Myopathies without EOM Weakness: Facioscapulohumeral + Myotonic Dystrophy

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MYOPATHIES & NEURONOPATHIES
WITH NO EOM WEAKNESS ± FACE & PERIOCULAR INVOLVEMENT

Myotonic Dystrophy
Facioscapulohumeral dystrophy
Scapuloperoneal syndromes
Other myopathies

FSH dystrophy: Asymmetric triangular shoulders

MYOTONIC DYSTROPHY

Genetic loci
Differential diagnosis: DM1 vs DM2

Myotonic dystrophy 1 (DM 1)
Clinical features
Disease mechanisms
Epidemiology
Genetic testing
Laboratory features
Myotonin protein kinase (DMPK)
Gene
Protein
Pathology

DM 2 (PROMM)
Pathology

Also see: Review U Wash

1st picture of myotonic dystrophy
Weakness of face & sternomastoids

Myotonic Dystrophy: General

2 Genetic loci
- DM 1 : 98% of families
  l Myotonin protein kinase (DMPK) ; Chromosome 19q13.3; Dominant
- DM 2 (PROMM)
  l Zinc finger protein 9 (ZNF9) ; Chromosome 3q21; Dominant

Myotonic Dystrophy 1 (DM1)

Clinical features
Comparison to DM2
Congenital
General
Onset
Myotonia
Neural
Prognosis
Systemic
Weakness
Disease mechanisms
Epidemiology
Genetic testing
Laboratory features
Myotonin protein kinase (DMPK)
Genetic & Molecular
CTG repeats
Disease mechanisms
Generation effects: Anticipation
Protein

Also see: U Wash Review

DM1 Gene Locus

From: Neil Miller, Johns Hopkins
Christmas Tree Cataracts

DM 1: DMPK Genetic & molecular features

CTG repeats
Disease mechanisms
Generation effects: Anticipation

CTG repeats: Different numbers of copies
- Location of CTG repeat sequence in DMPK gene
  - Terminal (15th) exon of DMPK gene
  - Downstream from translation termination codon: In 3' untranslated region
- Normal ranges of CTG repeat numbers
  - Overall pattern
    - 3 to 37 CTG repeat copies (CTG_4-37)
    - Trimodal distribution
    - Alu repeat insertions (polymorphism) in CTG repeats: Associated with CTG repeat size
      - Alu repeat insertions present (Alu+): CTG₅, CTG_16-30 & expanded CTG alleles
      - Alu repeat insertions absent (Alu-): CTG_11-13
  - Low-normal number: 5 CTG repeats
    - Most common single allele in many regions
      - African Biaka & Bantu speaking; Middle East; Europe; Southeast Asia
    - Low frequency (1% - 8%) regions
      - Amerindians (Siberian Yakut; Cheyenne; Jemez Pueblo; Maya)
    - Absent in: New Guinea Highlanders; Brazil (Rondonia Surui, Ticuna, Karitiana)
  - Midsize-normal number: 9 - 17 CTG repeats
    - Most frequent (46% to 100%) range in all populations
    - Most common sizes: 11-13 repeats (15% of alleles each)
  - High-normal number: 18 to 35 repeats
    - Present mainly in Ethiopian Jews & non-Africans
    - High frequency (9% to 18%) regions
      - Ethiopian + Yemenite Jews; Japan; Danes; Yakut;
        New Guinea Highlanders; Nasioi Melanesia
    - Largest sizes (32 & 35 repeats): Ethiopian + Yemenite Jews
    - Alleles with > 19 (CTG) repeats
      - Have significant instability
      - Possible predisposing alleles for DM1 disease mutations
- Intermediate range of CTG repeat numbers: 36 to 50
  - "Premutation" alleles
  - May expand into disease range (> 50 repeats)
- Disease range of CTG repeat numbers: 50 to 4,000
  - "Protomutation" range: 50–80 repeats
    - Very mild disease: May be cataracts only
    - Transmission is mostly stable
  - Mildly affected or unaffected: 50 to 150 repeats
  - Classic disease range: 100 to 1,000 repeats
  - Severely affected range: Often congenital presentation
    - Up to 4,000 repeats
    - Hypermethylation of DMPK gene proximal to the expanded CTG repeat
  - Homozygous vs. heterozygous genotype: No clinical difference
  - Somatic (mitotic) variation in repeat size
    - More likely with repeat size > 55
    - High Initial CTG repeat size leads to
      - Progression of CTG repeat size heterogeneity over time
    - No relation to tissue proliferation capacity
  - Ancestral mutation(s)
    - Single mutation responsible for disease in patients from different ethnic origins
    - Total linkage disequilibrium DMPK mutation & nearby polymorphisms
    - Mutation arose on a predisposing haplotype(s)
    - Mid-size (CTG) repeat allele was most ancient chromosome
  - Congenital DM1
    - Aberrant methylation of Dinucleotide CpGs in region of the CTG repeat at DM1 locus
    - Increased levels of DMPK transcripts: Adult form has decreased transcripts
    - Mutation transmitted only from mother: ? Maternal imprinting
- Other disease expansions in transcribed but untranslated DNA
  - DM2/PROMM (CCTG)
  - SCA8 (CTG)
  - SCA10 (ATTCT)

Genetic disease mechanisms in DM1

All mutations in 19q-linked DM1 have expanded CTG repeat
? Multigene syndrome + toxicity of transcribed CUG RNA repeat

3 postulated disease mechanisms

Myotonic dystrophy: Molecules & Signs
Molecule change	Related features	Disease Mechanism
DMPK reduction	Muscle weakness Cardiac conduction Δ Na⁺ channel defects	Reduced Protein from mutated gene
SIX5 reduction	Cataracts	Reduced Protein from neighboring gene
RNA with longer CUG repeats	Myotonia Diabetes Cl^- channel defects	Long CUG repeat RNA Retained in nucleus Disrupts splicing of ClC-1 pre-mRNA

DMPK (Myotonin) gene effects
- DMPK gene: Hypermethylated in congenital DM1
- DMPK protein tissue specificity
  - Heart & Skeletal muscle: Epecially 80 kDa form of DMPK
- Reduced DMPK protein levels in mice produce
  - Muscle weakness: Excitation-contraction coupling disorder
  - Cardiac conduction disorder
  - Na⁺ channel abnormalities
    - Channel number reduction lowers Na⁺ current amplitude
    - Channel gating changes: More Na⁺ channel reopenings cause inactivation
    - Repetitive activation of muscle fibers
    - Channel lesions more prominent with increasisng age after single stimulus
- Myotonic dystrophy phenotype in other tissues
  - ? Not related to abnormal DMPK protein production
CTG repeats modify production or function of other proteins coded for by neighboring genes
- Mechanisms: Enlarged CTG repeat effects on neighboring genes
  - Chromatin condensation & Hypermethylation
  - ? Chromatin disruption or Excessively stable nucleosomal region
    - Produces dysfunction of several transcription units
    - Adjacent gene expression changed: Inhibition, or Alternate splicing
- Neighboring genes of DMPK with reduced expression in DM
  - DM locus-associated homeodomain protein (DMAHP)(SIX5)
    - Myotonic dystrophy CTG repeat near, & 5' of, enhancer element for SIX5
    - SIX5 sequence homology
      - Homeodomain-encoding genes
      - To gene involved in development of muscle in lower legs (mouse)
    - ? SIX5 may regulate transcription from Na⁺/K⁺-ATPase α-1 subunit (ATP1A1) promoter
    - Activator that directs Igfbp5 expression
    - SIX5 disease: Branchio-Oto-Renal Syndrome
    - SIX5 deficiency in mice
      - Produces ocular cataracts
      - ? Increased ATP1A1 activity
      - Heterozygosity: Cardiac conduction abnormalities
      - Normal skeletal muscle
  - DMWD
    - Contains WD repeat
    - WD repeat is found in some proteins that regulate development
    - DMWD mRNA levels in DM1 skeletal muscle are normal
Elongated CTG repeat DNA produces RNA with excessive numbers of CUG repeats: Dominant negative effect
- Mutant, elongated (CUG)_n DMPK transcripts accumulate
  - Develop stable secondary structure in vitro
    - C-G & G-C base pairs separated by U-U mismatch
  - Accumulate in nuclei
- Proteins or DNA bind to (CUG)_n repeat RNA
  - RNA binding proteins: General
    - Regulate alternative splicing of specific pre-mRNAs by binding to U/G–rich motifs
  - Candidate proteins binding to (CUG)_n repeat RNA
    - (CUG)_n triplet repeat expansion (EXP) ds-RNA binding (Muscleblind) proteins⁴
      - Muscleblind-like protein (MBNL)
      - MBLL
      - MBXL
  - Features of protein binding to repeat RNA
    - Proteins bind to expanded CUG hairpins
    - Binding is stronger than to CAG repeats or non expanded CUG repeats
    - May produce: Sequestration or dysfunction of muscleblind proteins
      - Muscleblind proteins localized with expanded CUG repeats in nuclear foci
      - Muscleblind proteins reduced in other regions of nucleoplasm
      - Changes associated with abnormal regulation of alternative splicing of pre-mRNAs
      - Aggregates present in neuronal nuclei: May be associated with CNS signs in DM1
  - Cell localization of muscleblind proteins in myotonic dystrophies
    - Along with expanded CUG or CCUG repeat RNA
    - Location: Nuclei of DM1 & DM2 cells
- Functional effects of long CUG repeat RNA: Varies in different tissues & with repeat length
  - Aberrantly spliced RNA action in muscle: Produces altered CLC1 (chloride) channel proteins
    - Abnormal channel proteins have no Cl^- conductance
    - Interfere with function of normally spliced Cl^- channels
    - Altered splicing variants: Two common types
      1. Inclusion of novel exons 6b and 7a: Causes a frameshift & premature truncation at codon 283
      2. Skips exon 6 & includes exons 6b and 7a: Results in premature truncation at codon 257
    - Reduced overall Cl^- channel function: Produces myotonia
    - Abnormal splicing effect is expressed as mosaic
      - Some muscle fibers with more reduction of Cl^- channel than others
  - Aberrantly spliced RNA action in brain: Produces altered splicing of several proteins
    - NMDA receptor 1 (NMDAR1): 3-fold increase in fraction of mRNA that includes exon 5
      - Altered pharmacology, gating & cellular distribution (somatic rather than somato-dendritic expression)
    - Microtubule-associated protein tau (MAPT): Increased fetal isoforms (Absent exon 10)
    - APP protein: Fetal splice isoforms (Exon 7 exclusion products)
  - Longer CUG repeat RNA
    - Produces more abnormal splicing of Cl^- channel
    - More myotonia
  - DM2 (PROMM): Similar pathological splicing effect of elongated CCUG repeat sequence
- Mouse models: Insertion of long CTG repeat in muscle²
  - Expresses long untranslated (CUG)_n RNA repeat
  - Effects of long CUG repeat RNA: Abnormal splicing of other muscle RNA
    - CLC1 (chloride) channel
      - Altered splicing adds exon 7a to RNA
      - Aberrantly spliced RNA produces altered Cl^- channel protein with reduced function
      - Reduced Cl^- channel function produces myotonia
    - Insulin receptor
      - Altered splicing reduces number of insulin receptors
      - Associated with diabetes
  - Clinical: Myotonia beginning at 4 weeks of age; No clear weakness
  - Electrophysiology: Myotonia
  - Microphysiology: Markedly reduced Cl^- channel conductance
  - Pathology: Myopathy
    - Central nuclei
    - Varied fiber size, ring fibers
    - High SDH & COX activities
    - No muscle wasting or weakness
- Brain CTG repeat expansion: Autosomal dominant cerebellar degeneration (SCA8)

Generation effects on mutations & disease: Increased Severity with progressive generations
- CTG repeat # in normal range: Population genetics
  - Mutations in small CTG repeats probably occur in small increments or decrements
  - (CTG)₅ allele probably arose from mutation of (CTG)_9-17 allele on Alu+ chromosome
- Possible origin of large CTG repeat #: Many DM mutations descend from a few founder chromosomes
  - Mutation from: (CTG)_18-35 on a Alu+ chromosome
  - Alu+ chromosome
    - May predispose (CTG)_18-35 expansion (mutation) to pathological range
  - Founder mutation populations
    - Ancestral to non-Africans in Africa: Prior to population divergence
    - Occasional other families
  - Mutation to (CTG)_50-80 allele with higher frequency than shorter CTG repeat #'s
- Features of CTG size variability
  - Repeats & disease severity often increase in successive generations
    - 50 to 80 repeats often show intergenerational stability in number
    - Repeats with > 80 elements especially prone to large amplifications
    - Repeat contractions are reported
  - CTG expansions < 100 more unstable in sperm than egg
    - Change from minimal to classical DM1 usually transmitted through male germline
  - Intergenerational variation
    - Increases in expansion sizes occur during gametogenesis but not during meiosis
    - Repeats increase most with maternal transmission
      - Increases in number of repeats: In embryos from DM1 females & in their immature and mature oocytes
      - Bias against very large expansions in sperm
      - Maternal transmission mostly responsible for congenital myotonic dystrophy
  - Somatic variation in CTG repeat length also occurs
    - More likely with repeat size > 55
    - High Initial CTG repeat size leads to
      - Progression of CTG repeat size heterogeneity over time
    - Repeat sizes may increase ~50–80 repeats per year
    - Tissue variability: Repeat expansion sizes
      - Smallest in blood
      - Largest in heart, muscle, and kidney
    - Marked somatic mosaicism
      - Becomes apparent from the 2nd trimester of development onward
      - Increases during adult life
    - Repeat lengths in muscle are very large
      - 2x to 13x greater in muscle than in peripheral blood cells
      - No correlation between size of repeats in muscle and degree of weakness
    - Somatic instability probably more related to DNA repair mechanisms than to mitosis
      - 1st & 2nd trimester fetuses have homogeneous distribution of repeat lengths in different tissues
      - Enlargement of expanded repeats can occur throughout life: Even in post mitotic cells
  - Instability of expanded CTG repeats varies among species
    - Transgenic CTG repeat sequences in mice are relatively stable

DM1: Myotonin protein kinase (DMPK) protein
- 68 to 80 kDa protein
  - 6 Splice variants
  - Splice variant sub-types localized in different tissues
- Action
  - Sub-family: Rho-kinases
  - Serine/Threonine protein kinase
  - Possible cell functions
    - Cell shape determination
    - Regulation of actin-myosin contractility
    - Modulation of activity of voltage-gated ion channels
  - Loss of DMPK
    - Abnormalities of Ca⁺⁺ homeostasis
    - Altered excitation-contraction coupling
    - Homozygous knockout mice: Cardiac conduction defects
- Structure: PK catalytic domain - Coiled coil domain - Hydrophobic domain
- Cell localization
  - Near sites of dense channel clustering
  - Major proportion is cytosolic
  - Muscle DMPK: NMJ; Terminal cisternae of sarcoplasmic reticulum; I-band
  - Heart: Intercalated discs (focal adhesions)
- Tissue localization
  - Present in all tissues
  - Heart & Skeletal muscle: 80 kDa form especially prominent; Highest levels
  - Non-muscle tissues: 72 kDa form predominates
- DMPK in Myotonic dystrophy
  - Nuclear retention of DMPK transcripts with expanded CUG repeats
  - Reduced DMPK poly(A)⁺ mRNA in DM fibroblasts & muscle biopsies
  - DMPK protein levels in muscle
    - Adult myotonic dystrophy: Mild decrease or increase
    - Congenital myotonic dystrophy: Minor reduction
    - Myotonic dystrophy myoblasts: Normal
DM1: Epidemiology
- Most prevalent inherited neuromuscular disease in adults
- Prevalence in West: 13.5 per 100,000 live births
- Disease distribution: ? Associated with founder mutation arising after migration out of Africa
  - Especially common in Saguenay region of Quebec, Canada: 1:500
  - Western Europe: 4/100,000
  - Japan: 5/100,000
  - Southeast Asia: Less common
  - South & Central (sub-Saharan) Africans: Rare or absent
- Male: Female = 1:1
- Variable penetrance
- Earlier onset & more severe disease with longer CTG repeats
- Original description by: Steinert; Batten & Gibb
DM1: Clinical features

Congenital
General
Onset
Myotonia
Neural
Prognosis
Systemic
Weakness
- General
  - Marked variation in severity within families
  - Anticipation
    - Mean symptom onset 29 years earlier in child compared to parent
    - Due to tendency of GTG repeat to enlarge when transmited from 1 generation to next
  - Strong relationship of clinical syndromes to age of patient and age of onset
- Onset: Neonatal to late adulthood
  - Childhood
    - Mental retardation
    - Motor delay
  - Adult: Especially 2nd to 4th decade
    - Weakness: Finger flexors; Neck flexors; Face
    - Myotonia: Grip
  - Older adult (Minimal DM1; Onset may be > 60 years): Cataracts
  - Age of onset: Correlates with length of repeat when CTG # is les than ~ 400
    
    Myotonic dystrophy
    Distal leg wasting
- Weakness
  - Cranial
    - Face: Superficial muscles; Eye & mouth closure; Temporalis
    - Ptosis (Symmetric; Partial): Levator palpebrae superioris
    - Masseter
    - Palate ± Tongue: Indistinct speech
    - No ophthalmoplegia
  - Neck: Flexors & Sternomastoids
  - Proximal
    - Quadriceps; Diaphragm & Intercostals
    - Affected later in disease
  - Distal
    - Wrist & Finger extensors
    - Grip
    - Ankle > Toe dorsiflexors
  - Muscles frequently spared: Pelvic girdle; Hamstrings; Soleus & gastrocnemius
  - Late in disease course: Diffuse weakness
  - Wasting: Common; Early in volar forearm
- Myotonia
  - Evoked by percussion or muscle contraction
  - Onset: 5 to 25 years; Not congenital
  - Severity
    - Rarely causes disability
    - Milder than myotonia congenita
    - Correlates with leukocyte CTG repeat length¹⁵
  - Treatment: Little functional benefit
- Muscle pain: Occasional patient
- Neural
  - CNS
    - Personality: Avoidant; Apathy
    - Hypersomnia
      - Excessive daytime sleepiness
      - ? Related to loss of serotonin (5-HT) neurons
        
        Dorsal raphe & Superior central nucleus of brainstem
      - Treatment
        
        ? Modafinil 200 to 400 mg/day⁵
        
        Avoid arrhythmogenic drugs
    - Mental retardation (10% to 24%): Congenital; Non-progressive
    - MRI: Subcortical white matter changes
  - PNS: Mild sensory neuropathy (Rarely functionally significant)
- Systemic
  - Face
    - Frontal balding
    - Temporal wasting
    - Ptosis
    - Hatchet face
  - Eyes
    - Cataracts
      - Features: Posterior subcapsular; Multiple; Punctate
      - Detection: Slit lamp needed
    - Ptosis
    - Retinal degeneration
    - Ciliary body weakness (Low intraocular tension)
  - Endocrine
    - Hypogonadism
      - Testicular atrophy
      - 1° Tubular degeneration
      - Testosterone: Reduced
      - Oligospermia
    - Pituitary
      - Follicle Stimulating Hormone (FSH) may be increased
      - Growth hormone: Reduced release
    - Insulin resistance
    - Pregnancy: Frequent fetal loss & major complications
    - Insulin-like growth factor-1 (IGF-1): Reduced
  - Respiratory
    - Reduced response to hypoxia; Hypercapnia
    - Hypoventilation: Pickwickian syndrome
    - Aspiration pneumonia: 2° esophageal dysfunction
  - Cardiac: Screen with yearly EKG
    - Conduction defects: Ectopic beats; Sudden death
    - Tachyarrhythmias
    - ± Cardiomyopathy: Especially late in course
    - Increased with increased age & greater # CTG repeats
    - Occasional involvement in patients < 18 years
      - Childhood or Congenital DM1: Ventricular arrhythmias
      - Initial event in previously asymptomatic DM1 teenagers: Cardia arrest; Atrial arrhythmias
  - Gastrointestinal
    - Dysphagia (Pharyngeal or Esophageal)
    - Hypokinesis: Megacolon; Constipation;Pseudo-obstruction
    - Cholelithiasis
  - Skeletal
    - Small sella turcica
    - Frontal bossing
    - High arched palate
    - Air sinus size: Increased
  - Smooth muscle: Esophagus; Colon (Constipation); Anal Sphincter; Uterus; Gall bladder
  - Skin: Calcifying epithelioma
  - Neoplasms: Multiple pilomatricomas
- Medications to avoid
  - Amitriptyline, Digoxin, Procainamide, Propranolol, Quinine, Sedatives
- Prognosis with adult onset
  - Reduced survival to age 65: Mean age at death 60 years
  - Minor correlation between CTG repeat length & younger age at death
  - 50% of patients wheelchair bound shortly before death
  - Causes of death
    - Pneumonia & Respiratory insufficiency (> 30%)
    - Cardiac arrhythmia (sudden death) (30%): Heart block; Ventricular tacharrhythmia
DM1: Congenital onset & Mental retardation

from A Kornberg
Congenital myotonic dystrophy
- CTG repeats
  - 730 to 4,300 repeats
  - Hypermethylation of mutated allele
- Occurrence
  - Frequency
    - 10% to 15% of DM1
    - 25% of offspring of myotonic mothers
    - Very rarely from fathers
  - Obstetric problems
    - Inversely correlated with age at onset of maternal DM
  - No effects on gestational outcome
    - Age at delivery
    - Birth order
- Onset: Prenatal
- Pregnancy
  - Polyhydramnios
  - Decreased fetal movements
  - Breech presentation
  - Prematurity: Pre-term labor
- Clinical
  - Motor
    - Hypotonia
    - Failure to thrive: Due to an inability to suck
      - Caused by: Bilateral facial & jaw muscle weakness
      - Facial appearance: Mouth open; Tented upper lip; High-arched palate
    - Neonatal respiratory distress (50%)
      - Patient may eventually be weaned from respirator
    - Delayed motor milestones
      - Parallels degree of hypotonia
      - Delayed speech
      - Slow improvement
      - Most patients eventually walk independently
  - Muscle: No myotonia
  - Tendon reflexes: Absent
  - CNS: Mental retardation
    - IQ levels: 40 to 80 in 50%–90% of patients
    - No progression
    - Behavioral abnormalities: Hyperactivity attention deficit; Autistic behavior
    - Most able to care for themselves
    - Neuroimaging: Ventricular dilatation from birth (50%)
  - Skeletal
    - Craniofacial: Tapered chin, High-arched palate, Prominent brow
    - Arthrogryposis
- Laboratory
  - EMG: No myotonia
  - CK: Usually normal
  - Muscle biopsy: Normal or non-specific
  - MRI
    - Enlarged ventricles
    - Some with hypoplasia of corpus callosum & Cerebral white matter change
    - Cerebral atrophy: Global
- Diagnostic (prenatal) tests
  - Amniocytes & villi may not accurately represent CTG repeats in fetal blood
  - Evaluate mother & pregnancy
  - Measure CTG triplet repeat in mother & fetus
  - High risk: 300 repeats in villi; 600 repeats in mother; Polyhydramnnios

DM1: Differential diagnosis vs DM2 (PROMM)

DM 1 vs DM 2 (PROMM) Comparative features
Feature	DM 1	DM 2
GENERAL
Epidemiology	Widespread	European
Onset Age	0 to Adult	8 to 60 years
Anticipation	+	Mild
Cogenital form	+	-
MUSCLE
Weakness Face Ptosis Sternomastoid Proximal legs Distal Any location	+ + + Late + +	Mild Mild Variable Early Hands +
Muscle pain	±	+
Myotonia	+	+
Calf hypertrophy	-	+
SYSTEMIC
Cataracts	+	+
Balding	+	+
Cardiac arrhythmias	+	Variable
Gonadal failure	+	20%
Hypersomnia	+	Variable
Hyperhidrosis	Variable	+
Cognitive disorder	Mild to Severe	Mild
LABORATORY
Hyperglycemia	+	20%
EMG: Myotonia	+	+
Chromosome	19q13.3	3q21
Mutated gene	DMPK	ZNF9
Mutation type	CTG repeats	CCTG repeats
Repeat size	100 to 4,000	Mean ~5,000

DM 1: Laboratory features
- Serum CK: Normal to 3x
- Endocrine
  - Testosterone: Low
  - FSH: High
  - Insulin insensitivity
- Serum IgG: Low
- MRI: Muscles prominently & consistently involved¹⁹
  - Medial heads of gastrocnemius
  - Soleus
  - Vastus medialis
- EMG
  - Myotonia
    - Onset
      - After 1st decade
      - Not present early in congenital Myotonic dystrophy
    - Distribution
      - Face
      - Distal > Proximal
    - Duration
      - Myotonic runs longer on average than myotonia congenita
      - Many > 2 sec & longest 30 sec
    - Pattern: Waxing & Waning
    - Severity
      - Correlates with degree of weakness
      - More with waxing & waning
  - Myopathic potentials: Distal > Proximal
- Genetic testing: Indications¹
  - Diagnosis in symptomatic patient: Confirm typical, or uncertain atypical, syndrome
  - Asymptomatic patient: Determine progenitor for genetic counseling & a priori risks of inheriting
  - Minors: Should generally not be tested unless symptomatic & diagnosis necessary
  - Prenatal testing: Assess fetal risk in diagnosed parent
  - Confidentiality & DNA property rights should be addressed in informed consent
- Muscle biopsy
  - Myopathic changes
    - Varied fiber size
    - Endomysial connective tissue: Mildly increased; Late
    - Occasional myopathic changes
      - Type I fiber smallness: Especially in deltoid or biceps; Early in disease process
      - Type I fiber predominance: Severely affected muscles
      - Ring fibers
      - Sarcoplasmic masses
  - Myonuclei
    - Internal nuclei: Numerous; Varied depths within muscle fiber
    - Increased number
    - Pyknotic nuclear clumps
    - Intranuclear RNA inclusions: Foci of CUG repeats
  - Muscle spindles: Intrafusil muscle fibers
    - Increased number
    - Reduced size
    - Abnormal fiber tyes: More type 1
  - Ultrastructure
    - Myonuclei: Irregular contours
    - Sarcoplasmic reticulum: Dilated terminal cisternae
    - Sarcoplasmic masses
  - Congenital DM1
    - Small muscle fibers
    - Occasional internal nuclei
    - Poor fiber type differentiation
    - Ultrastructure: Disordered myofibrils; Clustered tubules with electron dense cores

Myotonic Dystrophy, Type 3 (DM3)¹⁶
l Identified as IBMPFD

FACIOSCAPULOHUMERAL (FSH) DYSTROPHY

FSH 1A
Clinical features
Clinical correlations
Epidemiology
Genetics
Laboratory

FSH variants
Infantile FSH 1A
non 4q35 FSH
FSH 1B
Mitochondrial
Scapuloperoneal
VCP

External link
U Wash

FSH Dystrophy

NLM

Louis Théophile Joseph Landouzy

NLM

Joseph Jules Dejerine

FACIOSCAPULOHUMERAL (FSH) DYSTROPHY 1A (FSHMD 1A)

l Double homeobox protein 4 (DUX4)

(D4Z4 repeat DNA deletion); Chromosome 4q35; Dominant

Nosology
- Landouzy-Dejerine Syndrome: External link
FSH: Epidemiology
- Frequency
  - Prevalence: 1 to 5 per 100,000
  - 3rd most common dystrophy after Duchenne & Myotonic
  - Large family in Utah⁷
- Males more often symptomatic compared to Females
  - More females with gene defect are asymptomatic
  - Penetrance by age 30: 95% for Males; 69% for Females
  - Males have: Earlier onset; More common foot extensor weakness
- Onset
  - Symptomatic: 1st to 5th decade
  - Penetrance
    - Exam: 90% to 95% of patients with weakness by age 20
    - Symptoms: 1/3 of patients asymptomatic
  - Infantile onset
    - Frequency: 2% to 5% of FSH
    - Associated with severe general & facial weakness
    - Other systems often involved: Hearing loss; Visual loss (Coat's); ? Epilepsy
Genetics: FSH dystrophy and 4q35 DNA

Disease mechanisms
General principles
Genetic locus: Normal
Mutations
FSH
New
No disease
Size

Charcot
- FSH: General principles
  - FSH is caused by reduction in size of a DNA fragment at telomere of chromosome 4q (4q35)
  - The reduced fragment size is due to a deletion in units of a DNA repeat sequence (D4Z4)
  - D4Z4 repeats contain gene for: Double homeobox protein 4 (DUX4)
- FSH locus at Chromosome 4q35 telomere: DNA in Normals
  - Tandem repeat KpnI DNA (D4Z4) units
    
    FSH LOCUS AT CHROMOSOME 4q35
    Normal number of D4Z4 (KpnI) DNA repeats
    - Size of repeats: 3.3 kb
    - Number of repeats: 10 to 100
    - Location: Subtelomeric region of chromosome 4
    - KpnI Tandem repeat units at 4q35 contain
      - 2 homeobox sequences
      - 2 different GC-rich repetitive sequences
      - Open reading frame (DUX4)
      - Localization to Heterochromatin
        
        Highly condensed DNA
        
        Associated with: Highly methylated, hypoacetlyated histone H4
        
        Little transcription
    - Other features of repeated DNA at 4q35 in normals
      - Normal DNA size: 50 to 300 kb
      - No genes normally expressed
      - High (> 98%) homology to DNA repeats on telomere of chromosome 10qter
  - cis elements distal to the D4Z4 repeat: Polymorphic 4q DNA segment distal to D4Z4 repeats⁹
    Matt Harms
    - Size: 10 Kb
    - 2 or 3 Alleles: 4qA & 4qB; ? 4qC
      - 4qA: Contains beta-satellite & other cis elements sequences
      - 4qB: Lacks beta-satellite & other cis elements sequences
      - ? 4qC in 2% of population
      - General population
        
        Chromosome 4: 4qA 42% & 4qB 58%
        
        Chromosome 10: Only 4qA-like allele
    - FSH only occurs with cis 4qA type segment
  - 4q35 telomere features
    - Closely associated with the nuclear envelope¹⁷
      - 4q35.2 localizes to nuclear rim, an area rich in nuclear envelope proteins
      - Localization to nuclear rim: Requires lamin A/C; Not related to D4Z4 repeats
    - Most other telomeres clustered within nucleoplasm
- FSH and 4q35 DNA: 2 disease-related polymorphisms
  - Deletion in subtelomeric repeat sequence: Reduced numbers of D4Z4 DNA (KpnI) repeats
    - Normal D4Z4 repeat features
      - Size of single repeat element: 3.3 kb
      - Normal numbers of repeat elements: 11 to 150
    - FSH D4Z4 repeat features
      - FSH repeat number: 1 to 8 D4Z4 tandem repeats; 10 to 34 kb
      - Pathogenic feature: Number of KpnI DNA repeats is reduced to less than 9 but more than 0
    - Deletions in chromosome 10q DNA when on 4q35: ? Also related to FSH disease
  - cis elements distal to D4Z4 repeat: Only 4qA polymorphism is associated with FSH disease
  - FSH 4q35 genetic characteristics
    - Disease only occurs with: Both D4Z4 contraction and 4qA allele on same chromosome
    - FSHD alleles (deleted D4Z4, presence of beta-satellite): Marked hypomethylation relative to normal alleles
  - Mutation present but not detected by routine testing²²
    - Large proximal deletion that includes usual p13E-11 DNA probe site
    - Occasional FSH patients with no deletion have hypomethylation of 4q D4Z4 repeat block
- FSH: New mutations
  - Related to
    
    10qter LOCUS in most normals
    Repeat units with homology
    to units at 4q35
    - Somatic mutations: 40% of new mutations
    - Homologous DNA configuration to Chromosome 4q35 FSH locus
      - Location: Chromosome 10qter
      - Translocations between 4q35 & 10qter in 21% of normals
      - Deletions in 10qter DNA repeats do not cause disease
  - New mutations often associated with somatic mosaicism for large deletion
    - Mosaic males: Typically sporadic patients with (mild) FSH phenotype
    - Mosaic females
      - More often clinically unaffected
      - May be parent of non-mosaic de novo patient
    - Degree of somatic mosaicism
      - Correlates with severity & age at onset of FSH
      - Mosaic females higher degree than Mosaic males
      - Mosaic mutations often detectable in blood
  - Predisposition to somatic mutations
    
    10qter LOCUS with translocated 4q35 units
    Common in individuals with
    FSH somatic mosaicism
    - 4q35-type repeat arrays translocated to chromosome 10qter
      - 10% of chromosomes from normals
      - 50% of chromosomes in individuals with FSH somatic mosaicism
    - ? 4q35 Translocations to 10qter predispose to
      - Development of somatic mosaicism for 4q35 deletion
      - De novo appearance of FSH in individual or child
  - Postulated mechanism for predisposition to deletion at 4q35
    - Increased homology between chromosomes 10 & 4
      - Produced by extra 4q35 repeats on chromosome 10qter
    - Homology leads to recombination of 4q35 & 10qter DNA
    - Recombination produces reduction of 3.3k Kpnl DNA units
    - Reduction of DNA units below 9 produces disease
- FSH: Postulated mechanism(s) by which deletion in D4Z4 repeat sequence causes disease
  - Transcriptional misregulation of neighboring genes⁸
    - FRG1 protein
      - Localized in nucleoplasm: Most prominently in nucleoli, Cajal bodies & speckles
      - Present in protein complexes containing human spliceosomes : Involved in RNA biogenesis
      - Binding partners: SMN, PABPN1 & FAM71B (speckle & Cajal body protein) ²³
      - Over-expression
        
        Causes myopathy in mouse¹⁸
        
        Produces altered splicing of muscle mRNA
    - Other proteins from neighboring genes, FRG2 or ANT1, do not produce myopathy
  - Hypomethylation of 4q D4Z4 repeat block
    - Aberrant interaction of FSHD region chromatin with the nuclear envelope
  - Toxic effect: Open reading frame in tandem repeat expressed due to deletion
    - Candidate toxic gene: DUX4
    - Mechanism: Gene is transcribed only with shorter repeat sequences
    - DUX4 protein²⁵
      - Localized to nuclei
      - Actions: Pro-apoptotic
        
        Induces caspase 3/7 activity
        
        Alters emerin distribution at nuclear envelope
  - Telomeric silencing
    - Normal length of repeats prevents neighboring genes from telomeric silencing
    - Short repeat length allows telomeric silencing of neighboring genes
- Mutations (Deletions) in 4q35 DNA repeats producing no disease
  - Tandem repeats completely absent
    - Complete deletion of tandem repeats
    - Monosomy of distal end of 4q
  - Translocation of homologous chromosome 10qter DNA repeats to chromosome 4q35
  - Tandem repeat deletion on chromosome with telomeric 4qB polymorphism
FSH: Clinical-Genetic correlations
- Inheritance
  - Dominant: 70% to 90%
  - Sporadic mutation: 10% to 30%
    - May be related to somatic mosaicism in asymptomatic parent: Especially mother
    - ? Predisposition when 4q35 repeat DNA translocated to chromosome 10
  - FSH-like families not linked to 4q35: 0% to 5%
- Size of Chromosome 4q35 deletion: Related to Disease severity
  - Largest deletions
    
    FSH (4q35) LOCUS
    Congenital FSH
    - D4Z4 repeat size: Smallest remaining fragment
    - Disease features
      - Congenital onset FSH
      - CNS changes
    - Parents usually minimally (mother) or not affected
    - Mother may be somatic mosaic
      - Fragment sizes: Normal size & Very small
  - Large deletion
    - D4Z4 repeat size: 2 or 3 repeats; 10 to 13 kB DNA fragment
    - Usually results from new mutation
    - Disease features
      - Early onset (1 to 16 yrs)
      - Severe weakness
  - Intermediate deletion
    
    FSH (4q35) LOCUS
    Typical FSH
    - D4Z4 repeat size: 4 to 7; > 16 kB DNA fragment
    - Disease features
      - Onset: 8 to 22 yrs
      - Large typical families
      - Some non-penetrance¹³
  - Small deletion
    - D4Z4 repeat size: 8 to 10; > 35 kB DNA fragment
    - Small families; Later onset (Median 15 to 23 yrs)
    - Some non-penetrance @ 20 yrs
    - Clinical or subclinical syndromes
      - Abdominal weakness; CK high
      - Scapuloperoneal weakness
        
        Scapular winging
        
        Foot dorsiflexion weakness
        
        Also see scapuloperoneal syndromes
  - Indeterminate fragment size: 35 to 48 kb
    - Sub-clinical syndromes may occur
  - Normal fragment: 48 kb to 300 kb in healthy individuals
    
    FSH (4q35) LOCUS
    Normal number of D4Z4 (KpnI) DNA repeats
- Homozygote for deletion: 1 patient described¹³
  - Not necessarily more affected than heterozygotes in family
FSH: Clinical features
- Disease onset
  - Age: Congenital to Late age
  - Weakness
    - Usual: Face; Scapular; Often asymmetric
    - Other: Distal posterior leg¹⁰
- Weakness
  - Symptomatic in 80% of family members
  - Face
    - Initial manifestation: Often
    - Frequency: 95% at age 30 with examination
    - May be asymmetric
      - Especially orbicularis oris
      - Clinical test
        
        Opposition of lips
        
        Ask patient to pucker lips
    - Functional changes
      - Sleeping with eyes open
      - Bulbar dysfunction
        
        Using straws
        Blowing up balloons
      - Dysarthria
        
        Especially labial consonants
      - Transverse smile
      - Pouting mouth (Bouche de tapir)
    - Some 4q35 linked patients have no facial weakness
  - Upper extremity: Earliest disabling feature
    - Scapular: Latissimus dorsi; Trapezius; Rhomboids; Serratus anterior
    - Humeral: Especially biceps
    - Arm abduction: Weak 2° poor scapular fixation; Deltoids normal
    - Distal: Wrist extensors involved later in course
  - Lower extremity
    - Peroneal
      - Ankle dorsiflexion weaker than toe dorsiflexion
      - Rare in absence of face weakness
    - Proximal muscles
      - Involved with disease progression
      - 50% of gene carriers
  - Trunk weakness
    - Pectoral (Clavicular head)
    - Lower abdominal: Positive Beevor's sign
  - Asymmetric
  - Muscles usually spared: Bulbar, Extraocular, Deltoid & Respiratory
    - Tongue atrophy: With larger deletions
    - Respiratory support eventually needed in 1%
- Skeletal & morphologic
  
  Scapular winging
  - Rest: Slope shouldered; anterior rotation of shoulders
  - Scapular winging & triangular shoulders
    - Worse with arm forward movement & abduction
  - Pectus excavatum
  - Reversal (Upward slope) of axillary folds
- Progression
  - Descending: Face ® Arms ® Legs
  - Slow: ? Step-wise in some periods
  - Linear between 20 to 50 years
  - ? Strength stabilizes in later life
  - Wheelchair confinement in 20%
  - Prognosis: Worse with younger onset
  - Pregnancy²⁰
    - General outcome: Good
    - Child: Higher rates of low birth weight & total operative deliveries
    - Parent: Worsening in 24% of gestations; No resolution after delivery
  - Life expectancy: Often normal
- Intergenerational features
  - Anticipation: Probably none
    - Reported in some families
      - ? Relation to reduced severity in females
    - No changes in deletion size
  - Parental sex
    - Asymptomatic mothers
      - More affected sons than daughters
    - Severe disease: More commonly 2° to
      - New mutations, or
      - Mutations transmitted through maternal lines
  - New mutations: ~ 1/3 of cases
    - No effect on severity in offspring
    - Reduced male reproductive fitness
    - New mutations more frequent in females
- Other systems
  - Sensorineural hearing loss
    - High frequency: 75%
    - Progressive
    - Often not symptomatic
    - May be present in severe infantile cases
  - Coats' disease: Vasculopathy
    - Retinal telangectasia & detachment
    - Frequency of retinal disease: 60%
    - Often not symptomatic
  - Cardiovascular
    - Labile hypertension
    - Arrhythmia or Conduction block (2% to 5%)⁶: ? Mild increased incidence
  - CNS: With largest deletions (EcoRI fragment size 10 or 11 kb)
    - Mental retardation (89%)
    - Epilepsy (40%)
    - Japanese patients
- Variant syndrome: Severe infantile FSH dystrophy
  - Frequency: 2% to 4% of all FSH
  - Genetics
    - D4Z4 repeat sizes
      - Usually very short fragment: Especially with onset ≤ 1 year
      - Range: 9 to 21 kB
    - Inheritance: Several patterns
      - de novo mutation
      - Inheritance from a parent with somatic mosaicism,
      - Inheritance from a parent with classical adult FSHD
  - Early feature
    - Onset: Infancy to 5 years
    - Facial weakness
      - Onset < 5 years
      - Weak eye closure: Apparent during sleep
      - Inability to smile
    - Motor milestones: Normal
  - Clinical
    - Weakness
      - Onset < 10 years
      - Pelvic often ≥ Shoulder
      - Degree: Severe
    - Muscle pain: Legs
    - Course
      - Rapid progression
      - Wheelchair: 10 years after onset of weakness
    - Muscular wasting: Marked
    - Skeletal: Hyperlordosis
    - Other systems often involved: Hearing loss; Visual loss (Coat's); ? Epilepsy
    - No nocturnal hypoventilation or cardiomyopathy
FSH: Laboratory features
- CK: Normal (25%) to < 5-fold elevated
- EMG: Myopathic
- Muscle biopsy
  - Variable fiber size: Small fibers rounded & angular
  - Hypertrophic muscle fibers especially common
    - Often with few internal nuclei
    - Internal architecture relatively normal
    - More commonly type 2
  - Occasional necrotic muscle fibers
  - Inflammation (75%)
    - Location: Endomysial; Perivascular
    - Cells: Perivascular CD4+; Endomysial CD8+
  - Muscle to biopsy (Rarely necessary): Biceps or Suprascapular; Deltoid often spared
- Gene testing: See lab test requisitions
FSH: Treatment
- Albuterol treatment produces
  - Increased muscle mass
  - No significant change in strength
- OT & PT: Aids in ADLs
FSH: Differential diagnosis

FSH mechanisms
Transcriptional misregulation of neighboring genes⁸

General mechanism
- D4Z4 repeats in mutated region control expression of neighboring genes via a protein complex (DRC)
- FSH deletion produces altered expression of neighboring genes
D4Z4 action
- Active region of D4Z4
  - 27 base pair element (DBE) of D4Z4
  - Binds regulatory protein complex (DRC) via transcriptoin factor YY1
  - Action: Transcriptional repression of neighboring genes
- Components of DRC regulatory protein complex
  - YY1 : Transcriptional repressor; Binds to DBE on D4Z4
  - HMGB2 : Nonhistone chromatin-associated protein; Architectural protein
  - Nucleolin : Component of transcription factor complexes; Interacts with other nuclear components
- Function & action of DRC protein complex
  - Inhibits expression of neighboring genes
  - Reduced levels of elements of complex: Produces over-expression of neighboring 4q35 genes
Candidate regulated neighboring genes
- frg2: Not expressed in normal muscle; Expressed in FSH muscle
- frg1: Over-expressed in FSH muscle
- ANT1
  - Over-expressed in FSH muscle
  - Mutations produce PEO
  - Over-expression may induce apoptosis
Expression changes in 4q35 neighboring genes are associated with
- Distance from D4Z4
  - Normal muscle: Expression level of 4q35 genes increases with distance from D4Z4
  - FSH muscle: Level of overexpression varies inversely with distance from D4Z4
- Size of D4Z4 repeat sequence
  - FRG2 overexpression is inversely related to number of D4Z4 repeats
- Tissue: Over-expression in FSH is muscle specific
D4Z4 deletion effects
- Reduce ability of regulatory proteins to bind to D4Z4 repeat
- Allow increased expression of neighboring genes
- Increased expression of 1 or several neighboring genes leads to FSH myopathy by unknown mechanism
- D4Z4 hypomethylation¹²
  - Also occurs in FSH phenotype without D4Z4 deletion
  - May be common factor producing FSH phenotype

l FSHMD1B: Autosomal Dominant

Clinical
- Facial weakness
- Scapular winging
- Muscle weakness
  - Proximal
  - Distal legs: Occasional¹⁰
Pathology: Myopathic changes without inflammation

SCAPULOPERONEAL SYNDROMES: Without 4q35 linkage, ± Facial weakness

Centronuclear myopathy: Adult-onset; Dominant
Davidenkow's syndrome
Emery-Dreifuss Dystrophy
FSH phenotype with ragged red fibers & cardiomyopathy
Glycogen storage
Acid maltase deficiency with scapuloperoneal weakness
Phosphorylase deficiency (McArdles)
Kaeser: Desmin; 2q35
LGMD2A (Calpain 3)
Mitochondrial
Myopathy + Paget's disease of bone
with Dementia: 9p13
Type 2
Reducing body myopathy: Adult onset
Scapuloperoneal MD (SPMD) with Hyaline bodies
Type 1: FHL1; Xq26; Dominant
Type 2; Dominant
Type 3: 3p22; Recessive
Myosin storage myopathy: MYH7; 14q12
Scapuloperoneal MD with Retardation + Cardiomyopathy
Scapuloperoneal neuronopathy

Also see: Absent muscles; Holt-Oram; FSH

Scapuloperoneal muscular dystrophy, Type 1 (Hyaline body myopathy)
l Four-and-a-half-LIM protein 1 (FHL1) ; Chromosome Xq26-q27.2; Dominant ²⁶
- Epidemiology: Italian, Austrian & English families
- Nosology
  - X-linked myopathy with postural muscle atrophy (XMPMA)
  - Reducing body myopathy, Late onset
- Mutation: Missense (Trp122Ser) & In-frame insertion
- Genetic-clinical correlations
  - Penetrance 60% to 80%; ? allele specific
  - Succeeding generations of same sex more affected
- FHL-1 protein
  - Highly expressed in skeletal & cardiac muscles
    - Localizes to sarcomere & sarcolemma
    - May participate in muscle growth and differentiation + Assembly of sarcomere
    - Interactions: Slow & Cardiac isoforms of myosin binding protein C (MyBP-C), ERK2, HPC2, RING1 & KBP1
  - 3 isoforms: Generated by alternative splicing
    - FHL1A (Skeletal muscle LIM protein 1 (SLIM1)): Full-length protein
    - FHL1B (SLIMMER): Contains LIM domains 1–3, nuclear localization & export signals & RBP-J binding region
    - FHL1B (KyoT2): Shortest isoform; Contains LIM domains 1 & 2 & RBP-J binding region; Interacts with PIAS1
  - LIM domain: Double zinc finger motif
  - Regulates functional expression of KCNA5
  - Patients: Marked decrease in FHL-1 expression
- Onset: Age 20 to 58
- Clinical
  - Weakness
    - Early: in legs with foot drop
    - Arms: Proximal > Distal
    - Scapular winging
    - Postural muscles: Bent spine
    - Asymmetry
    - Variable Progression: Rapid or slow
  - Muscle hypertrophy
  - Other features in some patients
    - Contractures
    - Hearing loss
    - Cardiac disorders
  - Death: Cardiac or respiratory failure
- Laboratory
  - CK: High; 1.5 to 10 times normal
- Muscle pathology
  - Focal myopathic changes
  - Inclusions: Hyaline bodies
    - Eosinophilic on H&E
    - Location: Central or subsarcolemmal
    - Most often in type I fibers; Some in type II
    - Composition: Desmin, FHL1, & Dystrophin
- Variant syndrome: Reducing body myopathy
- Also see: Congenital hyaline body myopathy
Scapuloperoneal muscular dystrophy, Adult onset, Type 2 (Hyaline body myopathy)³
l Autosomal Dominant
- Clinical
  - Onset: 1st to 5th decade
  - Weakness: Scapuloperoneal
    - Neck flexion
    - Shoulder abduction
    - Knee flexion
    - Ankle dorsiflexion
  - Progression: Slow
- Laboratory
  - Serum CK: Mildly elevated
  - Muscle pathology
    - Variable fiber size
    - Hyaline bodies: Only in type I fibers; Subsarcolemmal
    - Stain for: Myosin heavy chain, Slow; ATPase, acid pH
Scapuloperoneal muscular dystrophy, Type 3 (Hyaline body myopathy)¹¹
l Chromosome 3p22.2–p21.32; Recessive
- Epidemiology: 1 Turkish family; 2 siblings
- Clinical
  - Onset: 1st to 4th decade
  - Weakness: Scapuloperoneal
    - Neck flexion
    - Shoulder girdle
    - Ankle dorsiflexion
  - Tendon reflexes: Normal
  - Systemic: 1 patient with cardiomyopathy
  - Progression: Slow
- Laboratory
  - Serum CK: 2x to 3x normal
  - Muscle pathology
    - Type I muscle fiber predominance
    - Central nuclei
    - Variable muscle fiber size
    - Muscle fiber splitting
    - Hyaline bodies: Only in type I fibers; Subsarcolemmal
    - Stain for: ATPase, acid pH (4.3)
Scapuloperoneal muscular dystrophy with mental retardation & lethal cardiomyopathy
l LAMP-2 ; X-linked; Recessive or Semi-Dominant
- Genetics: See Danon disease
- Course
  - Onset: 5 to 25 years
  - Death: 2nd or 3rd decade
- Weakness: Humeroperoneal; Distal
- CNS: Mental retardation
- Systemic
  - Cardiomyopathy: Hypertrophic
  - Myopia
- Laboratory
  - Serum CK: High
  - Muscle biopsy
    - Variable muscle fiber size
    - Vacuoles: Cytoplasmic; Small; Basophilic; Dystrophin +
- Mother (carrier) with cardiomyopathy
Kaeser scapuloperoneal syndrome ²⁴
l Desmin ; Chromosome 2q35; Dominant
- Epidemiology
  - 1 family: Originally reported as neuropathic
  - Same mutation found in other German families
- Genetics: Missense mutation; R350P
- Desmin protein: See Desmin myopathies
- Onset
  - Age: 3rd to 4th decade
  - Later for females
- Clinical
  - Weakness: Scapuloperoneal; Foot drop
  - Bulbar involvement: Late; Dysphagia; Face
  - Spared: Biceps
  - Myalgias: Some patients
  - Gynecomastia
  - Course
    - Progressive
    - More sudden death & respiratory failure in males
- Laboratory
  - Electrophysiology
    - EMG: Myopathic; Mildly neurogenic
  - Serum CK: High
  - Muscle pathology: Normal to Myofibrillar myopathy
Scapuloperoneal peripheral neuropathy (Davidenkow's Syndrome)
l Autosomal Dominant
- Some patients reported with HNPP mutations (PMP-22 deletions)²¹
- Onset: Childhood or adult
- Weakness
  - Distal legs: Early
  - Shoulder girdle
- Tendon reflexes
  - Generally decreased
  - Absent at ankles
- CK: Normal
- Electrodiagnostic: Axonal neuropathy; Absent sensory potentials
Scapuloperoneal neuropathy (motor neuron disease)
l Chromosome 12q24.1-q24.31; Dominant
- ? Similar locus to Distal HMN II
- Epidemiology
  - New England, French-Canadian family
  - Males more severely affected than females
  - Disease more severe in succeeding generations
- Clinical
  - Congenital absence of muscles
  - Weakness
    - Course: Progressive
    - Distribution
      - Scapuloperoneal
      - Distal
      - Laryngeal palsy
l Autosomal Dominant
- Weakness: Face & Pectoral muscles
- Onset: Early adult
- Electrophysiology: SMA, FSH type
l Autosomal Recessive
Other Scapuloperoneal syndromes
- Emery-Dreifuss Dystrophy
- Acid maltase deficiency with scapuloperoneal weakness
- Centronuclear myopathy: Adult-onset; Dominant
- FSH phenotype with ragged red fibers & cardiomyopathy

Other myopathies

Facioscapulohumeral muscular dystrophy gene testing

University of Iowa Hospitals & Clinics
200 Hawkins Drive
Microbiology Laboratory
BT 6004 GH
Iowa City, Iowa 52242-1009
319-356-2591
Fax: 319-384-9854

10 ml Lavender top (EDTA) tube