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 19q13.32; Dominant
- DM 2 (PROMM)
  l Zinc finger protein 9 (ZNF9) ; Chromosome 3q21.3; Dominant
DM1 & DM2 expansions: May have originated from few founder mutations

Myotonic Dystrophy 1 (DM1)

l Myotonin protein kinase (DMPK)

; Chromosome 19q13.32; Dominant

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

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

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
- See: Other disease expansions in transcribed but untranslated DNA

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
  - Muscle: Aberrantly spliced RNA action produces altered proteins
    - CLC1 (chloride) channel
      - Abnormal channel proteins have no Cl^- conductance
      - Interfere with function of normally spliced Cl^- channels
      - Altered splicing variants: Two common types
        
        Inclusion of novel exons 6b and 7a: Causes a frameshift & premature truncation at codon 283
        
        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
    - Ca_v1.1 (Calcium channel, L-type) ³⁶
      - Alternative (misregulated) splicing of exon 29: Reduced from presence in 93% of protein to < 30%
      - Associated with 2 splicing factors: MBNL1 & CUGBP1
      - May modify Ca_v1.1 channel function: Increased conductance & voltage sensitivity
      - Severity of weakness: Correlates with degree of alternative splicing
      - May also play a role in DM2
      - Mouse model: Increases frequency of central nuclei in muscle fibers
  - Brain: Aberrantly spliced RNA 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)
  - Other abnormal splicing
    - Insulin receptor: Insulin resistance
    - MTM1
    - SERCA
  - 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
    - Nuclear envelope stability ³⁸
  - 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: 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
  - Cause: Reduced chloride (CLC-1) channels in sarcolemma
- 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
    - Sleep disorders ³⁷
      - Obstructive sleep apnea (55%)
      - Periodic breathing
      - Sleep hypoventilation
  - Cardiac
    - General
      - Increased frequency & severity 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: Cardiac arrest; Atrial arrhythmias
    - Conduction & Rhythm defects
      - Ectopic beats
      - Tachyarrhythmias
      - Atrial fibrillation, flutter & tachycardia
      - Sudden death
    - ± Cardiomyopathy: Especially late in course
    - Indications for cardiac evaluation & treatment ³⁹: Screen with yearly EKG
      - PR interval > 200 ms
      - QRS duration > 100 ms
    - Treatment: Pacemaker
  - 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 ³⁴
    - Histochemistry
      - Normal or Non-specific
      - Internal nuclei: Some patients
    - MBNL1 nuclear staining
      - CDM: Foci, discrete
      - Controls: Diffuse & Hetergeneous
  - 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 Comparative features
Feature	DM 1	DM 2
GENERAL
Epidemiology	Widespread	European
Onset Age	0 to Adult	8 to 60 years
Anticipation	+	Mild
Cogenital form	+	Rare
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	+	+
Muscle Internal nuclei	Varied	Type 2 fibers
Chromosome	19q13.3	3q21
Mutated gene	DMPK	ZNF9
Mutation type	CTG repeats	CCTG repeats
Repeat size	100 to 4,000	Mean ~5,000
CNS MRI Δ	White & Gray matter	White matter

DM 1: Laboratory features
- Serum CK: Normal to 3x
- Endocrine
  - Testosterone: Low
  - FSH: High
  - Insulin insensitivity
- Serum IgG: Low
- Muscle 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
    - Fiber type differentiation: Poor
    - Nuclear foci with muscleblind-like 1 (MBNL1) protein ³⁴
    - Ultrastructure: Disordered myofibrils; Clustered tubules with electron dense cores
- CNS (MRI) ³⁵
  - Gray matter
    - Reduction of frontal & parietal gray matter
    - Abnormal thalamic gray matter & hippocampus
  - White matter lesions
    - Frequency: > 50%
    - Extent correlated with: Psychomotor speed; Age; Disease duration
    - Prominent callosal body & limbic system involvement
    - Milder involvement: More depression & fatigue
  - More severe in DM1 than DM2
    - Gray matter involvement
    - Central motor pathways

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

FACIOSCAPULOHUMERAL (FSH) DYSTROPHY

FSH 1A
Clinical features
Clinical correlations
DUX4 protein
Epidemiology
Genetics
Laboratory
FSH Variants
Infantile FSH 1A
FSHD1
Bent spine
FSHD2

FSH Differential Dx
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 4q35.2; Dominant
l Double homeobox protein 4 (DUX4)

(D4Z4 repeat DNA deletion); Chromosome 10qter; 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
FSHD1
FSHD2
FSHD 10qter
General principles
FSH 4q35 locus: Normal
Mutations
FSH
New
No disease
Size

Charcot

FSH locus at 4q35: Normal structure

FSH Disease Locus at 4q35 in FSHD: 2 possible abnormalities in and near D4Z4 DNA fragment ^29, ³¹

General
- D4Z4 repeat: DNA methylation in FSHD1 & FSHD2 patients
  - Reduced
  - Causes open chromatin structure
  - May affect DUX4 transcriptional activity (on 4qA161 haplotype)
- 4qA allele: FSH disease permissive haplotypes telomeric to D4Z4 repeat
  - Contains FSHD-predisposing single nucleotide polymorphisms (SNPs)
  - Creates canonical polyadenylation signal for transcripts derived from DUX4
  - Polyadenylated DUX4 transcripts: More stable
  - Stabilized, expressed distal DUX4 transcript: May produce toxic gain of function
  - FSH Pathogenic 4qA types: 4A161, 4A161L, 4A159 & 4A168
  - Non-pathogenic 4qB types: 4B163, 4B168, 10A166, 10A164, 10B161T & 10A176T

FSHD1

FSHD1 LOCUS AT CHROMOSOME 4q35
Number of D4Z4 DNA repeats: Reduced
D4Z4 Methylation: Low
Chromatin: Open
DUX4 gene: Increased expression
Permissive 4qA region distal to repeats: Allows
expression of stable polyadenylated DUX4

Due to
- Deletion in units of D4Z4 DNA repeat sequence: Reduced D4Z4 fragment size
  - Allows: Increased expression of DUX4 gene in distal repeat
- Permissive sequences distal to D4Z4 repeats
  - Lead to: Polyadenylation & Stabilization of distal DUX4 transcript
FSH disease expression requires
- D4Z4 repeat: At least 1 remaining; Hypomethylated
- 4qA allele (with β-satellite sequences) (4qA161) distal to repeats
D4Z4 repeats in fragment
- Contain gene for: Double homeobox protein 4 (DUX4)
  - Double homeobox gene
  - Function: Unknown
  - FSHD relevant DUX4 gene
    - Straddles distal D4Z4 repeat unit & adjacent sequence
    - Encompasses two facultative introns in the 3'UTR
    - Contains pLAM sequence immediately distal to D4Z4
      - Polymorphisms affect polyadenylation of distal DUX4 transcript
  - Non-FSH 4qA distal alleles: DUX4 transcript not adenylated; Short half-life
  - FSH 4qA alleles: Polyadenylated DUX4 transcript; Stabilized
- Hypomethylated D4Z4 repeat
  - Selective for D4Z4 repeat
  - Neighboring DNA: Normal methylation
  - May allow increased expression of DUX4 transcript
- D4Z4 chromatin structure: Open
Most common mutation

Facioscapulohumeral Dystrophy 2 (FSHD2; FSHMD1B)

l Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1)

;
Chromosome 18p11.32; Dominant (Digenic with permissive DUX4 allele)

FSHD2
SMCHD1 gene: Mutations
LOCUS AT CHROMOSOME 4q35
Number of D4Z4 DNA repeats: Normal
D4Z4 Methylation: Low
Chromatin: Open
DUX4 gene: Increased expression
Permissive 4qA region distal to repeats: Allows
expression of stable polyadenylated DUX4

Epidemiology: ~30 families, Dominant & Sporadic
Genetics
- SMCHD1 gene ⁴⁰
  - Mutations: Missense; Splice site; Deletion
  - Disease mechanism: Haploinsufficiency
  - FSH penetrance with permissive D4Z4 allele: 80%
- D4Z4 repeat
  - Hypomethylation: D4Z4 genetic repeats
    - Location: Normal (or small) D4Z4 alleles
    - D4Z4-restricted: On both alleles on chromosomes 4q & 10q
  - No D4Z4 deletion (contraction)
  - D4Z4 chromatin structure: Open
  - Genetic defect in D4Z4 methylation may cause disease
  - DUX4 expression: Permissive sequences distal to D4Z4 repeats required
    - Lead to: Polyadenylation & Stabilization of distal DUX4 transcript
- DNA telomeric to D4Z4 repeat
  - At least one 4qA161 subtelomere on 4q35 required for disease expression
SMCHD1 protein
- Regulates chromatin expression
- Hypermethylation of subset of CpG islands associated with X-chromosome inactivation
- Mutation: Increased DUX4 expression in muscle
Clinical
- General: Similar to FSHD1
- Onset age: > 30 years
- Severe weakness: May have both FSHD1 & FSHD2 mutations

FSH Disease locus at Chromosome 10qter telomere in FSHD
- Epidemiology: 1 patient identified
- D4Z4 repeat: Mosaic pathogenic
  - Start D4Z4 unit: Chromosome 10-type, 2 1/2 repeats
  - Distal end of D4Z4 unit: Chromosome 4-type, 1 1/2 repeats
- Terminal 4qA locus: Contains directly adjacent polyadenylation-promoting pLAM sequence
- No FSHD candidate genes located proximal to D4Z4 repeat
FSH locus at Chromosome 4q35 telomere: DNA in Normals
- Tandem repeat KpnI DNA (D4Z4) units
  
  NORMAL FSH LOCUS AT 4q35
  Number of D4Z4 DNA repeats: Normal
  D4Z4 methylation: High
  Chromatin: Closed
  4q region distal to repeats: Variable
  Distal DUX4 gene: Not expressed
  - Only disease-related macrosatellite repeat
  - Location: Subtelomeric region of chromosome 4
  - Size of repeats: 3.3 kb
  - Number of repeats
    - Usual: 11 to 100 (> 40 kB)
    - Other: Contracted D4Z4 repeats on nonpathogenic haplotypes
  - KpnI Tandem repeat units at 4q35 contain
    - 2 homeobox sequences
    - 2 different GC-rich repetitive sequences
    - Heterochromatic features
      - Highly condensed DNA
      - Associated with: Highly methylated, hypoacetlyated histone H4
      - Little transcription
      - Contain low-copy heterochromatic repeats: hhspm3 & LSau
    - Euchromatic features
      - Open reading frame (DUX4)
  - Other features of repeated DNA at 4q35 in normals
    - Normal DNA size: >40 to 300 kb
    - No genes normally expressed
    - High (> 98%) homology to DNA repeats on telomere of chromosome 10qter
    - D4Z4 methylation: Reduced with repeat lengths less than 11
- 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 4qA161 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 10 D4Z4 tandem repeats; 10 to 34 kb
    - Pathogenic feature: Number of KpnI DNA repeats is reduced to less than 11 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 of D4Z4 repeat unit 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: Other 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
  - Mechanism not confirmed
- Hypomethylation of 4q D4Z4 repeat block
  - Aberrant interaction of FSHD region chromatin with the nuclear envelope
- Toxic effect of DUX4: Open reading frame in tandem repeat has changed expression due to disease deletion
  - Candidate toxic gene: DUX4
  - Mechanism: DUX4 gene is transcribed only, or has increased transcription, with shorter repeat sequences
- 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

DUX4 protein²⁵
- Only DUX4 gene in most distal D4Z4 element is likely to be translated
- Homeobox: Homebox domains confer nuclear targeting
- Localized to nuclei: Actively transported through nuclear pore complex
- Actions
  - Pro-apoptotic
    - Induces: Caspase 3/7 activity
    - Alters: Emerin distribution at nuclear envelope
  - May be involved in transcriptional regulation
  - DUX4 expression: Represses MyoD and its target genes²⁷
    - Diminished myogenic differentiation
    - Repression of glutathione redox pathway components
    - Sensitivity to oxidative stress
    - Competes with Pax3/Pax7: Pax3 or Pax7 expression at high levels reduces DUX4 toxicity
    - ? DUX4 expression interferes with Pax7 in satellite cells: Inappropriately regulates Pax targets during regeneration
- DUX4 expression in myoblasts
  - Normal
    - Low levels
    - No adenylation
  - FSH dystrophy
    - Upregulated
    - Polyadenylated
- Other associations: Club foot
  - Interacts with 30-bp sequence in PITX1 promoter: Transcriptional activator
FSH: Clinical-Genetic correlations
- Inheritance
  - Dominant: 70% to 90%
  - Sporadic mutation
    - FSHD1: 10% to 30%
      - May be related to somatic mosaicism in asymptomatic parent: Especially mother
      - ? Predisposition when 4q35 repeat DNA translocated to chromosome 10
    - FSHD2: 67%
  - FSH-like families not linked to 4q35: ~5%
- Size of Chromosome 4q35 deletion: Related to Disease severity
  - Largest deletions
    
    FSH (4q35) LOCUS
    Congenital FSH
    1 D4Z4 repeat
    - 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
    
    FSH (4q35) LOCUS
    Typical FSH
    Few D4Z4 repeats
    - 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
    - D4Z4 repeat size: 4 to 7; > 16 kB DNA fragment
    - Disease features
      
      FSH (4q35) LOCUS
      Mild or atypical FSH
      Mildly reduced number
      of D4Z4 repeats
      - 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
      
      NORMAL FSH LOCUS AT 4q35
      Number of D4Z4 DNA repeats: Normal
      D4Z4 methylation: High
      Chromatin: Closed
      4q region distal to repeats: Variable
      Distal DUX4 gene: Not expressed
      - 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
- D4Z4 hypomethylation
  - No relation to severity in FSHD1
  - Possible relation to severity in FSHD2
- Homozygote for deletion: 1 patient described¹³
  - Not necessarily more affected than heterozygotes in family
- FSHD2 severity: No relation to D4Z4 repeat size
FSH: Clinical features
- FSHD1 vs; FSHD2 ³³
  - Clinical features: Same
  - Symptom onset: Possibly later in FSHD2
- Disease onset
  - Age: Congenital to Late age; Mean 3rd decade
  - Weakness: Symptoms & Signs ¹⁰
    - Usual (72%-85%): Face & Scapular; Often asymmetric (40%)
    - Face predominant (7%): Usually have scapulo-humeral involvement on exam
    - Face sparing (5%-15%): Usually later onset (4th or 5th decade); Smaller deletion
    - Foot drop (13%): May be unilateral; Face & Scapulo-humeral weakness on exam
    - Proximal leg (7%): More common in females; Bilateral; Older onset; Larger deletion
    - Other: Distal posterior leg (1%); Bent spine
- 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 mutation 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%
  - Variant patterns
    - Hemiatrophy³²
    - Bent spine: Axial myopathy³⁰
- 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
  
  Duchenne
  - 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 ⁴¹
  - Frequency: 2% to 4% of all FSH
  - Genetics
    - D4Z4 repeat (EcoRI fragment) sizes
      - Usually very short fragment: Especially with onset ≤ 1 year
      - Range: 9 to 21 kB
      - Shortest EcoRI fragment: Most severe syndromes
    - Inheritance: Several patterns
      - de novo mutation
      - Inheritance from a parent with somatic mosaicism,
      - Inheritance from a parent with classical or mild adult FSHD with large deletion
  - 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
      - Foot drop (60%)
      - Degree: Severe
      - Asymmetric (70%)
      - Respiratory (50%): Failure in 10%
      - Dysphagia (20%)
      - Course: May be rapid progression in legs to loss of ambulation
    - Muscle pain: Legs
    - Course
      - Rapid progression
      - Wheelchair: 10 years after onset of weakness
    - Muscle wasting: Marked
    - Skeletal: Hyperlordosis; Kyphoscoliosis
    - Other systems often involved
      - Hearing loss (90%): Sensorineural; Bilateral
      - Visual loss (100%)
        
        Coat's
        
        Tortuous retinal vessels
      - CNS (30%)
        
        Epilepsy (20%)
        
        Mental retardation (30%): Moderate to severe; Smallest EcoRI fragments
    - Cardiac arrhythmias (50%): AV block; Echocardiography normal
  - Laboratory
    - Serum CK: 70 to 1,400
    - Muscle biopsy
      - Muscle fiber size: Varied; Type 2 hypertrophy; Small angular
      - Inflammatory cells: Perivascular & Endomysial
- FSH variant: Bent spine syndrome ³⁰
  - Epidemiology: 1 family
  - Mutation: 4q35 repeat contraction
  - Clinical
    - Onset: 6th to 7th decade
    - Bent spine
    - Strength: Arm & Leg normal
  - Laboratory
    - MRI: Paraspinous muscle atrophy
    - Serum CK: Normal
  - Differential diagnosis
FSH: Laboratory features
- CK: Normal (25%) to < 5-fold elevated
- EMG: Myopathic
- Muscle biopsy
  - Fiber size: Varied
    - Small fibers: Rounded & Angular
    - Hypertrophic muscle fibers especially common
      - Often with few internal nuclei
      - Internal architecture relatively normal
      - More commonly type 2
  - Necrotic muscle fibers: Occasional
  - Inflammation (75%)
    - Location: Endomysial; Perivascular
    - Cells: Perivascular CD4+; Endomysial CD8+
  - MHC Class I upregulation by muscle fibers: Common
  - Muscle to biopsy (Rarely necessary): Biceps or Suprascapular; Deltoid often spared
- MRI
- 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): MYF6; 12q21; Dominant
Davidenkow's syndrome
Emery-Dreifuss Dystrophies
FSHD with ragged red fibers & cardiomyopathy
Glycogen storage
Acid maltase deficiency with scapuloperoneal weakness
Phosphorylase deficiency (McArdles)
Kaeser: Desmin; 2q35
LGMD2A: Calpain 3; 15q15
Mitochondrial
Myopathy + Paget's disease of bone
with Dementia: VCP; 9p13
Type 2
Reducing body myopathy (Adult onset): FHL1; Xq26
Retardation & Cardiomyopathy: LAMP-2; Xq24
Scapuloperoneal MD (SPMD) with Hyaline bodies
Type 1: FHL1; Xq26; Dominant
Type 2: MYH7; 14q12; Dominant
Type 3: 3p22; Recessive
Myosin storage myopathy: MYH7; 14q12
Scapuloperoneal neuronopathy: TRPV4; 12q24

Also see: Absent muscles; Holt-Oram; FSH

FHL1 mutations: Common features
Scapular winging
Joint contractures
Rigid spine
Respiratory weakness
Cardiomyopathy
Reducing bodies
FHL1 levels: Reduced
Except: Reducing body myopathy

Scapuloperoneal muscular dystrophy, Type 1 (Hyaline body myopathy)
l Four-and-a-half-LIM protein 1 (FHL1) ; Chromosome Xq26.3; Dominant ²⁶
- Epidemiology: Italian, Austrian & English families
- Nosology & Other associated syndromes
  - X-linked myopathy with postural muscle atrophy (XMPMA)
  - Reducing body myopathy, Late onset or Severe
  - Rigid spine syndrome
  - Myofibrillar myopathy
  - Emery-Dreifuss 6
- 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
    - FHL1C (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
  - Regulation of ultra-rapid activating delayed rectifier K⁺ current & atrial arrhythmia
  - Patients: Levels of FHL1 protein decreased in milder & increased in more severe disease
    - Marked decrease in FHL-1 expression: XMPMA; Emery-Dreifuss
    - Slightly decreased: X-SM; RBM, late onset
    - Increased: RBM, early onset
- Onset: Age 20 to 58
- Clinical
  - Weakness
    - Early: Legs; Foot drop
    - Arms: Proximal > Distal
    - Scapular winging
    - Postural muscles: Bent spine
    - Asymmetry
    - Variable Progression: Rapid or slow
  - Muscle hypertrophy
  - Other features in some patients
    - Skeletal: Contractures; Rigid spine
    - 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 FHL1 syndrome: Reducing body myopathy
- Also see: Congenital hyaline body myopathy
- Variant FHL1 syndrome: X-linked myopathy with postural muscle atrophy (XMPMA)
  - Mutations: C terminal of FHL1 gene
  - Onset age: 15 to 75 years
  - Clinical
    - Milder disease than other FHL1 mutations
    - Postural muscle atrophy
    - Respiratory failure
    - Rigid spine
    - Muscle hypertrophy
    - Ankle: Tendon contracture
  - Laboratory
    - Serum CK: High; Range Normal to 10x elevated
    - EMG: Myopathy + Spontaneous activity
    - Muscle
      - Type 2A: Hypertrophy
      - Type 2B: Atrophy
      - Desmin: Stains aggregates in muscle fibers
- Variant FHL1 syndrome: Emery-Dreifuss Muscular Dystrophy 6 ²⁸
  - Genetics
    - Recessive or Semi-Dominant; 1 Sporadic patient
    - Mutations: Missense (Cys209Arg, Cys276Tyr); Loss of termination codon (X281Glu); Out-of-frame insertions or deletions
  - FHL1 protein: Mutation effects
    - Severely reduced in all tested patients
    - Severe delay in myotube formation
  - Clinical
    - Onset age: 4 to 48 years; Mean = 15
    - Myopathy
      - Distribution: Scapulo-Peroneal and/or Axial
        
        Legs (100%): Pelvic, Peroneal or Pelvi-peroneal
        
        Arms (85%): Scapular
        
        Axial (55%)
        
        Face (28%)
        Respiratory
      - Hypertrophy (28%)
      - Ptosis (14%)
    - Dysphonia (45%): Abnormal vocal cords
    - Cardiac disease: Only feature in some patients
      - Arrhythmias: Supraventricular or Ventricular
      - Hypertrophic cardiomyopathy
      - Conduction defects
    - Joint contractures
      - Neck stiffness
      - Rigid spine
      - Limb-joint: Ankles (100%), Elbows; Knees, Hips, Wrists (one patient), Fingers, Shoulders
      - Scoliosis
    - Course
      - Progressive
      - Patients usually remain ambulant
  - Laboratory
    - Serum CK: Normal to 6x elevated
    - Muscle: Myopathy
      - Fiber size variation
      - Endomysial connective tissue increased
      - Rimmed vacuoles: Some muscles
      - FHL1: Reduced; Remaining protein near nucleus
      - No reducing bodies (Menadione-NBT) or aggregates (myotilin, desmin or αB-crystallin)
      - Normal: Lamin A & C; Emerin
  - Female heterozygote carriers
    - Asymptomatic, or
    - Cardiac disease and/or Myopathy, mild
Scapuloperoneal muscular dystrophy, Adult onset, Type 2 (Hyaline body myopathy)³
l MYH7 ; Chromosome 14q11.2; 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 (4.3)
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 ; Xq24; 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 (SPSMA)
l TRPV4 ; Chromosome 12q24.11; Dominant
- Allelic with
  - Distal SMA, Congenital
  - HMSN 2C
  - Familial digital arthropathy-brachydactyly (FDAB)
- 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
- Pathology
  - Muscle: Chronic denervation
    - Grouped atrophy
    - Fiber type grouping
    - Internal nuclei
    - Pyknotic nuclear clumps
  - Motor neurons
    - Normal numbers in Spinal cord & Brain
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