Myopathy: Distal Weakness

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DISTAL WEAKNESS IN MYOPATHIES

Distal Myopathies: Hereditary ^⁷

DISTAL WEAKNESS: Differential Dx General Features Pathology Myopathies Centronuclear, Type 2: Dynamin 2; 19p13 Congenital myopathies Cystinosis, Nephropathic: CTNS; 17p13 Cytoplasmic body Distal dystrophy: 19p13 Emery-Dreifuss Finnish: Titin; 2q31 FSH dystrophy Glycogenoses Acid maltase Debranching Enzyme Phosphorylase b Kinase Gowers-Laing (MPD1): MYH7; 14q11 Hereditary IBM Dominant Recessive Respiratory failure LGMD variants 1A: Myotilin; 5q31 1C: Caveolin-3; 3p25 1D: DNAJB6; 7q36 2B: Dysferlin; 2p13 2G: Telethonin; 17q12 2L: ANO5; 11p14 Mitochondrial: POLG1; 15q26 Miyoshi (MMD) MMD1: Dysferlin; 2p13 MMD2: ? 10p MMD3: ANO5; 11p14 MPD3 Myofibrillar αB-crystallin: 11q22 CCDC78: 16p13 Desmin: 2q35 Filamin C (MPD4): 7q32 Scapuloperoneal: 12q13 ZASP: 10q23 Myofibrillary (Cytoplasmic body) Myopathy + Paget's disease of bone with Dementia: VCP/p97; 9p13 Type 2 Myotonic Dystrophy 1: DMPK; 19q13 Nebulin: 2q23 Nemaline (Rod) myopathies Neutral lipid storage: PNPLA2; 11p15 Nonaka-HIBMR: GNE; 9p13 Oculopharyngodistal Scapuloperoneal syndromes Ring fiber myopathy Vocal cord (MPD2): MATR3; 5q31 Welander: TIA1; 2p13 Other Myopathy or Motor Neuropathy Distal weakness: KLHL9; 9p22 Distal weak, Hoarse, Deaf: MYH14; 19q13 Neuropathies Uncertain NSUN2 Acquired (Sporadic) disorders Myasthenia gravis Myopathy + Neuropathy Hyperthyroid IIM + VAMP (IBM-like) syndromes Inclusion Body Myositis	Type	Inheritance Pattern	Gene & Locus	Early Weakness	CK	Muscle
	Welander	Dominant	TIA1 2p13	> 40 years Hands: Extensor	Normal, or Slight é	Myopathic ± Vacuoles
	Finnish (Tibial)	Dominant	Titin 2q31	40 to 50 years Legs: Anterior	Normal, or Slight é	Myopathic Vacuoles
	HIBM + Respiratory failure	Dominant	Titin 2q31	18 to 75 years Distal legs Respiratory	Normal or Slight é	Myopathic Eosin inclusions Cytoplasmic body Vacuoles
	Gowers-Laing (MPD1)	Dominant	MYH7 14q11	1.5 to 25 years Legs: Anterior	é up to 3x	Myopathic: Mild Vacuoles: Some
	Distal dystrophy + Rimmed vacuoles	Dominant	19p13.3	10 to 50 years Legs: Distal	Normal, or Slight é	Myopathic Vacuoles
	HIBM1	Dominant	Desmin 2q35	25 to 40 years Legs: Distal; Quadriceps	Normal, or Slight é	Myopathic Vacuoles
	Oculopharyngodistal	Dominant	Autosomal	40 years Extraocular	3x é	Myopathic Vacuoles
	Vocal cord & Pharyngeal (MPD2)	Dominant	Matrin 3 5q31	35 to 57 years Legs, Hands or Vocal cord	Normal to é 8x	Myopathic Vacuoles
	Myopathy + Paget's & Dementia	Dominant	VCP 9p13	20 to 40 years Legs Proximal & Distal	Normal or Slight é	Myopathic Vacuoles
	Myopathy + Paget's	Dominant	Autosomal	35 to 42 years Legs: Distal Scapular	Normal or High	Myopathic
	Cytoplasmic body	Dominant	Autosomal	40 to 50 years Hands	Normal or Slight é	Myofibrillary inclusions
	MPD3	Dominant	8p22-q11 & 12q13-q22	32 to 45 years Distal Legs & Hands	Normal or Slight é	Myopathic Vacuoles
	Myopathy with Anterior leg sparing (MPD4)	Dominant	Filamin C 7q32	0 to 30 years Distal Legs & Hands	Normal or Slight é	Varied fiber size No vacuoles
	Nonaka-HIBMR (HIBM2)	Recessive, or Sporadic	GNE 9p13	20 to 40 years Legs: Anterior	é up to 5x	Myopathic Vacuoles
	Miyoshi ± LGMD 2B	Recessive, or Sporadic	Dysferlin 2p13	20 to 50 years Legs: Posterior	10x to 150x é	Myopathic No vacuoles
	LGMD 2G	Recessive	Telethonin 17q12	12 years Legs: Proximal & Anterior distal	3x to 17x é	Myopathic Vacuoles
	Miyoshi-like 3 (MMD3)	Recessive	Anoctamin 5 11p14.3	11 to 50 years Legs: Posterior	3x to 100x é	Myopathic Sarcolemmal lesions
	Nebulin	Recessive	Nebulin 2q23	Child or Adult Toe & finger extensor	Normal	Myopathic Rods, Small
	Myofibrillar myopathies
	Desmin	Dominant or Recessive	2q35	20 to 40 years Legs	Mild é	Myopathic Desmin é
	αB-crystallin	Dominant	11q22	Adult Distal	Mild é	Myopathic Desmin é
	Scapuloperoneal	Dominant	FHL1 Xq26	20 to 58 years Distal; Legs	1.5x to 10x é	Myopathic, Focal Desmin inclusions
	ZASP, Markesbery	Dominant	ZASP 10q23.2	Child to 73 years Distal in 9%	Normal to 6x é	Myopathic Desmin inclusions Vacuoles: Small

Distal myopathies: Weakness & Muscle involvement
Clinical Common weakness pattern Muscles around wrist & ankle Very distal muscles (Hand & Foot intrinsics) Often relatively spared Intrinsic hand muscles involved Filamin C Welander Desmin Possible myopathy KLHL9	Lower leg: Patterns Posterior prominent MYOT ZASP FLNC DYSF ANO5 DNM2 Anterior prominent MYH7 NEB GNE Titin MATR3 VCP + Lateral DES CRYAB Hanging big toe MYH7	Muscle fiber pathology Rimmed vacuoles GNE Titin MATR3 VCP Welander MPD3 Myofibrillar αB-crystallin Desmin Filamin C Scapuloperoneal ZASP Myotilin Cytoplasmic body

Welander (Late onset type I) distal myopathy

l TIA1 cytotoxic granule-associated RNA-binding protein (TIA1)

; Chromosome 2p13.3; Dominant

Epidemiology
- Especially common: Mid-Sweden & Finland gene frequency 1/4000
- Penetrance: Relatively low due to late age of onset
Genetics¹⁰
- Mutation: E384K
- Finnish & Swedish patients have shared haplotype
- Homozygotes: Weakness is more severe & proximal
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
- May be involved in induction of apoptosis in CTL targets
- Expressed in many tissues including muscle: Nuclear + some cytoplasmic
- Accumulates in stress granules: Prion-like aggregation
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
  - 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
- Sural nerve: Aδ fiber loss

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

l Titin

; Chromosome 2q31.2; Dominant

Epidemiology
- Finland
  - Large population with same mutation
  - Most common muscle disease
- Other regions: French, Belgian & Spain families
Genetics
- Finnish population
  - Probably arose from single ancestor
  - 20 per 100,000 population
  - Mutation: 11 base pair deletion of nucleotides 293,269 to 293,279 (In terminal exon)
- Allelic with
  - LGMD 2J
  - Dilated cardiomyopathy 1G
  - Myopathy with Early Respiratory Failure: R279W mutation
  - Congenital myopathy + Fatal dilated cardiomyopathy
- Genotype-Phenotype
  - Same (11 bp) mutation may produce different patterns of weakness
    - Most common: Tibial MD
    - Other: Proximal; Posterior leg
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; Gluteusn 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

l ZASP

; Chromosome 10q23.2; Dominant ¹⁷

Epidemiology: English, French & Finnish families
Genetics
- Mutation: A165V; Common in European families
- Allelic with
  - ZASP myofibrillar myopathy
  - Dilated cardiomyopathy ± Isolated non-compaction of left ventricular myocardium
Onset: > 40 years
Clinical
- 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

Hereditary Inclusion Body Myopathy (IBM2; Nonaka) : Recessive

l GNE

; Chromosome 9p13.3; Recessive

Nosology: Same disorder as Nonaka distal myopathy
Genetics: Mutations in GNE gene
- GNE: UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase
- Mutations
  - Usually missense
  - Iranian-Jewish & Sangesar (Mahdishahr) in Northern Iran: Homozygous for Met712Thr
  - Japanese (Nonaka) & Korean: V572L (60%; Founder effect); Homozygous or Heterozygous
  - Korean: C13S
  - Other families: Heterozygous; Missense or occasional Stop
  - Location: Epimerase or kinase domain
  - Milder or atypical phenotype: H333R; Y361X
  - Other mutations in epimerase domain cause: Sialuria
    - Dominant inheritance
    - Functional defect: Loss of feedback inhibition
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
- Mutants: No correlation between disease pattern and changed enzyme activity
Epidemiology
- Iranian-Jewish families: Prevalence in Jews of Persian ancestry: 1:500
- Other families: Mexico; India; Bahamas; Georgia
Clinical

from M Sadeh

Quadriceps sparing
CT of thigh in HIBM2
- Onset
  - Age: 2nd or 3rd decade; Occasionally as late as 6th decade
  - 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
    - Shoulder girdle
      - Scapular winging: Some patients
  - Neck: Flexors or Extensors may be weak
  - Respiratory: 30%; Especially with earlier onset
  - Sparing
    - Quadriceps
      - Spared in most patients
      - Weak in few patients (4%): Disease progression
    - Deltoids
    - Cranial nerves
      - Ptosis: Rare
      - Facial weakness: Occasional patient
  - Progression: Slow
    - Disability within 10 to 20 years of onset
    - Often become wheel chair dependent
    - Weakness may remain distal or involve proximal muscles of arms legs or neck
  - Variants
    - Upper extremity early: Distal arm weakness
    - Proximal leg: Hamstring weakness, No foot drop ³²
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
  - Most, but not all, patients
- Aggregates
  - Constituents: βAPP; Ubiquitin; SMI-31 binding; ApoE; LC3
  - 15 to 18 nm filamentous inclusions in cytoplasm & nucleus
- Abnormal sialylation of muscle proteins
  - Mainly affects O-glycan sialylation
  - 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 present¹¹
- α-Dystroglycan staining: Reduced¹³
- LAMP2: Increased granular staining

Miyoshi Myopathies

Miyoshi 1 (MMD1): Dysferlin; 2p13.2
Miyoshi 2 (MMD2): ? 10p
Miyoshi 3 (MMD3): ANO5; 11p14

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

l Dysferlin

; Chromosome 2p13.2; Recessive

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

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: Increased 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

Miyoshi Myopathy 2 (MMD2) ⁶

l ? Chromosome 10; Recessive

Gowers (Laing; Early adult onset distal myopathy type III; MPD1)^3,4

l Myosin heavy chain 7 (MYH7)

; Chromosome 14q11.2; Dominant or Sporadic

MYH7 mutations
- Types: Missense; Charge reversing
- General location
  - LMM region
  - α-Helicoidal rod domain
  - Exons 32, 34, 35, and 36
- Specific mutations: Arg1500Pro, Glu1508del, Lys1617del, Ala1663Pro, Leu1706Pro, Lys1729del, Leu1793Pro
- Leu1793Pro: May also produce neonatal hypotonia & Cardiomyopathy
- Predicted effect: Disrupts
  - Ability of myosin tail to form normal coiled coil structure
  - Myosin dimerization: Altered structure of thick filament
- Clinical correlations
  - Individual mutations may produce widely varied phenotypes²¹
  - Severe phenotype: L1591P
- Allelic disorders
MYH7 protein
- Present in type I (Slow) muscle fibers
Epidemiology
- Australian, German, Italian & Austrian families
Possible associations
- Locus near oculopharyngeal muscular dystrophy: No PABP2 mutations
- ? Similar to "Childhood onset distal myopathy"
Clinical Features
- Onset
  - Age
    - Common: Childhood or Young adult; 1.5 to 26 years
    - Occasional: Neonatal or 6th decade
    - Interfamilial variation
  - Steppage gait
- Weakness: Intrafamilial variation
  - Legs
    - Ankle dorsiflexion: Often severe with foot drop
    - Hanging big toe
    - Proximal muscles may be involved
  - Neck: Sternocleidomastoids & Neck flexors
  - Hands
    - Finger (esp 5th) & wrist extensors
    - Onset: 3rd to 5th decade; 5 to 10 years after legs
    - Later: Infraspinatus & Supraspinatus
    - Intrinsic hand muscles normal
  - Later in course: Some families
    - Neck flexors; Hip & Shoulder abductors & external rotators
    - Face: Mild
  - Usually symmetric: Asymmetry reported
- Tendon reflexes: Reduced at ankles; Present elsewhere
- Muscle discomfort: Some patients
- Muscle size: Anterior tibial usually atrophic
- Progression
  - Slow
  - Proximal weakness: Legs, Neck flexors, Abdominal muscles
  - Mild disability at later age
- Tremor: Hands, then postural
- ? Peripheral neuropathy with hypomyelination: Some patients
- Cardiomyopathy
  - Dilated or Hypertrophic
Laboratory
- CK: Normal or Mild elevation
- EMG: Myopathic; Some spontaneous activity
- Pathology
  - Myopathic: Varied fiber size; Internal nuclei
  - Type I muscle fibers: Small; Grouped; Predominance in some patients
  - Hyosin 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
Variant: Distal myopathy with Hypertrophic cardiomyopathy¹⁹
- Mutation: Val606Met; Homozygous
- Later onset: 6th decade
- Muscle hypertrophy: Anterior tibial
- Cardiomyopathy: Hypertrophic
Variant: Proximal weakness & Cardiomyopathy
- Mutation: Homozygous Glu1883Lys
- Weakness: Proximal
- Cardiomyopathy: Hypertrophic
- Pathology: Hyaline bodies in skeletal & cardiac muscle fibers

Distal dystrophy with rimmed vacuoles

l Chromosome 19p13.3; Dominant

Epidemiology: 2 Italian families
Onset: Late teens to 50's; Occasional asymptomatic patient in 60's
Weakness
- Early: Distal legs
- Distribution
  - Most involved: Distal legs > Knee extensors + flexors & Intrinsic hand muscles
  - Least involved: Face; EOM; Forearm flexors & Proximal upper extremity muscles
- Progression
  - To proximal weakness & upper extremities
  - Variable in families: Some patients severely disabled, others mildly affected
  - Respiratory failure: Some patients
- Dysphonia & Dysphagia: Early in disease course in some patients
- Tendon reflexes: Absent
- Pes cavus
- Tremor (30%)
Seum CK: Normal, or mildly elevated
EMG: Mixed features
- Myogenic: Proximal muscles
- Neurogenic: Distal muscles
NCV: Normal
Muscle pathology¹⁴
- Necrosis
- Focal phagocytosis of muscle fibers
- Rimmed vacuoles
  - Mainly in hypertrophic muscle fibers
  - Located near fiber surface
  - Lysosomal features
    - Acid phosphatase positive
    - LAMP-1 & LAMP-2 negative
    - LIMP-I on surface of vacuoles & fibers
  - Proteasome: Staining for ubiquitin & proteasome (19S & 20S) complex
  - Sarcolemmal proteins present
  - Contain basophilic granular debris
  - No amyloid or filaments

Hereditary Inclusion Body Myopathy (IBM1; HIBM1) : Dominant

l Desmin

; Chromosome 2q35; 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; Proximal & Distal 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: Chromosome 9p13; Dominant; Proximal & Distal weakness
- Differential diagnosis of rimmed vacuoles

Distal Myopathy with Vocal Cord & Pharyngeal Weakness (MPD2)

l Matrin 3 (MATR3)

; Chromosome 5q31.2; Dominant

Epidemiology: North American & Bulgarian families
Genetics ²²
- Mutation: Ser85Cys
Matrin 3 protein
- Cell location: Nuclear matrix
- Tissue expression: Muscle & Other tissues
- Contains RNA-DNA binding motif
Onset
- Age: 35 to 57 years; Average 46 years
- Weakness: Legs (Anterior & Distal); Occasionally Hands or Voice
Clinical

Congo red stain
MPD2: Large vacuoles
- Weakness
  - Initially asymmetric; May become symmetric
  - Legs
    - Peroneal distribution
    - May also involve inversion
    - Gastrocnemius: Relatively spared
  - Hands
    - Variable weakness in different finger extensors
    - Early in abductor policis brevis
  - Proximal
    - Shoulder weakness: Especially deltoid
    - Asymmetric
- Bulbar dysfunction
  - Voice (65%)
    - Onset usually after limb weakness
    - Initially: Hypophonic & Breathy
    - Later: Wet, gurgling, hoarse with hypernasal resonance
  - Pharyngeal: Dysphagia & Aspiration
Laboratory
- Serum CK: Normal to 8x High
- EMG: Myopathic (especially pharynx & vocal cords) or neuropathic changes
- Nerve conductions: Normal or Mildly slowed
- Muscle pathology
  - Myopathic: Gastrocnemius > Quadriceps
  - Internal nuclei
  - Rimmed vacuoles: Subsarcolemmal; Often elongated
  - MATR3
    - Patient: Variable staining of myonuclei
    - Normal: All nuclei stain strongly

HEREDITARY INCLUSION BODY MYOPATHY (HIBM) + PAGET DISEASE

VCP: 9p13; Dominant
HNRNPA2B1: 7p15; Dominant
HNRNPA1: 12q13; Dominant

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

l Valosin-containing protein (VCP, p97)

; Chromosome 9p13.3; Dominant

Epidemiology
- Worldwide: > 30 families
- Male = Female
Genetics ¹²
- Mutations: Missense; 19 different; Several involve same amino acid residues
- Locations
  - N-terminal: Exons 1 to 6
  - R95G; P137L; R155C; R155H; Arg155Leu; R155P; R155S;
    G157R; R159H; Leu198Trp; R191Q; A232E; A439S
- Clinical genetic correlations
  - A232E: Fractures & Paget disease at earlier age
  - Arg159His: Interfamily variability
    - Some families: No dementia, Milder disease ¹⁶
    - Other families: Patients may present with frontotemporal dementia ²⁴
    - Pathology: All have Ubiquitin+ intranuclear inclusions & Dystrophic TDP-43+ neurites
  - R155C: Frontotemporal dementia with intraneuronal inclusions
- Allelic with
VCP protein
- Locations: Ubiquitous
- Functions
  - Protein degradation pathways (Autophagy): Regulatory role
  - Cell cycle & Membrane fusion
- Binds ubiquitin
- AAA ATPase
- 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
  - Causes increased levels of ubiquitinated cell proteins
  - Sensitization to proteasome stress
  - Impairs degradation of proteins by endoplasmic reticulum-associated degradation (ERAD)
  - Promotes formation of aggregates
    - Contain p97/ VCP, ubiquitin conjugates & ER-resident proteins
    - Impaired protein aggregate clearance
  - Upregulation of autophagy-related proteins
  - Normal: Polymerization into hexamers; ATPase activity
Clinical ²³
- Intrafamilial variability: Prominent
- Onset
  - 3rd & 4th decade
  - Variable: Back pain; Weakness; Dementia
    
    IBM + Paget's: Scapular winging
- Myopathy: Weakness (90%)
  - Presenting symptom in > 50%
  - Marked variability in severity & pattern within families
  - Onset: Mean 43 years; Range 3 to 66 years
  - 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; Tongue
    - Posterior neck: Head ptosis
    - Back: Camptocormia
  - Asymmetric: Often
  - Progression
    - Slow: Over 1 to 2 decades
    - To severe disability: Loss of independent walking
      - Severe weakness
    - Death in 40's to 60's
- Bone disease
  
  IBM + Paget's: Paget's disease of bone
  - 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 54 years; Range 39 to 62 years
    - Usually after Paget's or Myopathy
  - Frontotemporal
    - Language: Anomia; Aphasia; Mutism
    - Personality change: Apathy; Agitation
    - Hallucinations: Visual; Auditory
    - Relatively preserved memory
- Cardiomyopathy: Occasional
  - Heart failure late in disease course
  - Dilated
  - 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
  - Atrophy: Regional
  - Hypertrophy: Scattered muscle fibers
  - Increased Endomysial connective tissue: Patchy
  - Rimmed vacuoles
  - VCP staining inclusions: Sarcoplasmic & Myonuclear
  - 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
Variant syndrome: ALS, Familial (ALS 14 ) ²⁷
- Epidemiology: 1% to 2% of Familial ALS
- Genetics
  - Dominant or Sporadic
  - VCP Mutations: Ile151Val; R155H; R159G; R191Q; D592N
- 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
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
Varant 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

Myopathy with Paget disease of Bone ± Cognitive change or Motor Neuron Disease ^8, ³⁴

l Heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1)

; Chromosome 7p15.2; Dominant

Epidemiology: 1 US family, 5 patients
Mutation: Missense; D290V/D302V; Located in prion-like domain
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

Myopathy with Paget disease of Bone ³⁴

l Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1)

; Chromosome 12q13.13; Dominant

Epidemiology: German family
HNRNPA1 Mutations: Missense; D262V/D314V; Located in prion-like domain
HNRNPA1 protein
- Localization: Nucleus & Cytoplasm
- 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
    - HNRNPA2B1: Myopathy + Pagets ± Motor neuron disease or Cognitive disorders
    - TIA1: Welander distal myopathy
- 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
- Recruited to stress granules
Clinical ³⁵
- Onset
  - Childhood: Clumsy
  - Weakness: 35 to 43 years
- Myopathy (100%)
  - Early: Proximal legs; Iliopsoas
  - Foot dorsiflexors
  - Abdominal wall
  - Arms: Usually spared
  - Scapular winging: Slight
  - Progressive: Wheelchair in 5th or 6th decade
- Paget disease (50%)
- 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
- Epidemiology: 1 Family & 1 Simplex patient
- Inheritance: Dominant
- Mutations
  - Family: Same as myopathy (D262V/D314V)
  - Single ALS patient: N267S/N319S
- Clinical
  - Motor neuron disease: ? ALS-like or Scapuloperoneal SMA
  - Onset age: Adult

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

l Titin (TTN)

; Chromosome 2q31.2; Dominant

Nosology
- Hereditary IBM with Early Respiratory Failure
- Distal myopathy with Early Respiratory Failure
- Myofibrillar myopathy with Early Respiratory Failure
Epidemiology: English & Swedish families
Genetics
- TTN mutation
  - Missense
    - Common: Cys30071Arg (British founder mutation)
    - Other: P30091L; N30145K; R32450W
  - Location: Myosin binding A-band
- See: Allelic disorders
Titin protein
Clinical
- Onset: Variable
  - Age: 18 to 71 years; 5th decade most common
  - Weakness: Symmetric; Foot dorsiflexion; Respiratory, or Proximal
- Weakness: Variable patterns
  - Patterns
    - Distal 30%; Proximal 40%; Other 30%
    - Legs > Arms
  - Legs: Distal & Proximal; Anterior tibial
  - Arms: Wrist flexion & extension; Deltoid; May be diffuse
  - Trunk: Severe weakness common
  - 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
- Calf hypertrophy
- Contractures: None
- Cardiac: Normal
Laboratory
- Serum CK: 98 to 966
- EMG: Myopathic; Irritable
- Nerve conduction studies: Normal
- MRI of muscles
  - Proximal legs
    - Selective early involvement of semitendinosus & obturator externus
    - Proximal more than distal involvement in individual muscles
    - Adductor longus spared
  - Distal legs: Most involvement of tibialis anterior; Relative sparing of gastrocnemius & soleus
  - Shoulder girdle: Moderate involvement of supraspinatus, infraspinatus, serratus anterior, subscapularis & trapezius
Muscle pathology
- Fiber size: Varied
- Myofibrillar pathology
- Eosinophilic inclusions: Congophilic; Variably contain β amyloid, desmin, SMI-31 binding
- Cytoplasmic bodies: Stain for F-actin (Phalloidin); Some patients
- Muscle fiber splitting: With more severe weakness
- Vacuoles: Rimmed, blue; With more severe weakness
- Fiber types: Type 1 predominance (50%)
- Internal nuclei
- No necrosis or inflammation
- No cytoplasmic bodies
- Calpain-3: Reduced on Western blot
- Ultrastructure: Z-line streaming

Myopathy with ringed muscle fibers¹

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: MPD3 ⁹

l Autosomal Dominant

Genetics: Two possible loci 8p22-q11 & 12q13-q22
Epidemiology: Single Finnish family
Onset
- Age: 32 to 45 years
- Clumsiness of hands or 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
- Asymmetric
- Intrafamilial variability
- Course: Progressive
  - Over years
  - To more proximal limbs: Forearm, Triceps, Infraspinatus, Proximal legs
  - Patients remain ambulatory
Laboratory
- EMG: Myopathic
- Serum CK: Normal or Slightly elevated
Muscle biopsy
- Myopathy: Severe; Endomysial fibrosis; Fiber size variation
- Rimmed vacuoles
- Cytoplasmic inclusion bodies

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

l Filamin C (Filamin 2; FLNC)

; Chromosome 7q32.1; Dominant

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
Onset
- Age: 0 to 30 years
- Weakness
- Muscle discomfort
Clinical
- Variable within family: Some affected members are asymptomatic
- 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 mutation
  - c.5160delC frameshift deletion: Produces stop codon
  - 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

Distal nebulin myopathy ²⁰

l Nebulin

; Chromosome 2q23.3; Recessive

Genetics
- Mutations: Missense; Often homozygous
- Different from Rod myopathy in which at least 1 mutation causes protein termination
- Allelic with: Rod myopathy
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

Cystinosis, Nephropathic

l Cystinosin (CTNS)

; Chromosome 17p13.2; Recessive

Genetics: Mutations
- General: Missense & Stop
- French-Canadians: 57-kb deletion
CTNS protein
- Lysosomal membrane
Clinical
- Onset
  - Age: 1st year to Adult
  - Failure to thrive: 1st year
- Skeletal: Short stature; Frontal bossing; Hypophosphatemic rickets
- Eyes: Retinopathy; Corneal cysteine crystals
- GI: Hepatomegaly; Pancreatic insufficiency; Splenomegaly
- Renal: Fanconi syndrome; Renal failure
- Endocrine:
  - Hypothyroidism, Primary
  - Diabetes mellitus: Insulin dependent
  - Delayed puberty
- Skin
  - Hypohidrosis
  - Light hair pigmentation
- Muscle
  - Distal weakness & Wasting
  - Dysphagia
- CNS: Cerebral atrophy; Visuo-spatial processing defect
- Treatment
  - Replacement of renal losses
  - Cystine-depleting agents
Laboratory
- Diagnosis: Leukocyte cystine measurement
- Urine: Proteinuria; Glucosuria; Microscopic hematuria
- Blood: Hyponatremia; Hypokalemia; Hypophosphatemia
- Carnitine deficiency
- Aminoaciduria, Generalized
- White blood cell cystine: Elevated
Muscle
- Muscle fiber size: Varied
- Vacuoles: Rimmed; Mildly acid phosphatase positive

Distal weakness, Early onset ²⁵

l Kelch-like homologue 9 (KLHL9)

; Chromosome 9p22; Dominant

Nosology: May be distal myopathy or predominantly motor neuropathy
Epidemiology: German family
Genetics
- Mutation: Missense; L95F
KLHL9 protein
- Complexes with Culllin 3
- Ubiquitin-dependent protein degradation pathway
Clinical
- Onset age: 8 to 16 years
- Weakness
  - Hands: Intrinsic muscles
  - Legs: Distal
  - Proximal: Normal
- Atrophy: Anterior tibial
- Contractures: Ankles
- Sensory loss
  - Distal
  - Arms & Legs
  - Later in disease course
- Course
  - Very slow progression
  - Remain ambulant
Laboratory
- Serum CK: 110 to 1400; Usual 150 to 260
- NCV
  - Motor: Velocities normal; Distal latency occasionally long
  - Sensory: Normal
- EMG: Distal fibrillations & Polyphasic large potentials
- Muscle biopsy: Varied fiber size
- MRI: Atrophy of distal leg muscles

Distal Weakness, Hoarseness, Hearing loss (PNMHH) ²⁸

l Myosin heavy chain 14, non-muscle (MYH14)

; Chromosome 19q13.33; Dominant

Epidemiology: Korean family
Genetics
- Mutation: Missense; Arg941Leu; In tail domain
- Allelic with: Deafness, autosomal dominant 4 (DFNA4)
- Contains microRNA, miR-499
MYH14 protein
- Non-muscle myosin
- Locations: Heart, Slow muscles, Extraocular (EO) muscles
Clinical
- Onset age: 5 to 13 years
- Weakness
  - Distal: Occasionally also proximal
  - Legs > Arms
  - Slow progression over decades
- Hoarseness (50%)
- Sensory loss: None
- Tendon reflexes: Variable
- Foot deformity (50%)
- Hearing loss (30%)
- Cardiac: Normal
Laboratory
- Serum CK: Normal to mildly high (< 2.5-fold high)
- EMG: Fibrillations, distal
- NCV: Normal velocities; CMAP amplitudes small
- Muscle biopsy
  - Fiber type grouping
  - Grouped atrophy
  - Ultrastructure: Abnormal mitochondria; Paracrystalline inclusions

Intellectual Disability ³¹

l NOL1/NOP2/SUN domain family, member 2 (NSUN2)

; Chromosome 5p15.31; Recessive

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

Syndromes with Neuropathy & Myopathy

Paraneoplastic (with weight loss > 15%)
- Neuropathy: Distal; Sensory > Motor
- Myopathy: Proximal with type II muscle fiber atrophy
Inclusion Body Myositis
Systemic disorders
- Uremia
- Acromegaly
- Collagen vascular disorders
- Sarcoid
- HIV Infection
  - Myopathy: Inflammatory;
  - Several types of neuropathy
Hereditary
- Debrancher deficiency
- Lamin A/C mutations
- Congenital muscular dystrophy: Merosin deficiency
- Marinesco-Sjögren
- Mitochondrial: MNGIE Syndrome
- Tyrosinemia
Drugs & Toxins
- Amiodarone
- Chloroquine
- Chlorphenoxy
- Clofibrate: Risk factor - renal failure
- Colchicine: Risk factor - renal failure
- Doxorubicin
- Eosinophilia-myalgia syndrome
- Ethanol: Risk factor - fasting
- Hydroxychloroquine
- Organophosphates
- Perhexiline
- Vincristine

Return to Myopathy & NMJ Index
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3/5/2013

DISTAL WEAKNESS IN MYOPATHIES

Distal Myopathies: Hereditary 7

Welander (Late onset type I) distal myopathy

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

Markesbery (Late adult onset type IIb) distal myopathy

Hereditary Inclusion Body Myopathy (IBM2; Nonaka) : Recessive

Miyoshi Myopathies

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

Miyoshi Myopathy 2 (MMD2) 6

Gowers (Laing; Early adult onset distal myopathy type III; MPD1)3,4

Distal dystrophy with rimmed vacuoles

Hereditary Inclusion Body Myopathy (IBM1; HIBM1) : Dominant

Distal Myopathy with Vocal Cord & Pharyngeal Weakness (MPD2)

HEREDITARY INCLUSION BODY MYOPATHY (HIBM) + PAGET DISEASE

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

Myopathy with Paget disease of Bone ± Cognitive change or Motor Neuron Disease 8, 34

Myopathy with Paget disease of Bone 34

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

Myopathy with ringed muscle fibers1

Distal Myopathy: MPD3 9

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

Distal nebulin myopathy 20