B; 22q12
    Ectodermal dysplasia
    Emery-Dreifuss MD 4: SYNE1
    Fetal Akinesia Deformation Sequence (FADS)
      1: MuSK
      2: RAPSYN
      3: DOK7
      4: NUP88
    Jarcho-Levin: DLL3
    Lethal congenital contractures (LCCS)
    Lethal congenital myopathy: CNTN1
    Lissencephaly
    Mental retardation & Seizures: SLC35A3
    Multiple pterygium (Escobar)
    Neurogenic
    Pelvic hypoplasia
    Pulmonary hypoplasia
    Renal dysfunction
    Spinal muscular atrophy (SMA)
      5q-linked Congenital: SMN1
      SMA + Congenital fractures
        TRIP4; 15q22
        ASCC1: 10q22
      SMA + Pontocerebellar hypoplasia
        PCH1A: VRK1
        PCH1B: EXOSC3
      HMND8: TRPV4
    Spondylospinal Thoracic dysostosis

  X-linked
    Aarskog–Scott: FGD1
    Infantile SMA + Arthrogryposis: UBE1
    Intellectual disability & Weak: ZC4H2
  Dominant
    Clubfoot, asymmetric: PITX1
    Contractural arachnodactyly (DA9): FBN2
    Distal arthrogryposis: Types
        1A: TPM2
        1B: MYBPC1
        1C: MYLPF
        1 Other: TNNI2, TNNT3, MYH3
        2A: MYH3; NALCN
        2B1: TNNI2
        2B2: TNNT3
        2B3: MYH3;
        2B4: TPM2
        3 (Gordon): PIEZO2; 18p11
        4 (Scoliosis): PIEZO2
        5 (Ophthalmoplegia)
        5A: MYH2; 17p13
        5B: MYH13; 17p13
        5C: 11
        5E: PIEZO2; 18p11
        6: FGFR3; 4p16
        7 (Trismus-Pseudocamptodactyly): MYH8; 17p13
        8 (Multiple pterygium): MYH3; 17p13
        9 (Contractural arachnodactyly): FBN2; 5q23
        10 (Plantar syndrome): TTN; 2q
        11: MET; 7q31
        12: ADAMTS15; 7q31
        Cardiac
          Myxomas: MYH8; 17p13
          Cardiomyopathy: TTN
        HSAN 6: DST
        Rienhoff: TGFB3; 14q24
    Möbius Syndrome
    Oculomotor abnormalities (DA5)
    Saethre-Chotzen syndrome: TWIST
    Stiffness: TPM3

  Mitochondrial
  Neuropathy-Neurogenic
    AR-CMT: GDAP1
    SMALED
      CMT-2O: DYNC1H1; 14q32
      + Polymicrogyria: BICD2; 9q22
  Sporadic
    Amyoplasia
    Neurogenic
    Trisomy 18
Fetal Akinesia Syndromes: Genes
  Motor neuron
    Development & Survival
    ASXL3
    SMN1 (SMA)
    GLE1 (LCCS1)
    ERBB2
    ERBB3 (LCCS2)
    MAGEL2
    PIP5K1C (LCCS3)
    UBE1 (SMAX2)
  Neuronal
    BICD2
    DYNC1H1
    DST
    ECEL1 (DA5D)
    NALCN
    NMNAT2
    PIEZO2 (DA5E)
    SCN1A
    SCYL2 (AMC4)
    TOR1A (AMC5)
  Neuromuscular junction
    Agrin
    CHRNA1
    CHRNB1
    CHRND
    CHRNG
    CNTN1 (MYPCN)
    DOK7 (FADS3)
    MuSK (FADS1)
    MYO9A
    RAPSN (FADS2)
    SLC18A3
    SCN4A
    SLC5A7
    UNC50
    ZC4H2

  Skeletal muscle
    ACTA1
    ACTC1
    ADAMTS15
    BIN1
    CACNA1S
    FILIP1
    FKRP
    KLHL41
    LMOD3
    MTM1
    MYBPC1
    MYH2
    MYH3
    MYH8
    MYLPF
    MYOD1
    NEB
    RYR1
    RYR3
    STAC3
    SYNE1
    TPM2
    TNNI2
    TNNT3
    TTN
  Nuclear proteins
    ASCC1
    LMNA
    NUP88 (FADS4)
    SYNE1
    TRIP4
  Myelin development
    ADCY6
    CASPR (CNTNAP1)
    GLDN
    GPR126 (ADGRG6)
    LGI4
    P0
  Other genes
    DMPK
    FGFR2
    GBE1
    ERGIC1
    KIF21A

Arthrogryposis: General
Arthrogryposis: Clinical features
  • Contractures
    • Often symmetric involvement of 4 limbs
    • Distal > Proximal
    • Flexion posture ± Joint dislocation
    • Elbows > Knees > Feet > Hips > Hands > Shoulders
    • Camptodactyly: Flexion deformity at proximal interphalangeal joints
  • Limbs
    • Shape: Often fusiform or cylindrical
    • Length: Mildly short
  • Skin (At joints)
    • Absent creases
    • Dimpling ± Webbing
    • Pterygia or Webs
      • Early & sustained lack of movement in utero
      • Onset > 8 weeks: After joint formation
  • Skeletal
    • Micrognathia
    • Palate: High arched or Cleft
    • Scoliosis
    • Long bones: Osteoporosis
  • Systems
    • Renal + Cholestasis
      • ARCS1 : VPS33B ; 15q26.1
      • ARCS2 : VIPAR ; 14q24.3
    • Cardiac defects
    • Pulmonary hypoplasia : RAPSYN ; 11p11.2
    • CNS
    • Ectodermal dysplasia
    • GI: Short or immature gut
  • Polyhydramnios: Later in pregnancy
  • Prognosis
    • Improvement over time with
      • Early physiotherapy
      • Orthopedic care
    • Worst with CNS involvement: 50% death in infancy
    • Best: Amyoplasia
  • Treatment
    • Physical therapy: To achieve
      • Lower limbs: Weight bearing joints
      • Upper limbs: Maximum functionality
    • Surgery: Reduce contractures
   
Camptodactyly

Arthrogryposis: Associated disorders Distal Arthrogryposes (DA) 44 Arthrogryposis Syndromes 1

Aarskog–Scott syndrome 25
  FYVE, RhoGEF and PH Domain-containing protein 1 (FGD1) ; Chromosome Xp11.22; Recessive
Arthrogryposis Multiplex Congenita & Intellectual Disability 27
  Zinc finger C4H2 domain-containing protein (ZC4H2) ; Chromosome Xq11.2; Semi-Dominant
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3/7/2024