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Neuromuscular Disorders (SPINAL CORD/MOTOR UNIT Screen Shot 2018-09-15…

- - - - Down Syndrome
      - Prader-Willi Syndrome
        Small Size
        Dysmorphic Features
        Hypotonia
        Lethargy
        Feeding Difficulty
        Deletion or UPD Chromosome 15
- - - - Periodic paralysis
        Hypokalemic
        Hyperkalemic
        
        Thyorid disorders
        
        Steroid
        
        Glycogen storage
        
        Mitochondrial
    - - Variable progression
        
        CPK/SGOT enzymes may be normal
        
        Characteristic Pathology
        
        Central core
        
        Nemaline
        
        Centronuclear
        
        Congenital fiber type disproportion
    - - Limb-Girdle
        Muscular Dystrophy
        
        Weakness of limb muscles
        proximal > distal
        shoulder, upper arms, thighs, pelvic girdle
        
        Involvement of the skeletal muscle
        
        Elevated CPK
        
        Distinguish from the dystrophinopathies (Neuro exam)
        
        Autosomal Dominant --> LGMD1
        
        Autosomal Recessive --> LGMD2
        
        Childhood or adult onset
      - FSHD
        Facio-scapulo-humeral Dystrophy
        
        GENETICS
        1/20,000
        AD
        10-30% de novo
        
        FSHD1: 95%
        Contraction of the D4Z4 at 4q35 leads to chromatin relaxation including DUX4 promoter which leads to DUX4 expression in muscle cells (hypomethylation)
        Normal size: 11-100 repeat units
        FSDH1: <10
        A particular truncated haplotype/allele allows DUX4 transcription and normal expression
        Alleles: 4qA that allows DUX4 transcription
        Larger contractions (smaller size): earlier onset, more rapid progression
        
        FSDH2
        SMCHD1 (Chromatin modifier)
        Chromatin relaxation without the shortened D4Z4
        Low methylation of D4Z4 (<25%)
        Allows DUX4 expression which should not be expressed
        Plus permissive allele
        
        Adult, adolescent onset (< 20y)
        
        Infantile form exists also
        
        Facial muscle weakness
        Ptosis, decreased facial expression, difficulty whistling
        
        Scapular winging
        
        Sloping shoulders
        
        Humeral: weakness of upper arms
        
        Atrophy of the muscles around the eyes, mouth, shoulders, upper arms, lower legs, dorsiflexors of the foot (foot drop)
        
        Later: abdominal and hip muscles involved
        lumbar lordosis, protuberant abdomen
        
        Wheelchair 20%
        
        Ventilatory support (minority)
        
        Normal life span
        
        Sensorineural hearing loss
        
        Retinal vasculopathy
        
        Disease onset - the second decade of life
        Begins initially with weakness of shoulder and facial muscles
        The spectrum of disease severity is wide, ranging from mildly affected to severely affected wheelchair-bound individuals
      - Dystrophinopathies
        
        Duchenne Muscular Dystrophy #
        
        Delayed milestones
        
        Learning difficulties
        
        Progressive symmetrical muscular weakness, proximal>distal
        
        Calf hypertrophy
        
        Symptoms < 5y
        
        Wheelchair-dependent < 13y
        
        Cardiomyopathy
        death usually by 3rd decade
        
        Gower maneuver
        
        GOWER MANEUVER
        
        Shoulders/arms held back awkwardly when walking
        Weak butt muscles
        Knees amy bend back to support weight
        Thick lower leg muscles (mostly fat and not strong)
        Foot drop causes weak muscles in front of leg
        Poor balance, falls often
        Thin, weak thighs
        Belly sticks out due to weak belly muscles
        
        Treatments for DMD
        
        Domagrozumab: ongoing trial
        Myostatin inhibitor
        Goal to see if blocking myostatin will increase muscle strength
        
        Exondys51
        Exon-skipping drug
        
        Labs:
        
        Elevated CPK > 10x normal
        
        EMG: characteristic myopathic changes
        
        Muscle biopsy: variation fiber size, necrosis, regeneration, fat, connective tissue deposition
        
        X-Linked
        2/3 of mothers with sporadic cases carriers
        70% deletions or duplications of 1 or more exons
        30% small deletions, insertions, point mutations
        protein: dystrophin
        
        Becker Muscular Dystrophy
        
        Progressive symmetrical muscle weakness and atrophy
        
        Later onset than DMD
        
        Activity-induced cramping
        
        Flexion contractures later in course
        
        Wheelchair-dependent > 16y
        
        Preservation of neck muscles (can support their necks)
        Not seen in DMD
        
        #
        
        Cardiomyopathy - heart failure
        
        mean age of death in mid-40's
        
        Milder affected forms exist also
        
        85% are deletions
        (in-frame as opposed to frameshift with DMD)
        
        Deletions in frame tend to be milder than frameshift, but there are some exceptions to this rule in BMD
        
        Some dystrophin produced > 20%
        
        Labs show elevated CPK (5x normal)
        
        Some dystrophin present on muscle biopsy IHC
        
        X-Linked Dilated Cardiomyopathy
        
        Dilated cardiomyopathy with CHF
        
        Presentation in males 20-40y
        
        Presentation is later in females
        
        Usually no evidence of skeletal muscle involvement
        (Can actually be "subclinical BMD")
        
        Rapid progression to death in males, slower in females
        
        GENETICS
        
        Mutations in the DMD gene affecting the muscle promotor and 1st exon
        
        No dystrophin produced in the cardiac muscle
        
        Alternative promotors usually only active in brain are active in the skeletal muscle
    - - Myotonia (inability to relax), weakness
        
        Hair loss, diabetes, cataracts, ECG changes
        
        CTG repeat expansion
        
        Maternal transmission of severe neonatal syndrome
        
        CUG RNA binding protein
        
        Normal Range 5-37
        No symptoms 38-49
        Mild 50-150
        Classical 100-1500
        Congenital >1000
        Trials:
        Ranolazine
        Tideglusib
        GSKepsilonbeta enzyme inhibitor
        GSKepsilonbeta important in formation of muscle fibers, abnormal high levels with DM1 gene expansion
  - - - SMA TYPES
        
        SMA I
        
        Infantile - Werdnig-Hoffmann Type I
        
        Onset <6 months
        Profound hypotyonia
        frog-leg posture
        Proximal weakness
        Progressive weakness
        Intercostal weakness plus spared diaphragm
        Paradoxical Breathing Pattern
        Bell-shaped chest
        areflexia
        tongue atrophy
        fasiculations
        sit with support
        survival <3 years
        
        SMA II
        
        Intermediate Type II
        
        Onset 6-18 months
        proximal weakness
        most sit or walk until teens
        scoliosis
        hypo- or areflexia (little/no reflexes)
        contractures
        independently sit if placed
        postural tremor of fingers (put hands out --> tremor)
        70% alive at 25 years
        survival several year to 20s
        
        SMA III
        
        Late-onset Type III
        (Kugelberg-Welander)
        
        Onset >18 months (5-15 years)
        proximal weakness
        hip and shoulder atrophy
        hypo- or areflexia (little/no reflexes)
        ambulatory into 4th decade
        normal life span
        
        SMA IV
        
        Adult Type IV (Adult onset)
        
        Normal life span
        Weakness
        
        SMA0
        
        Neonatal (arthrogryposis) Type 0
        
        Prenatal onset
        Facial Diplegia
        Contractures
        Respiratory Failure
      - Imaging/Testing
        
        Muscle Biopsy
        
        Large groups of small round dark, brown fibers next to groups of normal size or large light muscle fibers
        
        EMG/NCS
        
        fibrillations at rest: active denervation
        
        decreased motor unit potentials on voluntary effort (nerve is fine, but the connection isnt working)
        
        nerve conduction velocities normal
      - SMA Genetics
        
        SMN Protein
        
        Role in snRNP biogenesis and function
        
        Required for pre-mRNA splicing
        
        Role in the reassembly and regeneration of these splicing components
        
        Necessary for lower motor neuron function
        
        Autosomal Recessive
        Carrier Freq = 1/54 in the USA
        SMN1
        
        95-98% homozygous for deletions in exon 7 and 8
        
        The rest are compound heterozygotes with point mutations
        
        full length transcripts
        
        SMN2
        
        can occur in multiple copies
        
        appears to modify the disease
        
        codes for a protein slightly different than SMN1 which lacks exon 7 modifier
        
        Carrier Testing
        
        number of exon 7's
        
        pitfalls whether 2 copies are in cis or in trans
        
        2% de novo (paternal origin)
        
        plastin3 at Xq23 is another modifier of SMA
        
        SMA Alleles
        
        A: Normal (4-10% homozygous deletion of SMN2)
        
        B: Hemizygous deletion SMN1 (Carrier)
        
        C: Homozygous deletion of SMN1 (Type I)
        
        D: Complete gene conversion of SMN1 by SMN2
        
        E: Hybrid SMN1-SMN2 retaining exon 8 of SMN1
        
        D and E most are types II and III
      - Developments in SMA
        
        Carrier testing
        
        Newborn Screening
        
        New treatment
        - Spinraza (FDA approved) - antisense oligonucleotide treatment - it corrects SMN2 splicing - Binds SMN2 mRNA and promotes exon 7 inclusion - Improvement in motor function in all types including SMAIII - Early treatment leads to more improvement - Improvements in life expectancy
  - - - Metabolic
        
        Diabetes
        
        Uremia
        
        Porphyria
        
        Pernicious Anemia
        
        Absent vitamin B12
        
        Abetalipoproteinemia
        
        Refsum Disease
        Autosomal Recessive
        Retinitis Pigmentosa
        Sensorineural hearing loss
        Neuropathy
        Cardiomyopathy
        Increased phytanic acid
        Phytanic axid oxidase deficiency
        
        TangIer Disease
        Low HDL
        Coronary Artery Disease
        Corneal deposits
        Hepatosplenomegaly
        Neuropathy
        Orange tonsils
        ABCA1 gene
        Autosomal Recessive
      - Toxic
        
        Diptheria
        
        Polyneuroparhy (many nerves involved)
        
        Involvement of the CNS
        
        Botulism
        
        Large, sluggish pupils
        
        Constipation
      - Hereditary
        
        Clinical signs reflect which nerves are involved
        
        Can be motor and/or sensory nerves
        
        NCS useful
        
        Polyneuropathy: weakness and sensory impairment
        
        Distal weakness
        
        More severe in legs
        
        Gait affected
        
        Foot drop (high foot steps, stomping steps)
        
        Charcot-Marie-Tooth Syndrome
        
        Chronic motor and sensory polyneuropathies
        
        Progressive distal muscle weakness and atrophy
        
        Mild to moderate sensory loss
        
        Decreased DTR's
        
        Pes Cavus (high-arched feet)
        
        40 different genes
        Involvement of myeline
        (demyelinating) versus axonal
        
        CMT1
        40-50% of all CMT
        17p Duplication
        Variability
        Pathology > Abnormal Myelin
        Autosomal Dominant
        
        Progressive weakness and atrophy in most distal foot muscles
        
        Pes cavus
        
        Hammer toe
        
        Foot drop
        
        Progresses to hands
        
        Hypertrophic palpable nerves
        
        Demyelinating (Myelin is formed but it's not functional --> Forms onion bulb)
        
        Decreased motor conduction velocities
        
        "Onion-bulb" formation on nerve biopsy
        
        CMT1A
        70-80%
        PMP22 duplication
        2/3 inherited
        1/3 de novo
        
        CMT1E
        <5%
        PMP22 point mutations
        
        CMT2
        
        Similar to CMT1
        
        Less severe
        
        Axonal, nondemyelinating
        
        Peripheral nerves not hypertrophic
        
        Normal to near normal NCS
        
        Multiple types (25 genes) distinguished by testing
        
        Can be AD or AR
        
        Intermediate AD CMT
        
        Typical CMT with abnormal myelin and axonopathy
        
        Overlapping NCS with CMT1 and CMT2
        
        DNM2, YARS, MPZ, GNB4
        
        CMT4
        
        AR
        
        Slow NCS
        
        11 genes
        
        CMTX
        
        X-Linked
        
        Connexin32 in 90%
        
        Moderate to severe in males
        
        Sensorineural deafness
        
        CNS symptoms (CMTX1)
        
        5 other loci
        
        2 unknown
        
        HNPP
        
        PMP22 gene deletion --> truncating mutation
        
        Hereditary Neuropathy with Liability to Pressure Palsy
        
        Friedrich Ataxia
        
        Metachromatic Leukodystrophy
        
        Familial Dysautonomia
        
        FEATURES
        
        Poor feeding, vomiting, irritability as an infant
        
        Abnormal temperature regulation, absent tearing, blotching of skin, hypotension
        
        Smooth tongue, lack of fungiform papillaie
        
        Decreased DTR's
        
        Sensory neuropathy
        
        Involvement of the autonomic nervous system
        
        Rare
        
        Autosomal Recessive
        
        9q31
        
        IKBKAP gene, 1/30 Ashkenazi Carrier Freq
        
        Onset in Infancy
      - Inflammatory Demyelinating
        
        Guillain-Barre
        
        CIDP
        Chronic Inflammatory Demyelinating Neuropathy