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Distal Weakness in Myopathies

Distal Myopathies: Hereditary ⁷

Welander (Late onset type I) Distal Myopathy

• Epidemiology
  • Especially common: Mid-Sweden & Finland gene frequency 1/4000
  • Penetrance: Relatively low due to late age of onset
• Genetics ¹⁰
  • Mutation: Glu384Lys
    • Finnish & Swedish patients have shared haplotype
    • Homozygotes: Weakness is more severe & proximal
  • Allelic disorders
    • ALS-FTD (ALS 26)
    • Digenic Distal myopathy ⁵³
      • TIA1 mutation: Asn357Ser
      • SQSTM1 mutation: Pro392Leu most common
    • MYH7 related myopathies: Asn357Ser
• TIA1 protein (Nucleolysin TIA-1 isoform p40)
  • Nucleic acid-binding protein: Preferentially recognizes poly(A) homopolymers
  • Induces DNA fragmentation in permeabilized thymocytes
  • Component of cytoplasmic stress granules
    • Other components: eIF3, G3BP & TIAL1
  • ? Involved in induction of apoptosis in cytotoxic lymphocyte targets
  • Expressed in many tissues including muscle: Nuclear + some cytoplasmic
  • Accumulates in stress granules: Prion-like aggregation
  • RNA metabolism
• Clinical: Typical disease
  • Onset
    • Age: Usually > 40 years; Median 5th decade; Range 20 to 77
    • Location
      • Arms; Wrist & Finger extensors: Most common
      • Legs (Foot drop): 25%
  • Weakness
    • Hands > Legs in most
    • Muscles involved: Long finger extensors; Intrinsic hand; Thumb & index-finger
    • Progression to legs: Toe & ankle extensors
    • Only rarely proximal weakness
  • Tendon reflexes: Reduced at ankles
  • Slow progression with normal life span
  • Sensory loss: Some patients; Subclinical neuropathy common
  • Autonomic: Altered peripheral vasomotor response after vasoconstriction
• Homozygotes: Subset with more severe disease
  • Earlier onset
  • Rapid progression
  • Early: Leg & Proximal weakness
  • Wheelchair < 50 years
• Laboratory
  • CK: Normal or mildly elevated
  • EMG: Myopathic; Some irritability
  • Muscle Pathology: Digenic subtype
    • Chronic myopathic: Varied fiber size; Splitting
    • Rimmed vacuoles: Variably present; contain increased p62, Ubiquitin & TIA1
    • Tubulo-Filamentous inclusions (15 to 18 nm): Sarcoplasm & muscle fiber nuclei
    • Neurogenic changes
    • TIA1: Increase in cytoplasm with occasional aggregates in atrophic & vacuolated muscle fibers
    • Also see: Distal Myopathy
  • Sural nerve: Aδ fiber loss
• TIA1 variant: ALS 26 (ALS-FTD) ⁴²
  
  • Epidemiology: 1 family, 5 patients; 5 other ALS mutation carriers
  • Genetics
    • Inheritance: Dominant or Sporadic
    • Mutations
      • Missense: P362L, V294M, M334I, G355R, V360M, A381Y, Glu384Lys
      • Low-complexity domain
    • Other ALS: Increased burden of TIA1 low-complexity domain mutations in ALS patients vs controls
    • ~ 2% of Familial ALS
    • Allelic disorder: Welander distal myopathy
  • TIA1 protein
  • Clinical
    • Onset ages: 28 to 73 years; Mean 59 years
    • Weakness
      • Bulbar
      • Limb
    • Aphasia
    • Fronto-Temporal dementia
    • Disease course: Death in 2 to 6 years
  • Laboratory
    • Brain pathology
      • Inclusions: Round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive; Lewy body like
      • Locations: Extra-motor neocortex, Motor cortex, Substantia nigra, Spinal cord corticospinal tracts & ventral horn

Finnish (Tibial) (Late onset type IIa; Udd) Distal Myopathy

• Epidemiology
  • Finland
    • Large population with same mutation
    • Most common muscle disease
  • Other regions
    • French, Belgian & Spain families
    • Iberian mutation: c.107889delA
• Genetics
  • Finnish population
    • Probably arose from single ancestor
    • 20 per 100,000 population
    • Mutations
      • Common: 11 bp insertion-deletion of nucleotides 293,269 to 293,279 (In terminal exon)
      • Other: Missense or Truncating; Last 2 TTN exons
  • Allelic Disorders
  • Genotype-Phenotype
    • Same (11 bp) mutation may produce different patterns of weakness
      • Most common: Tibial MD
      • Other: Proximal; Posterior leg
    • Severe or variant phenotype
      • Often have 2nd titin mutation (Recessive LGMD 2J)
• Clinical
  • Onset age
    • Heterozygotes
      • 4th to 8th decade; Most in 40's
      • Many remain asymptomatic
    • Homozygotes: Childhood; LGMD 2J
  • Distribution of weakness
    • Legs: Anterior tibial selectively involved
    • Arms
      • Never hand weakness in Finnish patients
      • Some Non-Scandinavian families with hand weakness
    • Proximal weakness: 15%; Mild
  • Progression
    • Slow: Foot drop 10 to 15 years after onset when long toe extensors become weak
    • Proximal legs may become weak late in disease
    • Quadriceps weak in rare male
    • Many remain ambulatory
      • Earlier onset (2nd decade) may lose ambulation in 3rd to 6th decade
    • Homozygotes: Loss of ambulation by 3rd decade
  • Cardiomyopathy
• Laboratory
  • CK: Mild elevation or normal
  • MRI: Selective fatty replacement of muscles
    • Early: Anterior tibial; Gluteus minimus
    • Later: Gastrocnemius
• Pathology: Dystrophic (100%)
  • Muscle fibers: Size variation; Splitting; Internal nuclei
  • Basophilia
  • No inflammation
  • Rimmed vacuoles (30%): Contain degenerative cytoplasmic debris & organelles
  • Calpain 3: Reduced
  • Apoptosis in muscle nuclei
  • Anti-titin antibodies
    • Normal binding for most
    • Binding to C-terminal epitope reduced

Markesbery (Late adult onset type IIb) Distal myopathy

• Epidemiology: English, French & Finnish families
• Genetics
  • Mutation: A165V; Common in European families
  • Allelic disorders
• Clinical
  • Onset age: > 40 years
  • Weakness
    • Early: Distal legs
    • Hands: Distal finger & wrist extensors
    • Late: Proximal arms & legs
  • Progression
    • Slow: Slower in Finnish tibial type
    • Disability common
  • Cardiomyopathy: Occasional patient
• Laboratory
  • Serum CK: Normal or Slightly elevated
  • Muscle pathology: Rimmed vacuoles
  • MRI

Hereditary Inclusion Body Myopathy 2 (HIBM2; Nonaka) : Recessive ⁵⁷

Nosology Epidemiology Genetics GNE protein Clinical Laboratory Muscle Pathology Variant	from M Sadeh
	HIBM2: Quadriceps sparing CT of thigh

• Nosology: Same disorder as
  • GNE myopathy
  • Nonaka distal myopathy
  • IBM2
• Epidemiology
  • Iranian-Jewish families: Prevalence in Jews of Persian ancestry = 1:500
  • Other families: Mexico; India; Bahamas; Georgia, Japan, China
  • Prevalence range: 1 to 21 per 1,000,000
• Genetics: GNE gene mutations
  • Number described: > 320
  • Type
    • Missense >> Stop
    • Heterozygous > Homozygous
  • Mutation locations
    • Across entire gene
    • Domains: Epimerase or Kinase
    • GNE myopathy: Outside allosteric
    • Sialuria: Within allosteric site
  • Geographic
    • Iranian-Jewish & Sangesar (Mahdishahr) in Northern Iran: Homozygous for Met712Thr
    • Japan (Nonaka) & Korean: V572L (60%; Founder effect); Homozygous or Heterozygous
    • Japan, China, Other
      • Val603Leu homozygotes: Early onset, Rapidly progressiion
      • Asp207Val: Late onset; Asymptomatic if homozygous; Interferes with GNE oligomerization
      • Val603Leu: Often homozygous; Respiratory involvement
    • Korean: C13S
    • Northern Britain: Ala662Val; Asp409Tyr
    • Roma Gypsy & Indian (Rajasthan): Ile618Thr (Homozygous)
    • Indian/South Asia subcontinent ⁵⁰;
      • Val727Met: May be milder in homozygotes
      • Ala662Val: More severe clinical course
    • Middle Eastern (Persian Jews): Met743Thr
  • Earlier onset: L539S
  • Milder or Atypical phenotype: H333R; Y361X
  • Allelic disorders
    • Sialuria, Dominant
    • ALS, Juvenile: 1 family ⁴⁸
    • Thrombocytopenia, Congenital or Adult, Recessive 12
      • Mutations in: Kinase nucleotide binding site
    • Complete GNE knockout: Embryonic lethal
• GNE protein: Bifunctional
  • Catalyzes 1st 2 steps in synthesis of N-acetylneuraminic (sialic) acid: Rate-limiting step
  • Epimerase activity: N-terminal
  • Kinase activity: C-terminal
  • Tissue expression
    • Full length protein: Liver; Salivary glands; Intestinal mucosa
    • Shorter form (exon 4 missing)
      • Predominantly expressed in skeletal muscle
      • Present in similar levels in control & myopathy patients
  • GNE Mutants: No correlation between Disease pattern & Changed enzyme activity
  • Sialic acid disorders
  • External link: GeneTests
• Clinical
  
  • Onset
    • Age: 2nd to 4th decade; Range 12 to 78
    • Weakness: Foot drop
  • Weakness
    • Early: Peroneal & Anterior tibial
    • Distal & Proximal
    • Asymmetry: Some muscles
    • Lower extremity
      • Onset: Peroneal weakness (Anterior distal legs), Ankles & Toes
      • Then: Hips, Hamstrings & Gastrocnemius
    • Upper extremity
      • Wrist: Extension & Flexion
      • Hands: Intrinsic muscles; Grip
      • Shoulder girdle
        • Scapular winging: Some patients
    • Neck: Flexors or Extensors may be weak
    • Respiratory
      • Frequency: 30%
      • Especially with earlier onset
      • Rarely severe
    • Sparing
      • Quadriceps
        • Spared in most patients
        • Weak in few patients (4%): Disease progression
      • Arms: Deltoids
      • Legs
        • Hip muscles
        • Ankle: Plantar flexors
      • Cranial nerves
        • Ptosis: Rare
        • Facial weakness: Occasional patient
    • Progression: Slow
      • Usual: Weakness progresses to proximal & trucnal muscles
      • Disability within 10 to 20 years of onset
      • Often become wheel chair dependent
      • Few patients: Weakness remains distal
      • Lifespan: Not substantially reduced
    • Variants
      • Upper extremity early: Distal arm weakness
      • Proximal leg: Hamstring weakness, No foot drop ³²
      • Axial early
      • Late onset
  • Extramuscular
    • Thrombocytopenia: 4%
    • Sleep apnea
    • No cardiac
• Laboratory
  • CK: Mild elevation, 2x to 5x
  • Urine sialic acid: Not elevated
  • EMG: Spontaneous activity; Myopathic potentials
  • MRI: Quadriceps sparing
• Muscle Pathology
  • Myopathic
    • Varied muscle fiber size
    • Necrosis & Regeneration: Some patients
  • Vacuoles: Red-rimmed
    • Contain paired helical filaments
    • ? Autophagic
    • Many, but not all, patients
  • Aggregates
    • Constituents: βAPP; Ubiquitin; SMI-31 binding; ApoE; LC3; α-synuclein; Tau; TDP-43.
    • 15 to 18 nm filamentous inclusions in cytoplasm & nucleus
  • Sialylation: Abnormal on muscle proteins
    • Mainly affects O-glycan sialylation
    • Sambucus nigra agglutinin (SNA) lectin
      • Predominantly recognizes terminal sialic acid in α(2,6)-linkage in N-glycans
      • Reduced sialylation of ~50% in muscle
    • Peanut (PNA) lectin staining of Gal(β1-3)GalNAc disaccharide: Increased on sarcolemma ²⁶
    • NCAM pathology: Migrates as single, smaller 130 kD band on Western blot in some patients
  • Myopathic groups: Vacuolar & small fibers clustered in regions
  • Inflammation uncommon, but occasionally present ¹¹
  • α-Dystroglycan staining: Reduced ¹³
  • LAMP2: Increased granular staining
• GNE variant: Sialuria
  • Epidemiology: 10 patients
  • Genetics
    • Inheritance: Dominant
    • GNE Mutations
      • Epimerase domain
      • Binding site of cytidine monophosphate-sialic acid of GNE/MNK
      • Missense
  • GNE protein
    • Functional defect with mutation: Loss of feedback inhibition
  • Clinical
    • Developmental delay
    • Seizures
    • Hepatosplenomegaly
    • Skeletal: Scoliosis; Syndactyly
    • Dysmorphism: Face; Nipples small
  • Laboratory
    • Urine: Free sialic acid high

Miyoshi Myopathies

Miyoshi (Early adult onset distal myopathy type II; MMD1)

Genetic associations Allelic with: Limb-girdle muscular dystrophy 2B Genetic heterogeneity ? Some families linked to chromosome 10 & other loci Protein: Dysferlin Skeletal muscle > Heart Attached to cell membrane Clinical features Presymptomatic: Mild gastrocnemius wasting Early Adult Onset: Teens to 38 years Weakness & Wasting Posterior Legs: Gastrocnemius; Soleus Symmetric Arms & Proximal muscles involved late Calf wasting Progression: Related to disease duration Asymmetry in families not linked to 2p Laboratory CK: Very high up to 20,000 MRI Selective involvement of hamstring, gastrocnemius & soleus Early muscle edema Pathology: Dystrophic Muscle Necrosis & degeneration of muscle fibers Endomysial connective tissue Greater in more involved muscles Muscle fibers: Size variation; Splitting No vacuoles Inflammation Perimysial & perivascular cell infiltrates Variable: May occur in some muscles but not others Variant: Anterior tibial onset Epidemiology: Spanish family Dysferlin mutation: 5966delG Onset: 14 to 28 years Weakness: Rapidly progressive Serum CK: Very high Muscle: No vacuoles; Absent dysferlin Differential diagnosis: Calpain-3 mutation Muscle CT scan: Abnormal medial head of the gastrocnemius Muscle: Absent calpain-3; Normal dysferlin

From: C Angelini     Miyoshi distal myopathy: Straight legs & Small calves

Miyoshi Myopathy 2 (MMD2) ⁶

• Epidemiology: 3 Dutch families

Gowers (Laing; Early Adult Onset Distal Myopathy Type III; MPD1) ^{3, 4}

● Myosin heavy chain 7 (MYH7) ; Chromosome 14q11.2; Dominant or Sporadic Epidemiology Australian, German, Italian & Austrian families Genetics: MYH7 mutations Types: Missense; Charge reversing General location LMM region α-Helicoidal rod domain Exons 32, 34, 35, 36 Specific mutations: Arg1500Pro, Glu1508del, Lys1617del,     Ala1663Pro, Leu1706Pro, Lys1729del, Leu1793Pro Leu1793Pro: May also produce neonatal hypotonia & Cardiomyopathy De novo mutations: 20% to 35% Clinical correlations Individual mutations may produce widely varied phenotypes 21 Severe phenotype: L1591P Allelic disorders May have additional TIA1 mutations MYH7 protein Present in type I (Slow) muscle fibers Predicted mutation effect: Disrupts Ability of myosin tail to form normal coiled coil structure Myosin dimerization: Altered structure of thick filament Clinical Features Onset Age Common: < 5 years Range: Childhood or Young adult, 1.5 to 26 years Occasional: Neonatal or 6th decade Interfamilial variation Distal leg weakness: Steppage gait; Foot drop Hypotonia Weakness: Intrafamilial variation Legs Ankle dorsiflexion: Often severe with foot drop Hanging big toe Proximal muscles: Later in disease course Neck: Sternocleidomastoids & Neck flexors Arms Extensors: Finger (esp 5th) & Wrist Onset age: 3rd to 5th decade; 5 to 10 years after legs Later: Infraspinatus & Supraspinatus Intrinsic hand muscles: Normal Later in course: Some families Hip & Shoulder abductors & external rotators Face: Mild Usually symmetric: Asymmetry reported Muscle discomfort: Some patients Muscle size: Anterior tibial usually atrophic Tendon reflexes: Reduced at ankles; Present elsewhere Scoliosis (50%) Tremor: Hands, then postural ? Peripheral neuropathy with hypomyelination: Some patients Cardiomyopathy (50%) Dilated, Hypertrophic or Non-compacted left ventricle Course Slow progression Proximal weakness with disease progression Legs, Abdominal muscles Later ages: Mild disability Life expectancy: Normal Laboratory CK: Normal or Mild elevation to 8x high EMG: Myopathic; Some spontaneous activity NCV: Normal Muscle Pathology Myopathic: Varied fiber size; Internal nuclei Type I muscle fibers: Small; Grouped; Predominance in some patients Myosin heavy chain expression: Abnormal; Double positive fibers Hyaline inclusions: Light green-stain on Gomori trichrome Vacuoles: None in most patients; Autophagic rimmed reported Cytoplasmic bodies Severe, early onset patient Contents: Myotilin & Actin; Desmin+ rim Intranuclear tubulo-filamentous inclusions: 15 to 20 nm Some muscle fibers (3%) express both fast & slow myosin Distal muscles may be more abnormal MRI Leg: Atrophy & later Increased signal in tibialis anterior & EHL Thigh: Abnormal Biceps & Semimembranosus MYH7 Variant: Distal myopathy with Hypertrophic cardiomyopathy 19 Genetics Inheritance: Dominant Mutation: Val606Met; Homozygous Clinical Later onset: 6th decade Muscle hypertrophy: Anterior tibial Cardiomyopathy: Hypertrophic MYH7 Variant: Proximal weakness & Cardiomyopathy Genetics Inheritance: Recessive Mutation: Homozygous Glu1883Lys Clinical Weakness: Proximal Cardiomyopathy: Hypertrophic Pathology: Hyaline bodies in skeletal & cardiac muscle fibers

From: Wikipedia William Gowers "Hanging" Big Toes Patient is attempting to dorsiflex toes

Dystrophy, Distal ± Proximal, with Rimmed Vacuoles (MRUPAV) ¹⁴

• Epidemiology: 3 families; 33 patients
• Genetics
  • Mutation
    • Type: Large repeat insertion
      • 9 or more Extra 99-mer nucleotide repeats
      • In-frame
      • Amphipathic domain repeat expansion
    • Location: Coding; Exon 3
• PLIN4 protein
  • Highest expression: Skeletal muscle
  • Coats: Phospholipid monolayer surrounding lipid droplets
  • Regulates: Lipid droplets
  • Absent perilipin-4: No phenotype
  • Amphipathic domain: Normal protein
    • 11-mer: Repeated 3 times; Forms a 33-mer
    • 33-mer: Repeated 29 or 31 times
  • Amphpathic domain: Mutated protein
    • 33-mer: Repeated 40 times
    • Size: Increased by 297 amino acids
  • Perilipin disorder: Other
    • Lipodystrophy, familial partial, type 4
• Clinical
  • Onset age
    • Adult; 25 to 65 years
    • Younger with longer repeat mutation
  • Weakness
    • Early: Distal legs
    • Distribution
      • Distal legs (Foot dorsiflexion) (86%): Most involved
      • Proximal
        • More with disease progression
        • Proximal predominant (13%)
      • Respiratory: Later in disease course
      • Other: Neck flexion; Wrist & Finger extensors; Scapular
      • Severity: Varied Asymptomatic to Severely disabled
      • No cardiac, bulbar involvement
    • Progression
      • Slow
      • Wheelchair 17 years from onset
  • Myotonia, Percussion (50%)
  • Contractures (47%): Ankles
• Laboratory
  • Seum CK: Normal, or Mildly elevated (Up to 4x)
  • EMG: Myopathic; Myotonia
  • NCV: Normal
  • Cardiac: Normal
• Muscle MRI
  • Most affected: Semimembranosus; Anterior tibial; Gastrocnemius, medial
  • Least affected: Rectus femoris; Biceps, short head; Posterior tibial
• Muscle pathology ¹⁴
  • Fiber size: Varied, atrophy & hypertrophy
  • Inernal nuclei
  • Necrosis
  • Focal phagocytosis of muscle fibers
  • Rimmed vacuoles
    • Mainly in hypertrophic muscle fibers
    • Located near fiber surface
    • Contents: Basophilic granular material
    • Lysosomal features
      • Acid phosphatase positive: Around vacuoles
      • LAMP-1 & LAMP-2 negative
      • LIMP-I on surface of vacuoles & fibers
  • Inclusions
    • Sarcoplasmic: p62; FK2; Perilipin-4; NBR1
    • Ultrastructure: Cytoplasmic; Contain membranous bodies
  • PLIN4: Subsarcolemmal & Vacuole accumulations
  • Muscle Western blot: 2 PLIN4 bands, Normal & Increased sizes

Hereditary Inclusion Body Myopathy (IBM1; HIBM1) : Dominant

• Nosology
  • Originally identified as HIBM1
  • Desmin mutations found: Myofibrillar myopathy
• Clinical
  • Onset: Adult; 25 to 40 years
  • Weakness
    • Quadriceps early
    • Distal: Foot Dorsiflexion
    • Proximal: After disease progression
  • CNS involvement: Some families
  • Progression: Slow
• Laboratory
  • Serum CK: Normal or Mildly increased
  • Pathology
    • Red rimmed vacuoles: Prominent on GT stain
    • Multifocal myopathic changes
      • Myopathic fascicles: Variation in fiber size; Endomysial fibrosis
      • Vacuoles more common in myopathic fascicles
    • ± Inflammation
• Also see: Other IBM
  • Inclusion body myositis, Sporadic: Wrist & Finger flexors & Quadriceps weakness
  • IBM2: Sporadic or Recessive; GNE; Chromosome 9p12; Distal weakness
  • IBM3: Joint contractures & ophthalmoplegia: Myosin heavy chain IIa; Chromosome 17p13; Dominant; Proximal weakness
  • IBM + Paget's & Dementia: VCP; Chromosome 9p13; Dominant; Proximal & Distal weakness
  • SQSTM1: 5q35; Dominant or Sporadic
  • Differential diagnosis of rimmed vacuoles

Vocal Cord & Pharyngeal Weakness (MPD2; VCPDM; ALS21; MSP5) 37   ● Matrin 3 (MATR3) ; Chromosome 5q31.2; Dominant Nosology Multisystem proteinopathy 5 (MSP5) Reclassified as ALS21 Epidemiology: 16 families Genetics 22 Mutation: Ser85Cys Allelic disorders Familial ALS 21, Dominant Fronto-Temporal Dementia Mutation: Retrotransposed Full-Length Transcript of Matrin-3 Variant 5 Matrin 3 protein 46 Cell location Nuclear matrix Inner face of nuclear envelope May move to cytoplasm in diseased cells Tissue expression: Muscle & Other tissues Contains RNA-DNA binding motif Interacts with Proteins: TDP-43; DHX9 ; PABN1 DNA sequences: Repetitive; Adenine/Thymine-rich RNA: RNA stabilized by MATR3 binding Self association Functions Transcriptional control Splicing regujlation DNA repair Stabilizes mRNA encoding Rad51 Clinical Onset Age: 30 to 57 years; Average 46 years Weakness: Legs (Anterior & Distal); Occasionally Hands or Voice Weakness Initially asymmetric; May become symmetric Legs > Arms Peroneal distribution: Foot drop May also involve inversion Gastrocnemius: Relatively spared until later in course Hands Different finger extensors: Varied weakness Abductor policis brevis (Thenar): Early 1st dorsal interosseus > Hypothenar Proximal Shoulder weakness: Especially deltoid Neck: Anterior Asymmetric Respiratory: < 86% of expected in 60% Bulbar dysfunction Voice (65%) Onset usually after limb weakness Initially: Hypophonic & Breathy Later: Wet, gurgling, hoarse; Hypernasal resonance Pharyngeal: Dysphagia & Aspiration Tendon reflexes: Brisk; Absent or normal at ankle Course Slow progression Respiratory failure: After 1 to 2 decades Laboratory Serum CK: Normal to 8x High EMG Myopathic (especially pharynx & vocal cords) Neuropathic: Spontaneous activity; Complex repetitive discharges Nerve conductions: Normal or Mildly slowed MRI: Fat replacement Leg: Soleus & Medial gastroc Thigh: Posterior, Semimembranosus; Adductors in some patients Trunk: Paraspinal (50%); Gluteus minimus & medius Asymmetric in some Muscle pathology Myopathic: Gastrocnemius > Quadriceps Fiber size: Varied Internal nuclei Rimmed vacuoles: Subsarcolemmal; Often elongated Myonuclei ? Varied staining Aggregates: Perinuclear, Cytoplasmic Type 2 predominance: Some patients Matrin-3: Present, as normal, in nuclei Ultrastructure Absent perinuclear sarcomeres Nuclei: Abnormal invaginations MATR3 variant syndrome: Amyotrophic Lateral Sclerosis (ALS), Familial 21 (ALS21) 36 Epidemiology: Sardinian & British families Genetics 46 Inheritance: Dominant Mutations Missense Phe115Cys, Thr622Ala, Pro154Ser; Ser85Cys (Most common); Ser707Leu Cluster outside functional domains Allelic with: Vocal Cord & Pharyngeal Weakness (MPD2) MATR3 protein Clinical: Amyotrophic Lateral Sclerosis Onset age: 4th to 8th decade Weakness: Asymmetric; Arms & Legs; Dysarthria; Respiratory Muscle atrophy: Distal > Proximal Fasciculations Tendon reflexes: Brisk Cognitive disorders: Some patients (Phe115Cys, Ser707Leu) Course Death < 6 years Common: Rapidly progressive Ser85Cys: More slowly progressive Pathology Normal neurons: Nuclear, granular Disease: c9orf72 ALS = Cytoplasmic

Congo red stain MPD2: Large vacuoles

HEREDITARY INCLUSION BODY MYOPATHY (HIBM) + PAGET DISEASE (IBMPFD)

MSP ⁵⁴: Oligosystem features

• Systems involved
  • Muscle: Inclusion body myopathy
  • Asymmetric, often
  • Proximal: VCP
  • Finger extensor: TIA1
  • Serum CK: May be normal; Usually < 1,000
  • EMG: Small & Large motor units
  • Muscle pathology: Rimmed vacuoles
  • Nervous system
    • Brain: Dementia
    • Motor: Motor neuron disease
  • Bone: Paget disease
• Protein aggregates in cells
  • Ubiquitin-positive inclusions
  • Contents
    • RNA-binding protein: TDP-43)
    • Ubiquitin-dependent autophagy proteins: p62
    • AMPDA
• Causes
  • Proteins with
    • RNA-binding
    • Role in quality-control pathways
  • Most common disorder: VCP

Inclusion Body Myopathy with Paget disease of Bone & Dementia 1 (IBMPFD1) ²

Nosology: Multisystem proteinopathy 1 (MSP1) Epidemiology Worldwide: > 70 families Male = Female Genetics 12 Mutations Missense > 66 different Several involve same amino acid residue Locations N-terminal: Exons 1 to 6; N-, L1, or D1-ATPase domains Hotspot: Arginine 155 Arg95G; Ile126Phe; P137L; Arg155C; Arg155H; Arg155Leu; Arg155P; Arg155S; G156S; G157Arg; R159H; Leu198Trp; Arg191Gln; A232E; A439S Clinical genetic correlations Arg93Cys: Later disease onset; Most with Myopathy + PDB or FTD 52 R155C: Frontotemporal dementia with Intraneuronal Inclusions Arg159His: Interfamily variability Onset age: Later for myopathy Bone disease: Uncommon Some families: No dementia, Milder disease 16 Other families: Patients may present with frontotemporal dementia 24 Pathology Ubiquitin+ intranuclear inclusions & Dystrophic TDP-43+ neurites A232E: Fractures & Paget disease at earlier age Glu185Lys: Axonal CMT Asp395Gly: Vacuolar tauopathy Homozygous mutation: Arg159His Allelic disorders (% of VCP mutations) IBMPFD1 Myopathy Inclusion body (90%) Distal myopathy + Dementia ALS ALS, Familial 14 ± FTD (9%) sALS: Course modification Neuropathy CMT 2Y Demyelinating neuropathy Sensory neuropathy CNS Frontotemporal dementia (30%) Parkinson disease (4%) Alzheimer disease (2%) Familial Spastic Paraparesis: Case reports Encephalopathy, Childhood-onset Autism Non-neurologic Paget disease of bone (40%) Cardiomyopathy (Occasional) VCP protein Locations: Ubiquitous Functions Protein degradation pathways (Autophagy): Regulatory role Cell cycle & Membrane fusion Segregates ubiquitinated protein complexes Normal: Polymerization into hexamers; ATPase activity Binds ubiquitin AAA ATPase Chaperone Expression: Most tissues Aggregate-related Associates with aggregate prone polyglutamine containing proteins Present in inclusions from ALS, Parkinson’s disease & Huntington disease Mutated protein 18 Basal ATP hydrolysis activity: Increased with most pathogenic mutations Other mutation effects on ATP hydrolysis No change in ATPase activity: Glu185Lys; Axonal CMT Reduced ATPase activity: Asp395Gly; Vacuolar tauopathy Other mutation effects Increased levels of ubiquitinated cell proteins Sensitization to proteasome stress Impaired endoplasmic reticulum-associated degradation (ERAD) of proteins Promote formation of aggregates Contain p97/ VCP, ubiquitin conjugates & ER-resident proteins Impaired protein aggregate clearance Upregulation of autophagy-related proteins Clinical 23 Intrafamilial variability: Prominent Onset Age: 3rd & 4th decade; Range 2nd to 7th decaade Variable: Back pain; Weakness; Dementia Myopathy: Weakness (90%) Onset Ages: Mean 43 years; Range 3 to 66 years Presenting symptom in > 50% General Marked variability in severity & pattern within families More prevalent in males (92%) than females (72%) Limb-Girdle+ pattern (45%) Legs: Distal & Proximal Arms: Proximal & Distal Respiratory Often involved: Vital capacity 29% to 70% Failure: With disease progression Scapular winging: Supraspinatus & Infraspinatus weakness Other regions: Some patients Cranial nerves: Face (50%); Tongue Posterior neck: Head ptosis Back: Camptocormia Dysphagia (22%) Finger flexion Ophthalmoplegia: 1 family (R155S) Asymmetric: Often Progression Slow: Over 1 to 2 decades To severe disability Severe weakness: Common Loss of independent walking in 13 years Death in 5th to 7th decade Bone disease (42%) Paget disease (43% to 49%) Spine: Most common lesion location Other lesion locations: Hip; Skull; Pelvis Pain Onset: Mean 42 years; Range 29 to 61 years External link: Paget disease Skeletal: Lumbar lordosis Dementia (30% to 37%) Onset Mean 52 to 55 years; Range 30 to 86 years Usually after Paget's or Myopathy More prevalent in famales (51%) than males (31%) Frontotemporal (Behavioral variant) Language: Anomia; Aphasia; Mutism Personality change: Apathy; Agitation Hallucinations: Visual; Auditory Relatively preserved memory Cardiomyopathy: Occasional 56 Types: Dilated, Hypertrophic, Conduction disorders Heart failure: Late in disease course Amyloid may be present Sensation: Normal Other: Occasional Hepatic disorders Cataracts Polyneuropathy: Sensory-Motor Motor neuron loss Parkinsonism Laboratory Serum CK: Normal (80%), or Mildly increased (400 to 1165) Serum Alkaline phosphatase: High with Paget disease EMG: Variable Myopathy: Small amplitude, Polyphasic Brief motor unit potentials Spontaneous activity: Fibrillations; Positive sharp waves Chronic denervation: Some patients NCV: Normal Muscle biopsy Fiber sizes Varied Atrophy: Regional or Grouped; Some angular fibers, scattered Hypertrophy: Scattered muscle fibers Endomysial connective tissue: Patchy Increased Vacuoles: Rimmed Aggregates VCP staining inclusions: Sarcoplasmic & Myonuclear Other aggregates: TDP43; p62 MHC-I on muscle fibers: Varied Ultrastructure: Tubulofilamentous inclusions Muscle MRI: Widespread changes including axial muscles Echocardiogram: Cardiomyopathy (Late) Radiology: Paget disease of bone Brain pathology Cortical atrophy Inclusions: Intranuclear; Ubiquitin & TDP-43 positive VCP Variant syndrome: ALS, Familial 14 ± FTD (FTDALS6; ALS 14 ) 27 Epidemiology: 1% to 2% of Familial ALS Genetics Dominant or Sporadic VCP Mutations: Ile151Val; R155H; R159G; R191Q; D592N Allelic disorders: sALS course 186 Mutation: VCP inversion Clinical Survival: Longer Onset & Death age: Younger Cognitive impairment: More Clinical Onset Age: 4th to 6th decade Weakness: More commonly in legs Upper motor neuron Spasticity: Arms & Legs Bulbar: Dysarthria; Dysphagia Tendon reflexes: Brisk, including jaw jerk Lower motor neuron signs Atrophy Weakness: Patterns not well described Respiratory failure Progression: Variable Respiratory failure Death: 1 to 12 years May also have VCP multisystem disease Dementia Paget Myopathy Laboratory EMG: Denervation & Reinnervation Fibrillations Fasciculations Serum CK: Normal to 900 Brain pathology Corticospinal tract pallor Ubiquitin-positive inclusions in surviving neurons TDP43 or p62 (SQSTM1) aggregates tau (MAPT ) aggregates: D395G mutation (601023.0014) VCP Variant syndrome: Distal myopathy + Dementia 29 Epidemiology: Finnish family VCP mutation: P137L Clinical Onset Age: > 35 years Leg weakness Weakness: Distal, anterior legs Dementia: Onset > 50 years Paget disease: 1 patient Muscle pathology (Anterior tibial) Myopathic Endomysial fibrosis Atrophy Hypertrophy Ring fibers Vacuoles, rimmed: Some staining for TDP-43 or p62 VCP Variant syndrome: Progressive spastic paraplegia + Paget’s disease of bone 33 Epidemiology: Dutch family VCP mutation: Arg159Cys Clinical Onset Age: 5th to 6th decade Gait disorder Spastic paraparesis Tendon reflexes: Increased in legs Spasticity: Legs Weakness: Distal legs (Anterior tibial) Tongue fasciculations: 1 patient Paget’s disease of bone Cognition: Normal Course Progressive to wheelchair over 10 years Survival: > 2 decades Laboratory Alkaline phosphatase: High EMG: Denervation VCP Variant syndrome: CMT 2Y Sensory-Motor neuropathy Epidemiology: 1 family VCP genetics Mutation: Glu185Lys Inheritance: Dominant Clinical Onset age: 1st to 6th decade Weakness: Distal; Legs > Arms Sensory loss: Distal; Legs > Arms; Panmodal Laboratory NCV CMAP & SNAP amplitudes: Reduced Velocities: Normal VCP Variant syndrome: Demyelinating Neuropathy 45 Epidemiology: 1 patient, others in family with ALS or IBM Genetics Mutation: Arg191Gln in family, patient not studied Clinical Onset age: 6th decade Weakness: Diffuse, Arms & Legs Sensory loss: Vibration Tendon reflexes: Absent Cardiomyopathy Laboratory NCV: DL prolonged; CV 25 to 39 M/s; F-waves absent Nerve biopsy: Schwann cells with intranuclear ubiquitin; No demyelination CSF: Normal Serum CK: Normal VCP Variant syndrome: Neurodevelopmental Encephalopathy, Childhood-onset 51 Epidemiology: 13 patients Genetics Mutations: Missense (Most common); Deletions, in-frame; Frameshift; Splice Inheritance: Dominant, de novo (90%) Mutation effects: Often reduced ATPase activity Clinical Onset: Childhood Developmental delay: Language Intellectual disability (70%) Behavioral disorders (50%): ADHD; Autism; Anxiety Hypotonia & Motor delay (100%) Macrocephaly Face: Dysmorphism Congenital anomalies Laboratory Brain MRI: Non-specific abnormal; Atrophy Serum CK: Normal EMG/NCV: Neuropathy in 20% VCP allelic disorder: VCP homozygous mutation 43 Epidemiology: Belgian male Genetics Mutation: Homozygous; Arg159His Families (Heterozygous): Myopathy; Parkinsonism; Dementia Clinical General: May be similar severity to heterozygotes Onset age: 29 years Weakness Limb-Girdle Distal legs Legs > Arms Periscapular Paraspinal Muscle wasting: Legs Paget disease of bone Laboratory Serum CK: 1100 Muscle Rimmed vacuoles Endomysial macrophages Necrosis & Regeneration MHC1: Patchy increase EMG: Mixed myopathy & Neuropathy MRI: Asymmetric, patchy involvement; Paraspinal & Legs Bone: Paget lesions

IBM + Paget's: Scapular winging IBM + Paget's: Paget's disease of bone

Myopathy with Paget disease of Bone ± Cognitive change or Motor Neuron Disease (IBMPFD2) ^{8, 34}

• Nosology: Multisystem proteinopathy 2 (MSP2)
• Epidemiology: 4 familes
• Genetics
  • Mutations: Missense; Asp290Val/D302V; P310L; Located in prion-like domain
  • Allelic disorders
    • Paget disease of Bone, P310L mutation
    • Oculopharyngeal Muscular Dystrophy, Early onset
• HNRNPA2 protein
  • Most abundant isoform of hnRNPA2B1
  • Localization: Nucleus > Cytoplasm (mRNP granules containing untranslated mRNAs)
  • RNA binding
  • Contains: Prion-like domain
  • Essential for assembly of ribonucleoprotein granules
  • Tends to assemble into self-seeding fibrils: Exacerbated by disease mutations
  • Recruited to stress granules
• Clinical
  • Onset age: 3rd to 5th decade
  • Myopathy (100%)
    • Weakness
      • Legs: Distal, Ankles & Toes
      • Upper extremity: Proximal; Scapular winging
    • Muscle atrophy
    • Slowly progressive
  • Paget disease of bone (100%)
    • May be severe & widespread
    • Location: Long bones
  • Cognitive disorders (40%)
  • Motor neuron disease (40%)
    • Weakness
    • Rapidly progressive
• Muscle pathology
  • Fiber size: Varied; Atrophic groups
  • Internal nuclei
  • Increased endomysial connective tissue
  • Vacuoles: Rimmed
  • TDP-43 inclusions
  • Muscle fiber degeneration & Regeneration: Occasional
• Laboratory
  • Radiology: Paget disease of bone
  • EMG: Myopathic
  • Serum CK: High or Normal; May become normal with progressive disease
  • Serum Alkaline phosphatase: High
  • Serum Osteocalcin: High in some patients
• HNRNPA2B1 variant: Oculopharyngeal Muscular Dystrophy, Early onset (OPMD2) ⁴⁹
  • Epidemiology: 10 families
  • Genetics
    • Inheritance: Dominant or de novo
    • Mutations: Frameshift
      • Locations: Exons 10 & 11
      • Abolish native stop codon
      • Extend reading frame
      • Novel transcripts: Produce hnRNPA2/B1 protein with neomorphic C-terminal sequence
        • Reduced affinity for nuclear import receptor karyopherin β2
        • Cytoplasmic accumulation of hnRNPA2 protein
  • Clinical
    • Onset: Birth to Early childhood
    • Eye: Ophthalmoplegia; Ptosis
    • Weakness: Axial; Proximal; Distal; Legs > Arms; Dysphagia
    • Respiratory insufficiency
    • Course: Progressive
  • Laboratory
    • Serum CK: High
    • Muscle MRI
      • Atrophy
      • Heterogeneous T1 signal
      • Affected muscles
        • Thigh
          • Anterior: Rectus femoris & Gracilis spared
          • Posterior & Medial: Selectively affected
        • Leg
          • Soleus & Lateral gastrocnemius: Selectively affected
        • Tongue: affected
  • Muscle pathology
    • Atrophy
    • Vacuoles
    • Acid phosphatase stain
    • Inclusions
      • Cytoplasmic hnRNPA2/B1-positive
      • Partially co-localize with: P62, TDP43, TIA1
      • Cytoplasmic & Intranuclear
      • Tubulofilamentous

Myopathy (IBM) with Paget disease of Bone without Dementia (IBMPFD3) ³⁴

• Nosology: Multisystem proteinopathy 3 (MSP3)
• Epidemiology: 5 families
• Genetics
  • Mutations
    • Missense; D262V/D314V; Located in prion-like domain
    • Frameshift & Stop: *321Eext*6, *373Tyrext*6
  • Allelic disorders
    • ALS20 & Motor syndromes
    • IBM + Paget without Dementia 3
    • MPD3
• HNRNPA1 protein
  • Localization: Nucleus & Cytoplasm
  • Ribonuclear proteins & Disorders
  • Contains: Prion-like domain (PrLD)
    • Enriched in uncharged polar amino acids & glycine
    • Other proteins with PrLD
      • TDP-43: ALS 10
      • FUS: ALS 6
      • EWSR1: ALS, Sporadic
      • TAF15: ALS, Sporadic
      • TIA1: Welander distal myopathy
      • HNRNPA1: IBMPFD3
      • HNRNPA2B1: IBMPFD2
      • CAPRIN1: Ataxia
      • ATXN2: SCA2
  • Involved in
    • RNA binding
    • Packaging of pre-mRNA into hnRNP particles
    • Transport of poly(A) mRNA from nucleus to cytoplasm
  • Essential for assembly of ribonucleoprotein granules
  • Tends to assemble into self-seeding fibrils: Exacerbated by disease mutations
  • Stress granules
    • Cytoplasmic membrane-less organelles
    • Contain mRNA & proteins
      • Small ribosomal subunits
      • Translation initiation factors (eIF3, eIF4E, eIF4G)
      • hnRNPs
      • Other RBPs: TIA1, HuR, PABP
    • Mutations: Abnormal stress granule dynamics
• Clinical ³⁵
  • Onset
    • Childhood: Clumsy
    • Weakness: 35 to 43 years
  • Myopathy (100%): Weakness
    • Early: Proximal legs; Iliopsoas
    • Distal legs: Foot dorsiflexors
    • Abdominal wall
    • Arms: With disease progression
    • Scapular winging: Slight
    • Face
    • Respiratory muscles
    • Progressive: Wheelchair in 4th to 6th decade
  • Tendon reflexes: Normal or Reduced
  • Skeletal
    • Paget disease (50%)
    • Joint contractures
  • Cognition: Normal
• Muscle pathology
  • Fiber size: Varied
  • Internal nuclei
  • Vacuoles: Rimmed
  • TDP-43 inclusions
• Laboratory
  • Serum CK: 225 to 1250
  • Alkaline phosphatase: Normal to 8x high
• HNRNPA1 Variant syndrome: Motor neuron disease only (ALS20)
  • Nosology: ALS19 or ALS20
  • Epidemiology: 2 Families & 1 Simplex patient
  • Genetics
    • Inheritance: Dominant; de novo
    • Mutations
      • Family: Same as myopathy (D262V/D314V)
      • ALS: N267S/N319S; P288A
      • Flail arm: c.862/1018C>T (p.P288S/P340S)
      • Motor neuropathy: c.908-2A>G (G304Nfs*3) splice site
  • Clinical
    • Onset age: Adult
    • Motor neuron syndromes
      • ALS-like
      • Flail-arm syndrome
        • Muscle wasting & weakness: Distal or Proximal; Arms > Legs
        • Also: Bulbar features, Dysphagia, Dysarthria
        • Tendon reflexes: May be brisk
        • Course: Slow progression (3 decades)
      • Scapuloperoneal SMA
    • Other CNS: Normal
  • Electrodiagnostic
    • EMG: Ongoing & Chronic denervation
    • NCV: Normal

Distal Myopathy: MPD3 ⁹

• Epidemiology: Finnish family
• HNRNPA1 Genetics
  • Inheritance: Dominant
  • Mutation: 160 bp deletion in Exon 10
  • Allelic disorders
• Clinical
  • Onset
    • Age: 32 to 45 years
    • Clumsiness of Hands > Legs
  • Weakness
    • Legs
      • Distal
      • Anterior & Posterior
      • Muscles involved: TA, EDL, Gastrocnemius, Gluteus medius; TFL
    • Arms: Hands
      • Distal
      • Abductor pollicis; Opponens policis; 1st Dorsal interossei; Abductor digiti minimi
    • Proximal: With disease progression
    • Asymmetric
    • Intrafamilial variability
    • Course: Progressive
      • Slow: Over years
      • To more proximal limbs: Forearm, Triceps, Infraspinatus, Proximal legs
      • Patients remain ambulatory
• Laboratory
  • EMG: Myopathic
  • Serum CK: Normal or Slightly elevated
  • Muscle MRI: Fat replacement
    • Legs: Anterior Tibial, Long toe extensors & Lateral soleus
    • Thighs: Rectus femoris
• Muscle biopsy
  • Myopathy: Severe
    • Endomysial fibrosis
    • Fiber size variation
  • Rimmed vacuoles
  • Inclusions
    • Cytoplasmic eosinophilic
    • p62 & TDP-43
  • HNRNPA1: 50% reduced on Western blot

Myofibrillar Myopathy with Early Respiratory Failure (MFM9; HIBM-ERF; HMERF; ADMERF) ⁵

• Nosology
  • Hereditary IBM with Early Respiratory Failure
  • Distal myopathy with Early Respiratory Failure
  • Myofibrillar myopathy with Early Respiratory Failure
  • Edstrom myopathy
  • Myopathy with Proximal Weakness, Early Respiratory Failure & Cytoplasmic aggregates
  • Necklace body myopathy
• Epidemiology: > 30 families
• Genetics
  • TTN mutations
    • Missense
      • Common: Cys31712Arg; Cys30071Arg (British founder mutation)
      • Other: W30088 (Hotspot); P30091L; N30145K; G30150 (Hotspot); R32450W
    • Location: Myosin binding (Fibronectin; FN3 119 domain) A-band; Exons 343-344
    • Commonly private
    • May be de novo
  • See: Allelic disorders
• Titin protein
• Clinical
  • Onset: Variable
    • Age: 12 to 71 years; 4th & 5th decade most common; Mean 35 to 42 years
    • Weakness
      • Legs: Most common
      • Patterns: Symmetric; Foot dorsiflexion; Respiratory; Proximal
  • Weakness: Variable patterns
    • Patterns
      • Distal 30%
      • Proximal 40%
      • Other 30%: Distal + Proximal
      • Legs > Arms
    • Legs: Distal & Proximal; Anterior tibial
    • Arms: Wrist flexion & extension; Deltoid; May be diffuse
    • Trunk: Severe weakness common
    • Neck flexors
    • Ankle extension: Strong
    • Face: Mild in some patients
    • Symmetric (90%)
    • Progression
      • Slow
      • Cane & occasionally wheelchair needed after 5 to 15 years
      • Weakness: Proximal legs; Shoulders; ? Quadriceps sparing
      • Nocturnal non-invasive ventilatory support
  • Respiratory failure
    • VC & FEV1 < 75% of predicted in most patients at presentation
    • Course: Progressive
  • Muscle hypertrophy: Posterior leg (Calf)
  • Contractures: None
  • Cardiac
    • Conduction Δ (32%)
    • Mild cardiomyopathy (18%)
• Laboratory
  • Serum CK: 65 to 966
  • EMG: Myopathic; Irritable
  • Nerve conduction studies: Normal
  • MRI: Muscle
    • Proximal legs
      • Selective early involvement: Semitendinosus & Obturator externus
      • Proximal more than distal involvement in individual muscles
      • Adductor longus spared
    • Distal legs
      • Most involvement: Antero-Lateral; Tibialis anterior
      • Relative sparing: Gastrocnemius & Soleus
    • Shoulder girdle
      • Moderate involvement: Supraspinatus, Infraspinatus, Serratus anterior, Subscapularis & Trapezius
• Muscle pathology
  • Fiber size: Varied
  • Myofibrillar pathology: Cytoplasmic aggregates
    • Contain: Actin; Desmin
    • In type I muscle fibers
    • Myofibrillar pathology
    • Not typical Cytoplasmic bodies
  • Eosinophilic inclusions
    • Congophilic
    • Variably contain: β amyloid, desmin, SMI-31 binding
  • Cytoplasmic bodies (95%)
    • Stain for F-actin (Phalloidin)
    • "Necklace" pattern in muscle fibers ³⁸
  • Muscle fiber splitting: With more severe weakness
  • Vacuoles (50%): Rimmed, blue; With more severe weakness
  • Fiber types: Type 1 predominance (50%)
  • Internal nuclei
  • No necrosis or inflammation
  • Calpain-3: Reduced on Western blot
  • Ultrastructure
    • Z-line streaming
    • Thin filaments & Dense material related to Z-discs

Myopathy with Ringed muscle fibers ¹

• Inheritance: Sporadic
• Clinical features
  • Onset: 3rd decade
  • Weakness: Proximal (quadriceps) + Ankle dorsiflexion
  • Progression: Moderate 1 to 5 years
• Lab
  • Serum CK: Normal
  • EMG: Irritable myopathy
• Muscle Pathology
  • Myopathic: Fiber size variation; Increased connective tissue; Central nuclei
  • Rings in fibers: Outer sarcoplasmic pad; Middle annular myofibrils; Center normal

Distal myopathy with spared anterior leg muscles (William's myopathy) (MPD4) ¹⁵

• Epidemiology: Australian & Italian families
• Genetics
  • Missense mutations
    • In actin binding domain
    • Met251Thr, Ala193Thr
  • Allelic with
    • Myofibrillar myopathy
    • Distal myopathy with upper limb predominance
• Filamin C protein
• Clinical
  • Variable within family: Some affected members are asymptomatic
  • Onset
    • Age: 0 to 30 years
    • Weakness
    • Muscle discomfort
  • Weakness
    • Symmetric
    • Distal
    • Arms + Legs
      • Arms: Forearm pronators, Finger flexors, Intrinsic hand muscles
      • Legs: Ankle evertors, Plantar-flexors (Calf atrophy)
        • Differential diagnosis: LGMD 2B
    • Sparing: Anterior leg; Posterior arm
  • Muscle wasting: Distal
  • Discomfort
    • Type: Cramps; Deep pain
    • Worse after exercise
  • Tendon reflexes: Absent at ankles
  • Systemic
    • Cardiomyopathy: 2 patients
    • No respiratory involvement
  • Course
    • Slowly progressive
    • Patients remain ambulatory
• Laboratory
  • Serum CK: Normal or Mildly elevated
  • EMG: Myopathic
  • MRI
    • Involvement of posterior & lateral leg muscles
    • Some asymmetry
  • Muscle
    • Varied fiber size: Small angular fibers
    • Internal architecture: Irregular in some biopsies
    • No myofibrillar aggregates, vacuoles or inflammation
    • Dysferlin normal
• FLNC variant syndrome: Distal myopathy with upper limb predominance ³⁰
  • Epidemiology: Bulgarian families, 13 patients
  • FLNC mutations
    • Stop: c.5160delC frameshift deletion; p.Phe1720Leufs*63
    • Missense: Actin binding domain; p.Ala193Thr, p.Met251Thr
    • Mechanisms: Haploinsufficiency of filamin C
    • Inheritance: Dominant
    • Penetrance: Partial
  • Clinical
    • Onset
      • Age: 20 to 54 years
      • Weakness: Fingers
      • Walking difficulty: Steppage gait
    • Weakness
      • Distal > > Proximal
      • Arms before Legs in some
      • Finger extensors & Interossei
    • Atrophy: Distal arms & legs
    • Sensory: Loss in 40%
  • Other
    • Pes cavus (20%)
    • Hypertension (30%)
    • Cardiomyopathy (10%)
  • Laboratory
    • Serum CK: Normal to 6x high
    • NCV: CMAP amplitude reduced
    • EMG: Myopathic
    • Muscle
      • Varied fiber size
      • Necrosis
      • Pyknotic nuclear clumps
      • Type I predominance
      • No or Few myofibrillar aggregates
      • Ultrastructure: Myofibrillar disorganization

Nebulin myopathy, Distal, Recessive ²⁰

• Genetics
  • Mutations: Missense; Often homozygous
  • Different from Rod myopathy in which at least 1 mutation causes protein termination
  • Allelic disorders
• Clinical
  • Onset age: Child or Adult
  • Weakness: Similar to MPD1 (Gowers-Laing myopathy)
    • Distal
    • Hanging big toe sign
    • Extensor finger weakness: Index finger spared
    • Neck flexors
  • Slender stature
• Muscle
  • Rods: None or Small
  • Ultrastructure: Z-line streaming; Minor rod changes

Distal Myopathy 5 (MPD5; Rod Myopathy) ⁴⁰

• Epidemiology
  • Korean, Indian & Japanese families
  • Japan: Most common nemaline rod myopathy ⁴⁴
• Genetics
  • Mutations: Compound heterozygous; D304N (c.910G>A), I350fs (c.1048delA), L407P (c.1220T>C)
  • Common in
    • Japan: c.781G>A; c.919delA
    • India: Asp261Asn
• ADSSL1 protein
  • Location: High in skeletal muscle
  • Muscle isozyme of adenylosuccinate synthase
  • Conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP): Catalyzes initial reaction
• Clinical
  • Onset age: 5 to 8 years
  • Weakness
    • Early: Diffuse
    • Distal > Diffuse
    • Legs > Arms: Hands commonly spared
    • Quadriceps: 4th decade
    • Face: Common; Ptosis
    • Neck
    • Dysphagia (38%)
    • Respiratory
  • Fatigability
  • Muscle size: Mild atrophy
  • Sensory: Normal
  • Disease course: Slow progression; Remain ambulant
  • Cardiomyopathy: Hypertrophic; Arrhythmias
• Laboratory
  • Serum CK: 108 to 1,500
  • Muscle MRI
    • Lower extremity
      • General: Hyperintense signal in lower leg muscles
      • Posterior > Anterior
      • Thigh
        • Vastus lateralis (Periphery), Adductor, Biceps femoris, Semimembranosus
        • Quadriceps: Involved later
        • Spared: Rectus femoris; Sartorius; Semitendinous
      • Leg: Soleus; Gastrocnemius
    • Tongue & Masseter: Fat replacement
    • Trunk: Neck & Upper thoracic
  • EMG: Normal or Irritative myopathy
  • RNS: Decrement in 1 family
  • Muscle pathology
    • Fiber size: Varied
    • Internal architecture: Internal nuclei; Splitting
    • Nemaline rods ⁴⁴: Some patients
    • Rimmed vacuoles (50%): Few fibers
    • Lipid droplets (Type 1 fibers)
    • Endomysial connective tissue: Increased
    • Type I fiber predominance: ? Fiber type groups
    • ADSSL1 expression: Absent or Reduced

Cystinosis, Nephropathic (CTNS)

• Epidemiology
  • Prevalence: 0.5 to 1/100,000 live births
• Genetics: Mutations
  • General: Missense & Stop
  • French-Canadians: 57-kb deletion
• CTNS protein
  • Lysosomal membrane
  • Transport of cystine from lysosomal lumen to cytoplasm
  • Mutant protein: Cystine accumulates & crystallizes in lysosome
• Clinical
  • Frequency ⁴¹
    • 30% to 40% of patients with cystinosis
    • Similar frequency in patients with & without cysteamine treatment
  • Onset
    • Age: 1st year to Adult
    • Failure to thrive: 1st year
  • Skeletal
    • Short stature
    • Frontal bossing
    • Hypophosphatemic rickets
    • Contractures (15%): Hands
  • Eyes: Retinopathy; Corneal cysteine crystals
  • GI: Not frequent
    • Hepatomegaly; Pancreatic insufficiency; Splenomegaly
    • GI complaints related to Cysteamine treatment: Treat with protein pump inhibitor
  • Renal
    • Fanconi syndrome
    • Renal failure: Transplant often necessary
  • Endocrine
    • Hypothyroidism, Primary
    • Diabetes mellitus: Insulin dependent
    • Delayed puberty
  • Skin
    • Hypohidrosis
    • Light hair pigmentation
  • Cardiac: Coronary artery calcifications
  • Muscle (24% to 50%)
    • Weakness
      • Distal > Proximal
      • Hands (Thenar & Hypothenar; Grip) > Feet
      • Proximal muscles involved: Neck flexion; Arm abduction; Hip flexion
      • Dysphagia (30% to 60%)
      • Respiratory
      • Face (10%)
    • Wasting
  • CNS: Visuo-spatial processing defect
  • Treatment
    • Replacement of renal losses
    • Cystine-depleting agents: Cysteamine
• Laboratory
  • Diagnosis: Leukocyte cystine measurement
  • Urine: Proteinuria; Glucosuria; Microscopic hematuria
  • Blood: Hyponatremia; Hypokalemia; Hypophosphatemia; Hyperlipidemia
  • Carnitine deficiency
  • Aminoaciduria, Generalized
  • White blood cell cystine: Elevated
  • Brain: Cerebral atrophy
  • Muscle imaging: Fat infiltration of posterior thighs & legs
• Muscle pathology
  • Muscle fiber size: Varied
  • Vacuoles: Rimmed; Mildly acid phosphatase positive
  • Aggregates: AMPDA+

Distal weakness, Early onset ²⁵

• Nosology: May be distal myopathy or predominantly motor neuropathy
• Epidemiology: German & Japanese families
• Genetics
  • Mutation: Missense, L95F; Heterozygous
• KLHL9 protein
  • Complexes with Culllin 3
  • Ubiquitin-dependent protein degradation pathway
  • Potential targets of KLHL9-Cul3 complex
    • Aurora B kinase (AURKB)
    • Mitochondrial inner membrane
• Clinical
  • Onset ages: 8 to 20 years
  • Weakness
    • Hands: Intrinsic muscles
    • Legs: Distal
    • Proximal: Normal
  • Atrophy: Anterior tibial
  • Contractures: Ankles
  • Sensory loss (60%)
    • Distal
    • Arms & Legs
    • Later in disease course
  • Tendon reflexes: Reduced at ankles or diffusely
  • Course
    • Very slow progression
    • Remain ambulant
• Laboratory
  • Serum CK: 110 to 1700; Usual 150 to 260
  • NCV
    • Motor: Velocities normal; Distal latency long; Peroneal CMAP amplitudes reduced
    • Sensory: Normal
  • EMG: Distal fibrillations & Polyphasic large potentials; Some myopathy
  • Muscle biopsy
    • Fiber sizes: Varied
    • Internal nuclei
    • Cytoplasmic bodies: Few
    • COX- muscle fibers
    • Endomysial connective tissue: Midly increased
    • KLHL9 levels & distribution: Normal
  • Muscle MRI
    • Atrophy & Fat replacement
    • Distal leg muscles: Most in Gastrocnemius & Soleus

dHMN: Distal Weakness, Hoarseness, Hearing loss (PNMHH) ²⁸

• Epidemiology: Korean & North American families
• Genetics
  • Mutation: Missense; Arg941Leu (c.2822G>g;T); In tail domain
  • Allelic with: Deafness, autosomal dominant 4 (DFNA4)
  • Contains microRNA, miR-499
• MYH14 protein
  • Myosin: Non-muscle
  • Locations: Heart, Slow muscles, Extraocular (EO) muscles; GI tract; Renal
  • Myosin disorders
• Clinical
  • Onset age: 4 to 23 years
  • Weakness
    • Distal: Occasionally also proximal
    • Legs > Arms
    • Symmetric
    • Slow progression over decades
  • Hoarseness (50%)
  • Sensory loss: None
  • Tendon reflexes: Variable
  • Foot deformity (50%)
  • Hearing loss (30% to 100%): Onset after weakness
  • Cardiac: Normal
• Laboratory
  • Serum CK: Normal to mildly high (< 2.5-fold high)
  • EMG: Denervation, More distal
    • Fibrillations
    • Motor unit potentials: Large
    • Recruitment: Reduced
  • NCV
    • Velocities: Normal
    • CMAP amplitudes: Small
    • SNAPs: Normal
  • Muscle biopsy
    • Fiber type grouping
    • Grouped atrophy
    • Ultrastructure: Abnormal mitochondria; Paracrystalline inclusions

Intellectual Disability ³¹

• Epidemiology: Pakistan & Iran families
• Mutation: Homozygous; Missense; Gly679Arg
• NSUN2 protein
  • RNA Methyltransferase
  • Catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA)
  • Role in spindle assembly during mitosis & chromosome segregation
  • Localization: Nucleolus
• Clinical
  • CNS
    • Intellectual disability
    • IQ: 40 to 50
    • Developmental delay: Motor; Speech
  • Upper motor neuron
    • Muscle tone: Increased
    • Tendon reflexes: Brisk
  • Morphology
    • Face: Long; Pointed nose & chin
    • Microcephaly
    • Fingers: Tapering
    • Height & Weight: Low
    • Feet: Pes cavus; Abnormal toe separation
  • Strabismus
  • Distal myopathy: Not well documented
• Laboratory
  • Head CT: Normal
  • Serum CK: Mildly high in 2 patients

MPD7: Distal Myopathy with Protein Inclusions ⁴⁷

• Epidemiology: 11 families, 15 patients
• Genetics
  • Mutations: Missense
  • Founder mutations: Northern Europe P7T; Italian/Maltese S78N; French P27A
  • Allelic disorder
    • Deafness, X-linked 4 (DFNX4), Dominant : Loss of function mutations
• SMPX protein
  • Expression: Hair cells of inner ear; Skeletal muscle (Slow), Heart
  • Subcellular: Costamere; Intermyofibrillar
  • Associated molecules: Vinculin ; MUSTN1
  • Upregulation: Passive stretch
• Clinical
  • Onset age: 20 to 60 years
  • Weakness
    • Distal > Proximal
    • Arms Finger extensor Proximal: Some patients
    • Legs: Ankle dorsiflexor
    • Respiratory: Normal
    • Scapular winging (40%)
  • Course: Slow progression; Ambulation retained
  • Hearing loss (Pro21Gln mutation)
  • Cardiac: Normal
• Laboratory
  • Muscle MRI: Anterior legs; Hamstrings late; Paraspinous
  • Muscle biopsy
    • Fiber sizes: Varied
    • Internal nuclei
    • Rimmed vacuoles
    • Sarcoplasmic inclusions
      • Contents: SMPX, SQSTM1/p62, SMI-31, Ubiquitin, Vinculin
      • Congo red +
      • Cytoplasmic bodies
    • Ring fibers
    • Ultrastructure: Z-band streaming; Rods; Minicores

Myopathy/Neuropathy ¹²⁹

• Epidemiology: 1 patient
• Genetics
  • Mutation: p.P15S
• DNAJB5 protein
  • DNAJ family
  • Other DNAJ disorders
• Clinical
  • Onset age: 20 years
  • Myoclonus
  • Muscle
    • Weakness
    • Atrophy: Distal
• Laboratory
  • NCV: Median motor 52 m/sec; Median CMAP 6 mV
  • EMG: Spontaneous activity; Motor units small or large

Syndromes with Neuropathy & Myopathy

• Systemic disorders
  • Paraneoplastic (with weight loss > 15%)
    • Neuropathy: Distal; Sensory > Motor
    • Myopathy: Proximal with type II muscle fiber atrophy
  • Metabolic
    • Uremia
    • Acromegaly
  • Immune
    • Collagen vascular disorders: Sjögren
    • Sarcoid
    • Graft vs Host disease
    • HIV Infection
      • Myopathy: Inflammatory
      • Neuropathy: Several types
    • Checkpoint inhibitors
• Inclusion Body Myositis
• Hereditary ⁵⁵
  • BICD2
  • Debrancher deficiency
  • DNM2
  • HMSN: BAG3
    
  • Lamin A/C
  • Congenital muscular dystrophy: LAMA2
  • Dynamin-2
  • HSPB3
  • HSPB8
  • Marinesco-Sjögren
  • Mitochondrial: MNGIE; MERRF
  • Motor neuropathy + Myopathy: VWA1
  • Multisystem/Oligosystem proteinopathies
  • MYH14
  • Trifunctional protein deficiency
  • Tyrosinemia
  • Some patients/Either-Or
    • CRYAB
    • DNAJB2
    • GNE
    • HMSN-P/HMSNO: TFG
    • HSPB1
    • LRP12
    • NOTCH2NLC
    • SORD
    • SPTAN1
    • TRIP4
• Drugs & Toxins
  • Amiodarone
  • Checkpoint inhibitors
  • Chloroquine
  • Chlorphenoxy
  • Clofibrate: Risk factor - renal failure
  • Colchicine: Risk factor - renal failure
  • Doxorubicin
  • Eosinophilia-myalgia syndrome
  • Ethanol: Risk factor - fasting
  • Hydroxychloroquine
  • Organophosphates
  • Perhexiline
  • Vincristine