Differential Diagnosis in Neurology

12.1. Inherited Myopathies

The recent explosion of molecular genetics has been particularly illuminating for the understanding of inherited muscle disease. Mutations in the dystrophin gene and genes that transcribe proteins that connect the contractile protein actin and myosin to the exterior of the cell and ultimately basal lamina. Lamina make up a significant proportion of inherited muscle disease.

The Muscular Dystrophies

• X-Linked muscular dystrophies
  • Duchene muscular dystrophy
  • Becker muscular dystrophy
  • Emery Dreifuss muscular dystrophy
• Autosomal dominant muscular dystrophy
  • Myotonic dystrophy
  • Fascioscapula humeral dystrophy (FSHD)
  • Distal (adult onset) myopathy
  • Scapuloperoneal dystrophy
  • Oculopharyngeal dystrophy
• Autosomal receive muscular dystrophy
  • Limb girdle muscular dystrophy
  • Distal myopathy
  • Congenital muscular dystrophy
  • Scapulohumeral muscular dystrophy

X-Linked Recessive Dystrophinopathies

• Duchenne muscular dystrophy (DMD)
• Becker's muscular dystrophy (BMD)
• Isolated X-linked cardiomyopathy
• Isolated quadriceps myopathy
• Muscle cramps with myoglobinuria
• Asymptomatic elevation of muscle enzymes
• DMD/BMD-manifesting female carriers

General Features of Dystrophinopathies

• All are allelic and are generated by different mutations of the dystrophin gene
• Dystrophin gene:
  • One of the largest genes known (2.4 mega bases)
  • Xp21; codes dystrophin
• Genetics
  • In DMD:
    • There is either no dystrophin expression or there is production of a truncated or dysfunctional protein
    • Dystrophin is involved in the contractile function of muscle cells by its link between the plasmalemmal component of the sarcoplasmic membrane and laminin of the extracellular membrane via dystrophin associated protein complex
    • Dystrophin deficiency destroys the mechanical stability of the muscle sarcolemmical membrane with consequent contraction induced rupture of the cell, influx of calcium and activation of proteolytic enzymes
    • DNA analysis:
      • Deletions 66% of patients
      • Duplications 5%
      • Rare inversions
    • May be manifest in heterozygous females:
      • Carriers with gene translocations
        • Break points at Xp21 with preferential inactivation of the normal chromosome
      • Biased X-chromosome inactivation (Lyon's hypothesis):
        • Most common in twin pregnanciescr
      • Turner's syndrome or mosaic
        • XO/XX
        • mosaic XO/XX/XXX
          • X-chromosome carries a mutated gene; female child is affected
    • Other genetic mechanisms:
      • Spontaneous mutation of a single germ cell of the mother
      • Mutation of probands gene early in post zygotic embryo development
      • Germline mosaicism:
        • Mother is not a somatic carrier
        • Has more than one affected child
        • 20% of new DMD mutations
        • Due to mutation at the mitotic stage of germ cell lineage development
        • Maternal mutation
          • Risk of more than one affected male child
        • Paternal mutation
          • Female children at risk of being carriers
    • "Hot Spots" of deletion
      • Intron 44 and 45
      • Exon 45

Clinical Manifestations of Dystrophinopathies

• Elevated enzymes at birth
• Delayed walking (some patients)
• Weakness usually apparent at 2–3 years
  • Proximal muscles prior to distal
  • Lower extremities prior to upper
• By ages 3–6
  • Waddling gait (hip flexors are weak; function substituted by hip abduction)
  • Exaggerated lumbar lordosis
  • Calf enlargement ("rubbery" feel)
  • By pain
  • Gower's maneuver noted
  • Neck flexor weakness:
    • More severe in DMD than in Becker's or intermediate forms
  • May have pseudohypertrophy of:
    • Deltoids
    • Gluteal muscles
    • Quadriceps
    • Masseter (rare)
  • Ankle flexors and invertors stronger than dorsiflexors
    • Equinovarus position of feet
    • Toe walk
    • Heel cord contraction
      • May be accelerated if gastrocnemius muscle is biopsied
• Boys clinical pattern of weakness, ages 6–11
  • Linear loss of muscle strength
  • Loss of proximal muscle strength accelerates
  • Loss of deep tendon reflexes
    • Exception is resistance of brachioradialis and ankle jerks
      • Involvement of intrafusal fibers of the muscle spindle
• Scoliosis and contractures develop
  • Contractures start at ankle, hip > knee > elbow > wrist
• Usually wheelchair bound by 12 years of age
  • Death during the late teens:
    • Pulmonary complications
    • Cardiomyopathy
  • 25% of patients survive past 21

Duchenne's Muscular Dystrophy

Systemic Involvement in DMD

• Cardiac:
  • Fibrosis of the ventricular wall
  • Greatly enlarged R waves across the precordium
  • Q waves in limb, body and precordial leads
  • Decreased rate of relaxation in diastole
  • Mitral valve prolapse
  • Intra atrial conduction defects
  • Infranodal conduction defects
  • Arrhythmias are most common during infections
  • Echocardiography:
    • Diminished contractility of the posterolateral ventricular wall and left ventricle
    • Rarely congestive heart failure may occur prior to respiratory involvement

Respiratory Musculature

• Cough is ineffective due to decreased maximum end expiratory and inspiratory pressures
• Death occurs:
  • In the second or third decade from pulmonary infection
  • Respiratory and cardiac failure

Cognitive Function

• Most patients demonstrate a non-progressive intellectual impairment (at least 1/3); IQ < 75
  • One standard deviation below normal
  • Brain type 427 isoform of dystrophin
  • Verbal ability > performance skill
  • Occasional child with normal or above average IQ

Smooth Muscle Dysfunction

• Degeneration of gastrointestinal tract smooth muscle:
  • Intestinal pseudo obstruction
  • Presentation with: pain, distention, vomiting, gastric dilatation

Osteoporosis

• May be severe and starts while patients are walking

Adverse Anesthetic Reactions

• Occur with the use of halothane and succinylcholine:
  • Malignant hyperthermia
  • Acute hyperkalemia in absence of hyperthermia
  • Acute cardiac failure (cardiomyopathy)

Becker's Muscular Dystrophy (BMD)

• General features:
  • Allelic disorder to DMD
  • Mutations or deletions maintain the reading frame which results in the production of some functional dystrophin
    • Longer or shorter dystrophin
  • Dystrophin reduced to <20–30%
  • Less common than DMD
    • Incidence is 1 in 30,000 male births
• Clinical presentation:
  • Age of onset between 5–15 years of age (mean 12 years)
    • Rarely 3d or fourth decade
  • Milder involvement than DMD but same pattern
    • Pelvic girdle > tibialis anterior and peroneal muscles > shoulder girdle
    • Early calf muscle pseudohypertrophy
    • Neck flexors are affected later in the course
      • Differential point between DMD and other dystrophinopathies
    • Fewer contractures; develop in wheelchair stage
    • Scoliosis develops after patients are wheelchair bound
    • Slow progression into age 30–40's
    • Cardiomyopathy occurs; its severity may not correlate with degree of muscle weakness:
      • EKG abnormalities not as frequent as in DMD
    • pes Cavus is noted in 15–70% of patients
    • Cardiac involvement:
      • RBBB
      • T wave changes
      • May precede muscle involvement by several years
    • Intellectual function:
      • Minority of patients are mentally retarded
      • Cognitive impairment may be the presenting symptom
    • Cryptorchidism; hypogenitalism; testicular atrophy have been reported
      • Fertility is approximately 70% of unaffected brothers
    • EMG
      • Myopathic; short duration small amplitude polyphasic potentials
      • Rare fibrillation potentials
    • Patients survive to 30–60 years of age
    • Cause of death:
      • Respiratory insufficiency
      • Cardiomyopathy
      • Cor pulmonale

Laboratory Evaluation of Dystrinopathy

• Genetic testing for DMD/BMD
• Muscle enzymes:
  • Less than 5 years of age, CK levels are 20–100 times normal in BMD
  • Less than 5 years of age: CK levels are 50–100 times normal in DMD
  • CK levels decline with age (20% per year)
  • 70% of carriers have elevated enzymes
    • Decline with age
  • CK is the most specific muscle enzyme:
    • AST is least organ specific
    • ALT more liver specific
    • Aldolase is elevated in BMD/DMD

Electromyographic Evaluation of BMD/DMD

• Myopathic in proximal muscles (early):
  • May demonstrate fibrillation potentials and increased insertional activity
  • Late changes:
    • CMAP decreases
    • Insertional activity decreases
    • Very small muscle action potentials
    • Disappearance of fibrillation potentials

Muscle Biopsy Evaluation of BMD/DMD

• Histopathologic findings:
  • Degeneration
  • Regeneration
  • Isolated opaque fibers
  • Replacement of muscle by fat and connective tissue
  • Increased variability of muscle fiber size:
    • Larger than normal in younger patients
    • Smaller than normal fibers with disease progression
  • Internal nuclei in 2–4% of fibers
  • Type I fiber predominance
  • Inflammatory cells in the perimysium, endomysium and perivascular spaces
    • Monocytes and macrophages
  • Gomori trichome stain:
    • Striking endomysial and perimysial increase of connective tissue
• Dystrophin immunostaining:
  • DMD patients:
    • No detectable dystrophin of the sarcolemma
    • 80% of DMD patients:
    • a) Dystrophin expression is noted <1% of fibers
    • BMD patients
      • Normal or partial dystrophin staining of the sarcolemma
  • Symptomatic and asymptomatic carriers of DMD/BMD
    • Mosaic pattern of muscle fiber staining for dystrophin
  • Western blot: the gold standard for dystrophin analysis; determines:
    • Quantity of dystrophin
    • Molecular size of the molecule:
      • 80% small in BMD patients
        • Deletion mutation primarily
      • 5% increased:
        • Duplication mutation of the dystrophin gene
  • Rarely there is no correlation between phenotype and genotype as regards quantity of dystrophin in BMD/DMD patients

Intermediate Phenotype ("Outliers") of Muscular Dystrophy

• Mild DMD or severe BMD:
  • Ambulatory greater than 12 years of age
  • Wheelchair bound less than 16 years of age
  • Preservation of ability to flex their neck against gravity
  • Cardiomyopathy
  • Cognitive impairment

Isolated X-Linked Dilated Cardiomyopathy

• General characteristics and clinical features:
  • Progressive and fatal heart disease
  • Presents in the second or third decade
  • Congestive heart failure patients without skeletal muscle weakness
  • Muscle isoenzyme of CK elevated
• Genetics:
  • Specific mutations in the dystrophin gene:
    • Selective absence of dystrophin in heart muscle
    • Mutations of the 5th exon of the gene result in a more severe cardiomyopathy than those in the spectrin-like region (exons 48–49)
    • Exclusive cardiac involvement is related to a difference in RNA splicing regulation between heart and skeletal muscle

Isolated Quadriceps Myopathy

• Clinical characteristics:
  • Mild slowly progressive
  • Limited to the quadriceps muscles
  • Some patients have concomitant cardiomyopathy
  • Mutation of the dystrophin gene is causative
  • Some patients with calf hypertrophy

Muscle Cramps with Myoglobinuria

• Genetics:
  • Exon 40–44 and 45–57 of the dystrophin gene is important
  • X-linked
• Clinical presentations:
  • Exercise induced myalgias and cramps without skeletal weakness
  • May have normal or borderline elevated CK; no pathology on muscle biopsy
  • Family with cardiomyopathy and muscle cramps without clinical weakness has been reported
  • Association of myoglobinuria without weakness seen in patients with:
    • Exercise induced cramps
    • Exercise induced myalgias
    • Cardiomyopathy and exertional cramps
  • Differential point: Need to rule out metabolic myopathy without fixed weakness
  • Isolated Elevation of Muscle Enzymes:
    • Possible mutation of the rod domain of the dystrophin gene
  • Female Relatives of Boys with DMD/BMD:
    • Heterozygous carriers with mutated dystrophin gene:
      • Random "X" inactivation
      • Inversions
    • Clinically evident weakness in 2.5–10% of carriers (proximal muscles)
    • 70% of carries have elevated CK
    • Mosaic of fibers with either normal or absent dystrophin
    • May have calf hypertrophy

• Differential Diagnosis:
  • Limb girdle muscular dystrophies:
    • Absence of cognitive deficit
    • Less frequent cardiomyopathy
    • Less marked calf hypertrophy
    • Autosomal receive or autosomal dominant inheritance (the later rules out dystrophinopathy)
  • Limb girdle clinical presentation in a girl:
    • Rule out DMD or BMD with 45 XO
    • Non-random X chromosome inactivation
  • Acid maltase deficiency:
    • Childhood proximal muscle weakness
    • Rare calf hypertrophy
    • Irritative EMG
    • Subsarcolemmal vacuoles on muscle biopsy
  • Spinal muscular atrophy:
    • May have prominent proximal muscle weakness in childhood
    • CK is minimally elevated
    • EMG is neuropathic
  • Emery–Dreifuss muscular dystrophy:
    • AD not X-linked
    • No pseudohypertrophy
    • Early elbow and heel contractions
    • Mild CK elevation
    • Prominent cardiac abnormalities
  • Unexplained persistent elevation of liver enzymes (ALT) alanine aminotransferase and aspartate aminotransferase (AST)
    • Present in muscle tissue
    • May represent dystrinopathy in:
      • women who later become symptomatic (DMD/BMD)
      • asymptomatic carriers
    • Other muscular dystrophies
    • CK is elevated if the other enzymes elevations are from muscle
  • Isolated dilated cardiomyopathy
    • Need to rule out dystrinopathy

Emery–Dreifuss Muscular Dystrophy (EDMD)

• Genetics:
  • EDMDI:
    • X-linked
    • Emerin mutations: are non-sense, frame shift or splice:
      • A few in-frame mutations result in residual or normal expression of the protein
      • Function of emerin:
        • Cell cycle events
        • Membrane anchorage to the cytoskeleton
• EDMDII:
  • AD and AR forms
  • Mutation of the lamina A/C gene (LMNA):
    • Encodes two proteins of the nuclear lamina; A and C by alternative splicing
• Clinical Features:
  • Three major presentations:
    • Muscle weakness
    • Contractures > cardiac signs
    • Cardiac onset with sudden death
  • Myopathy with contractures
    • Onset in childhood
    • Contractures involve elbow extension, neck flexion and ankle dorsiflexion; occur in all patients with muscle weakness
    • Proximal weakness:
      • Equinovarus position (rare)
      • Muscle weakness in upper arms noted early (rare)
    • Flexion contraction at 4–6 years of age
      • No concomitant muscle weakness
    • Contractures exacerbate during growth
    • Flexion contracture of the wrist in adults
    • Contracture of lower back muscle causes rigid spine
    • Wasting is severe in the posterior leg compartment and the biceps
      • Hypertrophy of the extensor digitorum brevis
    • Weakness of elbow flexion and finger extension > hip girdle and pelvic musculature weakness
• Rare muscular involvement:
  • Orbicularis ores and oculi
  • A severe phenotype with inability to walk by adolescence
  • Hyperextension of the neck and thorax
• EDMD/carriers
  • No musculoskeletal symptoms

Associated Findings

• Scoliosis is not usually severe
• Hyperextension of the neck and thoracic spine lordoscoliosis, is rare
• Decreased cognitive function (rare)
• No correlation of cardiomyopathy and skeletal myopathy

Cardiac Presentation

• Presents between second to fourth decades in EDMD1; 3rd to 4th decades in EDMD2
• Atrial paralysis:
  • Seminal in EDMDI
• Atrial paralysis and dilated cardiomyopathy occur in EDMD2
• EDMDI:
  • Sudden death frequent between 25–49 years of age
  • Few patients demonstrate syncope or dizziness
  • Cardiac disease occurs in female carriers
• Isolated cardiac involvement is more frequent in EDMD2
  • Defects in LMNA genes are associated with:
    • Adult onset dilated cardiomyopathy
    • Conduction defects
    • No weakness or contracture
• Cardiac pathology
  • Replacement of muscle by fat and fibrosis
• Differential diagnosis of EDMDI vs. EDMD2
  • EDMDI:
    • Musculoskeletal weakness and early joint contracture
    • Late cardiac conduction defects
    • Maintain ambulation
  • EDMD2:
    • Heterozygotes may be asymptomatic
    • Rarely aggressive from causes loss of ambulation
    • Isolated dilated cardiomyopathy
• Laboratory Diagnosis of EDMD
  • Elevation of CK to 10× normal in younger patients
• EMG:
  • Myopathic
  • NCVs are normal
• Muscle Biopsy
  • Myopathic:
    • Variation of fiber size
    • Endomysial fibrosis
    • Type I fiber atrophy or fibrosis
• Emerin is absent in the nuclei of 95% of patients (EDMDI)
  • Emerin may be detectable in missense or promotor mutations
• EDMD2
  • Perinuclear LMNA and emerin is present
• EKG findings in young patients with early cardiac involvement:
  • Low amplitude P waves
  • Prolongation of the P-R interval
  • Atrial fibrillation and atrial flutter occur with progression of the disease
  • Sentinel pattern:
    • Functional escape rhythm at 40–50 beats/minute
    • No P wave due to atrial standstill
    • No electrical or mechanical activity of the atria
    • Inability to pace the atria
• Molecular diagnosis of EDMDI:
  • Western blot and immunohistochemistry
  • Absent emerin in muscle, skin and buccal smears in male patients
    • Reduction of protein and mosaic expression in female carriers

EDMD2

• AD and AR forms
  • Emerin is normal and genetic analysis is necessary

Emerin Mutations (EDMD1)

• Non-sense frame shift or splice mutations
  • Result in absence of the protein
• In-frame deletions and missense mutations:
  • May be associated with residual or normal expression of the protein

LMNA Gene Mutations (EDMD2)

• Non-sense and missense mutations
  • Rod domain mutations
    • Isolated cardiomyopathy with A-V block

Differential Diagnosis of the Rigid Spine Syndrome

• X-linked Emery–Dreifuss muscular dystrophy
• Bethlehem myopathy
• Congential muscular dystrophy with rigid spine (CMDRS)
• Scapuloperoneal syndrome of Thomas

Bethlehem Myopathy

• Genetics
  • AD
  • Chromosome 21q22:
    • Decrease in beta laminin expression
  • Mutations in collagen type VI genes:
    • Collage IV deficiency in the extracellular matrix
• Clinical Presentation:
  • Decreased fetal movements
  • Weakness or contractures during the first two years of life
  • Neonatal hypotonia; torticollis at birth (rare)
  • Contractures change during childhood
  • Pattern of muscle involvement:
    • Pelvic weakness in early childhood
    • Slow progression
    • Early flexion contractures of elbows, ankles and last four fingers
    • No cardiac involvement (one patient described with septal hypertrophy)
    • May cause progressive respiratory compromise (rare)
    • Some patients over 50 are wheelchair bound

CMD with Rigid Spine Syndrome

• Genetics:
  • Chromosome 1p 35–36; rigid spine (RSDMD) locus; sporadic cases are noted
  • Families with rigid spine and CMD that have been excluded from RSMDI have been identified
  • Merosin positive congenital muscular dystrophy (CMD) with rigid spine ARC
• Clinical presentation:
  • Majority of patients are male
  • Delay in reaching motor milestones; wobbly gait
  • Proximal muscle weakness noted by age 8
  • Weak sternocleidomastoid muscles
  • Non-painful progressive limitation of flexion of the neck and trunk
  • Progressive scoliosis
  • The neck is hyperextended, the trunk is tilted forward, flexion only occurs at the hips
  • Contractions of the elbows and knees
  • Decreased deep tendon reflexes
  • The heart may be involved:
    • Complete heart block
    • Ventricular hypertrophy
    • Cardiomyopathy
• Laboratory evaluation:
  • CK is moderately elevated
  • EMG-myopathic
  • X-ray of the spine is normal
• Muscle biopsy:
  • Fiber size variation
  • Regeneration and degeneration
  • Increased endomysial and perimysial connective tissue (particularly axial muscle)
  • Type I fiber disproportion (not universal)

Scapuloperoneal Syndrome of Thomas

• Clinical features
  • Proximal muscle weakness of the upper limbs and distal muscles of the lower limbs
  • Contractures of the elbows
  • Pes cavus (as the disease progresses)
  • Scoliosis and flexion contraction of the neck is rare
  • Cardiomyopathy in adult life
  • Color blindness

Myotonic Dystrophy Type I (DM1)

• Autosomal Dominant Muscular Dystrophies 
  • Epidemiology:
    • Incidence of 13/100,000 live births
    • Prevalence 3–5/100,000 population
• Genetics:
  • CTG repeat in the gene in chromosome 19
  • Enlarged section of a CAMP-dependent kinase gene due to CTG repeats
  • CTG expansion interferes with a neighboring homeobox gene
  • Several genes may be rendered dysfunctional
  • Abnormal RNA produced has detrimental effect on RNA homeostasis
  • Anticipation is noted with age at onset from teens to old age:
    • Normal 5–35 repeats
    • Mild and late onset greater than 50 repeats
    • Congenital severely involved patients have 1000–2000 repeats
  • Severity worse with maternal inheritance
    • Greater CTG length
  • Variable penetrance, anticipation and somatic gene variability:
    • Mutation size varies over time in the same tissue of an individual
    • Varies between tissues in a single individual at a single time
    • Best correlation of repeat length:
      • Strength 3) Intelligence
      • Age at onset
    • Variations in age of onset correlate with repeat length for short repeats only
• Clinical Presentation
  • General onset:
    • Usually in early adult life; there is an infantile from
    • Heterogeneity among family members is common
    • Anticipation with succeeding generations
      • Maternal imprinting; greater increase in repeat length when disease is inherited from the mother
• Muscle Weakness
  • Weakness of facial muscles and ptosis is often present prior to the diagnosis
  • Jaw muscle weakness and wasting is characteristic; temporalis and masseter weakness is associated with TMJ dysfunction
  • Sternocleidomastoid weakness and wasting is prominent; relatively well preserved posterior neck and shoulder girdle muscles (differential point from FSH dystrophy)
  • Distal greater than proximal limb muscle weakness; dorsal and volar interossei, intrinsic foot muscle weakness; wrist extensors are prominently involved; quadriceps and proximal pelvic girdle strength allow patients to walk
  • Long finger flexors; weakness of mouth closure and lower facial musculature; differential involvement of lateral fingers (similar finger and forearm involvement to inclusion body myositis)
  • Rare muscle hypertrophy
    • Similar to that noted with myotonia congenita
• Facial Dysmorphism
  • Long; "hatchet" like
  • Transverse smile
  • Slight backward head tilt (looking under ptotic lids)
• Muscle Pain
  • Deep ache; different from discomfort of myotonia but coexistent with it
• Myotonia
  • Primary symptom is "stiffness" of muscle
  • Aggravated by cold
  • Generalized myotonia is rare; often the hand and tongue are most easily noted. Generalized myotonia is common in myotonia congenita.
  • Grip myotonia is the predominant myotonic symptom
  • Percussion myotonia is easily induced in tongue, extensor forearm and thenar muscles
  • EMG:
    • Electrical myotonia highly penetrant feature in adults
    • Diffuse fibrillation potentials and occasional fasciculations may be seen during myotonic runs
  • Molecular basis for myotonia:
    • Increased muscle fiber expression of a calcium activated potassium channel
      • Apamin receptor
    • Possible alteration of chloride channel conductance
• Cardiac Disease
  • Often causes death
  • EKG abnormalities:
    • First degree heart block is most common
    • Atrial flutter
    • His bundle recordings demonstrate conduction defects
      • Intraventricular
    • Does not correlate with disease severity or repeat length
  • Hypotension
  • Sudden death
  • Anesthetics (quinidine, procainamide) may exacerbate conduction defects
  • Rare: congestive heart failure, mitral valve prolapse and cardiomyopathy
  • Rare posterior wall myocardial infarction
• Respiratory Involvement
  • Diaphragm weakness
    • Myotonia may be causative
  • Alveolar hypoventilation
  • Aspiration pneumonia and bronchitis
  • Post anesthetic respiratory failure
• Smooth Muscle Dysfunction
  • Swallowing disturbance with aspiration:
    • Delayed relaxation of hyoid musculature
    • Abnormal esophageal peristalsis
  • Colonic dysfunction:
    • Abdominal pain
    • Reduced colonic motility
    • Dysfunction of internal and external anal sphincter
    • Obstipation
  • Ureter
    • Rare dilatation
  • Uterus
    • Uncoordinated contractions during labor
  • Gallbladder
    • Delayed emptying
    • Increased incidence of gallstones
  • Eye
    • Dysfunction of ciliary muscle which is responsible for low intraocular pressure
• Ocular Abnormalities
  • Posterior subcapsular cataracts ("stellate") in almost all adult patients
  • Retinal degeneration:
    • Peripheral pigmentary
    • Macular involvement
  • Enophthalmos
  • Low intraocular pressure
  • Corneal lesions
  • Blepharitis
  • Ptosis
  • Slow saccades
  • Ophthalmoplegia is rare
• Central Nervous System
  • Proportion of patients with low IQ:
    • 2/3 are normal
    • Possible early memory deficit
  • Deficits on behavioral and psychometric testing
  • Hypersomnia:
    • Some related to alveolar hypoventilation
    • Centrally mediated hypoventilation
  • Imaging abnormalities
    • CT:
      • Ventricular dilatation
      • Progressive atrophy
    • MRI
      • T2 non-specific abnormalities
• Endocrine System Dysfunction
  • Hyperinsulinism; flat glucose tolerance curve; rare to have overt diabetes
  • Testicular atrophy:
    • Primary tubular degeneration
    • Leydig cells are intact
    • Oligospermia
    • High LSH levels
    • Low serum testosterone
  • Women:
    • High rate of fetal loss
    • Severe complications of pregnancy
  • Pituitary
    • Increased FSH levels
    • Slightly increased LH levels
    • Increased luteinizing hormone releasing response
  • Hypothyroidism (rare)
  • Hyperresponsiveness to exogenous growth hormone (rare)
  • Pituitary adenoma (rare)
  • Abnormal adrenocortical function
  • Some indications of abnormal parathyroid function
• Miscellaneous Abnormalities
  • Hair
    • Early male frontal balding
  • Calcified epitheliomata and pilomatrixomata
  • Hypogammaglobulinemia
    • Lower levels of IgG and IgM
  • Liver involvement
    • Increased serum transaminase
    • γ-glutamyltransferase elevation in some patients
  • Putative relationship with neoplasia

Myotonic Dystrophy Type 2 (DM2 ) and Proximal Myotonic Myopathy

• General features:
  • 10 cm region on chromosome 3q ( DM2)
    • CCTG finger 9 gene
    • Toxic RNA repeat expansions
  • Gene for proximal myotonic myopathy (PROMM) also maps to DM2 locus
  • DM2 locus
    • Disease linked to this locus
  • PROMM
    • Multisystemic myotonic disorder that is not due to DM1 locus and have not been mapped to DM2 locus
• Clinical features:
  • DM2 has muscle pain similar to DM1
  • Muscle weakness:
    • Less severe than DM1 patients
    • Neck flexors, long finger flexors, hip girdle musculature; lower extremity proximal weakness
    • DM2 same facial weakness as DM1
  • Electrical and clinical myotonia:
    • Less severe myotonia than DM1
    • Same pattern of myotonia in muscle as DM1
    • Occasional brief high-frequency 250–300 Hz discharges in DM2 (possibly specific to PROMM and DM2)
  • Eye findings:
    • Ptosis
    • Cataracts
  • Cardiac:
    • Conduction defects and fatal arrhythmias
      • Atrioventricular defects less common than in DM1
    • Rare cardiomyopathy and congestive heart failure
• Endocrine:
  • Hyperinsulinemia, hyperglycemia, flat glucose tolerance curve, insulin insensitivity
    • Rare frank diabetes
  • Hypothyroidism (rare)
  • Testicular failure
• Central nervous system:
  • DM2 with mental retardation
  • MRI and PET abnormalities have been reported in some PROMM families

Miscellaneous System Dysfunction in Myotonic Dystrophies

• DM1 has frontal balding
• Hypogammaglobulinemia
  • Decreased IgG and IgM
• Liver dysfunction possible in DM2

Muscle Biopsy Evaluation of DM1 and DM2

• Atrophic and hypertrophic fibers
• Scattered severely atrophic fibers
• Nuclear bags
• Scattered necrotic fibers
• Split and ring fibers (ringbinden)
• Eosinophilic cytoplasmic inclusions in DM1
• Type 1 fiber predominance in DM1 and DM2

Congenital Myotonia

• General features:
  • Mother the most often affected parent
  • Poor fetal movements; hypohydremias
• Clinical features:
  • Hypotonia at birth
  • Bulbar involvement with consequent feeding and respiratory difficulty
  • No clinical or electrical myotonia
  • Severe facial diplegia (85% of patients)
  • "Tented" upper lip
  • Skeletal abnormalities:
    • Talipes
    • Congenital hip dislocation
• Clinical progression:
  • Delayed muscle tone
    • Children can walk
  • Mental retardation
  • Myotonia develops
  • Distal weakness
• Laboratory evaluation:
  • CPK is mild to moderately elevated
  • EMG:
    • Spontaneous trains of motor unit firing that vary in amplitude and frequency (myotonic discharges)
• Muscle biopsy:
  • Variation of fiber size
  • Internal nuclei
  • Type I fiber atrophy
  • Sarcoplasmic masses
  • Ring fibers (ringbinden)
  • Fibrosis
  • Prominent fiber splitting

Differential Diagnosis of Myotonic Dystrophy

• Myotonia congenita
• Paramyotonia
• Schwartz–Jampel syndrome
• Drug induced myotonia

Fascioscapulohumeral Muscular Dystrophy

• General characteristics:
  • Third most common dystrophy
    • MD > DMD > FSHD
    • Prevalence of 1/20,000 population
    • Incidence .4–5/1000 population
• Genetics:
  • Gene on chromosome 4q35:
    • Deletion of variable size in a 3.3-kilobase repetitive element D4Z4 repeats
    • D4Z4 repeat alter chromosomal structure:
      • Influences the expression of more centromerically located genes
        • Position effect variegation
    • Size of the deletion determines disease severity
    • Possible deleterious gain of function from mutations within D4Z4
• Clinical features:
  • Age at onset (7–27 years of age; infantile from has been noted rarely)
    • Perhaps 30% of patients may be asymptomatic
  • Facial muscle weakness occurs first:
    • Orbicularis oculi
    • Zygomaticus
    • Orbicularis oris
  • Facial involvement may be asymmetrical
  • Ocular, masseters, temporalis, pharyngeal muscles are spared
  • Patients may sleep with their eyes slightly open
  • Early in the course patients cannot whistle or drink from a straw
  • Descending sequence of muscle involvement
  • Initial weakness of the scapular muscles and shoulder fixators:
    • Latissimus dorsi
    • Lower fibers of the trapezius
    • Rhomboids
    • Serratus anterior
• This pattern of weakness causes the clavicle to assume a more horizontal location and to angle downward:
  • Winging of the scapula with abduction
  • Sternocostal head of the pectoralis muscle is weak and atrophic which causes an upward slope of the axillary fold; flattening of the anterior chest wall; pectus excavatum in severely affected patients
  • First, 25 degrees of arm abduction is affected by the supraspinatus muscle; 25 degrees to the horizontal is accomplished by the deltoid; over the head position of the arm requires scapular rotation and fixation to the chest wall which fails in FSHD.
  • Coincident with shoulder girdle weakness:
    • Significant weakness of the anterior tibialis > peronei muscles
    • Foot drop is often noted
    • Posterior leg muscles are spared
    • Proximal hip girdle muscle may be significantly involved early in some patients
    • Differential involvement of lower abdominal musculature that produces a positive Beevor's sign; exaggerated lordosis
    • Relative sparing of neck flexors
  • Progression of weakness: Facial musculature > shoulder girdle > biceps and triceps > ankle dorsiflexors > pelvic girdle
  • Slow progression is the rule: periods of accelerated weakness occur
  • Wheelchair confinement is rare: life expectancy is normal. Mean age at death for males is 64 years of age and for females 70 years of age.
  • Associated clinical features:
    • Ptosis
    • Sensorineural hearing loss:
      • Largely asymptomatic; may be severe in the infantile presentations
      • High frequency hearing loss
    • Retinal telangiectasis:
      • Usually is asymptomatic
      • Rarely cause an exudative retinal detachment
    • Lordosis and kyphosis
    • Depressed deep tendon reflexes
    • Cardiac involvement:
      • 60% of patients demonstrate EKG abnormalities involving:
        • Atrial
        • Atrioventricular-node
        • Infranodal arrhythmias
        • Inducible atrial flutter or fibrillation
      • Approximately 5% of patients have significant cardiac abnormalities
• Laboratory evaluation:
  • Molecular diagnosis:
    • Highly specific and sensitive
    • Performed on DNA of leukocytes
  • CK is elevated (<10 times the upper limit of normal)
  • EMG is myopathic; rare fibrillation potentials
  • Muscle biopsy; myopathic; occasional small angulated fibers; rapidly progressive disease and infantile forms demonstrate inflammatory changes

Differential Diagnosis of Weakness in the Facio-Scapular Distribution

• Scapuloperoneal syndromes:
  • Heterogenous
  • Neurogenic and myogenic forms
  • Myogenic forms:
    • In the near future will be genetically reclassified as LGMD
  • May have mild facial weakness
  • Some FSHD patients may have minimal facial weakness
• Hereditary proximal spinal muscular atrophy:
  • No facial involvement
  • Entire shoulder girdle including deltoid muscles are involved
• Restricted polymyositis:
  • Course similar to FSHD
  • AD inheritance in two patients
  • Facial scapular and anterior tibialis muscle involvement
  • Muscle biopsy: similar to polymyositis
  • EMG compatible with polymyositis
  • Differential points in patients with restricted polymyositis (FSHD) distribution versus true polymyositis:
    • Facial atrophy is greater in FSHD, but strength is surprisingly good
    • Polymyositis has minimal facial atrophy
• Coat's disease (VIIIth nerve defects with retinal disease):
  • Begins in infancy
  • Hearing loss is unilateral or bilateral (sensorineural)
  • Retinal telangiectasis with exudate of proteinaceous material; retinal detachment

Scapuloperoneal Syndrome

• General features:
  • Separation from FSHD is putative at present
  • Davydov variant:
    • Scapuloperoneal weakness
    • Distal sensory loss
    • Pes cavus
    • Depressed reflexes
    • Decreased motor and sensory NCVs
  • Kaiser variant:
    • 12 members over five generations
    • Anterior horn cell as primary pathology
  • AR and sporadic cases of scapuloperoneal syndrome have been reported
• Clinical Presentations:
  • Neuropathic and myopathic forms present in a similar manner
  • Age of onset is late childhood to early adulthood; onset may be either in infancy or as late as 50 years of age
  • Weakness is initially noted in the shoulder girdle and progresses to the anterior tibialis muscles and then to the pelvic girdle.
  • Facial weakness is mild; late concomitant of the disease
  • AR and sporadic cases tend to be neuropathic
  • Penetrance in AD forms is incomplete; inter and intra familiar variation is common
  • Mild to moderate elevation of CK

Further Differential Diagnosis of Fascioscapulohumeral Muscular Dystrophy

• Differential Aspects
  • Limb-girdle dystrophy:
    • Less prominent facial weakness
    • Proximal upper and low limb girdle weakness
  • Emery–Dreifuss Muscular Dystrophy:
    • Prominent contractures
    • Severe atrioventricular conduction defects; cardiac arrhythmia; atrial paralysis
  • Inclusion body myositis:
    • Prominent swallowing abnormalities
    • Early long finger flexion contraction
    • Quadriceps involvement
    • Commonest inflammatory myopathy over the age of 50
  • Mitochondrial myopathy:
    • Ophthalmoplegia
    • Fatigue with exercise
    • Short stature
    • Symptomatic VIIIth nerve deficits
    • Severe dilated cardiomyopathy
  • Acid maltose deficiency:
    • Enlarged tongue
    • Congestive heart failure
    • Fibulation potentials
  • Desmin storage myopathy:
    • Cardiomyopathy 
    • Peripheral neuropathy
    • Proximal muscle involvement (usually) 
  • Congenital centronuclear myopathy:
    • Prominent ptosis
    • Upper and lower girdle weakness
    • Less prominent cardiac defects

Oculopharyngeal Muscular Dystrophy (OPMD)

• Genetics:
  • French Canadians (1:1000); France putatively 1:100,000 (older studies 1:200,000); Bukhara Jews of Israel (1:600); Worldwide distribution
  • AD; chromosome 14q 11–13; rare AT form
  • Short poly alanine (GCG) expansion in the poly (a binding nuclear protein PABPN1) gene that accomplishes polyadenylation of nuclear messenger RNA
  • Poly alanine expansion is stable; normal < 15; disease GCG₇ to GCG₂₄
  • Decade specific penetrance of dominant GCG allele:
    • 63% (60–69 years)
    • 99% (>70 years)
  • AR: double GCG polymorphism
• Clinical Features:
  • Geographic areas of occurrence
    • Quebec, Southern California, Northern New Mexico and Arizona
  • Manifests in general 5th to 6th decade
    • Dominant GCG, allele:
      • 21% (<40 years; 6% 40–49 years)
      • 31% (50–59 years)
      • 63% (60–69 years)
  • Ptosis:
    • Bilateral and asymmetric
    • Earlier than dysphagia in most patients
  • Hutchinson's posture (head back to look out from under the eyelids) with frontalis contracture; may aggravate the dysphagia
  • As disease evolves:
    • Impairment of eye movements; rare complete external ophthalmoplegia
    • Rarely diplopia
    • Eyelids become thin and transparent
    • Intrinsic eye muscles are spared
    • No cardiac disease
  • Dysphagia (67%):
    • Solids > liquids early
    • Impaired gag reflex; decreased palatal mobility
    • Palatal and laryngeal weakness with dysphonia
    • Weakness and atrophy of the tongue (primarily Hispanic-Americans)
  • Weakness of facial, temporal and masseter muscles
  • Proximal leg weakness
  • Decreased upgaze 61%
  • Decreased deep tendon reflexes in some patients
  • Weakness and atrophy of the neck, shoulders, hip and arms occur in the late stage of disease
  • Muscle cramps in some patients
  • Early onset dominant OPMD is severe (5–10% of patients):
    • Ptosis/dysphagia < 45 years of age
    • Leg weakness < 60 years of age
    • Allele GCG
    • Severe case cluster in families
• Laboratory Evaluation:
  • DNA testing (99% specificity and sensitivity)
  • EMG:
    • Facial, limbs and pharyngeal muscles are myopathic
    • May have abnormalities in the extremities
    • Sensory and motor conduction velocities are normal or occasionally slightly decreased
  • Serum CK and aldolase are often normal; CK may be 2–3 × normal in some patients
  • Manometric and video fluoroscopy studies:
    • Weak prolonged and repetitive pharyngeal contractions
    • Normal upper esophageal sphincter
    • Sphincter relaxation is late and incomplete
  • A few patients demonstrate bundle branch block on EKG
  • Muscle biopsy:
    • intra nuclear filamentous inclusions (INIs)
    • Rimmed vacuoles
• Differential Diagnosis:
  • Myotonic muscular dystrophy:
    • Predominant systemic manifestations
    • Cardiac involvement
    • Myotonia
  • AD distal myopathy:
    • Welander
    • Marksberry/Gregg's/Udd
    • Noneka
    • Specific distal leg compartment atrophy
    • Less swallowing abnormality
    • No ophthalmoplegia
  • MG:
    • Fluctuating symptoms
    • Pattern of weakness
    • Severe ocular involvement that fluctuates
  • Mitochondrial myopathy with or without external ophthalmoplegia:
    • Severe cardiac involvement
    • Fatigue with exercise
    • VIIIth nerve deficits
    • Kearns–Sayre syndrome:
      • Dysphagia
      • Cardiac involvement (heart block)
      • Ptosis and ophthalmoplegia predominant
    • Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE):
      • Pseudo gastrointestinal obstruction
      • Pes cavus
  • Polymyositis and progressive bulbar palsy
    • No ptosis
  • Late onset familial ptosis:
    • onset in the sixties
    • No dysphagia
  • Recessive OPMD:
    • Late onset ptosis and dysphagia
      • Requires DNA testing

Distal Myopathies

• General Features:
  • Exclusive or predominant involvement of distal muscles
  • Primarily inherited muscular dystrophies
    • Some inflammatory and metabolic myopathies have a distal phenotype
  • Compatible with normal life span and function

Hereditary Distal Myopathies

• Late Adult Onset
• Type I: Welander Distal Myopathy
  • Large Kindred from Southern Sweden
  • Genetics:
    • AD; chromosome 2p13
      • 80% penetrance in males and 70% in females
      • Same locus for Miyoshi distal myopathy and LGMD Type 2B
      • Putative dysferlin gene
• Clinical Features:
  • Age at onset is greater than 40 years; mean is 47 years, a few patients have presented greater than 70 years of age; recorded in patients less than 30 years of age
  • Site of onset:
    • Finger and wrist extensors
    • Later evolution to toe and ankle dorsiflexors
  • Proximal involvement has been noted in some families
  • No neck weakness
  • Slow progression; compatible with a normal active life
• Laboratory Evaluation:
  • CK: normal or mildly increased
  • EMG:
    • Myopathic pattern
    • Rare neuropathic features
    • Some spontaneous activity and fibrillation potentials may be noted
  • Muscle biopsy:
    • Ringed vacuoles
    • Tubulo filamentous inclusions:
      • 15–18 mm cytoplasmic and nuclear filaments
    • Split fibers

Unusual Features of Hereditary Distal Myopathies

• Loss of reflexes (primarily ankle jerks) late in the course of the disease
• Autonomic dysregulation with cold hands and feet in 90% of patients
• Weakness of toe and finger flexors early in the illness
• Some progress subacutely rather than the usual insidious pattern

Type 2: Late Adult Onset (Marksberry/Gregg's/Udd)

• Genetics:
  • English, French; Finnish patients
  • AD; Chromosome 2q 31
• Clinical features:
  • Age at onset is greater than 40 years
  • Site of onset:
    • Anterior leg important; ankle and toe dorsiflexors
  • Proximal weakness:
    • Limb girdle pattern in some families
    • Occurs late in the course of the illness
    • Weakness is usually confined to the legs
  • No neck weakness
  • Late distal finger and wrist extensor weakness
• Laboratory Evaluation:
  • Serum Creatine Kinase: is normal or mildly increased (2–5 times normal)
  • EMG:
    • Myopathic pattern
    • Spontaneous activity: fibrillations and positive sharp waves
  • Muscle biopsy:
    • Rimmed vacuoles (more prominent than Welander's)
    • Tubule-filamentous inclusions
  • Infantile from (AD; foot drop; no progression after childhood)
  • Juvenile onset (AD: Biemond variant; onset at 5–15 years of age)

Early Adult Onset (Type I) Nonaka

• Genetics:
  • Patients reported from Japan, Italy; North and South America
  • Chromosome 9p1-q1 (also sharing this locus is: familial inclusion body myopathy, quadriceps sparing myopathy)
• Clinical features:
  • Site of involvement:
    • Ankle, dorsiflexors and toe extensors
  • Foot drop and steppage gait
  • Mild distal upper extremity involvement
  • Late onset proximal weakness in some patients
  • Quadriceps is strong in the face of proximal weakness
  • Neck flexor weakness
• Laboratory Evaluation:
  • Muscle Enzymes:
    • Serum CK elevated (less than 5 times normal)
  • EMG:
    • Myopathic; some fibrillation potentials
  • Muscle biopsy:
    • Prominent rimmed vacuoles
    • Dystrophic features
    • Nuclear or cytoplasmic 15–18 mm filaments associated with the vacuoles

Type 2: Miyoshi Distal Myopathy

• Genetics:
  • AR or sporadic; families linked to chromosome 10
  • Chromosome 2p18; LGMD-2B (same locus)
  • Dysferlin is the gene product
  • Japanese, Dutch, Hispanic and other ethnic groups
  • Dysferlin:
    • Muscle membrane bound protein
• Clinical features:
  • Presents between 15–30 years of age
  • Initial site of weakness is posterior leg compartment:
    • Gastrocnemius atrophy
    • Difficulty standing on their toes
    • Pain in the calves
    • Loss of ankle jerks
    • Later progression of weakness to the anterior leg compartment
    • Leg involvement may be unilateral
    • Late stages of the diseases:
      • May have proximal weakness
    • Weakness is related to duration of illness
• Laboratory Involvement:
  • CK markedly elevated (20 to 150× normal)
  • EMG:
    • Myopathic features in partially affected muscle
    • Weak and atrophic muscles:
      • Long duration polyphasic motor unit potentials
  • Muscle biopsy:
    • Myopathic features:
      • Rare rimmed vacuoles
      • Two patients demonstrated inflammatory features

Type B: Laing Distal Myopathy

• Genetics:
  • Chromosome 14q 11; AD
  • Sites of involvement:
    • Patients between 4–25 years of age
    • Weakness of the anterior compartment and neck flexors > finger extensors > shoulder girdle
• Laboratory evaluation:
  • Slight increase of CK
• Muscle biopsy:
  • Myopathic changes
  • No vacuoles

Distal Myopathy with Vocal Cord and Pharyngeal Weakness

• Genetics:
  • Autosomal dominant; Chromosome 5q31
• Clinical features:
  • Onset 4th to 6th decades
  • Site of involvement:
    • Anterior leg compartment is usually first; finger extensor weakness may be initial site; may be asymmetric initially
  • Vocal cord and pharyngeal involvement occurs after extremity weakness
• Laboratory evaluation:
  • CK is normal or moderately elevated
  • EMG:
    • Myopathic in vocal cord and pharyngeal muscles
    • Extremity muscles may have neuropathic features
  • Muscle biopsy:
    • Myopathic
    • Rimmed vacuoles
    • No neurofilaments

Myofibrillar Myopathy with Desmin

• Genetics:
  • AD primarily; desmin gene
  • X-linked and sporadic cases noted
  • Chromosome 2q 35
  • Gene mutation on 11q 21–23; primary family with scapuloperoneal phenotype noted with mutation on chromosome 12
• Clinical features:
  • Onset 25–45 years of age; cases occurring in infancy and late life have been reported
  • Site of involvement varies in different pedigrees:
    • Hands
    • Distal lower extremities
      • Anterior compartment of the leg
    • Scapuloperoneal distribution
  • Cardiomyopathy:
    • Arrhythmia
    • Congestive heart failure
    • Heart block
    • May precede muscle weakness
  • Proximal muscle involvement occurs in later stages
  • Rare respiratory insufficiency
• Laboratory evaluation:
  • Elevated CK (< 5 times normal)
  • EMG:
    • Myopathic
    • Complex repetitive discharges
  • Muscle biopsy:
    • Non-specific myopathic features
    • May have rimmed vacuoles
    • Immunohistochemistry reveals cytoplasmic bodies that contain:
      • Desmin (intermediate filament protein)
        • Skeletal, cardiac, and smooth muscle are involved
      • Actin, myosin, dystrophin, gelsolin, P-amyloid pre cursor protein also noted in cytoplasmic bodies
    • Electron microscopy reveals:
      • Paci of myofibrillar degeneration
      • Hyaline structures (cytoplasmic or spheroid bodies)
      • Primarily 15–18 mm filaments associated with rimmed vacuoles
    • Desmin noted in:
      • Congential myotonic dystrophy, nemaline myopathy, X-linked myotubular myopathy

Childhood Onset Distal Myopathy

• Genetics:
  • AD
• Clinical Features:
  • Onset in infancy less than 2 years of age; stabilizes in adolescence
  • Affects ankle dorsiflexors and distal upper extremity muscles

Differential Diagnosis of Distal Myopathy

• Myotonic dystrophy:
  • Severe ptosis
  • Mental behavioral abnormalities
  • Frontal baldness
  • Stellate cataracts (posterior)
  • Severe facial muscular atrophy
  • Systemic manifestations
• Emery–Dreifuss Muscular dystrophy:
  • Contractures
  • Cardiac abnormalities
• Oculopharyngeal dystrophy:
  • French connection
  • Severe ptosis and swallowing abnormalities
• Scapuloperoneal dystrophy:
  • Early and more symmetrical involvement of shoulder girdle and anterior compartment of the legs
• Fascioscapulohumeral dystrophy:
  • Severe facial involvement in association with biceps and humeral weakness early in the course
• Inflammatory myopathies:
  • Neck flexor weakness
  • Skin changes (PM/DM complex)
  • Swallowing dysfunction (PM/DM)
  • Finger flexion contractures (IBM)
• Debrancher deficiency:
  • Enlarged liver and spleen
  • Hypoglycemic attacks
• Acid maltase deficiency
  • Cardiac abnormalities
  • Enlarged tongue
• Nemaline myopathy:
  • Dysmorphisms; long face; high arched palate
  • Proximal > distal weakness
  • Slowly progressive
  • Thin muscles by adolescence
  • Facial muscle involvement
• Central core:
  • Kyphoscoliosis, short stature, contractures of fingers
  • Cardiomyopathy occurs
  • Proximal weakness; legs > arms
• Centronuclear (AD variant):
  • Limb girdle weakness
  • Distal muscles may be affected
  • May have facial and neck flexor weakness
• Childhood onset distal myopathy
  • Infantile onset (less than two years)
  • Juvenile onset

Neurogenic Causes of Distal Muscular Atrophy

• Hereditary sensory motor neuropathy Type II (axonal form)
• Distal spinal muscular atrophy
• Scapuloperoneal syndromes (neurogenic variants)
• Acute intermitted porphyria
• Multifocal motor neuropathy with conduction block