Neuromuscular

Question 1

Friedrich’s Ataxia (FRDA)

Answer 1

Inheritance: ONLY AUTOSOMAL RECESSIVE EXPANSION DISORDER!!!!
Gene: FXN
Trinucleotide repeat: GAA
Mutations are located in the intronic regions

Question 2

Friedrich’s Ataxia: Major Features

Answer 2

Major features:
•Slowly progressive, disabling ataxia
•Vision impairment
•Hearing impairment
•Slurred speech
•Scoliosis
•Pes cavus
•Diabetes
•Pyramidal signs
•Nystagmus
•Cardiac involvement
    oCardiomegaly
    oDCM
    oHypertrophy 
    oHeart murmur
    oConduction defects
  •Average lifespan is approximately 35 years

Question 3

Spinal and Bulbar Atrophy (SMA) (Kennedy Disease)

Answer 3

Inheritance: X-linked recessive
Gene: AR
Trinucleotide repeat: CAG
Major features:
•Onset age 30-50
•Muscular atrophy
•Difficulty walking/clumsiness
•Wheelchair dependence 10-20 years after onset of symptoms
•Bulbar signs
    oSpeech difficulties
    oSwallowing difficulties
•Endocrine dysfunction (Androgen insensitivity)
     oBegins in adolescence
     oGynecomastia
     oErectile dysfunction
     oTesticular atrophy
Allelic to AI, likely androgen-dependent, so females (even homozygotes) are often unaffected or very mildly affected

Question 4

Spinocerebellar Ataxia

Answer 4

Inheritance: Autosomal dominant
Genes: Over 60 types
Trinucleotide Repeat: CAG, CTG

Most types onset in the 3rd or 4th decade of life and can have a short duration before death or normal lifespan depending on subtype

Question 5

Spinocerebellar Ataxia: Features

Answer 5

Major features:
•Slowly progressive ataxia
•Poor hand-eye coordination
•Poor speech coordination
•Irregular eye movements
•Chorea
•Pyramidal signs
•Tremors
•Peripheral neuropathy
•Cognitive impairment (rare, only some types)
•Seizures
•Cerebellar atrophy

Question 6

Charcot-Marie-Tooth Disease (CMT)

Answer 6

Inheritance: AD,AR, X-linked
Genes: Many, Duplications of PMP22 are responsible for 70-80% of cases (AD)

Question 7

CMT: Features

Answer 7

Major features:
•Onset of symptoms in early childhood or early adulthood
•Foot drop
oForefoot drops due to muscle weakness
oCan cause hammer toe
•Muscle wasting and weakness
•Neuropathy and loss of feeling in feet, ankles, legs, hands, and arms
•Painful, spasmodic muscular contractions
•Damage of sensory nerves while pain nerves are left intact
•Bruxism
•Scoliosis
•Pregnancy and emotional stress can exacerbate disease progression
•Vocal tremor from muscle wasting
•Neuropathic pain
•Eventual wheelchair dependence
•Milder forms exist

Question 8

Emery-Dreifuss Muscular Dystrophy

Answer 8

Inheritance: X-linked, AD,AR
Genes: EMD, LMNA, SYNE1, SYNE2, FHL1
Major features:
•Muscle wasting and weakness
•Toe walking
•Joint contractures
•Arrhythmia
•Wheelchair dependency/respiratory insufficiency

Question 9

Facioscapulohumeral Muscular Dystrophy

Answer 9

Inheritance: Autosomal Dominant
Genes: Due to deletions of 4q35 which cause deletions of the microsatellite repeat D4Z4. Normally 11-100 repeats units on wild-type alleles. Deletions leading to 10 or fewer repeats lead to FSHD

Question 10

Facioscapulohumeral Muscular Dystrophy: Features

Answer 10

Major features:
•Normal lifespan
•Slowly progressive weakness of the facial muscles, scapular muscles, and humeral muscles
•No weakness in bulbar or ocular muscles
•Winged scapula
•Onset of symptoms by 20 years of age

Question 11

Limb-Girdle Muscular Dystrophy

Answer 11

Inheritance: Autosomal dominant, autosomal recessive
Gene: Too many
Major features:
•Symmetric proximal slowly progressive muscle weakness
•Difficulty walking and using stairs
•Difficulty bending over
•Frequent falls
•Difficulty holding arms above head
•Pseudohypertrophy
•Respiratory difficulties
•Lower back pain
•Heart palpitations
•Facial muscle weakness
•Distal muscle weakness
•Shoulder weakness
•Age of onset typically between 10-30
     oFaster progression with earlier onset
•Not typically fatal, but can weaken heart or lungs and lead to death

Question 12

Nemaline Myopathy

Answer 12

Inheritance: Autosomal dominant, autosomal recessive
Genes: ACTA1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3, NEB, TNNT1, TPM2, TPM3
Major features:
•Muscle weakness, most severe in the face, neck flexors, and proximal limbs
•Hypotonia
•Depressed/absent deep tendon reflexes

Question 13

Severe congenital NM

Answer 13

Severe congenital NM
•Severe hypotonia and muscle weakness at birth
•Feeding difficulties
•GI reflux
•Respiratory insufficiency
   oOften leads to early mortality

Question 14

Amish NM

Answer 14

Amish NM
•Neonatal onset with early childhood onset
•Hypotonia
•Contractures
•Muscle tremors
•Severe pectus carinatum
•Muscle atrophy
•Respiratory insufficiency

Question 15

Intermediate NM

Answer 15

Intermediate NM
•Early development of joint contractures
•Motor delay due to muscle weakness
•Wheelchair/respiratory deficiency by age 11

Question 16

Typical (mild) congenital NM

Answer 16

Typical (mild) congenital NM
•Hypotonia, weakness, and feeding difficulties
•Spontaneous anti-gravity movements
•Respiratory involvement is limited (recurrent lower respiratory tract infections and/or nocturnal hypoventilation)

Question 17

Childhood-onset NM

Answer 17

Childhood-onset NM
•Slowly progressive symmetric weakness of ankle dorsiflexion with foot drop
•Onset in 1st or 2nd decade of life
Motor milestones usually met

Question 18

Adult-onset NM

Answer 18

Adult-onset NM
•Generalized muscle weakness onset between ages 20-50 without antecedent symptoms
•May have cardiomyopathy
May present with “head drop”

Question 19

Spinal Muscular Atrophy (SMA) I & II

Answer 19

Inheritance: Autosomal recessive
Gene: SMN1

SMAI:
•Onset 0-6 months
•Hypotonia with muscle weakness
•Absence of motor development
•Involuntary twitching of the tongue
•Mild joint contractures
•Absent tendon reflexes
•Normal brain function and intellect

SMAII
•Onset after age 6 months
•Can sit independently once placed in a seated position
•Hypotonia
•Absent tendon reflexes
•Normal intellect

Question 20

Spinal Muscular Atrophy (SMA) IIII & IV

Answer 20

SMAIII
•Onset after age 10 months
•Most motor milestones achieved
•Muscle weakness manifesting as frequent falls and trouble with stairs
•Proximal limb weakness
   oLegs worse than arms

SMAIV
•Adult onset muscle weakness

Question 21

Significance of SMN2

Answer 21

Severity can be affected by number of SMN2 copies. SMN2 can compensate for absent SMN1, the more SMN2 copies, the less severe the phenotype

Question 22

Walker Warburg Syndrome

Answer 22

Inheritance: Autosomal recessive
Genes: POMT1, POMT2

Question 23

Walker Warburg Syndrome: Features

Answer 23

Major features:
•Hypotonia
•Muscle weakness
•Developmental delay
•Absence of motor skill development
•Severe Intellectual disability
•Seizures
•Brain defects
   oLissencephaly
   oHydrocephalus
   oCerebellar malformations
•Encephalocele
   oGap in skull that won’t seal
   oMeninges of brain can protrude through this gap
•Microphthalmia
•Retinal abnormalities