Neurogenetics Flashcards
Describe the different kinds of signs/maneuvers that can help evaluate neuromuscular disease.
Gowers' Maneuver (rolls over to get up from laying down; uses hands to pull up stairs) Trendelenburg gait (weakness of abductor muscles of lower extremity noted with waddling gait or on stairs)
generalized weakness and muscle wasting
generally affects hips, pelvic muscles, and thighs first
first presenting sign may be difficulty climbing stairs or arising from the floor (Grower’s maneuver), though delayed motor milestones, abnormal gait (toe-walking), and speech delays/LD are also seen
some degree of static cognitive impairment (specifically deficits in short-term/working memory; deficits in executive function which takes some time to emerge)
scoliosis develops in most after loss of ambulation
+/- cardiomyopathy
eventually the heart and lungs are also affected leading to respiratory and cardiac failure
DMD associated conditions (general)
Describe the difference in onset of Duchenne vs Becker Muscular Dystrophy.
Duchenne- onset of symptoms 2-4 years; wheelchair bound before 13 y/o; lifespan into 4th (sometimes 5th) decade
Becker- onset variable; wheelchair bound >16 y/o (though some remain ambulatory throughout life); lifespan very variable
How are DMD associated conditions diagnosed?
Clinical phenotype and elevated CK
Molecular genetic testing (tier 1- CNVs in the dystrophin gene; tier 2- full DMD sequencing; X-linked) - DMD typically is associated with out of frame exonic deletions; in frame exonic deletions typically are associated with BMD
Immunofluorescent staining with dystrophin antibody on muscle biopsy (only if genetic etiology is not found)
What kinds of management are recommended for boys with DMD associated conditions.
Chronic, low dose corticosteroids
Follow-ups with GI/nutrition (for dysphagia) and pulmonology (for diaphragmatic dysfunction)
ECHO at diagnosis and periodically as per recommendations of cardiology
Beta blockers/ACE inhibitors (for cardiomyopathy when/if it is identified)
Orthopedic management/rehab/appropriate assistive technology/PT/bracing (these approaches only prolong muscle function)
Psychosocial care
Endocrinology (for growth/adrenal insufficiency/bone health due to the chronic steroid use)
What new treatments are now available for DMD associated conditions?
exon skipping (For reading frame deletions- changes from Duchene to Becker by restoring the reading frame) available for exon 51 and exon 53; other exons are in clinical trials Premature stop-codon read-through (Ataluren/Translarna- aminoglycoside derivative that allows for read-through of early nonsense mutations) ONLY IN EU
progressive weakness that begins in the proximal limb muscles (facial and proximal muscle weakness with arms>legs) onset ranges from childhood to adulthood elevated CK (2000-5000) dystrophic changes on muscle biopsy cardiomyopathy nocturnal hypoventilation absence of bulbar symptoms normal brain MRI and IQ
Limb Girdle Muscular Dystrophy
FKRP LGMID2M, FKTN
AD or AR, but genetically heterogeneous- note that this is typically a purely descriptive diagnosis with many subtypes that are not easily distinguished between
progressive weakness that begins in the proximal limb muscles (especially affects the scapular muscles in the early stages)
onset between 3-15 y/o; may loose ambulation on average ~15 years after onset (though some remain ambulatory)
elevated CK
normal intellectual development
Sarcoglycanopathies (LGMD R3-R6)
four distinct genetic causes (not clinically distinguishable)- SGCA, SGCB, SGCG, SGCD
AR (so males and females affected equally)
myotonia; delayed relaxation of voluntary contraction
slowly progressive weakness (distal > proximal)
early onset posterior subcapsular cataracts
arrhythmias; cardiomyopathy
diabetes; hypothyroidism; decreased fertility in males
spectrum of learning disabilities to severe ID
Myotonic Dystrophy Type I
Describe the three clinical subdivisions of Myotonic Dystrophy Type I.
Mild- likely will only have extra-muscular findings
Classic- extra-muscular findings and spectrum of muscle involvement
Congenital- neuromuscular symptoms from birth/infancy
Describe the inheritance of Myotonic dystrophy.
RNA mediated condition CTG repeat disorder of the DMPK gene- normal- 5 to 37 premutation- 38 to ~49 (onset 20-70's) mild- 50 to ~150 (onset 10-30's) classic- ~100 to ~1000 congenital- ~1000 to >2000 (nearly all cases are inherited from affected mother who may only have subclinical symptoms)
polyhydramnios and decreased fetal movement
Neonatal period-
severe generalized hypotonia multiple joint contractures/arthrogryposis present at birth in some
significant facial diplegia
respiratory insufficiency; prolonged ventilatory support with inability to wean off
Childhood (those that survive)-
gradual improvement of motor function
usually able to walk
myopathy
mild to moderate ID
Congenital Myotonic Dystrophy
myotonia; slowly progressive weakness; proximal>distal
early posterior subcapsular cataracts
arrhythmias, AV conduction block, cardiomyopathy (rare)
diabetes, hypothyroidism, decreased fertility in males
NO ID
white matter changes; executive decision-making dysfunction
Myotonic Dystrophy Type 2
intronic tetranucleotide CCTG expansion in the CNBP gene (repeat size 75-11000)
Repeat size cannot predict severity
NO anticipation; repeat size can contract over generations and can expand during lifetime (increases with age)
severe hypotonia and weakness at birth
high CK (»1000)
independent walking not achieved in complete deficiency (complete absence of merosin staining on muscle biopsy); ambulation possible with partial merosin deficiency
mild neropathy
white matter changes/leukoencephalopathy on MRI
higher incidence of seizures, but intellectually normal
Merosm Deficient Congenital Muscular Dystrophy
LAMA2
AR
Previously diagnosed on CVS with merosin staining
significant hypotonia and weakness; initially contractures not obligatory
absent or temporary ambulation
CK normal to high
characteristic coexistence of very significant distal hyperlaxity and proximal contractures
kyphoscoliosis, torticollis, hip dislocation, talipes
palmar softness, proximal keratosis pilaris, abnormal scars
early respiratory compromise (nocturnal hypoventilation)
Ullrich Congenital Muscular Dystrophy
COL6A1, COL6A2, COL6A3
AR or de novo AD
congenital joint contractures and torticollis may be present but often resolve
CK normal to mildly elevated
after initial joint hypermobility, new development of contractures (achilles tendons, elbows, deep finger flexors, pectoralis, quadriceps)
very slow, progressive contractures may become a major problem +/- late loss of ambulation
palmar softness, proximal keratosis pilaris, abnormal scars
restrictive lung disease, nighttime hypoventilation
Bethlem Myopathy
COL6A1, COL6A2, COL6A3
Mostly AD (de novo) but few are AR
congenital presentation wtih variable weakness and evolving contractures, high CK
cobblestone lissencephaly (type 2) which can be mistaken for polymicorgyria, abnormal tectum and ponto-cerebellar malformation, hydrocephalus, encephalocele
seizures are common
Lifespan 1-3 years
Walker-Warburg Syndrome
POMT1 (also other genes associated)
congenital weakness, progressive contractures and weakness high CK cobblestone lissencephaly that can be misread as polymicrogyria; cerebellar dysplasia; abnormal white matter myopia, optic nerve hypoplasia seizures (40%); severe ID cardiomyopathy respiratory failure Lifespan ~10 year
Fukuyama Congenital Muscular Dystrophy
neonatal hypotonia and variable weakness
high CK
delayed milestones, but may walk
by 5 years deterioration with contractures, weakness, and spasticity
visual impairment (high myopia, cataract, glaucoma, progressively abolished ERG, retinal detachment)
cobblestone lissencephaly that can be “polymicrogyria-like”, occipital agyria, abnormal tectum, pontocerebellar hypoplasia, cerebellar cysts, abnormal white matter
mild to severe ID
Muscle-Eye-Brain disease
POMGnT1 (plus others)
severe hypotonia, early selective muscle hypertrophy
high CK
facial and proximal weakness (arms>leg)
respiratory failure and often cardiomyopathy
normal brain imaging
normal to mild ID
Congenital Muscular Dystrophy
FKRP
adult onset slowly progressive
face, shoulder, girdle, and upper arms affected
elevated CK (>1500)
myopathic EMG
non-specific myopathic changes on muscle biopsy
Facio-Scapulo-Humeral Muscular Dystrophy D4Z4 repeat of the DUX4 gene normal 11-100 units disease 1-10 units (gain of function) MUST happen on 4qA haplotype to be disease causing
List the different kinds of “classic: congenital myopathies.
Nemaline myopathy (named for Nemaline rods on muscle biopsy)- mostly AR; some AD
Centronuclear/myotubular myopathy (named for their muscle biopsy characteristic finding)- AD, AR, or XL (MTM1 gene)
Central core disease (“punched out lesion” look in the muscle fibers)- AD or AR
Multi/minicore myopathy (have small central cores on muscle biopsy)- mostly AR, some AD
NOTE- genetically heterogeneous with a broad phenotypic spectrum
onset in neonatal period with hypotonia that improves with age
slender habitus, atrophic muscles
delayed motor milestones (though they do improve)
generally non-progressive in childhood
nocturnal hypoventilation possible
typically normal CK
Classic Congenital Myopathies (common phenotype for all genes- difficult to distinguish clinically)
Diagnosed taking into consideration exam with muscle biopsy and/or genetic testing
long face, facial weakness, neck weaknes
dysphagia
diaphragmatic involvement
shoulder/arm weakness is more significant than the pelvic/leg weakness
Nemaline myopathy
diagnosed on muscle biopsy (looking for Nimaline rods)
variable phenotype with mild to moderate presentation most commonly…
mild hypotonia during early infancy
delayed motor milestones
generalized muscle weakness, quite stable
hip dislocation, spinal deformities, arched feet, pectus excavatum
Severe phenotype is typically lethal
Mild is adult onset (almost asymptomatic)
Central core disease
severe hypotonia and weakness at birth
distal arthrogryposis, congenital fractures
respiratory insufficiency (can result in neonatal death); decreased respiratory reserves; frequent infections
poor suck and swallow, dysphagia
tend to remain non-ambulatory
Central Core Disease- severe neonatal presentation
mostly AR in RYR1 gene
Muscle biopsy will most often show central cores, more dystrophic changes with less clear cores, or other muscle pathology findings
transient muscular rigidity, hyperthermia, rhabdomyolysis that is triggered by halogenated anesthetics, succinylcholine
Malignant Hyperthermia
RYR1 gene mutations (50% of cases), CACNA1S, and 4 other loci
AD
acutely managed with dentrolene
Can often be found in association with Central Core disease
feeding difficulties, failure to thrive hypotonia, reduced movements respiratory infections *hypertrophic cardiomyopathy* enlarged tongue and liver hearing loss *high CK* average onset between 1.6-2 m/o average age at death between 6-8.7 m/o (without treatment)
Pompe Disease (GSD II/acid maltase deficiency/acid alpha-glucosidase deficiency) Classic infant form
GAA gene
AR
<1% residual enzyme activity
Treatment with Genzyme is less effective than in later onset forms- may require immunomodulating therapy to prevent antibody development
