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CONTRACTURES & OTHER JOINT DISORDERS

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

• Emerin gene
  • 6 exons
  • Immediately distal to filamin gene
  • Emerin & filamin genes surrounded by 11 kb inverted repeats
• EDMD Genetic features
  • Allelic with
    • X-linked sinus node dysfunction: No muscle involvement
  • Mutations: Varied Types
    • ≥ 130 different: Unique in most families
    • Most common
      • Point mutations (49%)
      • Small deletions (33%)
      • Insertions (10%)
      • Small mutations usually result in stop codons
      • Missense mutations rare: Pro183His & Pro183Thr; Q133H; Del236-241; Del95-99
        • Weakened interactions of emerin with nuclear lamina components or membrane
        • Emerin protein in tissues
          • Normal or moderately reduced total amounts in tissues
          • Levels in nucleus reduced: Q133H; Del236-241; Del95-99
        • Later onset contractures & weakness; Same onset cardiac change
          • Pro183His & Pro183Thr
    • Occasional
      • Mutations in start codons: ? Prevent initiation of translation
      • Deletion in promoter: ? Emerin selectively reduced in muscle
      • Intronic
      • In-frame deletions: 878 del 15; 1763 del 18
        • Emerin expressed at low, variable level
        • Phenotype: Typical EDMD
      • Mutations in last exon
        • Emerin lacks C-terminal containing transmembrane domain
        • Emerin absent: Even when deletion is in-frame
      • Transpositions
      • Small deletion: Chimeric emerin protein with reduced levels in nuclear membrane
      • Large deletions of whole gene
        • Whole gene deletions related to mispairing of flanking repeat sequences
      • Skewed X-inactivation
    • Hot spot: Exon 2
  • Modifier genes: SUN1 ; SUN2 ⁴³
  • Mutation Database: HGMD
• Emerin protein⁵
  • 34 kD; Serine rich
  • Protein Family
    • Membrane proteins that interaqct with lamins or chromatin
    • Other family members: Lamina-associated (LAP1; LAP2); MAN1; Lamin B receptor
  • Sub-cellular distribution
    • Nuclear
      • Emerin is attached to
        • Inner nuclear membrane via C-terminus region (hydrophobic)
        • Nuclear lamina
      • Most of protein projects into nucleoplasm
    • Cytoplasm membranes
      • Associated with cadherins & vinculin
  • Tissue distribution
    • Muscle & Nerve
    • Mucosal epithlium & Skin
    • Cardiac: ?? Intercalated discs (focal adhesions), Desmosomes & fasciae adherentes
  • Other properties
    • Emerin contains multiple nuclear-membrane-targeting determinants
    • Emerin Interactions
      • A- & B-type lamins: Lamin A binding region is amino acids 70 to 164
      • Nuclear actin
    • Synthesis pathways
      • Newly synthesized emerin is inserted into endoplasmic reticulum via hydrophobic tail
      • Diffuses freely until trapped at nuclear rim: ? By interactions with chromatin & nuclear lamina
  • Homologies
    • 2 regions with similarities to thymopoetins
    • 1 region with APC tumor suppressor gene
  • Phosphorylated: 36 kD when highly phosphorylated
  • Mutations predict
    • Usually: Absent emerin protein (90%)
    • Rarely: Reduced, but present, emerin
  • Disease pathogenesis: Disorder of nuclear proteins
    • Lamin A/C–emerin complex
    • Members of large nuclear complex: Chromatin, Lamina, Membrane & associated nuclear rim proteins
• Clinical Features
  • Clinical-Genetic
    • Variation: Prominent inter- & intrafamilial, even with same mutation
    • No clear difference in families between mutation types
    • Skewed X-inactivation may produce
      • Pseudo-dominant inheritance
      • Females with typical EDMD phenotype
    • Occasional sporadic patients have emerin deficiency
  • Onset: Contractures & Weakness
    • Age: Neonatal hypotonia to 3rd decade; Mean in teens
    • Function: Difficulty walking or climbing stairs
    • Contractures before weakness
  • Weakness: Humeroperoneal
    • Bilateral
    • Symmetrical
    • Arms: Biceps & triceps; Deltoids spared
    • Scapular winging
    • Legs: Late
    • Face: Mild weakness or normal
  • Wasting: Biceps & triceps; Later Calf
  • Contractures: Often more limiting to function than weakness
    • Elbow (Flexion)
    • Spine
      • Posterior neck (extension)
      • Lower back: Usually later onset, but may present with rigid spine syndrome
      • Back pain
    • Ankle (Plantar flexion): Gait limitation
    • Progression: Slow; Loss of ambulation rare
  • Cardiac Disease
    • Frequency: Almost invariable
    • Onset
      • Early 2nd decade to 40's
      • Usually after some weakness or contractures
      • Occasional presenting feature in 1st decade: Associated with high CK ⁶
    • Progression
      • Syncope: Onset late 2nd & early 3rd decade
      • Usually require pacing by age 30
      • Severe: Emboli; Sudden death
    • Bradycardia
    • Atrial rhythm disturbances & paralysis; A-V conduction defects
    • Late: ± Left ventricular myocardial dysfunction (fibrosis)
    • EKG changes
      • Slow heart rate
      • P waves: Absent or Small
      • Rhythms: Regular nodal or Atrial fibrillation/flutter
    • Treatment: Pacemaker when rate < 50
    • Female carriers: 10% to 20% have
      • Conduction defects & arrhythmias: Monitor with annual EKG's
      • Weakness
• Laboratory
  • Serum CK: Mildly elevated to < 10x normal; Reduction in levels with age
  • EMG: Predominantly myopathic; Occasional fibrillations & high amplitude potentials
  • MRI, Muscle
    • Posterior calf: Soleus involved, Gastrocnemius relatively spared ⁷
    • Thigh: No differential involvement
• Muscle Pathology: Muscle & Other
  • Myopathic
    • Muscle fiber size: Variable
    • Endomysial fibrosis
  • Fiber type disorders
    • Type I fiber atrophy
    • Type I or II predominance
  • Nucleus pathology ¹⁴
    • Breakdown of nuclear membrane
    • Nucleoplasm extrusion
  • Other muscle changes in some patients: "IBM-like" ¹³
    • Rimmed vacuoles
    • Inflammation
    • Nuclear tubulofilamentous inclusions
  • Emerin absent in nuclei
    • Emerin loss in muscle in > 95% of patients
    • Skin or leukocytes
      • Emerin often lost
      • Residual or normal emerin with some missense or promoter mutations
  • Ultrastructure: Nuclei
    • Detachment of nuclear membrane & lamina
    • Detachment of heterochromatin from nuclear rim

• Epidemiology: > 500 mutations
• Genetic: Lamin A/C Mutations ⁴
  • Mutation types: Nonsense & Missense
  • Locations in gene: N-terminal head; Rod (Most common); Globular tail
  • Common dominant EMD2 lamin A/C mutation locations
    • Missense in hydrophobic C-terminal region: R453W; I469T R527P; L530P
    • Alter both Lamin A & C
  • Other dominant EMD2 Lamin A/C Mutations
    • 2A rod domain: R249Q
    • Atypical mutation
      • Causes early stop codon after 6 amino acids (E6Ter)
      • EDMD phenotype caused by absence of 1 allele
    • Trp520Ser: Adds potential new glycosylation site
  • Recessive (or Sporadic) EMD2 Lamin A/C Mutations
    • EMD2 syndrome: R225Q; R249Q; E358K; R453W; R482Q; R527P; T528K; R624H
    • No cardiac pathology: H222Y; R336Q; R453W
    • Male > Female
    • Carriers: May have lipodystrophy
  • Neuromuscular syndromes: Genotype-Phenotype correlations
    • Missense mutations
      • Onset: Childhood; Mean 2.4 years
      • Weakness: Scapuloperoneal & Facial; Paravertebral weakness or rigidity
      • Tendon contractures (70%)
      • EMG: Myopathy + Distal denervation
      • Mechanism: Dominant negative or Toxic gain of function
      • Glu383Lys: Severe, congenital disease
    • Frameshift mutations (? Truncated protein)
      • Onset
        • Age: Adult; Mean 30.5 years; Range
        • Cardiomyopathy more frequent than Weakness
      • Cardiac disorders: Common at onset
      • Weakness: Limb girdle distribution; Paravertebral
      • No tendon contractures
      • EMG: Myopathy + Distal denervation
      • Mechanism: Haploinsufficiency
  • Lamin A/C mutations: Disorders
    • Cardiac
      • Dilated cardiomyopathy with A-V block, Autosomal dominant (CMD1A): Mutations in rod domain
      • Atrial fibrillation: Early onset; Missense (E161K) mutation
      • Malouf syndrome: Dilated cardiomyopathy with hypergonadotrophic hypogonadism
      • Heart-hand syndrome, Slovenian type
    • Myopathy
      • Emery-Dreifuss MD 2 (EMD2; Dominant)
      • Emery-Dreifuss MD 3 (EMD3; Recessive)
      • Myopathy, Dominant (LGMD 1B)
      • Quadriceps myopathy with dilated cardiomyopathy: Missense (R377H) mutation
      • Congenital muscular dystrophy with rigid spine
      • Myopathy, early-onset, with progeroid features
      • Myopathy, posterior neck
    • Neuropathy: AR-CMT2A (CMT 2B1)
    • Lipodystrophy-related
      • Familial partial (Köbberling-Dunnigan Syndrome)
        • Mutations: In globular C-terminal domain
      • Lipoatrophy with diabetes, Hepatic steatosis, Hypertrophic cardiomyopathy & Leukomelanodermic papules (LDHPC)
        • Inheritance: Dominant
      • Mandibuloacral dysplasia (MADA)
        • Mutations: R527H (C-terminal domain) & Other missense, Recessive
        • May be associated with partial lipodystrophy
    • Premature aging
      • Hutchinson–Gilford progeria
        • Dominant, de novo
        • Common mutation: Gly608Gly activates cryptic splice site
        • Lamin protein
          • Shorter
          • "Progerin": Irreversibly farnesylated
        • Onset: Childhood
        • Death: Atherosclerosis in Mid-teens
        • Nuclear architecture: Abnormal
      • Werner syndrome , atypical
      • Restrictive Dermopathy, lethal (Tight skin-Contracture)
    • Metabolic
      • Metabolic syndrome
      • Increased susceptibility to type 2 diabetes: G-allele of rs577492
    • Lethal phenotype: Homozygous LMNA nonsense mutation
    • Lamin A/C null mouse
      • Muscular dystrophy: Onset soon after birth
      • Cardiomyopathy
      • Nucleus
        • Ultrastructural pathology
        • Mislocalization of emerin
    • ZMPSTE24 mutations: Cause abnormal posttranslational processing of lamin A
  • Other lamin disorders
    • LMNB1 : Leukodystrophy, Adult onset (ADLD)
    • LMNB2
      • Susceptibility to partial lipodystrophy
      • Barraquer-Simons syndrome
  • Other nuclear envelope & matrix disorders
• Lamin A/C proteins ⁵
  • Lamins
    • Intermediate filaments, Type V
    • Main constituents of Nuclear lamina (Protein network under inner face of nuclear envelope)
  • A & C
    • Products of alternate splicing of 3' end of same gene
    • Lamin A longer
  • Lamin protein type
    • Nuclear lamina protein
    • Intermediate filament family
  • Subcellular location: Inner nuclear membrane
  • Structure: Similar to other IF proteins
  • Central α-helical rod domain flanked by
  • Non-α-helical head
  • Globular carboxy-terminal tail domain
  • Expression
    • Onset: Late in embryonic development
    • Location: All somatic tissues except erythrocytes
  • Functions
    • Provides framework for nuclear envelope
    • May interact with chromatin
    • Formation of nuclear lamina: Lamins assemble into filaments
      • Lamin B1 assembles first, then lamin A & finally lamin C
      • The lamina extends throughout the nuclear interior
        • Partly as invaginations of the nuclear membrane
        • Also as a matrix component
  • Post-Translational modifications
    • Phosphorylation
      • Mitosis: Phosphorylation of lamins increases before nuclear envelope disintegration
      • Down regulates lamin associations with other proteins
    • Prenylation: Prelamin A
    • C-terminal
      • Farnesylation: Processing of prelamin A
      • Carboxymethylation
    • Mature lamin A
      • Acetylation
      • Phosphorylation
      • Addition of N-acetylglucosamine
      • Sumoylation: Rod domain by SUMO2 ; Tail domain SUMO1
  • Protein associations
    • Nuclear
      • Lamina-associated protein 1 (LAP1)
      • Emerin
      • Sun-1
      • Sun-2
      • Nesprin-2
    • Other
      • Actin
      • Titin
      • SREBP1

  Clinical features 3 Onset Most common: 1st or 2nd decade Early features Cardiac before contractures Some weakness may be detectable in many between 3 to 6 years Occasional patients as early as 2nd year Clinical features Scapulo-Peroneal weakness Contractures Variable penetrance of same mutation Similar to emerin mutations in some patients Other patients with mutations but no clinical manifestation Weakness Proximal ± Distal leg Humeroperoneal: More severe weakness in biceps brachii than EMD1 Bilateral Symmetrical Calf wasting Progression Slow to moderate Some patients with loss of ambulation by 8 to 13 years Muscle hypertrophy: Quadriceps; Extensor digitorum brevis Contractures Usual onset 2nd decade Locations Upper extremity: Elbows Trunk: Back (Rigid spine); Neck Lower extremity: Ankles; Knee Cardiac Onset Age: 2nd to 4th decade Later in patients with frameshift mutations Conduction defect Arrhythmias: Brady or Tachy Cardiomyopathy: Dilated or Restrictive Often require pacing or heart transplant Comparison to emerin (EMD1) mutations Isolated cardiac involvement more frequent Ventricular fibrillation more common Dilated cardiomyopathy more common Other: Some patients Ptosis Micrognathia Scoliosis Lipodystrophy Mild progeric appearance Laboratory Serum CK: Normal or mildly elevated to 1,500 Electromyography: Myopathic Muscle pathology Myopathic (Dystrophic) Nucleus 14 Chromatin reorganization Loss of nucleoplasm volume H222P mutation in mouse model: Increased intranuclear SMAD Fiber type changes Fiber predominance: Type 2, especially in older patients Type 1 fibers: Small MRI 7: T1W sequences Posterior calf: Medial head of gastrocnemius involved, lateral head spared Soleus: Spared in patients < 20 years or with milder phenotype Thigh: Involvement correlates with clinical severity Lamin A/C variant syndrome: Congenital muscular dystrophy + Rigid spine (CMD-L) Genetics Mutations Common: Exon 4 c.745 C>T Mutation types: Missense, Deletions (In-frame) & Duplications Inheritance: Dominant Allelic disorders Clinical Onset Age: < 1 year Fetal movements: Reduced Weakness Proximal & Axial Distal: Legs Symmetric Posterior neck: Some patients Respiratory Skeletal Rigid spine Talipes feet Thoracic lordosis Cardiac: Arrhythmia in some patients Other: Some patients Progeria Lipodystrophy

  From: A Kornberg Emery-Dreifuss: Rigid spine

  • Laboratory
    • Serum CK: High
    • Muscle: Myopathic; Irregular nuclei
• Lamin A/C variant syndrome: Severe phenotype
  • Genetics
    • Homozygous mutation
    • Inheritance: Recessive
  • Clinical
    • Fetal akinesia
    • Multiple joint contractures
    • Lung hypoplasia
    • Muscle: Severe dystrophy with fibrosis; Especially severe in diaphragm

• Epidemiology: 3 patients in 3 families
• Genetics
  • Mutations
    • Location: Nesprin-1α
    • Types: Missense (Arg257His, Glu646Lys); Splice (IVS136AS, A-G, -2 ); Truncating
  • Combined mutations in SYNE1 & SYNE2: More severe phenotype
  • Allelic with
    • SCAR8 (Ataxia, recessive): Proximal mutations
    • Arthrogryposis, Recessive (AMCM): Distal-truncating mutations
    • Cardiomyopathy: Dilated
    • ALS, Juvenile
• Protein: Nesprin-1
  • Spectrin-repeat
  • Multiple isoforms: Vary greatly in size
  • Localization: Nuclear membrane & other subcellular regions
  • Bind actin
  • Inner nuclear membrane isoforms
    • Highly expressed in muscle & heart
    • Bind: Lamin A & Emerin
    • Link nucleoskeleton & INM to Outer nuclear membrane (ONM) & cytoskeleton
      • Form a bridging LINC complex with SUN1 and SUN2
      • Location of LINC complex: Across luminal space between the inner & outer nuclear membranes
  • Muscle specific isoform: Nesprin-1α₂ (C-terminal)
  • Other isoforms: In cerebellar & cerebral neurons (KLNes1g)
  • Cytoskeletal, Nuclear & Vesicle anchoring
• Clinical
  • Onset: 11 years or Asymptomatic (E646K mutation)
  • Weakness
    • Shoulder girdle
    • Preogressive
    • Severe patient: Wheelchair at 26 years
  • Contractures: Limbs; Progressive
  • Cardiac involvement: No clinical changes
• Laboratory
  • Electromyography: Myopathic
  • Histopathology:
    • Muscular dystrophy
    • Normal dystrophin staining
  • Creatinine kinase (serum): Mildly elevated
  • ECG monitoring and echocardiography: Normal or mild changes
• Variant syndrome: Arthrogryposis, Myogenic, Recessive (AMCM; AMC3) ²²
  • Epidemiology: 3 families, 7 patients
  • SYNE1 mutations: Distal truncating
    • Homozygous A to G nucleotide substitution of tsplice acceptor site at junction of intron 136 & exon 137
    • Aberrant retention of intron 136 of SYNE-1 RNA: Leads to premature stop codons
    • Allelic disorders
  • SYNE1 protein
  • Clinical
    • Onset: in utero
    • Fetal movements: Decreased
    • Contractures
      • Clubfoot: Bilateral
      • Adducted thumbs
    • Scoliosis
    • Motor
      • Hypotonia
      • Delayed milestones
      • Face: Weakness, mild
      • Proximal weakness
    • Tendon reflexes: Absent or Reduced
    • CNS
      • Intelligence: Normal or Impaired
    • Course: Progressive motor decline after 1st decade
  • Laboratory
    • Serum CK: Normal
    • EMG: Mild denervation
    • Muscle biopsy: Varied fiber size, Mild; Nuclear membrane abnormal
    • Ultrasound: Fibrosis & Fatty replacement of muscle
• SYNE1 variant: Juvenile ALS, Recessive ⁴⁶
  • Epidemiology: 1 Japanese patient
  • Genetics
    • Inheritance: Recessive
    • Mutations: Stop; Compund heterozygous; c.21463C>T, .22835_22836delAA
    • Allelic disorders
  • Clinical
    • Onset
      • Age: Later childhood
      • Slow running
    • Upper motor neuron
      • Spasticity: Face; Arms; Legs
      • Dysarthria
      • Tendon reflexes: Increased except at ankles
    • Weakness: Fespiratory
    • Ataxia: Limb; Tremor
    • Cognitive decline: Mild
    • Pes cavus
    • Course
      • Progressive
      • Death at 39 years
  • Laboratory
    • EMG: Neurogenic changes, Diffuse
    • Brain MRI: Megacisterna magna; Cerebellar atrophy, mild

• Epidemiology: 2 patients in 2 families
• Genetics
  • Mutations
    • Location: Nesprin-2β
    • Type: Missense; T89M
  • Combined mutations in SYNE1 & SYNE2: More severe phenotype
• Proteins: Nesprin-2
  • Spectrin-repeat
  • Multiple isoforms: Vary greatly in size
  • Localization: Nuclear membrane & other subcellular regions
  • Bind actin
  • Inner nuclear membrane isoforms
    • Highly expressed in muscle & heart
    • Bind lamin A & emerin
    • Link nucleoskeleton & INM to Outer nuclear membrane (ONM) & cytoskeleton
      • Form a bridging LINC complex with SUN1 and SUN2
      • Location of LINC complex: Across luminal space between the inner & outer nuclear membranes
  • Muscle specific isoform: Nesprin-2α₁
• Clinical
  • Weakness
    • Onset: Childhood to 4th decade
    • Symmetric
    • Scapular winging: Variable
    • Respiratory insufficiency: Minor
    • Ptosis: 1 patient
  • Cardiomyopathy
• Laboratory
  • Serum CK: Elevated 2 to 14 fold
  • Muscle pathology
    • Internal nuclei
    • Muscle fiber size: Varied
    • Fat deposition
    • Subsarcolemmal metachromasia
    • Normal emerin, lamin A/C, sarcoglycan, desmin, emerin & caveolin staining

• Epidemiology: 2 Japanese families
• Genetics
  • Mutations: Missense; Glu85Lys; Ile91Val
  • Allelic disorders
    • ARVD5 (Ser358Leu mutation)
    • Auditory neuropathy spectrum disorder (Arg372Ter) ⁴⁷
• TMEM43 (LUMA) protein
  • Location: Inner nuclear membrane protein
  • Interacts with: SUN2
  • Expressed in many tissues, including skeletal muscle
  • Mutants
    • Protein fails to homo-oligomerize
    • Irregular nuclear shapes
    • Decreased staining of emerin & SUN2 on nuclei in transfected cells
• Clinical
  • Onset: Adult
  • Muscle
    • Atrophy & Weakness
    • Paraspinous
    • Neck
    • Proximal arms
    • Thighs
  • Contractures
  • Cardiac: Arrhythmias
• Laboratory
  • Muscle pathology
    • Fiber size: Varied
    • Necrosis & Regeneration
    • Chronic changes: Internal nuclei; Fiber splitting
    • Nuclear staining
      • LUMA: Reduced; Also low in lamin A/C mutations
      • Emerin: Variable
      • Nesprin: Normal

• Nosology: Myofibrillar myopathy 7 (MFM7)
• Epidemiology: 4 families, 5 patients; Arab-Israeli, Iranian & Kurdish
• Genetics
  • Mutations
    • Type: Stop common
    • c.1071delG, p.Thr358Leufs*3; c.405C>A, p.Y135*; Arg139Ter; Leu274Pro
• KY protein
  • Location: Z-disc
  • Complex: KY-protein/Filamin-C/KY-interacting protein IGFN1
  • Other interaction: MYBPC1
  • Stabilization of sarcomere
• Clinical
  • Onset
    • Age: Congenital to Early childhood
    • Joint contractures
  • Joints: Contractures
    • Legs: Ankles, Equinus; Hips
    • Arms: Elbows; Shoulders
    • Spine: Rigid; Scoliosis, Kyphosis or Lordosis
    • Course
      • May be progressive
      • Walking: May be impaired
  • Weakness
    • Trunk, Proximal & Distal
    • Most in: Distal legs
    • Biceps & Triceps in some patients
  • Atrophy
    • Tongue: Atrophy at lateral sides
    • Posterior leg
  • CNS: Intellect impaired in 1 patient
• Laboratory
  • Muscle MRI: Posterior leg; Asymmetric
  • EMG: Large motor units in posterior leg
  • Muscle biopsy
    • Targets & Targetoid changes
    • Fiber size
      • Varied
      • Some very small fibers: 2C; Express MYH3 or MYH8 myosins
    • Type 2 predominance
    • Aggregates: Filamin C; Xin
    • Ultrastructure: Small rods; Z-line thickening
  • Serum CK: Normal to High, Up to 1200
• Animal model: Ky-mouse

• Epidemiology: 1 patient
• Genetics
  • Mutations: c.422+5G>C; c.583dup
  • Allelic disorders: Reproductive anomalies, dominant
  • Differential diagnosis: Marden-Walker syndrome
• SOX8 protein
  • Expression: Many tissues
  • Transcription factor
  • Target: WNT/β-catenin pathway
  • Tissue-specific imprinting
  • Skeletal muscle
    • Regulator of differentiation
    • Impairs myogenic basic helix-loop-helix protein function
• Clinical
  • Onset age: Congenital
  • Weakness
    • Face: Severe
    • Respiratory failure
    • Bulbar: Dysarthria, Dysphonia
    • Limbs: Proximal & Distal
    • Course: Non-progressive
  • Skeletal
    • Dysplasia: Micrognathia, Palate High-arched, Kyphoscoliosis
    • Contractures: Distal & Proximal
    • Short stature
    • Body habitus: Thin
    • Scapular winging
    • Fingers: Hyperlaxity
  • CNS: Intellectual delay
  • Ovary: Amenorrhea
• Laboratory
  • Muscle: Fiber size variation; Type 2 predominance
  • Serum CK: Normal
  • EMG: Myopathic
  • RNS: No decrement
  • Brain MRI: 4th ventricles large
  • Muscle MRI: Fatty replacement, Asymmetric, Paraspinous & Legs > Arms

Nuclei: Muscle Fibers

• Myonuclei
  • Number: Many in each individual muscle fiber (100s)
    • Other multinucleated cells: Cardiomyocytes; Cytotrophoblasts; Osteoclasts
  • Position
    • Peripheral (Adjacent to sarcolemma): Adult muscle fibers
    • Internal (Separated from sarcolemma): Immature muscle fibers
    • Disorders
      • Centronuclear myopathies
      • Myotonic Dystrophy: 1; 2
  • Shape
    • Normal: Oval; Elongated parallel to myofibrils
    • Disorders
      • Nemaline (Rod) myopathies ¹⁵⁴
        • General: Pericentrin
          • Normal: Punctate around nucleus
          • Rod myopathies: Diffuse & Increased on nuclear surface
        • ACTA1: Elongated; Irregular shapes
        • NEB: Circular
      • Nuclear envelope: Laminopathies
      • Marinesco-Sjögren
      • Age
  • Size
    • Normal: 4 to 5 μm long; 1 to 2 μm wide
    • Larger: Infants & Younger children
  • Nuclear envelope
    • Signalling hub: Transduces chemical & mechanical signals to regulate gene expression
    • Emerin: More staining than fibroblast nuclei
    • Nuclear lamina: Inner side of nuclear membrane; Contains lamins
    • Disorders
  • Chromatin
    • Normal: Peripheral dense band + Small dense areas in nucleoplasm
    • Contains: DNA & Histones
    • Myopathy: Dispersed or Abnormal shapes
  • Nucleoli
    • Transcription of ribosomal DNA sequences
    • Stains: Bsasophilia; Acridine orange fluorescence
    • Size: Increased during muyscle fiber regeneration
  • Nuclear pores
  • Nuclear DNA
    • Stained by: Methyl green; anti-DNA antibodies; Acridine orange
  • Satellite cells
    • Frequency: ~ 4% of myonuclei
    • Chromatin: Denser than other myonuclei
    • Stain for: NCMAM; PAX7
  • Other disorders
• Myonuclear Domain
  • Definition: Cytoplasm surrounding nucleus for which gene expression is controlled
  • Sizes
    • Structural proteins
      • Size: 100 μm
      • Types: Myosin, heavy chain; Dystrophin
    • Soluble proteins: Larger size
    • Changes
      • Smaller: Muscle fiber atrophy
      • Larger: Muscle fiber hypertrophy
  • Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α; PPARGC1A)
    • Role in myonuclear domain size
      • PGC-1α over-expression → Myodomain size Smaller
    • Also regulates
      • Mitochondrial biogenesis
      • Hepatic gluconeogenesis
      • Muscle fiber-type switching
      • Adaptation to exercise
• Myonuclei linkages: Cytoskeletal components
  • Non-sarcomeric/cytoplasmic actins: Movement of nuclei to fiber periphery
  • Microtubules: Initial spacing & spacing of nuclei along fiber length
  • Intermediate filaments (Desmin): Movement of nuclei to fiber periphery
  • Disorder: Nemaline (Rod) myopathies
    • Irregular nuclear spacing & morphology
    • Abnormal nuclear envelope
    • Disordered Chromatin distribution

Nuclear Protein Disorders: Envelope & Matrix ⁵¹

• Nuclear envelope: General
  • Membrane: Separates nucleus from cytoplasm.
  • Layers: Inner & Outer
  • Nuclear pore complexes (NPCs)
    • Location: Regions of inner & outer nuclearmembrane fusion
    • Embedded in nuclear envelope
    • Components
      • Multiprotein subcomplexes: Form cylindrical ring structure
      • Anchored in membrane via 3 transmembrane nucleoporins: NDC1, POM121, GP2101
    • Functions
      • Facilitate nucleocytoplasmic transport of proteins
      • Transcriptional regulation
      • Chromatin organization
      • Mitotic progression
• Lamin disorders
• Transmembrane nuclear proteins
  • Emerin
    • Emery-Dreifuss muscular dystrophy 1 (EDMD 1)
  • Lamin B-receptor
    • Pelger-Huet anomaly (PHA)
    • Greenburg/HEM skeletal dysplasia (GSD/HEM)
  • MAN1 (LEMD3)
    • Buschke-Ollendorff syndrome (BOS)
    • Melorheostosis & Osteopoikilosis
  • Nesprin-1 (SYNE1)
    • Emery-Dreifuss muscular dystrophy 4 (EDMD 4)
    • Cerebellar ataxia (SCAR8)
    • Present in nucleus & other regions of cell
  • Nesprin-2 (SYNE2)
    • Emery-Dreifuss muscular dystrophy 5 (EDMD 5)
    • Present in nucleus & other regions of cell
  • TMEM43 (LUMA)
    • Emery-Dreifuss muscular dystrophy 7 (EDMD 7)
    • ARVD5
  • TMEM48 (NDC1)
    • Achalasia-Alacrimia + Peripheral neuropathy
• Nuclear Envelope-associated
  • BANF1: Motor neuropathy; Progeroid syndrome
  • RNP220: Ataxia & Deafness
  • VRK1: PCH1 with Spinal muscular atrophy
  • Torsin-1A : Torsion dystonia 1 (DYT1); AMC5
  • FACE-1 (ZMPSTE24)
    • Restrictive dermopathy (RD)
    • Mandibuloacral dysplasia with lipodystrophy
    • Metabolic syndrome
  • LAP1B (TOR1AIP1): Myopathy, Contractures & Cardiomyopathy
  • LAP2α (Thymopoietin; TMPO) : Cardiomyopathy, dilated 1T (CMD 1T)
  • Aladin: Triple A syndrome
  • Nup62 (Nucleoporin-62) : Infantile bilateral striatal necrosis
  • Chromobox homolog 5 (CBX5; HP1)
  • SUN1 : Inner nuclear membrane
  • SUN2 : Inner nuclear membrane
  • Torsin 1A
    • Nuclear envelope
    • AAA ATPase
    • Disease: Dystonia 1
  • TPR: Neurodevelopment disorder
  • GLE1
    • Lethal congenital contracture syndrome 1
    • Lethal arthrogryposis with anterior horn cell disease
    • Amyotrophic lateral sclerosis
  • MCM3AP (GANP): AR-CMT2 + Intellectual Disability
  • STIM1: TAM1
  • FUS: ALS 6
• Nuclear matrix related
  • FSH dystrophy
    • Deletion of D4Z4 repeat array: Causes delocation of adjacent matrix attachment regions from nuclear matrix
  • Matrin-3: Distal myopathy with vocal cord disorder (MPD2)
    • Nuclear matrix protein
  • FHL-2: Relative of FHL-1 that causes Reducing body myopathy & Scapuloperoneal myopathy
    • Binds to nuclear matrix protein NP220 & splicing factor PSF (Matrin-3 interaction partner)
  • THOC2: AMC7

Arthrogryposis Multiplex Congenita (AMC) ²⁹

• Definition
  • Contractures of 2 or more joints at birth
  • Nonprogressive
  • Excludes: Isolated bilateral clubfeet & dislocated hips
• 95% sporadic: Male:Female = 2:1
• Cause: Fetal akinesia
  • Most arthrogryposis results from limited fetal movement
  • Decreased joint movement is associated with
    • Increased connective tissue around joints (Collagenosis)
      • Further limits joint movement & increases contractures
    • Disuse atrophy of muscles associated with joint
    • Abnormal joint surfaces
      • Squared edges rather than rounded
      • May lead to fractures of joint surfaces with joint mobilization
  • Earlier & longer duration of decreased movements
    • More severe contractures at birth
• Frequency
  • Single joint congenital contracture: 1 in 200 to 500 live births
  • Arthrogryposis: 1 in 3,000 to 5,000 children
  • Most common diagnosis: Amyoplasia (1 in 10,000)
• Mutations ¹⁷
  • Protein types: Distal arthrogryposis
    • Often in fast-twitch contractile apparatus proteins
    • Cause increased contractility of developing fast muscle fibers
  • Specific conditions
    • > 150 genes identified
    • Other: Chromosomal abnormalities
    • Common genes (50% of families)
      • TPM2
      • TNNI2
      • TNNT3
      • MYH3
      • MYH8

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

• Congenital disorders of the neuraxis
  • Brain: Lissencephaly ; Agenesis of corpus callosum
  • Möbius Syndrome
    
  • Spinal cord: Meningocoele; Sacral agenesis
  • Anterior horn cell: Idiopathic loss; Spinal muscular atrophy
  • Peripheral nerve: Hypomyelination
  • Neuromuscular Junction: Congenital myasthenia gravis
  • Myopathy: With early onset
    • Myotonic dystrophy
    • Muscular dystrophy
    • Myopathies, Congenital
• Anatomical disorders
  • Skin & Connective tissue
    • Connective tissue dystrophy
    • Skeletal dysplasias & Chondroplasias
    • Congenital ichthyosis
    • Skin: Neu Laxova syndrome ; Restrictive Dermopathies
  • Impairment of fetal environment
    • Oligohydramnios
    • Crowding
    • Uterine structural abnormalities & Limited space
      • Respond rapidly to early physical therapy
• Genetic & Epigenetic syndromes
• Metabolic disorders
• Maternal illness & exposures
• "Amyoplasia" syndrome
  • Sporadic
  • Contractures: Symmetric
    • Shoulders: Internal rotation
    • Elbows: Extended
    • Wrists: Flexed
    • Knees: Flexed or extended
    • Feet: Equinovarus
  • Forehead: Hemangioma
  • IQ: Normal
  
  

• Prevalence: 1:3,000
• Inheritance: Autosomal dominant most common
• Clinical
  • Contractures: Congenital
    • Distal joint involvement
    • Limited proximal joint involvement
    • Two or more different body areas
  • Course: Nonprogressive
  • Expressivity: Varied
  • No primary neurological and/or muscle disease
• Types
  • DA1
    • Camptodactyly
    • Club foot
    • Face: Triangular face; Nasolabial folds prominent; Palpebral fissures downslanted
    • Intelligence: Normal
  • DA2
    • Leg involvement: Prominent
    • Subtypes: DA2A; DA2B
  • Other types

• Distal Arthrogryposis, type I (DA1; DA1A)
  ● Tropomyosin 2 (TPM2) ; Chromosome 9p13.3; Dominant or de novo
  • DA1 General: Contractures limited to hands and feet with no additional anomalies
  • Genetics
    • Mutation: Missense; Arg91Gly
    • Allelic disorders
    • Some DA 1A families: No TPM2 mutations
  • Tropomyosin 2 protein: Present in fast skeletal muscle fibers
  • Clinical features
    • Intrafamilial variation
    • Flexion contractures at birth
    • Predominant involvement: Hands & Feet
      • Hands: Tight fist with medial overlapping of fingers & adducted thumb
        
      • Feet: Equinovarus
    • Face: Normal
    • Intelligence: Normal
    • Good response to physical therapy
      • Adults with residual overlapping of toes & absent distal interphalangeal creases
  • Laboratory
    • Serum CK: High in some patients
    • Muscle pathology: No rods
  
  
• Distal Arthrogryposis, type I (DA1B)
  ● Myosin-binding protein C, Slow type (MYBPC1) ; Chromosome 12q23.2; Dominant ²³
  • DA1 General: Contractures limited to hands and feet with no additional anomalies
  • Genetics
    • Mutations
      • Missense; W236R, Y856H
      • M-motif in NH2 terminus
    • Allelic disorders
      • DA1B, Dominant
      • Distal Arthrogryposis 1, Severe, Recessive
      • Lethal Congenital Contracture Syndrome 4, Recessive
      • CMYP16: Myopathy with Myogenic tremor, Dominant
  • MYBPC1 protein
    • sMyBP-C
    • Expressed in types 1 > 2 muscle fibers
    • Subcellular location: C region of A-band where myosin & actin overlap
    • Accessory protein in muscle
      • Actomyosin: Regulates cross-linking
      • Thick filaments: Stabilization
      • Contractility modulation: Via dynamic interactions with myosin & actin
    • Interactions
      • Titin
      • Myosin: At S2 & light meromyosin (LMM) protein
      • Actin
      • Four and a half LIM domain 1 (FHL1)
      • COOH-terminus: Binding to titin, obscurin, FHL1, Creatine kinase
      • Ky
    • Also see: MYBPC3
  • Clinical
    • Clubfoot (100%): Congenital
      • Bilateral
      • Talipes equinovarus (Clubfoot) 75%
      • Vertical talus 25%
    • Hands 40%
      • Camptodactyly with ulnar deviation of fingers
      • Extension contracture of 4th digit
    • Strength: Normal
  • Muscle
    • Type I muscle fiber smallness
    • MYBPC1 staining: Normal
    • Ultrastructure: Normal
  • MYBPC1 variant syndrome: Lethal congenital contractural syndrome 4 (LCCS4)
    • Epidemiology: Bedouin, Southern Israel families
    • Genetics
      • Inheritance: Recessive
      • MYBPC1 mutation: Homozygous; R318X
      • Allelic disorders
    • Clinical: Multiple contractures
  • MYBPC1 variant syndrome: Myopathy with Myogenic tremor (CMYO16) ⁴⁰
    • Nosology: MYOTREM; CMYP16; CMYO16
    • Epidemiology: 8 families
    • Genetics
      • Inheritance: Dominant
      • Mutations: Missense; Leu219Pro, Y247H, E248K; NH₂-terminal M-motif
      • Allelic disorders
    • MYBPC1 (sMyBP-C) protein
      • Mutations cause: Increased binding of the NH2-terminus to myosin
    • Clinical
      • Onset age: Childhood
      • Weakness: Distal, Proximal & Axial; Legs & Arms; Face, mild
      • Calf pseudohypertrophy
      • Scapular winging, mild
      • Tremor: Postural; Tongue; May persist in sleep
      • Skeletal
        • Contractures: Feet, Elbows; With disease progression
        • Palate: High arched
        • Scoliosis
    • Laboratory
      • EMG: Myopathic
      • Muscle: Type 1 fibers predominant & smaller than type 2
      • Muscle MRI: Paravertebral & Tongue involvement
  • MYBPC1 variant syndrome: Distal Arthrogryposis, Severe, Recessive ⁵⁴
    • Epidemiology: 1 patient
    • Genetics
      • Inheritance: Recessive
      • Mutations: Carboxy terminus; c.2486_2492del (Stop), D888G (Missense)
      • Heterozygous parents: Normal
    • Clinical
      • Onset: Prenatal; Polyhydramnios
      • Craniofacial anomalies
      • Hypotonia
      • Clubfoot
      • Camptodactyly
      • Laryngomalacia
      • Weakness
        • Respiratory: Moderate involvement
        • Limbs
        • Fatigability
      • Spine: Rigidity; Scoliosis
      • Tremor: Postural
      • Cognition: Normal
      • Course: Slow improvement, then stable
    • Laboratory
      • Brain MRI: Normal
  
  
• Distal Arthrogryposis, type 2 (Freeman-Sheldon syndrome) (DA2A)
  ● Myosin, heavy chain 3, Skeletal muscle, Embryonic (MYH3) ; Chromosome 17p13.1; Dominant
  • Epidemiology: Common cause of DA2
  • Genetics
    • Mostly missense mutations
    • Common mutations: R672H; R672C; T178I
    • Allelic disorders
      • DA1
      • DA2A
      • DA2B
      • Multiple Pterygium Syndrome, Dominant (DA8; CPSFS1A)
      • Contractures, Pterygia, & Variable skeletal fusions syndrome 1B (CPSKF1B), Recessive
  • MYH3 protein
    • Present in muscle
      • From 6- to 24-wk gestational age
      • Immature, regenerating muscle fibers in myopathies
    • Myosin disorders, other
  • Clinical features
    • Mouth: Small; Pursed lips; Paramedian grooves between lower lip & tip of chin
    • Palpebral fissures: Down slanting
    • Face (Whistling): Hypoplastic alae nasi; Prominent nasolabial folds; Long philtrum
    • Cervical pterygia: Mild
    • Scoliosis
    • CNS
      • Dominant forms: Normal intelligence
      • Recessive forms: Some with developmental retardation
  • Muscle pathology
    • Myopathy: Scattered small type I muscle fibers
    • Fetal MyHC isoform (MYH8): Upregulated in 1 patient
  • MYH3 variant syndrome: Multiple Pterygium Syndrome, Dominant (DA8; CPSFS1A) ³²
    • Genetics
      • Inheritance: Dominant
      • Mutations
        • Type: Missense; Inframe deletions & duplications
        • Locations: Exons 8 & 25
      • Allelic disorders
    • Clinical
      • Onset age: Congenital
      • Contractures & Limbs
        • Flexion creases: Hypoplastic
        • Camptodactyly
        • Contractures: Elbow; Knee; Distal
        • Popliteal webbing
      • Spine
        • Scoliosis
        • Hemivertebrae
        • Vertebral fusion: C1-C2 or other levels
        • Neck: Short; Webbed
        • Short stature
      • Muscle: Atrophy
      • Face
        • Downslanting palpebral fissures
        • Ptosis
        • Ears: Low-set, Posteriorly rotated
        • Nasal bridge: Long
  • MYH3 variant syndrome: Contractures, Pterygia, & Variable skeletal fusions syndrome 1B (CPSKF1B)
    • Nosology: Spondylocarpotarsal Synostosis Syndrome, Recessive
    • Epidemiology
      • 4 families
      • Similar syndrome caused by: Filamin B
    • Genetics
      • Inheritance: Recessive
      • Allelic disorders
    • Clinical
      • Contractures
        • Proximal & distal joints
        • Fusions: Vertebral, Carpal, Tarsal
      • Pterygia: Neck, Elbows, Fingers, Knees, and variable
      • Inter- & intrafamilial variability
  
  
• Distal Arthrogryposis, type 2B (Freeman-Sheldon variant) (DA2B) ⁸
  ● DA2B1 : Troponin I, Fast-twitch skeletal muscle (TNNI2) ; Chromosome 11p15.5; Dominant
  ● DA2B2 : Troponin T, Fast-twitch skeletal muscle (TNNT3) ; Chromosome 11p15.5; Dominant
  ● DA2B3 : MYH3 ; Chromosome 17p13.1; Dominant
  ● DA2B4 : TPM2 ; Chromosome 9p13.3; Dominant or de novo
  ● Other genes: Many unidentified
  • DA2B: Clinical features
    • Face: Triangular; Small mouth; Prominent nasolabial folds
    • Palpebral fissures: Down slanting
    • Attached earlobes; Cervical webbing
    • Camptodactyly; Ulnar deviation; Positional foot deformities
    • Scoliosis
    • Vertical talus
  • DA2B1: TNNI2 ⁸
    • TNNI2 mutations
      • Locations: Missense Arg174Glu, F178C; Nonsense C-T466
      • Predicted to disrupt the carboxy-terminal domain of an isoform of troponin I (TnI)
      • Drosophila TNNI2 mutants
        • Hypercontracted intercostal flight muscles (IFM)
        • Protracted elevation of the wings
        • Reduced frequency of wing beats
        • Awkward, irregular gait
    • TNNI2 protein
      • Specific to troponin-tropomyosin (Tc-Tm) complex of fast-twitch muscle fibers
  • DA2B2: TNNT3 ⁹
    • Epidemiology: 5 patients
    • Genetics
      • Inheritance: Recessive
      • TNNT3 mutation: Missense or Splice; Arg63His, c.681+1G>A
    • TNNT3 protein: Binds actin & β-tropomyosin
    • Clinical
      • Weakness: Face & Limbs
      • Skeletal
        • Joints
          • Contractures
          • Camptodactyly
          • Thumb adductionU
          • Ulnar deviation
        • Scoliosis
        • Vertical talus
    • Face
      • Mouth: Small
      • Palpebral fissure: Down-slanting
      • Nasolabial fold: Slight
    • Muscle
      • Type 2 fibers: Very Small
      • TNNT3: Reduced
      • Nemaline rods
  • DA2B3: MYH3
    • Genetics
      • Mutations: Missense & In-frame deletions
      • Allelic disorder: DA2A
    • Clinical
    • Muscle pathology
      • Type I muscle fibers
        • Some are small
        • May be predominant
      • Fetal MyHC isoform (MYH8): Upregulated in 1 patient
  • DA2B4: TPM2 ⁸
    • Genetics
      • Mutations: Missense; Arg133Trp; Arg133Pro
      • Inheritance: Dominant or de novo
      • Allelic disorders: Nemaline myopathy; Cap myopathy; DA1
    • Clinical
      • Prenatal: Reduced fetal movements
      • Contractures: Distal & Proximal
      • Other skeletal
        • Face: Involved in some; Trismus
        • Neck: Pterygia; short
        • Short stature
      • Intelligence: Normal or Mild delay
      • Muscle
        • Reduced bulk (50%)
        • Weakness (50%)
    • Laboratory
      • Muscle pathology: No rods; Type 1 fiber predominance
  
  
• Distal Arthrogryposis with scoliosis (DA4; DA2D)
  ● Autosomal Dominant
  • Clinical features
    • Short stature
    • Short neck
    • Ptosis
    • Immobile facial expression
    • Camptodactyly with absent flexion creases on hands
      
      
• Arthrogryposis with Oculomotor limitation & Electroretinal abnormalities (DA5)
  ● Autosomal Dominant
  
  • Epidemiology: Heterogeneous group
  • Clinical features ¹²
    • Contractures
      • Limb: Hands; Elbows (Supination); Feet (50%)
      • Trunk: Rigid spine; Restricted pulmonary function (Adults); Scoliosis (25%)
      • Shoulders: Hunched
      • Course: Improvement with age
    • Face
      • Limited expression
      • Mouth: Narrow; Horizontal
    • Ocular
      • Movement limitation
        • Restrictive
        • All muscles
      • Ptosis: Occasional
      • Macula: Pigmentation; Retinal folds
      • Optic nervehead: Dysplastic
      • Malformations
        • Epicanthal folds
        • Keratoglobus
        • Corneal leukoma & high astigmatism
      • Deep set eyes
    • Limb muscles: Aplasia (Decreased mass)
    • Pyloric stenosis: Hypertrophic
      
      
  • Laboratory
    • Serum CK: Normal
    • NCV & EMG: Normal
    • Muscle pathology: Normal
    
    
• Distal Arthrogryposis 5D (DA5D) ²⁶
  ● Endothelin-converting enzyme-like 1 (ECEL1; DINE) ; Chromosome 2q37.1; Recessive
  
  • Epidemiology: 26 families
  • Genetics
    • Mutations: Stop; Splice; Missense
  • ECEL1 protein
    • Nosology: Damage-induced neuronal endopeptidase
    • Zinc metalloprotease
    • Membrane-bound
    • Endoplasmic reticulum
    • Neuronal expression
    • Absence in mice
      • Abnormal terminal branching of motor neurons to NMJs
      • Poor formation of NMJs
  • Clinical
    • Prenatal: Fetal movements reduced
    • Phenotypes: Varied from Severe arthrogryposis to DA5D
    • Limbs
      • Contractures: Distal > Proximal
      • Hands: Camptodactyly, severe; Adducted thumbs & wrists;
      • Feet: Mild camptodactyly; Clubfoot and/or Calcaneovalgus deformity;
      • Knees: Extension contractures
      • Hip: Dislocation
      • Severe patients: Pterygia, multiple
    • Spine: Scoliosis or Rigid
    • Head
      • Ptosis: Asymmetric
      • Face: Round-shaped; Arched eyebrows; Bulbous, upturned nose; Micrognathia; Cleft palate
      • Tongue: Grooved, central
    • Neck: Short
    • Eyes
      • Most: No ophthalmoparesis
      • Complex strabismus (29%): More severe syndromes
      • Duane retraction syndrome (CCDD): Few patients
      • Ptosis
      • Refractive error
    • Weakness
      • Proximal (50%)
      • Respiratory
      • Other mild: Face; Posterior neck
      • Exercise intolerance
      • More with disease progression
  • Laboratory
    • Serum CK: Normal
    • EMG: Myopathic
    • Muscle MRI
      • Patchy involvement: Neuropathic
      • Muscle size: Reduced
      • Muscles most small: Biceps femoris; Posterior calf; EDL
      • Muscle signal:Sartorius; Posterior thigh
    • Muscle pathology
      • Type 1 predominance
      • Fiber size variation: Mild
      • Central clear regions: Some fibers
  
  
• Distal Arthrogryposis, type 3 (Gordon syndrome) (DA3)
  ● Piezo-type mechanosensitive ion channel component 2 (PIEZO2) ; Chromosome 18p11.22-p11.21; Dominant
  
  • Genetics
    • Mutation: Ile802Phe
    • Allelic disorders
  • Clinical features
    • Skeletal
      • Camptodactyly
      • Club feet
      • Short stature
      • Vertebral abnormalities
    • Cranial
      • Ptosis
      • ± Cleft palate
    • Skin
      • Pterygium colli
      • Single transverse palmar creases
      • Absent interphalangeal creases
    • Genital
      • Cryptorch
      • idism
    • Muscle: Reduced mass
    • CNS: Chiari I malformation
  
  
• Distal Arthrogryposis 5E (DA5E)
  ● Piezo-type mechanosensitive ion channel component 2 (PIEZO2) ; Chromosome 18p11.22-p11.21; Dominant
  
  • Nosology: Oculomelic amyoplasia
  • Epidemiology: 24 families
  • Genetics
    • Mutations: Heterozygous
      • Ile802Phe; 3-BP Del, NT8179 (Glu2727del)
      • Effect: "Gain of function"
      • PIEZO2 dominant mutations: General
        • Most: Missense; C-terminus
        • Few: Deletion or Stop
    • Allelic disorders ⁵⁰
      • DA5E: Dominant
      • Syndromes with: Cleft palate & Mental retardation: Dominant
        • Gordon syndrome (DA3)
        • Marden-Walker syndrome (MWKS)
      • Distal Arthrogryposis, Scoliosis & Large fiber sensory neuropathy (DAIPT): Recessive
      • Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis & Scoliosis: Recessive
  • PIEZO2 protein
    • Piezo2 protein
      • Mechanically activated (MA), rapidly adapting currents
      • Neuronal expression
      • Functions
        • Somatosensory neurons: Principal mechanosensor
        • Proprioception
        • Spindles: Sensory axons
        • Endothelium-dependent pain: Stimulus-dependent hyperalgesia
      • Mutation effects ⁴⁹
        • Gain of function: Increased activity in PNS
        • MA currents: Recover faster from Inactivation or Slowed inactivation
        • Development
          • Increased activity in axons to muscle spindles & tendon organs → Joint contractures
        • Eicosapentaenoic acid (EPA; ω-3 polyunsaturated fatty acid): Reduces gain-of-function effect
    • Piezo proteins
      • Transmembrane
      • Rapidly adapting mechanically (stretch) activated (MA) currents in somatosensory neurons
      • Cation channel
      • May play roles in sensory function
        • Light touch
        • Proprioception
        • Nociception
  • Clinical
    • Arthrogryposis
      • Generalized: Jaw; Limbs; Neck; Spine
      • Limbs: Distal
      • Course: Remain despite physical therapy
    • Skeletal: Other
      • Short stature
      • Hypermobile first metacarpophalageal joint
      • Camptodactyly
      • Clinodactyly
      • Dimples over large joints
    • Skin
      • Absent phalangeal creases
      • Poorly formed palmar creases
    • Face: Decreased expression
    • Eye
      • Movement: Ptosis; Ophthalmoplegia; Duane anomaly
      • Morphology: Deep-set hypermetropic
      • Retina: Macular striae
    • Muscles
      • Neck muscles: Hypertrophic; Constricted
      • Strength: Normal
      • Mass: Generally reduced
      • Respiratory: Restrictive lung disease; Vital capacity reduced
    • Tendon reflexes: Reduced
    • Sensory: Altered pain sensation
    • Anterior cruciate ligament: Absent bilaterally
    • Pulmonary: Restrictive disease
    • Intellegence: Normal
  • Laboratory
    • Muscle biopsy: Normal
  • PIEZO2 variant syndrome: Distal arthrogryposis, Scoliosis & Sensory neuropathy, Large fiber (DAIPT) ³⁷
    • Epidemiology: 16 patients
    • Genetics
      • Inheritance: Recessive
      • Mutations: c.4723C>T (p.R1575*); c.5053C>T (p.R1685*); c.5053C>T (p.R1685*); c.5054G>C (p.R1685P)
    • Clinical
      • Onset age: Congenital
      • Prenatal: Reduced fetal movements
      • Motor
        • Hypotonia
        • Infancy
          • Delayed head control
          • Shallow breathing
          • Hypotonia
        • Childhood
          • Delayed walking to 6 to 7 years
          • Fine motor skills: Impaired
          • Difficulty with: Self-feeding & Dressing
      • Skeletal
        • Congenital hip dysplasia
        • Finger contractures
        • Foot deformities
        • Scoliosis: Early-onset; Severe; Progressive
      • Sensory
        • Ataxia
        • Gait: Unsteady
        • Pseudoathetosis
        • Loss: Vibration; Proprioception
        • Preserved: Pain; Pressure; Brushing hairy skin; Pain; Itch
        • Romberg: Positive
      • Tendon reflexes: Absent or Reduced
    • Laboratory
      • NCV
        • SNAP amplitudes: Reduced
        • Sensory CV: Borderline
        • Motor: Normal
      • EMG: Normal
  • Piezo2 variant syndrome: Muscular Atrophy with Perinatal Respiratory Distress, Arthrogryposis & Scoliosis
    • Epidemiology: 4 families; 10 patients
    • Genetics
      • Inheritance: Recessive
      • Mutations
        • N-terminal & Central region of gene
        • Lead to nonsense-mediated transcript decay
        • Loss of function
      • Allelic disorders
    • Piezo2 protein
    • Clinical
      • Onset age: Birth
      • Neonatal
        • Arthrogryposis
        • Respiratory insufficiency: Spontaneously resolving
        • Hypotonia
      • Muscle
        • Delayed milestones
        • Weakness & Atrophy: Distal; Legs
        • Dysarthria, Mild
      • Tendon reflexes: Absent
      • Skeletal
        • Short stature
        • Scoliosis
        • Camptodactyly
        • Pes planus
        • Sandal gap deformity
      • Sensory loss: Mild; Distal
      • Course: Slow progression
    • Laboratory
      • Serum CK: Normal or Mildly high
      • NCV: Sensory neuropathy
      • Brain MRI: Normal
  • Piezo2 variant syndrome: Marden-Walker syndrome (MWKS)
    • Genetics
      • Inheritance: Dominant
      • Mutations: Missense & Stop; R2686C, Y2417C, W2746*
    • Clinical
      • Psychomotor retardation
      • Contractures: Hands & Feet
      • Scoliosis
      • Eye: Ohthalmoplegia; Ptosis
      • Face: Mask-like, Micrognathia, Low ears
      • High-arched or cleft palate
      • Other anomalies
        • Dandy-Walker malformation + Hydrocephalus
        • Vertebral abnormalities
  
  
• Distal Arthrogryposis with Sensorineural hearing loss (DA6)
  ● Fibroblast growth factor receptor 3 (FGFR3) ; Chromosome 4p16.3; Dominant
  • Nosology: Deafness-Camptodactyly syndrome
  • Genetics
    • Allelic disorders
  • Clinical features
    • Joint contractures
    • Sensorineural hearing loss
    • Camptodactyly
    • Microcephaly
  
  
• Distal Arthrogryposis with trismus pseudo-camptodactyly (DA7; Carney complex )
  ● Myosin, heavy chain 8, Skeletal muscle, perinatal (MYH8) ; Chromosome 17p13.1; Dominant
  • Nosology: Beal's syndrome; Kentucky Dutch syndrome
  • Genetics
    • Mutation: Missense; Arg674Gln
    • Allelic with: Distal arthrogryposis with cardiac myxomas
  • MYH8 protein
  • Clinical features
    • Camptodactyly of digits on hand dorsiflexion
    • Trismus: Inability to open mouth completely
    • Short stature
    • Short leg muscles
  
  
• Distal Arthrogryposis with Cardiac myxomas ¹¹
  ● Myosin, heavy chain 8, Skeletal muscle, perinatal (MYH8) ; Chromosome 17p13.1; Dominant
  • Genetics
    • Mutation: Missense; Arg674Gln
    • Allelic with: Distal arthrogryposis with trismus pseudo-camptodactyly (DA7; Carney complex)
  • MYH8 protein
    • Skeletal muscle: Fetal development & Regeneration
    • Myosin
  • Clinical features
    • Trismus: Inability to open the mouth fully
    • Pseudocamptodactyly
      • Shortened flexor muscle-tendon units;
      • Wrist dorsiflexion produces flexion of distal and proximal interphalangeal joints
      • Foot contractures
    • Carney complex : Some families
      • Cardiac myxomas
      • Spotty skin pigmentation
  
  
• Distal Arthrogryposis 1C ⁴⁵
  ● Myosin light chain, Phosphorylatable, Fast skeletal muscle (MYLPF; MYL11) ; Chromosome 16p11.2; Dominant, de novo or Recessive
  • Epidemiology: 6 families; 10 patients
  • Genetics
    • Dominant mutations: c.487G>A (p.Gly163Ser), c.98C>T (p.Ala33Val)
    • Recessive mutations: Cys157 substitutions
    • Mouse null mutations: No muscle at birth
  • MYLPF protein
    • Function: Stabilize MyHC structure
    • Mutation effects
      • Dominant: Interaction with myosin affected
      • Recessive: Indirectly impair interaction with myosin
  • Clinical
    • Onset age: Birth
    • Contractures: Multiple; Congenital
      • Wrists
      • Recessive: Neck; Equinovarus
    • Mouth: Small; Retrognathia
    • Scoliosis
    • Short stature
  • Laboratory
    • Foot: Muscle absent; Segmental amyoplasia
  
  
• Multiple pterygium syndromes ¹⁵
  ● Cholinergic receptor, nicotinic, gamma (γ) polypeptide (CHRNG) ; Chromosome 2q37.1; Recessive
  ● Cholinergic receptor, nicotinic, alpha 1 (α1) polypeptide (CHRNA1) ; Chromosome 2q31.1; Recessive
  ● Cholinergic receptor, nicotinic, delta (δ) polypeptide (CHRND) ; Chromosome 2q37.1; Recessive
  ● Rapsyn (RAPSN) ; Chromosome 11p11.2; Recessive
  ● DOK7 ; Chromosome 4p16.3; Recessive
  ● β-Tropomyosin (Tropomyosin-2; TPM2) ; Chromosome 9p13.3; Recessive
  ● X-linked
  
  • Nosology
    • Also see
      • Fetal Akinesia Deformation Sequence (FADS)
      • Arthrogryposis
    • FADS1: MUSK
    • FADS2: RAPSN
    • FADS3: DOK7
    • Recurrent congenital arthrogryposis
  • Epidemiology
    • Geography: Arab, Pakistani, Turkish & Caucasian families
    • Many consanguinous families
  • Genetics
    • AChR Mutations: Truncating
      • Nonsense, splice site or frameshift
      • CHRNG: Escobar syndrome
    • TPM2 mutations
      • Homozygous: Gln210Stop
      • TPM2 mutations may also cause
        • Rod myopathy (NEM4): Dominant
        • Distal Arthrogryposis 1A: Dominant
        • Cap myopathy: Dominant
  • Mutation effects on AChR proteins & subunits
    • Fetal: AChR subunits present intracellular but not on cell surface
    • Normal expression of adult AChRs
  • Clinical
    • Onset
      • Age: Congenital
      • Decreased movements
      • Facial weakness
      • Respiratory insufficiency
    • Pterygia: Elbows, Axillae, Poplitea, Thumb, Neck
    • Contractures: Congenital
    • Face & Palate
      • Dysmorphic
      • Cleft palate
    • Pulmonary hypoplasia: Bilateral
    • Cardiac: Small heart
    • GI: Absene appendix; Attenuation of ascending and transverse colon
    • Skeletal
      • Vertebrae: Cervical (Klippel-Feil syndrome) or thoracic fusion
      • Kyphoscoliosis
      • Arachnodactyly
      • Short stature
      • Rocker-bottom feet
      • Scoliosis
    • Muscle
      • Strength: Normal after neonatal period
      • Bulk: Normal
    • Cryptorchidism
    • Disease course
      • Variable among families
      • Survival: Stillborn to adulthood
  • Laboratory
    • Repetitive nerve stimulation: Normal
    • Muscle histopathology: Denervation-like changes
      • Type I muscle fibers: Predominance; Small
      • Fiber-type grouping
      • Fat infiltration
  • Analogous human immune disorder
    • Recurrent congenital arthrogryposis: Serum IgG binding to Fetal AChRs containing γ-subunit
  • Variant syndrome: Fetal hypokinesia with inborn contractures (arthrogryposis)
    • Mutated subunits: CHRNA1; CHRND; RAPSN
    • Mutations: Missense or Stop
  • Differential diagnosis: Lethal congenital contracture syndromes (LCCS)
  • Mouse model
    • γ-AChR subunit inactivation: Lethal
  
  
• Arthrogryposis ³⁹
  ● UNC50, Inner nuclear membrane RNA-binding protein (UNC50) ; Chromosome 2q11.2; Recessive
  • Epidemiology: 1 family
  • Genetics
    • Mutation: Homozygous; Frameshift; c.750_751del:p.Cys251Phefs*4
  • UNC-50 protein
    • Location: Inner nuclear membrane
    • RNA binding
    • Functions: Retrograde trafficking of early endosomal vesicles to Golgi apparatus
      • Recruits GBF1 to Golgi
      • Regulator of Shiga toxin 2 endosome-to-Golgi trafficking
    • AChR trafficking
    • Mutation: Loss of AChRs
  • Clinical
    • Onset age: Fetal
    • Fetal contractures: Club feet, Elbows, Hips, Knees, Wrists
    • Cervical hyperextension
    • Subcutaneous edema: Diffuse
    • Muscles: Diffuse atrophy
  • Laboratory
    • Brain: Normal
    • Muscle: Fiber atrophy
  
  
• Congenital contractural arachnodactyly (DA 9)
  ● Fibrillin-2 (FBN2) ; Chromosome 5q23.3; Dominant
  • Genetics: Allelic disorder
    • Macular degeneration, early-onset, Dominant AD
  • Clinical features
    • Marfanoid habitus
    • Kyphoscoliosis: Severe
    • Osteopenia: Generalized
    • Contractures: Proximal involvement more common; Flexion of fingers
    • Ears: Crumpled
    • Cardiac: Aortic and valvular
    • Muscular hypoplasia
  
  
• Distal Arthrogryposis with Plantar flexion contractures (DA 10) ¹⁶
  ● Titin ; Chromosome 2q31.2; Dominant
  • Epidemiology: Utah family
  • Clinical
    • Onset age: Childhood; Time of ambulation
    • Contractures
      • Plantar feet: Flexion; Surgical treatment
      • Other (Milder): Elbows, Fingers, Wrists (Reduced extension & supination)
    • Gait: Toe walking
  • Laboratory
    • Serum CK: Normal
    • EKG: Normal
  
  
• Distal Arthrogryposis 11 (DA 11)
  ● MET protooncogene, receptor tyrosine kinase (MET) ; Chromosome 7q31.2; Dominant
  • Epidemiology: 1 family, 11 patients
  • Genetics
    • Mutation: Y1234C
    • Allelic disorders
      • Deafness, autosomal recessive 97
      • Arthrogryposis, distal, type 11
      • Hepatocellular carcinoma, childhood type, somatic
      • Renal cell carcinoma, papillary, 1, familial & somatic
      • Osteofibrous dysplasia, susceptibility to
  • MET protein
    • HGF receptor
    • Neutrophil chemoattraction & cytotoxicity
  • Clinical
    • Camptodactyly
    • Flexion creases absent
    • Forearm supination: Limited
  • Laboratory
    • Limb imaging: Reduced pronator quadratus, lumbricalis & 5th interosseous muscles
    • Distal muscles: Fiber size varied; Internal nuclei
  
  
• Distal Arthrogryposis 12 (DA 12)
  ● A Disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 15 (ADAMTS15) ; Chromosome 11q24.3; Recessive
  • Epidemiology: 4 families, patients
  • Genetics
    • Mutations: Missense & Splice
  • ADAMTS15 protein
    • Metalloprotease: Cleaves VCAN
    • Facilitates myoblast contact & fusion
    • Coexpressed with: Versican
  • Clinical
    • Contractures: Hands & Feet
    • Kyphoscoliosis
    • Small mouth
    • CNS: Normal
  
  
• Cerebrooculofacioskeletal syndrome
  ● Excision-repair cross-complementing, group 6 (ERCC6) ; Chromosome 10q11.23; Recessive
  • Genetics
    • ERCC6: Same gene as Cockayne syndrome, Type B
  • Clinical features
    • Microcephaly,
    • Hypotonia
    • Face: Eye defects; Large nose & ears; Overhanging upper lip; Micrognathia
    • Trunk: Widely set nipples; Kyphoscoliosis
    • Osteoporosis
    • Arthrogryposis
  
  
• Distal Arthrogryposis: Rienhoff syndrome (RNHF)
  ● Transforming growth factor, β-3 (TGFB3) ; Chromosome 14q24.3; Sporadic
  • Epidemiology: 1 patient
  • Genetics
    • Mutation: Missense; Cys409Tyr; Heterozygous
    • Alleic with: Arrhythmogenic right ventricular dysplasia 1
  • TGFB3 protein
    • Functions: Embryogenesis & Cell differentiation
    • Most abundant TGFB isoform in developing skeletal muscle
    • Mutation: Non-functional protein
  • Clinical
    • Onset age: Birth
    • Distal arthrogryposis: Hand & both feet
    • Motor: Hypotonia; Delay; Muscle bulk reduced
    • Tendon reflexes: Reduced
    • Skeletal
      • Pes planus
      • Pectus excavatum
      • Hyperextensibility of multiple large joints: Elbows; Knees
      • Retrognathia
    • Eyes: Prominent; Hypertelorism; Sclerae blue
    • Subcutaneous fat: Reduced
    • Skin: Normal
  • Laboratory
    • Muscle
      • Type 1 fiber predominance
      • Fiber size: Normal
  
  
• Ehlers-Danlos syndrome, Musculocontractural type 1 (EDSMC1; MCEDS; Adducted Thumb-Club Foot syndrome)
  ● Carbohydrate sulfotransferase 14 (CHST14) ; Chromosome 15q15.1; Recessive
  • Epidemiology: Turkish, Japanese & Austrian families
  • Nosology
    • Congenital disorder of glycosylation
    • Ehlers-Danlos syndrome VIB
    • Dermatan sulfate (D4ST-1) deficiency
    • Dündar syndrome
    • Sonoda syndrome
  • CHST14 protein: Functions
    • Dermatan sulfate biosynthesis
    • Collagen formation
    • Mutations: Impaired assembly of collagen fibrils
  • Clinical: Malformations, congenital
    • CNS: Psychomotor delay
    • Eye: Anterior chamber abnormality
    • Face: Broad, bossed forehead; Telecanthus ; Downturned mouth
    • Skeletal
      • Arachnodactyly
      • Distal arthrogryposis
      • Adducted thumbs & Clubfeet
      • Joint hypermobility
    • Other congenital: Cardiovascular, GI, Renal
    • Myopathy
      • Clinical
        • Weakness: Diffuse, Fatigable
        • Muscle hypoplasia
        • Tendon reflexes: Reduced
      • Laboratory
        • Serum CK: Mildly high
        • EMG: Large & Small MUAPs
        • Muscle ultrasound: Abnormal
        • Muscle pathology
          • Type 1 predominance
          • Fiber size: Varied
          • Lobulated muscle fibers
  • CHST14 Variant: Progressive multisystem fragility due to impaired assembly of collagen fibrils
    • Joint: Dislocations & Deformities
    • Skin: Hyperextensibility, Bruisability, Fragility; Recurrent subcutaneous hematomas
    • Cardiac valvular
    • Other: Respiratory, Gastrointestinal & Ophthalmologic
  
  
• Ehlers-Danlos syndrome, Musculocontractural type 2 (EDSMC2; MCEDS; SART2)
  ● Dermatan sulfate epimerase (DSE) ; Chromosome 6q22.1; Recessive
  • Epidemiology: Indian male
  • Genetics
    • Mutations: Missense; Ser268Leu
  • DSE protein
    • Converts D-glucuronic acid to L-iduronic acid residues during dermatan sulfate biosynthesis
    • Squamous cell carcinoma antigen
    • Localization: ER & Golgi
    • Mutation: Loss of epimerase activity
  • Clinical
    • Weakness: Generalized; Motor delay
    • Sclerae: Bluish sclerae
    • Skeletal
      • Facial dysmorphism: Frontal bossing , Palpebral fissures downward-slanting , Telecanthus , Lips tent shaped, Ears prominent
      • Head: Palate high arched, Anterior fontanel open, Brachycephaly , Dental crowding
      • Joints: Arachnodactyly, Adducted thumbs, Hypermobility, Talipes equinovarus
    • Soft tissue
      • Inguinal hernia
      • Wound healing: Delayed; Atrophic scarring
    • Cognition: Normal
  • Laboratory
    • Brain CT: Mild atrophy
  
  
• Saethre-Chotzen syndrome (SCS)
  ● TWIST1 ; Chromosome 7p21.1; Dominant
  • Genetics
    • Mutations: Stop; Missense
    • Allelic with: Craniosynostosis 1
    • Similar phenotypes
      • Muenke syndrome : FGFR3 mutations
      • SCS-like: FGFR2 mutation
  • Clinical
    • Face: Flat; Long nose; Hypertelorism; Plagiocephaly; Long and prominent ear crus
    • Eyes: Strabismus; Hydrophthalmos
    • Skull: Craniosynostosis; Acrocephaly; Cranial asymmetry
    • Limbs: Syndactyly; Bifid terminal phalanges (2 & 3); Absent first metatarsal
    • Cardiac: Congenital heart defect
    • Joints: Contractures of elbows and knees
  
  
• Arthropathy-camptodactyly-pericarditis syndrome
  ● Proteoglycan 4 (PRG4; Megakaryocyte-stimulating factor) ; Chromosome 1q31.1; Recessive
  • Joints
    • Arthropathy
    • Generalized morning stiffness
    • Large joint arthritis: Polyarticular
    • Contractures
      • Finger flexion contractures (Camptodactyly )
        • Onset: Congenital or childhood
      • Elbow & wrist
    • Synovial hypertrophy
  • Coxa vara
  • Constrictive pericarditis
  
  
• Arthrogryposis, Mental retardation & Seizures (AMRS)
  ● Solute carrier family 35 (UDP-N-Acetylglucosamine transporter), Member 3 (SLC35A3) ; Chromosome 1p21.2; Recessive
  • Epidemiology: 1 Ashkenazi Jewish family, 8 patients
  • Genetics
    • Mutations: Gln172Ter; c.886A-G
  • SLC35A3 protein
    • Nucleotide sugar transporter
    • Transports UDP-N-acetylglucosamine (UDP-GlcNAc): From cytosol synthesis site to Golgi
    • See: Glycosylation disorders
  • Clinical
    • Mental retardation
      • Mild to Moderate
      • Autism spectrum
      • Psychomotor development: Slow
    • Seizures
      • Onset age: 3 to 11 years
      • Focal or Atypical absences
    • Arthrogryposis (Distal) & Skeletal
      • Onset: Mid-gestation
      • Large joint disorders
        • Knee & Hip dislocation
        • Acetabular dysplasia
        • Similar to: Larsen syndrome (B3GAT3)
      • Fingers
        • Distal flexion contractures
        • Distal phalanges: Deviation
        • Swan-neck deformity
      • Toes: Claw
      • Retromicrognathia
      • Microcephaly
      • Course: Stable
    • Hypotonia: Generalized
  • Laboratory
    • Glycosylation functions: Tissue
      • Reduction of tetraantennary N-glycans
      • Accumulation of abnormal lower-branched glycoforms
    • Normal: CBC; Liver & Renal functions; Endocrinological
  • Animal disease: Complex Vertebral Malformation syndrome in cattle
    • Flexion contractures: Carpal, metacarpophalangeal tarsal & metatarsophalangeal joints; Symmetric
    • Scoliosis
    • Brachygnathia
    • Stillborn (80%)
  
  
• Asymmetric lower limb malformations (Club foot; CCF) ²¹
  ● Paired-like homeodomain transcription factor 1 (PITX1) ; Chromosome 5q31.1; Dominant with reduced penetrance
  • Epidemiology: North American family of European descent
  • Genetics
    • Mutation: Missense; E130K
    • Mutations not found in other club foot patients
  • PITX1 protein
    • Homeobox
    • Bicoid-related homeodomain transcription factor
    • Expressed predominantly in developing hindlimb
    • Mutation effect: Dominant negative
    • Other disorders: FSH Dystrophy
      • Increased PITX1 expression: Stimulated by interaction with DUX4
  • Clinical
    • Clubfoot
      • Asymmetric: Right side predominant
      • Often bilateral
    • Other lower-limb malformations
      • Patellar hypoplasia
      • Oblique talus
      • Tibial hemimelia
      • Hip dysplasia, developmental
      • Preaxial polydactyly
  
  
• LCCS9: Arthrogryposis Multiplex Congenita, Severe ³³
  ● G protein-coupled receptor 126 (GPR126; VIGR) ; Chromosome 6q24.1; Recessive
  • Epidemiology: 3 families
  • Genetics
    • Mutations: Homozygous; Missense, Nonsense, or Frameshift
    • Allelic with
      • Quantitative stature trait
      • Idiopathic scoliosis: Single nucleotide polymorphisms
  • GPR126 protein
    • Interacts with: Laminin-211
    • Functions
      • PNS axon myelination
        • Drives differentiation of promyelinating Schwann cells: Elevates cyclic AMP levels
        • Related disorder: ADCY6 arthrogryposis
      • Role in axon regeneration after injury
      • c-Jun level regulation
    • Pathway asssociations: Immune response; Coagulation
  • Clinical
    • Onset: Prenatal
    • Joints
      • Contractures: in utero; Distal
      • Camptodactyly
    • Facial dysmorphism
      • Micrognathia
      • Low-set ears
    • Course: Death in utero or neonatal
  • Laboratory
    • Brain & Spinal cord: Normal
      • Motor neurons: Normal
    • Muscle
      • Fiber size: Varied
        • Atrophy & Hypertrophy
        • Both fiber types large & small
      • Central nuclei: Some patients
      • Endomysium: Normal
      • Perimysium: Widened in some regions
      • Diaphragm: Severely affected
      • Intramuscular nerves: Loss of myelin basic protein
  
  
• LCCS10: Arthrogryposis Multiplex Congenita
  ● Never in mitosis gene A-related kinase 9 (NEK9) ; Chromosome 14q24.3; Recessive
  • Epidemiology: 2 Irish Traveller families
  • Genetics
    • Mutation: Arg497X
    • Allelic with: Arthrogryposis, Perthes disease & Up gaze palsy (APUG)
  • NEK9 protein
    • Nosology: Serine/threonine-protein kinase Nek9
    • Phosphorylates serine residues
    • Regulator of mitotic progression: Control of Spindle dynamics & Chromosome separation
    • Nuclear & Cytoplasmic
    • Associated with phosphorylation: BICD2, MBP, Histones
    • Complexes with FACT
    • Expressed in ciliated cells
  • Clinical
    • Onset: Prenatal or Birth
    • Fetal akinesia
    • Skeletal
      • Contractures: Multiple
      • Shortened limbs & ribs
      • Chest deformities
    • Pulmonary hypoplasia
    • Death: At birth
  • Laboratory
    • X-ray: Long bones shortened
    • Muscle: fiber size varied or normal
  
  
• Arthrogryposis, Lethal (LCCS) ³⁴
  ● Mage-like 2 (MAGEL2) ; Chromosome 15q11.2; Dominant, Paternal
  • Epidemiology: 2 families
  • Genetics
    • Mutations
      • Locations: c.2118delT; c.1996delC
      • Paternal allele
    • Allelic disorder
      • Schaaf-Yang syndrome : Prader-Willi like; Autism
    • Other Prader-Willi locus gene: NIPA1 (SPG6)
  • MAGEL2 protein
    • Ubiquitin ligase enhancer
    • Required for endosomal protein recycling
    • Neuronal development
  • Clinical
    • Onset: Fetal death
    • Microretrognathia
    • Eyes: Palpebral fissures short, Hypertelorism,
    • Neck: Short, Large
    • Club foot, flexion
    • Contractures: Elbows; Knees, Finger camptodactyly
    • Polyhydramnios
  
  
• LCCS11: Arthrogryposis, Lethal ³⁶
  ● Gliomedin (GLDN) ; Chromosome 15q21.2; Recessive
  • Epidemiology: 8 families
  • Genetics
    • Mutations: Missense & Stop
  • Gliomedin protein
    • Secreted
    • Cell adhesion molecule
    • Involved in formation of nodes of Ranvier
    • Binds to: Neurofascin-186 (NF186)
    • Initial clustering of Na⁺ channels at developing nodes
    • Mutations: Abolish cell surface localization of gliomedin
  • Clinical
    • Prenatal: Akinesia; Polyhydramnios
    • Arthrogryposis
    • Contractures: Arms & Legs
    • Micrognathia
    • Pulmonary hypoplasia
    • Muscle
      • Hypotonia
      • Size: Small
      • Weakness: Respiratory; Limbs
    • Course
      • Severe cases: Death in utero or Perinatal
      • Milder: Survival through adolescence
  • Laboratory
    • Nerve pathology
      • Myelinated axons: Reduced numbers
      • Nodal length: Increased
    • Muscle pathology
      • Central nuclei
      • Muscle fiber types
        • Type 2C: Increased numbers
        • Type 2 predominance
  
  
• Arthrogryposis, Distal ± Proximal (AMCNMY; AMC1) ³⁸
  ● Leucine-rich gene, glioma-inactivated, 4 (LGI4) ; Chromosome 19q13.12; Recessive
  • Nosology: Arthrogryposis multiplex congenita, neurogenic, with myelin defect
  • Epidemiology: 5 families
  • Genetics
    • Mutations: Loss of function; Stop & Splicing
  • LGI4 protein
    • Glycoprotein
    • Expressed by: Schwann cells; Satellite cellsd; Enteric glia
    • Secreted by Schwann cells
    • Regulates peripheral nerve myelination
    • Cognate receptor: ADAM22
      • Expressed by neurons
      • On axon membrane
    • Also binds to: ADAM23
    • Mutated proteins
      • Missense mutations: May be produced & functional, but secretion deficient
    • CIDP-like disease: Lgi-4 serum antibodies
  • Clinical
    • Onset age: In utero
    • Fetal akinesia
    • Contractures: Distal; Hands & Legs; Camptodactyly
    • Retrognathia
    • Course
      • Early death in most
      • Some survive with developmental delay
  • Laboratory
    • Nerve pathology: Lack of myelin in peripheral nerves
    • EMG: Chronic neurogenic changes
  • claw paw mice (LGI4-deficient): Peripheral hypomyelination
  • Lgi4 serum antibodies ⁴⁸
    • Antibody type: Serum IgG, Most with IgG₄
    • Epidemiology: 4 patients
    • Clinical association: CIDP
      • Onset
        • Age: Mean 58 years; Range 42 to 76
        • Course: Often subacute
      • Weakness: Limbs; May be asymmetric
      • Sensory loss: Panmodal; Distal; Romberg +
      • Tremor
      • Treatment: Possible benefit from IVIg or Corticosteroids
    • Laboratory
      • CSF protein: High
      • Tissue binding: Schwann cells; Satellite cells; Juxtaparanode
      • Spine MRI: Root hypertrophy in 1 patient
  
  
• Fetal Akinesia Deformation Sequence 4 (FADS4) ³⁸
  ● Nucleoporin, 88kD (NUP88) ; Chromosome 17p13.2; Recessive
  • Epidemiology: 2 families
  • Genetics
    • Mutations: Loss of function; Asp434Tyr; Arg509X; c.1899_1901del
  • NUP88 protein
    • Nuclear pore complex (NPC) component
    • CRM1-dependent nuclear export of proteins
  • Clinical
    • Prenatal: Reduced movements; Polyhydramnios
    • Arthrogryposis multiplex congenita (AMC)
      • Contractures: Fingers, Hands, Elbows
      • Kyphosis
      • Feet: Rocker-bottom
    • Muscle: Atrophy
    • Dysmorphic features
      • Microcephaly
      • Ears: Low-set, Posteriorly rotated ears
      • Nasal bridge: High, Broad
      • Palate: Hgh-arched
      • Microretrognathism
      • Rib pairs: Reduced
      • Neck: Short, Broad, or Hyperextended neck
    • Undescended testes
    • Course: Letal at birth or by 2 days of age
  • Laboratory
    • Muscle culture: Rapsyn levels & AChR clusters reduced
  
  
• Arthrogryposis multiplex congenita, Neurogenic type (AMCN; AMC2)
  ● Endoplasmic reticulum-golgi intermediate compartment protein 1 (ERGIC1) ; Chromosome 5q35.1; Recessive
  • Epidemiology
    • Arab family, 40 patients
    • Females less affected than males
  • Genetics
    • Mutation: Val98Glu
    • Females: Incomplete penetrance
  • ERGIC1 protein
    • Membrane-bound protein: In endoplasmic reticulum (ER) & Golgi
    • Stabilizes ERGIC2 /ERGIC3 complex
    • Location: Multiple tissues
  • Clinical
    • Contractures: Flexion; Elbows & Knees
    • Equinovarus
    • Course: Non progresive; Live to adulthood
  • Laboratory
    • Spinal cord: Motor neuron loss
  
  
• Arthrogryposis multiplex congenita, Neurogenic type with Corpus Callosum Agenesis (AMCNACC; AMC4)
  ● SCY1-like protein 2 (SCYL2) ; Chromosome 12q23.1; Recessive
  • Nosology: Zain syndrome
  • Epidemiology: Saudia Arabian & Omani families
  • Genetics
    • Mutations: Homozygous; Arg36X, 1-bp dup, 1624G
  • SCYL2 protein
    • Regulates protein trafficking along secretory pathways
    • Suppresses excitotoxicity in developing brain
  • Clinical
    • Antenatal: Fetal movements reduced; Polyhydramnios
    • Head: Forehead prominent; Nose bulbous; Nasal bridge depressed; Mouth small with thin lips; Micrognathia; Ears low & abnormal folds
    • Neck: Short
    • Skeletal: Hands clenched; Feet rocker bottom; Fractures; Arthrogryposis
    • Testicles: Undescended
    • CNS: Microcephaly; Spasticity; Tendon reflexes absent Psyhchomotor delay; Optic atrophy; Epilepsy
    • Polyneuropathy: Clinical
    • Course: Often death in childhood
  • Laboratory
    • Brain MRI: Corpus callosum agenesis; Cortical atrophy, fronto-parietal
  
  
• Arthrogryposis Multiplex Congenita 5 (AMCNACC; AMC5)
  ● Torsin 1A (TOR1A; DYT1) ; Chromosome 9q34.11; Recessive
  • Epidemiology: 6 patients, 5 families
  • Genetics
    • Mutations: Missense, Deletion, Stop
    • Allelic disorders
      • Arthrogryposis multiplex congenita 5
      • Dystonia-1, torsion, Dominant
  • TOR1A protein
    • Torsin ATPases: Associated with assorted cellular activities (AAA+) proteins
    • Location: CNS neurons
  • Clinical
    • Prenatal: Polyhydramnios
    • Onset age: Birth
    • Contractures: Severe; Large & small joints
    • Movements: Tremor & Stereotypic of hands; Face grimacing; Neck extension; Dystonic
    • Skeletal: Rocker-bottom feet, Hammertoes, Camptodactyly, Hip dislocation
    • Muscle
      • Tone: Increased
      • Respiratory failure
    • Face: Strabismus; Dysmorphism
    • Global developmental delay: Intellect impaired
    • Overall growth: Reduced
    • Course: Contractures & Tremor less with time; Strabismus worse
  • Laboratory
    • Brain MRI: Cerebral atrophy, occipital
    • Anemia
  
  
• Arthrogryposis Multiplex Congenita 7, X-linked (AMC7)
  ● THO complex, Subunit 2 (THOC2) ; Chromosome Xq25; Recessive
  • Epidemiology: 2 families, 3 patients
  • Genetics
    • Mutation: Splice site; c.2482-1_2484delGTCA
  • THOC2 protein
    • Location: Nucleus
    • TREX (transcription/export) mRNA export complex: Subunit
    • Recruited to spliced mRNAs late in the splicing reaction
    • Couples mRNA transcription, processing & nuclear export
    • Required for efficient export of polyadenylated RNA & spliced mRNA
  • Clinical
  • Onset: Prenatal
  • Subcutaneous edema
  • Joints: Contractures; Hyperextended knees; Clenched fists; Rocker bottom feet
  • Prenatal death
  • Laboratory
    • Muscle: Varied fiber sizes; Cytoplasmic inclusion bodies, Rare
  
  
• Arthrogryposis & Amyoplasia ⁴²
  ● Calcium channel, voltage-dependent, T type, α-1H Subunit (CACNA1H) ; Chromosome 16p13.3; Recessive
  • Epidemiology: 1 patient
  • Genetics
    • Mutations: Missense; V681L, D1233H
    • Allelic disorders
  • CACNA1H protein: Ca⁺⁺ T-type channel subunit
  • Clinical
    • Onset: Prenatal; Polyhydramios
    • Arthrogryposis
    • Weakness
      • No anti-gravity movement
      • Gag & suck: Absent
      • Respiratory failure
    • Tendon reflexes: absent
  • Laboratory
    • NCV: Motor responses absent; Sensory normal
    • Muscle MRI: Amyoplasia
    • Muscle biopsy: End stage or Type I predominance
  • CACNA1H variant: ALS
    • Epidemiology: 1 family
    • Genetics
      • Mutations: Missense; V1689M, A1705T; Loss of function
    • Clinical
      • Onset: Early, 27 years
      • Dysarthria
      • Lower motor neuron: All limbs
      • Upper motor neuron: All limbs; Spasticity
      • Course: Long duration
    • Laboratory
      • EMG: Denervation, acute & chronic
  
  
• X-linked Arthrogryposis
  • Infantile Spinal Muscular Atrophy with Arthrogryposis: UBE1; Xp11.23
  • AMCX5 : Xq23-q27
    • Mild
    • Only in lower extremities
  • Arthrogryposis + Intellectual Disability
  • Other
  
  
• Neurogenic arthrogryposis
  
  

  Distal Arthrogryposis   Neural molecules     5D: ECEL1; 2q37     5E: PIEZO2; 18p11   Neuropathy     Benign     CASPR (LCCS7)     ADCY6 (LCCS8)     GLDN (LCCS11)     GPR126 (LCCS9)     LGI4 (AMC1) AMCN: ERGIC1 (AMC2) Spinal muscular atrophy   Benign congenital   5q-linked, Congenital   X-linked Infantile

  
  
  • Benign congential spinal muscular atrophy with contractures
    ● Dominant
    • Selectively involves lower extremities
    • Non-progressive
    
    
  • Arthrogryposis: Neurogenic, Mild
    ● Chromosome 5q35; Recessive
    • Epidemiology
      • Israeli-Arab family
      • Male/Female 2:1: ? Incomplete penetrance in females
    • Onset: Birth
    • Flexion contractures: Elbows & Knees
    • Equinovarus: Marked
    • Weakness: Around involved joints
    
    
  • Arthrogryposis, Distal & Neurogenic (LCCS7) ²⁸
    ● Contactin-associated protein 1 (CNTNAP1; CASPR) ; Chromosome 17q21.2; Recessive
    • Epidemiology: 4 patients
    • Genetics
      • Mutations: exon18: c.2901_2902del; c.3009_3010insT; c.2993-2_2994del
      • Allelic disorders
        • LCCS7
        • CNS Hypomyelination & Neuropathy (CHN3)
        • CMT + Intellectual disability
    • CNTNAP1 protein
      • Neural immunoglobulin family
      • Cell adhesion molecule
      • Contactin-PTPRZ1 complex
      • Component of: Node of Ranvier (Paranode)
      • Antibodies
        • CASPR: CIDP-like syndrome
        • CNTN1: CIDP-like syndrome; Produces motor conduction block
    • Clinical
      • Onset age: Prenatal
      • Polyhydramnios
      • Motor
        • Hypotonia
        • Respiratory distress
        • Facial diplegia
        • Dysphagia
      • Tendon reflexes: Absent
      • Arthrogryposis: Distal
      • Age at death: Infancy most common; 10 days to 15 years
    • Laboratory
      • Motor NCV: 7 to 10 m/Sec
      • Nerve pathology
        • Nodes of Ranvier: Widened
        • Myelin sheath: Thin
    • CASPR variant syndrome: Congenital Hypomyelination, PNS & CNS (CHN3)
      • Epidemiology: 3 families, 5 patients
      • Genetics
        • Mutations: Stop or c.2290C>T (p.Arg764Cys)
        • Inheritance: Recessive
        • Allelic disorders
      • Clinical
        • Polyhydramnios
        • Motor
          • Hypotonia
          • Respiratory distress
          • Facial diplegia
          • Absent swallow
        • Skeletal
          • Micrognathia
          • Low-set ears 60%
          • Cleft palate 40%
          • Distal arthrogryposis multiplex congenita 40%
        • Epilepsy 60%
        • Course: Survival 1 day to > 12 years
      • Laboratory
        • Nerve biopsy
          • Axon number: Normal
          • Myelin
            • Hypomyelination
            • Node of Ranvier: Widened
            • Detachment: Myelin from Axolemma
          • Schwann cells: Long processes
        • Brain MRI
          • Hypomyelinating leukodystrophy
          • Cerebral & Brainstem: Atrophy
    • CASPR variant syndrome: CMT + Intellectual disability ⁴¹
      • Epidemiology: 1 patient
      • Genetics
        • Inheritance: Recessive
        • Mutations: Stop & Missense; c.2901_2902delCT, c.3047C>T
        • Allelic disorders
      • Clinical
        • Onset age: Infancy
        • Hypotonia
        • Development: Global delay
        • Weakness
          • Mild
          • Ambulation present
        • Muscle bulk: Reduced
        • Sensory loss: Small fiber
        • Tendon reflexes: Reduced or Absent
      • Laboratory
        • NCV: Multifocal slowing; Distal letency long; Conduction block
        • Brain MRI: Normal
    
    
  • Arthrogryposis, Distal & Neurogenic (LCCS8) ²⁸
    ● Adenylate Cyclase 6 (ADCY6) ; Chromosome 12q13.12; Recessive
    • Epidemiology: 1 patient
    • Genetics
      • Mutations: R1116C; Missense
    • ADCY6 protein
      • Adenylate cyclase family
      • PNS myelination
      • Related disorder: GPR126 arthrogryposis
    • Clinical
      • Onset age: Prenatal
      • Motor
        • Hypotonia
        • Respiratory distress
        • Facial diplegia
        • Dysphagia
      • Tendon reflexes: Absent
      • Arthrogryposis: Distal
      • Age at death: 80 days
    • Laboratory
      • Motor NCV: CMAPs absent
      • Nerve pathology
        • Myelin basic protein: Absent
        • Schwann cells (S100 protein): Present
        • Schwann cell basal lamina: Redundant
  
  
• Lethal congenital contracture syndromes (LCCS)
  
  

  LCCS (Recessive)   1: GLE1; 9q34   2: ERBB3; 12q13   3: PIP5K1C; 19p13   4: MYBPC1; 12q23   5: DNM2; 19p13   6: ZBTB42; 14q32   7: CNTNAP1; 17q21   8: ADCY6; 12q13   9: GPR126: 6q24   10: NEK9; 14q24   11: Gliomedin; 15q21   LCCS: MAGEL2; 15q11   LCCS: TTN; 2q31

  
  
  • General
    • Genes implicated in LCCS syndromes
      • Often linked to InsP₆-Gle1–mediated mRNA export pathway
      • Similar disorders produced by NMJ protein gene mutations
    • Nosology: Overlapping syndromes
      • Fetal akinesia syndromes
      • Lethal multiple pterygium syndromes (MPS) : AChR mutations
      • Arthrogryposis
      • Also see: Pena-Shokeir
    • Full syndrome
      • Earlier occurrence of akinesia/hypokinesia: 2nd trimester
      • Clinical associations: Joint webbing (pterygia); Fetal hydrops
  • LCCS1 + Anterior horn cell degeneration (LAAHD)
    ● GLE1 RNA export mediator (GLE1; GLE1L) ; Chromosome 9q34.11; Recessive
    
    • Epidemiology
      • Finnish families; 12 patients
      • Carrier frequency: Finland 1%; Northeastern Finland 2%
    • Genetics
      • Mutations
        • Finnish
          • Homozygous: c.432-10A4G; Located within intron 3
          • Most Finnish patients with same mutation
          • Effect of mutation: Insertion of 3 amino acids (Pro, Phe, Glu) into predicted coiled-coil domain
          • Disruption of coiled-coil domain: Absent fetal movements; Death in utero.
        • Arg569His
        • Other misense mutations: Survive prenatal period
      • Allelic with
        • Arthrogryposis with Anterior horn cell disease
        • ALS syndrome
    • GLE1 protein: mRNA export mediator
      • Isoform localization
        • hGle1A: Localized diffusely in nucleus & cytoplasm
        • hGle1B: Nuclear pore complex in nuclear envelope
      • Function: Export of mRNAs from nucleus to cytoplasm
      • Expression: High in ventral spinal cord cell population
      • GLE1 binds to inositol hexakisphosphate (InsP₆)
    • Clinical
      • Immobility of the fetus at all ultrasound examinations,
      • Multiple joint contractures: Upper & lower limbs
      • Hydrops
      • Fetal death: Before 32 weeks of pregnancy
    • Pathology
      • Anterior horn motor neurons: Degeneration
      • Ventral spinal cord: Atrophy & Hypoplastic
      • Skeletal muscles: Nearly absent
    • Variant syndrome: Arthrogryposis with Anterior horn cell disease (CAAHD)
      • Nosology: Lethal arthrogryposis with anterior horn cell disease (LAAHD)
      • GLE1 Genetics
        • Mutations: Missense; Val617Met, Ile684Thr
        • Inheritance: Recessive
      • Clinical
        • Prenatal: Fetal akinesia
        • Arthrogryposis
        • Weakness: Diffuse; Respiratory; Hypotonia
        • Muscle size: Small
        • Tendon reflexes: Absent
        • CNS: Developmental delay; Cognitive defects
        • Course
          • Fetuses often survive delivery
          • Some survival to Adult
          • Death: Some patients die early due to respiratory failure
      • Pathology
        • Spinal cord: Motor neuron loss
        • Muscle: Denervation
        • EEG: Slowing; Seizures
    • Variant syndrome: Amyotrophic lateral sclerosis
      • Epidemiology: 3 patients; 0.3% of ALS
      • GLE1 Genetics
        • Mutations: Stop (c.209C>A; p.S70X); Splice site (c.1965-2A>C); Missense (R697C)
        • Inheritance: Sporadic or Dominant
      • Clinical
        • Onset age: 7th decade
        • Limb or Bulbar onset
        • Course: Rapidly progressive; Death in 2 years
    
    
  • LCCS2 ¹⁸
    ● V-ERB-B2 Avian erythroblastic leukemia viral oncogene homolog 3 (ERBB3; Her3) ; Chromosome 12q13.2; Recessive
    • Epidemiology: Israeli-Bedouin kindreds
    • Genetics
      • Mutation: Truncation
      • Allelic disorders
        • Myelodysplastic syndrome: Germline activating variant
        • VSCN1 (HSCR syndrome)
    • ERBB3 protein
      • Receptor
        • Epidermal growth factor (EGF)
        • Neuregulin-1
      • ErbB receptor tyrosine kinase component
      • Modulator of Phosphatidylinositol-3-Kinase/Akt Pathway
      • Schwann cell precursors
      • Null mouse mutant: Death of sensory ganglion cells & motor neurons
    • Clinical
      • Joint contractures: Multiple
      • Urinary bladder: Markedly distended
      • Spinal cord: Anterior horn atrophy
    • ERBB3 variant: Visceral Neuropathy 1 (VSCN1) (Hirschsprung syndrome (HSCR))
      • Nosology: Neuronal intestinal dysplasia, type A
      • Epidemiology: 4 families, 6 patients
      • Genetics
        • Inheritance: Recessive
        • Mutations: Missense, Stop
      • Clinical
        • Onset age: 1st 2 decades
        • GI: Hirschsprung; Intestinal pseudo-obstruction
        • Ear: External Auditory Canal agenesis; Hearing loss
        • Olfactory bulb: Agenesis
        • Other: Ptosis; Cardiac
        • PNS or CNS features: Some patients
          • Ataxia
          • Pupils: Poorly reactive
          • Polyneuropathy
            • Tendon reflexes reduced
            • Sensory loss: Vibration & Position sense
            • Dysautonomia
      • Laboratory
        • Muscle: Fiber sizes varied; Internal nuclei
    
    
  • LCCS3 ¹⁹
    ● Phosphatidylinositol 4-phosphate 5-kinase, Type I, Gamma (PIP5K1C) ; Chromosome 19p13.3; Recessive
    • Epidemiology: 2 families, 7 patients
    • Genetics
      • Mutation: Missense (Asp257Asn) & Stop
      • Allelic disorder: Neurodevelopmental syndrome with altered phosphoinositide signaling, Dominant de novo ⁵²
    • PIPKIγ protein
      • Expression: Brain
      • Functions
        • Phosphatidylinositol pathway: Synthesis of PIP₂
        • Receptor-mediated Ca⁺⁺ signaling transmission
        • Actin cytoskeleton dynamics,
        • Endocytosis & Exocytosis
        • Bone development: Movement of calcium ions
      • Mutation: Abrogates kinase activity
      • Knockout mouse: Lethal; Abnormal synaptic vesicle cycle
      • Phosphinositide disorders
    • Clinical
      • Onset: Congenital or Prenatal
      • Prenatal: Reduced movements
      • Contractures: Multiple; Finger flexion
      • Muscle wasting: Especially legs
      • Dyskinesia
      • Death: Early after birth; Respiratory insufficiency
      • No hydrops, fractures or multiple pterygia
    
    
  • LCCS6 ³⁰
    ● Zinc finger- and BTB domain-containing protein 42(ZBTB42) ; Chromosome 14q32.33; Recessive
    • Epidemiology: Saudi family
    • Genetics
      • Mutation: R397H; Homozygous
    • ZBTB42 protein
      • Subcellular localization: Nuclear
      • Tissue: Skeletal muscle, subsynaptic regions
    • Clinical
      • Still births: Male & Female
      • Joint contractures: Multiple; Proximal & Distal
    • Zebrafish ZBTB42 deficiency model: Muscle
      • Fiber atrophy
      • Neuromuscular junctions: Small
      • Ultrastructure: Myofibrillar disarray; Absent H-zone
  
  
• Other: Recessive
  • LCCS4
  • Spondylospinal Thoracic dysostosis
  • Jarcho-Levin Syndrome
  • Prenatal growth retardation; Pelvic hypoplasia; Arthrogryposis in lower limbs

• Nosology
  • Facio-digito-genital syndrome
  • Tel Hashomer Camptodactyly
• Epidemiology: 59 patients
• Genetics
  • Mutations: Missense most common; also deletion & insertion
  • Allelic disorders
    • Mental retardation, X-linked syndromic 16 (MRXS16)
    • Tel Hashomer Camptodactyly
  • Carrier females: Face dysmorphism
• FGD1 protein
  • Guanine nucleotide exchange factor
  • Activates CDC42
• Clinical
  • Face
    • Ocular hypertelorism
    • Nostrils: Anteverted
    • Upper lip: Broad
    • Ptosis
  • Genital: ‘Shawl’ scrotum; Cryptorchidism
  • Joints: Arthropathy
    • Arthrogryposis: Distal, Symmetric
    • Fusiform swelling of proximal interphalangeal joints
    • Hyperextensibility
    • Genu recurvatum
    • Flat feet
• Laboratory
  • EMG: Myopathic
  • Muscle pathology: Varied muscle fiber sizes

• Epidemiology: US, European & Australian patients
• Genetics
  • Mutations: Missense (Arg198Gln; Pro201Ser; Arg213Trp; Arg213Trp), Deletion & Inversion
  • Allelic disorders
    • Carrier females
    • Wieacker-Wolff syndrome (WRWF)
    • Wieacker-Wolff syndrome, Female restricted (WRWFFR)
• ZC4H2 protein
  • Location: Postsynaptic compartment of excitatory synapses
  • Mutant protein: Abnormal dendritic spine density
• Clinical
  • Onset: Neonatal; Respiratory distress
  • Morphologic
    • ENT: Long (flat) philtrum; Low-set ears; Upturned nares; High-arched palate; Carp-shaped mouth
    • Neck: Short; Limited rotation
    • Narrow shoulders or thorax
    • Spine: Kyphosis, Lordosis or Scoliosis
    • Contractures: Hands; Elbows; Knees; Feet; Ankles; Humeroscapular
    • Camptodactyly
    • Proximal thumbs & toes
    • Short stature
  • Motor
    • Weakness: Face; Distal extremities; Ptosis (100%); Bulbar (60%), Poor feeding
    • Delayed development
  • CNS
    • Intellectual disability
    • Seizures
    • Spasticity (60%)
• Laboratory
  • MRI: Delayed myelination; Cerebral atrophy, diffuse
  • NCV: Normal
  • EMG: Normal
  • Muscle pathology: Muscle fiber atrophy in younger patients
  • Nerve pathology: Normal
• WRWF variant: Carrier famales
  • Face: Long (flat) philtrum
  • Joint
    • Equinovarus feet
    • Ankle contracturess
    • Camptodactyly
    • Short neck
  • Weakness: Distal extremities; Ptosis (20%)
  • CNS: Intellectual disability; Dysarthria
  • Urine incontinence
• WRWF variant: Wieacker-Wolff syndrome, Female restricted (WRWFFR)
  • Epidemiology: 14 females
  • Genetics
    • Inheritance: Sporadic de novo
    • Mutations: Loss of function
  • Clinical: Varied severity
    • Onset: in utero or birth
    • Arthrogryposis
    • Dysmorphic features
    • Intellectual development: Impaired
    • Eyes: Oculomotor apraxia, Duane syndrome
    • Bulbar: Facial paresis; Dysarthria; Dysphagia
  • Laboratory
    • Brain MRI: Atrophy; Myelination delayed; Ventricles large
    • Muscle: Denervation, chronic

• Epidemiology: 5 patients, 4 families
• Genetics
  • Mutations: Missense > Deletion
• HMGCS1 protein
  • Expression: Brain, Liver, Muscle (Especially satellite cells)
  • Mevalonate pathway
  • Related proteins
    • HMGCR
    • HMGCS2
• Clinical
  • Onset age: Birth to 4 years
  • Rigid spine: Especially cervical & dorsolumbar
  • Scoliosis
  • Weakness
    • Distribution: Proximal (80%) > Distal (40%); Bulbar (20%)
    • Exacerbations: Intercurrent disease; Drugs
  • Scapular winging (40%)
  • Palate: High arched (40%)
  • Treatment in animal models: Mevalonic acid
• Laboratory
  • Muscle MRI: Posterior thigh & Paraspinous abnormal
  • Serum CK: 190 to 7890
  • Muscle pathology
    • Core-like regions
    • Internal nuclei
    • Rimmed vacuoles
    • Myopathy: Later in course