Week 11: Hereditary Ataxia & Muscular Dystrophies

Primary cerebellar function

Integration center that processes input from the brain and spinal cord

• coordinates movements

• control the trunk

• facilitates smooth and precise movements

Cerebellar ataxia symptoms

• off balance

• deterioration of handwriting/clumsy hands

• tremor

• vision problems

• vertigo

• slurred/scanning speech

• dysphagia

Muscular dystropy (inherited)

defects in genes of muscle function (structural or metabolic) causing abnormalities on muscle biopsy due to change in the shape of muscle fibers

Myopathy

progressive weakness

Atrophy

loss of muscle mass

% of children with DMD with cognitive impairment

10%

Age of Dystrophy Manifestation

• some birth/childhood

• later manifestations

  • involved protein

  • fewer # of repeats

  • presence of modifying proteins

Gower’s maneuver

tell for DMD, person has to walk themselves up into a standing position from all fours

Evaluation for muscular dystrophy

• muscle examination

• FHx

• intial labs (ex. CK, TSH, T4)

• EKG and EMG

• MRI or ultrasound

• muscle biopsy

• genetic testing

Neurology Exam

• mental status

• cranial nerves

• motor exam (strength, tone, reflexes, quality)

  • 0-5 scale

• sensory exam

• cerebellar and gait

Duchenne/Becker Muscular Dystrophy (DMD/BMD) Genetic Cause

X-linked: pathogenic variants in DMD

• exonic deletions (70%)

• “out of frame deletions” = DMD

• “in frame” - some protein function = BMD

Difference between Duchenne and Becker

• Duchenne = early onset (2-3y/o, wheelchair by 12y/o)

  • death in late teens/30s

• Becker = similar symptoms, later onset and less severe

  • death in 40-50s

DMD Gene Hot Spots

Exons 45-55 (and exon 2-19)

DMD/BMD Symptoms/Presentation

• proximal muscle weakness

• cardiomyopathy

• cognitive abnormalities

• calf hypertrophy

• osteoporosis/scoliosis (from non-weight bearing and steroid use)

• respiratory failure (common cause of death)

DMD/BMD Diagnosis

• CK levels up to 20x normal

• EKG/EMG

• genetic testing

• muscle biopsy with dystrophin staining

  • atrophy, hypertrophy, increased connective tissue, fatty replacement

DMD/BMD Treatment/Management

• power wheelchair

• PT to avoid contractures

• respiratory care

• nutrition/dietary evals

• endocrinology eval

• steroids and exon skipping meds

Antisense Oligonucleotids (ASO) for DMD/BMD

• target messenger RNA to skip exons to restore the reading frame

  • exon 45 = casimersen

  • exon 51 = eteplirsen

  • exon 53 = golodirsen, viltolarsen

• 80% mutations amenable to exon skipping, create a more BMD phenotype

How many DMD cases are de novo?

• 1/3 of DMD cases are de novo

• 2/3 of DMD cases have a carrier mother

Females with DMD/BMD

• can present classically (larger deletions, Turner, UPD, compound het, skewed X chromosome inactivation)

• typically subclinical weakness

• cardiac findings

Myotonic Dystrophy Type 1 (DM1) Genetic Cause

AD: pathogenic CTG repeat expansions in DMPK

• Normal = 5-34

• Premutation = 35-49

• PATHOGENIC = 50+

Myotonic Dystrophy Type 1 (DM1) Genetic Considerations

• close to 100% penetrance by age 50

• anticipation expected from maternal inheritance

• mitotically unstable (somatic mosaicism with age)

• interruption with CCG or CGG repeats may have milder phenotype

Myotonic Dystrophy Type 2 (DM2) Genetic Cause

AD: pathogenic CCTG repeat expansions in CNBP

• normal: <30 (11-26 CCTG with interruptions)

• VUS: 27-29

• premutation: 30-54

• VUS: 55-74

• PATHOGENIC: 75-11,000 CCTG repeats

Myotonic Dystrophy Type 2 (DM2) Genetic Considerations

• no correlation between repeat number and phenotype

• no anticipation observed

Myotonic Dystrophy Symptoms/Presentation

• facial and distal weakness

• dysphagia/dysarthria

• executive dysfunction and cognitive abnormalities

• frequent falls

• hypersomnolence

• cardiac conduction defects

• premature cataracts

• hypogonadism and endocrine abnormalities

Facioscapulohumeral Muscular Dystrophy (FSHD) Pathophysiology

• DUX4 not typically expressed in somatic tissues

• FSHD caused by expression

• “protein created when it shouldn’t”

FSHD Genetic Cause

Autosomal Dominant

• Type 1: D4Z4 contraction (<10 repeats) with permissive haplotype (open heterochromatin)

• Type 2: SMCHD1 or DNMT3 pathogenic variants that result in hypomethylation

FSHD Symptoms/Presentation

• fascio = facial weakness

• scapulo = scapular winging and reduced shoulder stability

• humeral = bicep and tricep weakening, deltoid sparing

• hyperlordotic gait (exaggerated lumbar curvature)

FSHD Muscle Biopsy

• hypertrophy

• atrophy

• increased connective tissue

• inflammation around vessel

Emery-Dreifuss Muscular Dystrophy (EDMD) Genetic Causes

X-linked: pathogenic variants in EMD, FHL1

AD/AR: pathogenic variant(s) in LMNA

Emery-Dreifuss Muscular Dystrophy (EDMD) Symptoms/Presentation

• joint contractures

  • early in childhood

• slowly progressive muscle weakness

  • humeroperoneal, scapular and pelvic girdle muscles

• cardiac involvement

Limb-Girdle Muscular Dystrophy (LGMD) Genetic Causes

AR (90%): biallelic pathogenic variants in CAPN3 and DYSF

AD (10%): pathogenic variants in DNAJB6, TNPO3, and HNRNPDL

• 3 in 100,000 persons

Limb-Girdle Muscular Dystrophy (LGMD) Symptoms/Presentation

• progressive muscle weakness in shoulder and hips

  • falls on uneven surfaces, inability to get up from sitting

  • elbow to feed self, can’t lift objects

• winged scapula

• waddling gait

• increased CK levels

• sometimes cardiac and diaphragm involved

Spinal Muscular Atrophy (SMA) Genetic Cause

AR: biallelic pathogenic variants in SMN1

• can be modified by the presence of SMN2

Spinal Muscular Atrophy (SMA) Genotype-Phenotype Correlations

• 0 copies of SMN2 = severe in utero/birth, never sit

• 1-2 copies SMN2 = sit never walk

• 3-4 copies SMN2 = walk but not run

• 4 copies SMN4 = adult onset

Spinal Muscular Atrophy (SMA) Symptoms/Presentation

• motor neuron disease

• floppy baby syndrome

• “frog-leg”

• impaired head control

• respiratory failure

Friedreich Ataxia Genetic Cause

AR: biallelic pathogenic GAA repeat expansions in FXN

• Normal: 5-33 repeats

• Intermediate: 34-55 repeats

• Pathogenic: 56-1,300 repeats

Friedreich Ataxia Symptoms/Presentation

GAA (Gait Always Affected)

• progressive ataxia with early childhood/early adult onset

• hypertrophic cardiomyopathy (2/3)

• dysarthria/dysphagia

• neuropathy

• spasticity

• autonomic disturbance

• abnormal eye movements

Dentatorubral-pallidoluysian Atrophy (DRPLA) Genetic Cause

AD: pathogenic CAG repeat expansions in ATN1

• Normal: 6-35

• Intermediate: 35-47

• Pathogenic: 48-93

DRPLA Symptoms/Presentation

• ataxia

• cognitive decline

• myoclonus

• chorea

• epilepsy

• (looks like Huntington + seizures)

Spinocerebellar ataxias (general)

group of neurodegenerative disorders characterized by cerebellum degeneration leading to poor coordination and movement difficulties

• peripheral neuropathy

• pyramidal signs

• parkinsonism

• cognitive impairment

• dystonia

SCA7 Unique Feature

visual impairment, red-green colorblindness

• pyramidal signs

SCA17 Unique Features

Chorea, psychiatric symptoms

• Pyramidal signs, Parkinsonism

Classic/Most Common PolyQ SCAs

• SCA1

• SCA2

• SCA3/MUD

• SCA6

• SCA7

• SCA17

SCA1 Unique Features

Classic: peripheral neuropathy + pyramidal signs

SCA2 Unique Features

Psychiatric symptoms, ophthalmoplegia

• parkinsonism, cognitive impairment, peripheral neuropathy

SCA3/MUD Unique Features

Dystonia and ophthalmoplegia

• peripheral neuropathy, pyramidal signs, parkinsonism

SCA6 Unique Features

late onset, nystagmus, slow progression

SCA1 Genetic Cause

AD: pathogenic CAG repeat expansion in ATXN1

• Disease w/ 40+ repeats

SCA2 Genetic Cause

AD: pathogenic CAG repeat expansion in ATXN2

• Disease w/ 33+ repeats

SCA3/MUD Genetic Cause

AD: pathogenic CAG repeat expansion in ATXN3

• Disease w/ 55+ repeats

SCA6 Genetic Cause

AD: pathogenic CAG repeat expansion in CACNA1A

• Disease w/ 20+ repeats

SCA7 Genetic Cause

AD: pathogenic CAG repeat expansion in ATXN7

• Disease w/ 33+ repeats

SCA17 Genetic Cause

AR: biallelic pathogenic CAG repeat expansion in TBP

• Disease w/ 40+ repeats

Pyramidal signs

clinical manifestations of damage to corticospinal tracts

• spasticity

• hyperreflexia

• muscle weakness

• abnormal Babinski

Genetic Testing Considerations for Movement Disorders

• NGS does NOT detext short tandem repeats

• trinucleotide repeat analysis does not detect SNVs

• 40% of late-onset cerebella ataxia will not have an identifiable genetic cause

GC Considerations for Movement Disorders

• anticipation possible

• disruptions in repeats may modulate disease

• predictive testing may be offered

• testing of minors appropriate when symptomatic

Ataxia Epidemiology

• most commonly acquired (alcoholic cerebella degeneration and some medications)

• hereditary ataxia

Friedrich Ataxia Prevalence

1/20,000-50,000

Spinocerebellar Ataxia Prevalence

2.7/100,000

Cerebellar ataxia classification

• acquired (acute/subacute)

• neurodegenerative (chronic)

  • genetic vs. sporadic (ex. Parkinsonism, PSP)

Medication treatment for Friedreich Ataxia

Omaveloxolone (skyclarys), slows progression