Differential Diagnosis in Neurology

12.2. Congenital Myopathies

• General Features:
  • Genetic defects
  • Often specific muscle histopathology
  • Specific patterns of involvement and dysmorphisms
  • Starts in early childhood; slowly progressive
  • Compatible with a normal life in many instances:
    • Rarely display an aggressive course
    • Some demonstrate mild improvement over time
    • May only become symptomatic in adolescence or adulthood
  • Congenital muscular dystrophies:
    • Divided into those with and without brain involvement
    • Merosin: positive or negative
  • Usually have proximal muscle weakness and decreased deep tendon reflexes:
    • Many were floppy infants
    • Adolescents have difficulty in gym
• EMG:
  • Myopathic
  • CK (mildly elevated)

Central Core Disease (Shy-Magee Disease)

• Genetics:
  • AD; gene located on chromosome 19q 13.1:
    • Gene codes: ryanodine receptor of the calcium release channel of skeletal muscle sarcoplasmic reticulum; allelic with malignant hyperthermic locus
  • Gene coding for beta-myosin heavy chain (MYH7); patients demonstrate:
    • Hypertrophic cardiomyopathy
    • Central core changes in skeletal muscle
• Clinical features:
  • Dysmorphisms:
    • Kyphoscoliosis
    • Pes cavus
    • Dislocated hips
    • Short stature
    • Contractures (flexion deformities of the fingers)
  • Delayed acquisition of milestones; hypotonic only in infancy or childhood
  • Cardiac abnormalities:
    • Cardiomyopathy
    • Arrhythmia
    • Mitral valve prolapse
  • Proximal symmetrical motor weakness; legs > arms; rare facial and sternocleidomastoid weakness
  • High risk for malignant hyperthermia
    • RYRI receptor involved in calcium release from endoplasmic reticulum
  • Muscle cramps and myalgias occur in adults; stiffness after exercise
• Muscle biopsy:
  • Cores occur in the center of Type I fibers:
    • Demonstrated with NADH-TR (nicotinamide adenine dinucleotide-tetrazolium reductase histochemical stain)
    • Type I fiber predominance
    • May have associated nemaline rods
• Laboratory:
  • EMG:
    • Myopathic, no fasciculations
    • Some polyphasic potentials of long duration
  • Muscle biopsy:
    • Round or oval cores that lack oxidative enzyme activity
    • Absent mitochondria (in the cores)
    • Type I fiber predominance
  • CK, minimally elevated

Nemaline Myopathy

• Genetics:
  • AD from; NEMI; chromosome 1q 22–q23
    • TMP3 gene (tropomyosin–3)
  • AR; NEM2; chromosome 1q421.1 (α-actin gene)
  • NEM2 also caused by:
    • Mutation in gene coding for nebulin; 2q22
• Clinical features:
  • Congential form causes a rapidly fatal myopathy
  • Congenital progressive or slowly progressive form:
    • Non-progressive or exacerbation at adolescence; mild myopathy
    • Progression may only be apparent in middle or late life
    • Weakness and flaccidity in infancy; proximal > distal muscles
    • Facial and muscles of mastication may be involved
    • Slender muscle; decreased or absent deep tendon reflexes
    • Dysmorphic features:
      • Elongated face
      • High arched narrow palate
      • Kyphosis, lordosis, pes cavus, talipes equinovarus
• Asymptomatic variant:
  • Asymptomatic relatives
  • Muscle biopsy: rod bodies or Type I fiber predominance
• Adult-onset variant:
  • Lacks dysmorphic features
  • Sporadic inheritance
  • Usually proximal weakness in adult life a few patients have distal weakness at onset (usually leg muscles)
  • Bulbar musculature is not involved
  • Cardiomyopathy has been described; rod bodies in the contractile and conducting system of the heart
• Laboratory features:
  • EMG: myopathic
  • CK: rarely elevated
  • Muscle biopsy (adult from):
    • Rod bodies seen in atrophic fibers
    • Predominance of Type I and 2C fibers in the congenital forms
    • Rod bodies emanate from the z discs within the cytoplasm; reddish purple granules on Gomori trichrome stain; 27 μm in length that are subsarcolemmal membrane in Type I muscle fibers; rod bodies are composed of d-actinin.
  • Several late onset forms have had an elevated sed rate; some with associated monoclonal gammopathy
  • Rod bodies may be seen in:
    • Chloroquine myopathy (treatment of SLE)
    • Schizophrenia
    • Polymyositis
    • Hypothyroidism
    • Asymptomatic relatives of nemaline patients

HIV Associated Adult Onset Nemaline Myopathy (HAONM)

• Clinical features:
  • Neck, face and respiratory muscle may be involved
  • Similar skeletal abnormalities to central core disease
• Pathology
  • Rods noted in myofibrils

Centronuclear Myopathy

• Genetics:
  • Congenital sex-linked recessive form:
    • Xq28; mutation in the myotubular gene (MTMI); product is a tyrosine phosphatase
  • Congenital AR
    • Late infancy and childhood presentations
  • AD variant:
    • In one family the gene maps to chromosome 11q22
    • Adult variants
  • Non-hereditary late onset variant
• Clinical features:
  • General characteristics:
    • Early childhood onset
    • Weakness of extraocular, facial, neck and limb musculature
    • Slowly progressive

Congenital AR Variant

• Clinical features:
  • Respiratory weakness at birth
  • High arched palate; elongated face
  • Ptosis, strabismus, facial weakness, sternocleidomastoid weakness
  • Delayed motor milestones
  • Muscle weakness; proximal > distal
  • Talipes equinovarus
  • Depressed or absent deep tendon reflexes
  • Adolescence or early adult life: patients are unable to walk
  • At approximately age 12, patients develop scoliosis, accentuated lordosis, scapular winging

Congenital Sex-Linked Recessive Variant (Myotubular Myopathy)

• Clinical features:
  • Respiratory distress at birth; death
  • Weak suck, cry, cough; weak swallowing and neck muscles at birth
  • Bilateral ptosis, facial diplegia, poor extraocular movements
  • Depressed or absent deep tendon reflexes
  • Cardiomyopathy:
    • Extensive fibrosis
    • Right ventricular hypertrophy secondary to chronic pulmonary hypertension due to weak respiratory muscles
    • Autosomal dominant variant:
      • Limb girdle weakness; distal muscles may be affected; may have onset in oculo- cranial musculature
      • Some patients: facial and neck flexor weakness
      • Weakness is evident by the third decade; slowly progressive; some patients become wheelchair bound

Sporadic Adult Onset Variant

• Onset in adulthood
• Slowly progressive weakness of both proximal and distal musculature
• Facial and bulbar musculature are spared
• One patient described with pseudohypertrophy; one patient with extraocular muscle involvement
• Laboratory evaluation
  • EMG: myopathic; may have fibrillations and myotonic discharges
  • CK and aldolase are usually normal: occasionally they are slightly elevated
  • Muscle biopsy:
    • Central position of muscle nuclei (surrounded by vacuoles containing glycogen granules)
    • Increase of perimysial connective tissue
    • Small Type I fibers; normal Type II fibers
    • Type I fiber predominance; central nuclei may be restricted to Type I fibers or may be seen in both Type I and Type II fibers

Congenital Fiber Type Disproportion

• Genetics:
  • Most patients are sporadic
  • AD; possible location on chromosome 10 or 17
• Clinical features:
  • Infants are hypotonic and weak
  • Dysmorphisms:
    • Kyphoscoliosis
    • High arched palate
    • Dislocated hips
    • Pes cavus
    • Contractures of elbows and knees
  • Mental retardation (some patients)
  • Hyperinsulinemia; peripheral insulin resistance
  • Relation to rigid spine syndrome
  • Non-progressive; some patients have improved
  • Respiratory muscle weakness
• Laboratory evaluation:
  • EMG: normal or myopathic
  • CK: mildly elevated
  • Muscle biopsy:
    • Type I fiber predominance; small size (12–15% smaller than Type II fibers)

Reducing Body Myopathy

• Genetics:
  • AR (putatively related to LGMD)
  • Not established for most patients
• Clinical features:
  • Weak hypotonic infants
  • Proximal > distal weakness
  • Respiratory weakness
  • Hyporeflexia
  • Occasional facial weakness and ptosis
• Laboratory evaluation:
  • CK: usually normal
  • EMG: myopathic
  • Muscle biopsy:
    • Reducing bodies stain for glycogen, RNA and sulfhydryl groups
      • Round to ovoid masses (10–70 um)
      • EM composed of osmophilic granular and fibrillar material
    • Variation of fiber size, Type I fiber predominance, some degeneration
    • Strong staining with α-glycerophosphate dehydrogenase (enendione linked); autophagic vacuoles filled with filamentous material

Multicore Myopathy (Minicore Disease)

• Genetics:
  • Most patients are sporadic or AR
  • AD from: mutation at 12q
    • Codes for acyl-CoA dehydrogenase
• Clinical features:
  • Onset in infancy
  • Hypotonia, slow to pass motor milestones; slowly progressive
  • Proximal > distal weakness; rarely upper extremities weaker than lower; ptosis and weakness of extraocular muscles (rare)
  • Dysmorphisms:
    • Scoliosis
    • Multiple joint contractures
    • Dolichocephaly
    • High arched palate
    • Club foot
  • Cardiac involvement:
    • Atrial and ventricular septal defects
    • Cardiomyopathy
    • Heart attack
  • Respiratory involvement
  • Associated with malignant hyperthermia
  • Patients with microcephaly and mental retardation
    • Adult onset variety has slowly progressive weakness
• Laboratory evaluation:
  • CK: usually normal
  • EMG: myopathic
  • Muscle biopsy:
    • Multiple fusiform areas of Z-disk streaming (minicores)
      • Small Type I myofibers
    • Presence or absence of Type I fiber hypotrophy
    • Variations of muscle fiber size
    • Fiber splitting
    • Multicores found in both Type I and II fibers
      • Absent mitochondrial enzyme activity in the cores

Finger Print Body Myopathy

• Genetics:
  • Sporadic: AD; and X-linked; inheritance pattern has not been definitively identified
• Clinical features:
  • Weakness and hypotonia of the arms and legs
  • Slowly progressive or at times non-progressive muscle weakness
  • Proximal weakness atrophy and hypotonia since infancy
  • Cranial musculature spared
  • Kyphoscoliosis in some patient
  • Depressed or absent deep tendon reflexes
  • Mental retardation and febrile seizures have been noted
• Laboratory evaluation:
  • CK: normal
  • EMG:
    • Myopathic
    • Normal nerve conduction velocities
  • Muscle biopsy:
    • Ill-defined ovoid inclusions:
      • Beneath the sarcoplasmic membrane
      • Predominantly in Type I fibers
      • 1–10 μm in diameter
    • EM of fingerprint bodies:
      • Parallel osmophilic lamellae that resembles fingerprints; each lamellae has a serrated margin
    • Similar inclusions noted in:
      • Oculopharyngeal muscular dystrophy
      • Myotonic dystrophy (rare)
      • Inflammatory myopathies (rare)

Cytoplasmic Body Myopathy (Myofibrillar or Desmin Myopathy)

• Genetics:
  • AD; some families are AR or sex linked
  • AD patients:
    • Mutations in the desmin gene; Chromosome 2q 35
• Clinical features:
  • Congential onset
  • Adult onset
  • Weakness may be noted in second decade or later
  • Severe from of the disease:
    • Axial and intercostal weakness
    • Death from respiratory insufficiency and right heart failure
    • Cardiomyopathy may present as an isolated form of the disease
  • Feeding and bulbar dysfunction during infancy presentation
  • Delayed motor milestones
• Adult presentation:
  • Facial weakness
  • Nasal speech
  • Dysphagia
  • Tongue weakness
  • Proximal > distal weakness
  • Rare pseudohypertrophic calves
  • Neck flexor weakness
  • Occasional joint contractures
  • Chest muscle weakness and scoliosis
  • Cramps or pain after exercise (rare)
  • One family: thenar and flexor hand muscle weakness
• Laboratory evaluation:
  • CK: slight to moderate elevation
  • EMG: myopathic primarily; myotonic pattern and denervation in some patients
  • EKG changes:
    • Bundle branch block
    • Depressed ST segments
  • Muscle biopsy:
    • 25% of muscle fibers contain cytoplasmic bodies
    • May be seen in Type I or II fibers
    • Core of cytoplasmic body: filaments intermixed with dense amorphous material
    • EM of dense core:
      • Cytoplasmic bodies may arise from the Z disk:
        • Desmin and myofibrillar protein have been demonstrated
        • Desmin is a motor intermediate protein of skeletal and cardiac muscle
          • Links Z band with the sarcolemma and the myonuclei
    • Non-specific cytoplasmic bodies found in Type II fibers
    • Differential Diagnosis of cytoplasmic bodies:
      • Denervation atrophy
      • Inflammatory myopathy
      • Myotonic dystrophy
      • Periodic paralysis
      • Acropathic psoriasis
      • Menkes Kinky Hair Disease
      • Mitochondrial myopathy

Myopathy with Tubular Aggregates

• Genetics:
  • AD; AR forms
  • Familial variants
• Clinical features: Four clinical variants:
  • Myopathy with myasthenic features
  • Myopathy with pain and stiffening after exercise; or cramps
  • AD slowly progressive myopathy
  • AR limb girdle pattern

Myopathy with Myasthenic Features

• Slowly progressive myopathy since infancy
• Cardiomyopathy
• EMG response similar as to that seen with MG
• Response to acetylcholinesterase
• Hypoplasia of Type I fibers; tubular aggregates
• Relationship to congenital prolonged open channel MG not established

Myopathy with Exercise Induced Cramps, Pain and Stiffness

• Adult onset
• Pain and stiffness of lower extremities; with time it spreads to the upper extremities
• Weakness is minimal; no atrophy or fasciculations
• CK: normal or mildly increased
• EMG: normal
• Tubular aggregates: Type II fibers only

Autosomal Dominant Myopathy with Tubular Aggregates

• Genetics: AD
• Clinical features:
  • Insidious onset of a very slowly progressive myopathy
  • Pectoral and pelvic girdle involvement initially
  • CK:
    • Normal
  • EMG:
    • Myopathic
  • Muscle biopsy:
    • Tubular aggregates in 50% of muscle fibers

Autosomal Recessive Myopathy with Tubular Aggregates

• Genetics: AR
• Clinical features:
  • Onset in childhood and adolescence
  • Slowly progressive weakness of proximal limb muscles
• Laboratory evaluation:
  • CK: slightly elevated
  • EMG: myopathic
  • Tubular aggregates in both Type I and II fibers
• Pathology:
  • Tubular aggregates:
    • Double walled parallel tubules
    • 60–80 mm in diameter
    • Arranged in hexagonal arrays
    • Continuity of the sarcoplasmic reticulum with the tubular aggregates

Differential Diagnosis of Disease in Which Tubular Aggregates are Noted:

• Hypokalemic, normokalemic and hyperkalemic periodic paralysis
• Myotonia congenita
• Paramyotonia
• Congential myasthenic syndromes
• Acromegaly
• Hyperaldosteronism
• Myotonic dystrophy
• Hyperornithemia
• Denervation atrophy of muscle

Periodic paralysis and myalgic syndromes

• In general , patients with periodic paralysis and myalgic syndromes, the tubular aggregates are in Type II fibers.
• Genetic myopathies: Tubular aggregates are found in both Type I and II fibers

Sarcotubular Myopathy

• Genetics: possibly X-linked recessive
• Clinical features:
  • Decreased intrauterine movements
  • Mild proximal weakness of both upper and lower extremities
  • Weakness of neck flexors, facial and intercostal muscles
• Laboratory evaluation:
  • CK: slightly elevated
  • EMG: myopathic
  • Muscle biopsy:
    • Vacuolar myopathy of Type II fibers; vacuole origin may be membranes of the sarcoplasmic reticulum

Trilaminar Myopathy

• Genetics: not determined
• Clinical features:
  • Rigidity to passive movement at birth
  • High pitched weak cry
  • Decreased bulbar function
  • Decreased range of motion of the neck, shoulders and hips
• Laboratory evaluation:
  • CK: elevated
  • EMG: normal
  • Muscle biopsy:
    • Trilaminar bodies
    • Prominent filaments, mitochondria, vesicles, triads and glycogen particles

Familial Myopathy with Lysis of Myofibrils in Type I Fibers

• Genetics: not determined
• Clinical features:
  • Inactive, weakness and hypotonic at birth
  • Delayed motor milestones
  • Increased lumbar lordosis
  • Symmetric proximal myopathy
  • An adult documented with scapuloperoneal weakness
• Muscle biopsy:
  • Absence of myofibrils in the periphery of Type I fibers
  • Normal Type II fibers

Type I: Myofiber Predominance

• Genetics:
  • Possibly autosomal recessive
• Clinical features:
  • Non-progressive weakness and hypotonia
• Laboratory evaluation:
  • Muscle biopsy:
    • Type I fiber predominance
    • Weakness in many congenital myopathies may be correlated with the degree of Type I fiber predominance

Spheroid Body Myopathy

• Genetics: Autosomal dominant
• Clinical features:
  • Onset is adolescence; some late onset patients > 40 years of age
  • Slowly progressive proximal myopathy
  • Respiratory insufficiency in adult life
• Laboratory evaluation:
  • CK; normal
  • Muscle biopsy:
    • Spheroid bodies within Type I muscle fibers
    • Spheroid bodies contain:
      • Alpha-B-crystallin
      • Ubiquitin
      • Desmin
      • Compacted and degraded myofibrillar elements

Differential Diagnosis of Myopathy with Abnormal Foci of Desmin Positivity

• Mallory body myopathy
• Myopathy with granular filamentous inclusions
• Desmin storage myopathy
• Intermediate filament myopathy

Congenital Muscular Dystrophies

• General features:
  • Most are AR
  • Hypotonia and weakness are noted in the first year of life
  • All have muscle weakness and deformities from intrauterine decreased movements:
    • Arthrogryposis
    • Pes cavus
  • Lamina in chain is:
    • Extracellular protein
    • Connects the extracellular matrix and the dystrophin-associated glycoprotein complex of the muscle cytoskeleton
• Genetics:
  • Merosin deficient CMD
    • Deletion or mutation of the laminin 2 gene (LAMA2): chromosome 6q22-q23
• Clinical features of Merosin-negative CMD:
  • Hypotonia at birth
  • Some patients have multiple joint contractions
  • Generalized muscle weakness
  • Proximal weakness > distal
  • Face, neck, intercostals muscle involvement
  • Extraocular muscles are spared
  • Deep tendon reflexes depressed or absent
  • Mental development is often normal
  • Usually a delay in passing motor milestones
  • Some patients with respiratory deficits
  • Intra family muscle weakness similar between family members
  • May be rapidly progressive
• Laboratory evaluation:
  • CK and aldolase are normal or mildly increased; tend to return to normal with age
  • EMG: myopathic; rare fibrillation potentials
  • Muscle biopsy: variation of fiber size, rounded rather than polygonal; increase of endomysial and perimysial connective tissue
  • MRI evaluation:
    • Leukoencephalopathy is generalized

Clinical Features of Merosin-Positive CMD

• Non-progressive or slowly progressive proximal > distal weakness
• Usually no cognitive impairment
• 90% of patients can walk by four years of age

Congenital Muscular Dystrophy with Clinical Cerebral Involvement Fukuyama Congenital Muscular Dystrophy (FCMD)

• Genetics:
  • Chromosome 9q31:
    • 461 amino acid protein is deficient
    • 87% founder effect; ancient retrotransposal integration of a 3Kb in the non-coding region of the Fuji gene
    • probably allelic to Walker–Warburg Muscular Dystrophy
    • Missense and nonsense mutations
• Clinical features:
  • 30% of mothers of patients with FCMD have had spontaneous abortions
  • Infants have poor fetal movements; at birth weak suck and cry
  • Pectus excavatum in 30% of infants
  • Hypotonic generalized muscle weakness; proximal greater than distal
  • Mild contractures of knees and elbows are present at birth or develop
  • Deep tendon reflexes are decreased or absent
  • Convulsions (major motor) in 5i0% of patients; occasional status epilepticus
  • Severely retarded motor and intellectual development
  • Contractures of knees, elbows and hips develop
  • Death usually by age ten
• Laboratory evaluation:
  • CK: 10–15 times normal (after age six, enzymes decline) myoglobin is in the urine during the period of extremely high CK. LDH, SGOT, Aldolase are elevated.
  • EMG: myopathic
  • Serum cholesterol is elevated in approximately 50% of patients
  • Muscle biopsy:
    • Focal fibrosis in cardiac muscle
    • Variation of fiber size central nuclei; rounded fibers
    • Massive endomysial and perimysial fibrosis
  • EEG:
    • Diffuse and marked decrease in frequency, bihemispheric sharp waves
    • 50–75% of patients have focal paroxysmal discharge with spikes in the frontoparietal cortex
  • MRI evaluation:
    • Poor cortical gyral development particularly in the temporal and occipital lobes
    • Prominent sylvian fissures: dilated lateral ventricle (aqueductal stenosis in some); T2 abnormalities of periventricular white matter; polymicrogyria of the cerebellum
    • Pachygria and polymicrogyria; lissencephaly in some patients

Walker–Warburg Disease

• Genetics: chromosome 9q31; allelic to Fukuyama CMD
• Clinical features:
  • Severely affected at birth
  • Usually die in infancy
  • Brain abnormalities:
    • Cephalocele
  • Lissencephaly Type II
  • Hemispheric fusion
  • Agnesis of the corpus callosum

Ocular Findings Present in FCMD, WWS and MEBD (Muscle Eye Brain Disease)

• Myopia
• Microphthalmia
• Corneal opacities
• Congenital cataracts
• Retinal dysplasia and non-attachment
• Pre-retinal membrane
• Gliosis of the retina
• Mottling of retinal pigment epithelium
• Persistent hyperplastic primary vitreous
• Optic nerve atrophy
• Degree of ocular pathology
  • WWS > MEBD > FCMD

Muscle-Eye Brain Disease

• Genetics: chromosome 1p34-p32
• Clinical features:
  • Congenital hypotonia
  • Severe myopia
  • Mental retardation
  • Neuronal migration disorder
  • Hypomyelination
  • Leptomeningeal glial mesodermal proliferation
  • Pyramidal tract hypoplasia
• Ocular Abnormalities:
  • Optic atrophy
  • Retinal hypoplasia
  • Congenital glaucoma
  • Severe myopia
• Laboratory evaluation:
  • CK: increased
  • EMG: myopathic
  • Muscle biopsy:
    • Dystrophic features
    • Deficient laminin in central nervous system, eye and muscle
  • MRI evaluation:
    • Convoluted agyric pattern of the occipital lobe
    • Cobblestone cortex
    • Lissencephaly
    • Cytoarchitectural disorganization

Limb Girdle Muscular Dystrophy

Limb girdle muscular dystrophies are being rapidly characterized by molecular genetic techniques. The present classification rests on the basis of the 1994 criterion.

The disease may have its initial presentation in the pelvic or shoulder girdle musculature concomitantly or seriatim. The initial symptoms relate to weakness of these muscle groups. Early contractures may be noted in some of the AD forms, but not often in the AR varieties. Calf hypertrophy is frequent and often demonstrates intrafamilial variability. Exclusion criteria are onset of weakness in distal, facial or extraocular muscles. Onset of the disease may occur at any age. In recessive forms the process generally starts prior to 20 years of age. Later onset usually occurs in dominant disease.

The classification continues to be modified according to each entities specific genetic defect. Single gene mutations may cause specific phenotypic expression. Both Miyoshi distal myopathy and LGMD 2B may result from mutation of the dysferlin gene on chromosome 2p13. LGMD 2G and LGMD 2H involve distal lower extremity muscle compartments. LGMD 2H may have early facial involvement which usually is an exclusion criterion for LGMD.

Autosomal Dominant Limb Girdle Muscular Dystrophy

LGMD-1A

• Genetics:
  • Chromosome 5q22-q31.3
  • Gene product is myocilin:
    • Protein localizes to the I band or the Z line of the sarcomere
• Clinical features:
  • Onset is third decade (18–35 years of age)
  • Lower extremity limb girdle weakness > upper extremity
  • Facial muscles spared (several patients have weakness)
  • Dysarthric speech pattern
  • Absent ankle deep tendon reflexes
  • Frequent heel cord contractures
  • Anticipation may occur; a differential point from FSH dystrophy
    • In FSH facial involvement and ptosis are prominent at presentation
• Laboratory evaluation:
  • Serum CK is elevated (mild)
  • EMG: myopathic
  • Muscle biopsy
    • Dystrophic

LGMD- 1B

• Genetics: chromosome 1q11–12 (AD)
• Clinical features:
  • Slowly progressive
  • Symmetric proximal myopathy
  • Childhood presentation in 50% of patients:
    • Waddling gait
    • Hyperlordosis
    • Difficulty running
  • Middle age patients demonstrate:
    • Mild symmetric wasting and weakness of proximal upper extremity muscles. The biceps are particularly affected
    • A few patients demonstrate mild symmetric facial involvement and calf hypertrophy
    • Cardiac abnormalities:
      • Sudden death (young to middle age)
      • Dilated cardiomyopathy
      • Atrial fibrillation
      • Frequent supraventricular premature beats
• Laboratory evaluation:
  • Serum CK: slightly elevated
  • EMG: myopathic

LGMD-1C (Caveolaopathy)

• Genetics:
  • AD
  • Chromosome 3p25
  • Caveola 3 gene (CAV3):
    • There are three isoform of the membrane incorporated protein; caveola 3 is expressed in skeletal and cardiac muscle
    • Cevalin 3-MOS-α 1–syntropin-dystrophin
• Clinical features:
  • Onset at age five; initial motor milestones were achieved
  • Slow progression of proximal weakness
  • Cramps after exercise
  • Gower's sign in adults
  • Calf hypertrophy
• Laboratory evaluation:
  • CK: 4–25 times normal
  • EMG: myopathic

LGMD-1D

• Genetics:
  • AD
  • Chromosome 6q 23B
• Clinical features:
  • Adult onset
  • Proximal weakness without contractures
  • Facial musculature is normal
  • Mild weakness; ambulatory for life

Limb Girdle Muscular Dystrophies (autosomnal dominant)

• LGMD-2A (calpainopathy):
  • Genetics: AD; chromosome 15q 15.1–q 21.1; gene is calpain3; protein is located in the myofibril and the nucleus:
    • Calpain 3 transcribed; a Ca⁺⁺ dependent protease involved in catabolism and transcription regulation
    • Approximately 10% of heterogenous LGMD have calpain III mutations
    • Not associated with disruption of the dystrophin complex
    • Worldwide distribution
  • Clinical features:
    • Onset 3–30 years of age; the earlier the onset the more severely affected
    • Slowly progressive course; earliest muscles involved:
      • Gluteus maximus and thigh adductors; cause difficult with walking. Less involvement of gluteus medius
      • Minimal involvement of quadriceps
      • Abdominal muscles greater involvement than spinal muscles
      • Upper extremity, limb girdle weakness and atrophy
      • Rare calf muscle hypertrophy
      • Late stage:
        • Atrophy of quadriceps and other leg muscles
        • Atrophy of distal lower extremity muscles
        • Sparing of face and intrinsic hand muscles
        • Contractures of hips, knees and elbows
      • Intellect, heart, and pharyngeal muscles are spared
  • Laboratory evaluation:
    • CK: 10 times normal
    • EMG: myopathic
    • Muscle biopsy: variation in fiber size, interstitial fibrosis, dystrophic changes

Limb Girdle Muscular Dystrophy-2B (Dysferlinopathy)

• Genetics: chromosome 2p12–13; dysferlin gene:
  • Localization of the protein is the cell membrane
  • Allelic to Miyoshi distal myopathy
  • AR
• Clinical features:
  • Age at onset is 13–35 years
  • Lower extremities involved earlier than upper extremities
  • 15% of patients have calf hypertrophy
  • 70% of patients are unable to walk on their toes
  • Great phenotypic variability is noted within and between families
  • Late stages of the disease:
    • Atrophy of the anterior compartment of the lower extremities
    • Scapular muscle and distal upper extremity weakness and atrophy
  • Families may demonstrate members with myiosis and LGMD phenotype
• Laboratory evaluation:
  • CK: 10–150 times normal
  • EMG: myopathic
  • Muscle biopsy: dystrophic changes

LGMD-2C

• Genetics: Chromosome 13q12:
  • Disruption of the dystrophin complex
  • Deficit of alpha and beta sarcoglycan
• Clinical features:
  • Childhood onset; adult onset has been reported
  • Severe weakness of pelvic and pectoral girdle; usually symmetric
  • Lower extremity involved first; difficulty climbing stairs and standing up from the floor
  • Muscle pain and cramps
  • Affected muscles become atrophic
  • Hypertrophy of the calves may be seen early
  • Joint contractures may occur; particularly of the ankles
  • Rare facial muscular involvement (early)
  • Rare cardiac involvement:
    • Cardiomegaly
    • Cardiac conduction defects
    • Partial right or left bundle block

LGMD-2D (alpha sarcoglycan)

• Genetics: chromosome 17q21; AR:
  • Double null mutation causes a severe myopathy
  • Degree of sarcoglycan expression correlates with clinical severity
  • There is an associated dystrophin deficit
  • Ten missense mutations have been described
  • Located (alpha sarcoglycan) at the cell membrane
• Clinical features:
  • Symmetric involvement of trunk and limb muscles; similar to Duchenne Muscular Dystrophy
  • Calf hypertrophy
  • Absence of cardiac involvement

LGMD-2E

• Genetics: chromosome 4q12 (B-sarcoglycan)
  • B sarcoglycan deficit
  • Located in the cell membrane
• Clinical features:
  • Similar to DMD

LGMD-2F

• Genetics: chromosome 5q33–34 (gamma sarcoglycan)
  • Protein in the cell membrane
• Clinical features:
  • Similar to DMD

LGMD-2G

• Genetics: chromosome 17q11–12:
  • Telethionin gene:
    • Encodes a sarcomeric protein
    • Binding rite for other sarcomeric proteins
    • Important in the assembly of the sarcomere
• Clinical features:
  • Childhood onset (mean age of 12.5)
  • Difficulty climbing stairs, walking and running
  • Weakness of ankle, dorsiflex on and consequent foot drop
  • Proximal muscle weakness and atrophy in the arms
  • Distal and proximal involvement of the legs
  • Absent deep tendon reflexes
  • Patients are wheelchair bound in their thirties
• Laboratory evaluation:
  • CK: early stages is increased 3 to 17 times normal; late stages it may return to normal
  • EMG: myopathic
  • Muscle biopsy: variation in fiber size, rounded fibers, necrotic and regenerating fibers and central nuclei; rimmed vacuoles may be seen

LGMD-2H

• Genetics: chromosome 9q31-q33
  • Gene localized to Hutterite patients in North America (ancestors migrated from Switzerland)
• Clinical features:
  • Age of onset is the first decade
  • Early involvement of the pelvic girdle and quadriceps:
    • Waddling gait
    • Difficulty arising from a squat
  • Facial muscles involved
  • Some patients noted to have brachioradialis and anterior tibialis weakness
• Laboratory evaluation:
  • CK; markedly elevated
  • EMG: myopathic
  • Muscle biopsy: dystrophic

LGMD-2I

• Genetics: 19q 13.3
• Clinical features:
  • Variable age at onset
  • Proximal limb muscle weakness and wasting; pelvic girdle affected most severely
• Laboratory evaluation:
  • CK: elevated in younger patients
  • EMG: myopathic
  • Muscle biopsy: dystrophic changes:
    • Normal expression of dystrophin and:
      • AP complex that include: SG subunits, DG, and sarcospan

Differential Diagnosis of Limb Girdle Dystrophy

• Multicore disease (rare in adult life)
• Sarcotubular myopathy
• Reducing body myopathy
• Mitochondrial myopathy with primary limb girdle weakness
• Finger print myopathy
• Acid maltase deficiency (adult onset)
• Debrancher enzyme deficiency (adult onset)
• McArdle disease (adult type)
• Carnitine deficiency of muscle (adult onset)
• Myopathy with tubular aggregates (adult onset)
• Congenital fiber type disproportion (detected in adulthood)
• Myopathy with cytoplasmic bodies (early adult onset)
• Centronuclear myopathy (adult onset is rare)
• Central core disease (may be first detected in adulthood)
• Adult nemaline disease
• Scapuloperoneal myopathy
• FSHD
• DMD
• Becker Muscular Dystrophy
• Manifesting carrier of DMD
• Chronic spinal muscular atrophy
• Polymyositis/dermatomyositis complex