Differential Diagnosis in Neurology

13.3. Autosomal Dominant Ataxias

Autosomal Dominant Ataxias

• General characteristics:
  • General onset from the third to fifth decades (may be from childhood to old age)
  • Offspring are at risk (50% inherit the mutation)
  • Rarely the disease is not apparent in a parent:
    • Variable penetrance
    • Due to anticipation, the child may demonstrate the disease prior to the parent
    • Premature death of the parent
    • Origin of a new mutation
  • Genetic heterogeneity is widespread
  • The progressive cerebellar ataxia in most instances is associated with:
    • Ophthalmoplegia
    • Optic atrophy
    • Peripheral neuropathy
    • Pyramidal and extrapyramidal signs
    • Dementia is not an early feature
    • Differential SCAs have clinically seminal features that are helpful in diagnosis

ADCA 1

• General characteristics:
  • CAG repeats occur within SCA1, SCA2, SCA3, SCA6, SCA7, SCA12 and dentatorubral-pallidoluysian atrophy DRPLA
  • SCA12, the CAG is in the promoter region
  • Usual onset is a progressive gait disorder; loss of ability to walk occurs about 10 years after onset of the illness
  • Ocular signs include:
    • Nystagmus
    • Deficits of smooth pursuit
    • Gaze palsies
    • Ptosis
    • Blepharospasm
    • Ocular dysmetria
  • Cranial nerve deficits
    • Facial atrophy
    • Tongue fasciculation and atrophy
    • Dysphagia
    • Impaired cough
  • Peripheral nerve abnormalities
    • Stocking and glove distal sensory loss
    • Amyotrophy
    • Fasciculations
    • Usual is a dying back neuropathy
  • Upper motor signs include:
    • Often appear early in the course of the disease
    • Spasticity, Babinski response and increased reflexes
  • Basal ganglionic signs:
    • Bradykinesia, rigidity, tremor, dystonia and choreoathetosis
  • Cortical signs include:
    • Seizures, myoclonus, dementia
  • Retinal degeneration occurs
• Imaging evaluation:
  • SCA1, SCA2, SCA3 and SCA7
    • Pontocerebellar atrophy
    • Loss of pontine fibers that constitute the MCP
  • SCA3 and SCA6
    • Isolated cerebellar atrophy with sparing of the brainstem

Spinocerebellar Ataxia Type 1 (SCA1)

• General characteristics:
  • Most common of the ADCAs
  • Chromosome 6p 22–23
• Clinical features:
  • Onset from 15–65 years of age; symptoms usually occur in the third to fourth decade
  • Initial feature is progressive ataxia of gait
  • Arm involvement with associated dysarthria occurs later
  • Pure cerebellar syndrome early
  • Later associated features are:
    • Ophthalmoplegia (supranuclear)
    • Pyramidal tract dysfunction
    • Familial pneumothorax
    • Slow saccadic eye movements in Indian patients
  • Dementia
  • Parkinsonism, dystonia, chorea
  • Fasciculation of the face and tongue (rare)
  • Progressive loss of reflexes
  • Loss of vibration and proprioception
• EMG
  • Evidence of peripheral neuropathy
• MRI evaluation:
  • Cerebellar and brainstem atrophy

SCA2

• General characteristics:
  • Chromosome 12q 23–24; CAG repeat
  • High inter and intra family variability; anticipation is noted
  • Aggregation of ataxin protein in the cytoplasm of Purkunje cells
  • Slowing of saccades
• Clinical features:
  • Supranuclear gaze palsy
  • More frequent hyporeflexia than SCA1
• MRI evaluation:
  • Greater cerebellar and brainstem atrophy than SCA 1

SCA/ Machado Joseph Disease

• General characteristics:
  • Chromosome 14q 32.1
  • Initially reported in patients of Azorean or Portuguese descent
• Clinical features:
  • Bulging eyes
  • Extrapyramidal manifestations
  • CAG repeats > 62–80 the more parkinsonian features
  • Dopa-responsive parkinsonism; bradykinesia and rigidity respond initially
  • Peripheral neuropathy
  • Facial fasciculation and dystonia

MJD/ SCA3

• Type 1
  • Early onset
  • Extrapyramidal/pyramidal signs
  • Cerebellar ataxia
• Type II
  • Middle age onset
  • Ataxia
  • Pyramidal tract signs
  • Extrapyramidal features
• Type III
  • Cerebellar ataxia
  • Amyotrophy
• Type IV
  • Parkinsonism
  • Peripheral neuropathy

    	SCA1 # of CAG repeats	MJD # of repeats
    Normal	19–36	12–40
    Borderline	37–42	None
    Full mutation	>41	>61

SCA4

• General characteristics:
  • Chromosome 16q-ter
• Clinical features:
  • Similar to SCA1
  • Sensory axonal neuropathy
  • Generalized areflexia

SCA5

• General characteristics:
  • Chromosome 11 centromeric
• Clinical features:
  • Relatively pure ataxia

SCA6

• General characteristics:
  • Chromosome 19
  • Aggregation of calcium channel protein in the cytoplasm
• Clinical features:
  • Onset in adulthood
  • Benign course
  • Intermittent ataxia
  • Migraine associated
  • Interictal vertigo
  • Calcium channelopathy

SCA7 (DRPLA)

• General characteristics:
  • Dentatorubral pallidal Luysian atrophy
  • Chromosome 3 p12–21.1
  • Prominent anticipation
• Clinical features:
  • Onset in childhood
  • Upper motor neuron signs
  • Retinal degeneration
  • Personality disruption
  • Parkinsonism and chorea
  • Myoclonus
  • Seizures and dementia may start prior to age 20

SCA8

• General characteristics:
  • Chromosome 13; CTG expansion (54–79 repeats)
• Clinical features:
  • May start in infancy
  • Ophthalmoplegia
  • VIIIth nerve involvement
  • Seizures
  • Hypotonia

SCA10

• General characteristics:
  • Mexican kindreds
  • Chromosome 22; ATTCT expansion
• Clinical features:
  • Associated with seizures
  • Ataxia may precede or follow the onset of seizures
  • Seizures are partial or generalized

Autosomal Dominant Ataxias Related to Point Mutations

SCA 14

• Single Japanese family
• FGF 14 mutation
• Axial myoclonus

SCA 15

• Chromosome 3p24.3–3pter
• Pure cerebellar dysfunctions

SCA 16

• Chromosome 8q22.1–24.1
• Head tremor

SCA 18

• Seizures
• Peripheral neuropathy

SCA 20

• Palatal tremor
• Hypermetric saccades
• Dentate nuclei calcification

SCA22

• Chromosome 1 p21–q23
• Gait ataxia
• Dysarthria
• Hyporeflexia

SCA 23

• Chromosome 20p 12.3–20
• Late onset >40 years of age
• Pure cerebellar

SCA 25

• Peripheral neuropathy

Not completely classified ADCA I

• Cerebellar ataxia (AD)
  • Chromosome 7q22–q32
  • Sensory motor neuropathy
• Ataxia/pancytopenia (AD)
  • No gene identified
• Cerebellar ataxia (AD)
  • Chromosome 19q (telomeric)
  • Pure cerebellar symptoms
  • Onset at 31 years (mean age)
  • Mild to moderate dysarthria
  • Saccadic substitution for smooth pursuit
• Autosomal dominant congenital non progressive ataxia
  • Linkage to chromosome 3 pter
  • Overlaps SCA 15 locus
  • Cognitive decline
  • Dystonia
  • Nystagmus
  • Gait ataxia
• Autosomal dominant cerebellar cortical atrophy
  • Chromosome 16q
• SCA
  • Chromosome 19q 13.4 q ter
  • Onset third and fourth decades
  • No anticipation
  • Overlaps SCA 14 locus
  • No axial myoclonus

Episodic Ataxia (EA1)

• General characteristics:
  • Chromosome 12; mutation of the potassium channel gene
• Clinical features:
  • Brief episodes of ataxia
  • No interictal signs
  • Associated skeletal muscle myokymia

Episodic Ataxia Type II (EA2)

• General characteristics:
  • Point mutation alpha-1A subunit of the calcium channel gene on chromosome 19
  • CAG expansion in the same gene causes SCA6
• Clinical features:
  • Ataxia episodes last longer than in EA1
  • Permanent nystagmus
  • May develop permanent ataxia
  • Reduced penetrance in some families

Harding Clinical Features of Late Onset AD Ataxias

• Optic atrophy
• Ophthalmoplegia
• Dementia
• Amyotrophy
• Inability to vomit

ADCA Type 1

• General characteristics:
  • SCA 1, 2, 3, 12, 13, 17, 19; some patients in 4; 21

ADCA Type II

• General characteristics:
  • Chromosome 3p 12–21.1 gene
  • Paternal transmission increases anticipation
• Clinical features:
  • Pigmentary maculopathy is the distinguishing feature
    • Retinopathy involves the macula and leads to blindness
    • Extends to peripheral fundus
    • Early blue-yellow color discrimination deficit
    • Supranuclear ophthalmoplegia
    • Extrapyramidal features
    • Patients are wheelchair bound by 15 years of age; onset may occur between 2–65 years of age
    • Onset may be ataxia or visual loss
    • Genetically homogeneous
    • Adult onset cases usually have paternal transmission; there is reduced penetrance as obligate gene carries do not manifest disease although they live beyond 65 years of age
    • Chorea
    • Myoclonus and personality change
• Pathology:
  • Retinal atrophy
  • Cerebellar atrophy (cortex)
  • Atrophy of the spinocerebellar and the olivocerebellar tracts
  • Efferent cerebellar pathway atrophy

ADCA Type III

• General characteristics (noted above for ADCA Type II):
  • SCA5 (Abraham Lincoln relative); chromosome 11
  • SCA6

ACDCA IV

• DRPLA
• SCA 14
  • Myoclonus and seizures
  • Axial myoclonus (SCA 14)

ADCA V

• Periodic dominant ataxia
  • EAT 1
  • EAT 2
• Clinical features:
  • Essential tremor

Rare Dominant Ataxias

• May be associated with:
  • Cataract, deafness, peripheral neuropathy, Parkinsonism and essential tremor

Episodic Ataxic Type I (ETA 1)

• General characteristics:
  • Chromosome 12; potassium channel gene
  • Potassium channel mutation
• Clinical features:
  • Childhood or adolescent onset
  • Brief attacks (minute to hours)
  • Ataxia, dysarthria, vertigo and nystagmus
  • Myokymia
  • Acetazolamide may be effective

Episodic Ataxia Type II (ETA2)

• General characteristics:
  • Chromosome 19q; allelic to hemiplegic migraine; point mutations in a calcium channel gene
    • Missense mutations cause familial hemiplegic migraine
    • Truncating mutations cause episodic ataxia type II
    • SCA 6 has CAG repeat in the 3' region of the gene
• Clinical features:
  • Onset in childhood or adolescence
  • Longer attacks than ETA 1
  • Vertigo, nausea and vomiting
  • In childhood, attacks may be accompanied by headache, drowsiness and fever
  • Interictal nystagmus
  • Slowly progressive ataxia
  • Acetazolamide is effective

Idiopathic Late-Onset Ataxias

• General characteristics:
  • Approximately 2/3 of patients with ataxia after the age of 20 are singletons
  • Many of these patients in the past have been designated as olivopontocerebellar atrophies
  • Lose ability to walk independently, 5–20 years after onset
  • Those that evolve into MSA have a shortened life span
  • EMG/NCV of sensory neuropathy is present in 50% of patients
  • MRI evaluation:
    • Cerebellar and brainstem atrophy
    • Pure cerebellar atrophy
    • "Maltese cross"-degeneration of the ponto cerebellar fibers is seen with OPCA
  • Brainstem involvement portends a poor prognosis
  • AD inheritance is suspected
• Clinical features of Déjérine-Thomas variant:
  • Onset 35–55: male > female
  • Ataxia associated with:
    • Dementia
    • Peripheral neuropathy (sensory loss and depressed reflexes)
    • Rare supranuclear ophthalmoplegia
    • Rare pigmentary retinopathy and optic atrophy
  • Approximately 15% of this group develop multiple systems atrophy in association with cerebellar ataxia
    • Autonomic failure:
      • Postural hypotension
      • Fixed cardiac rate
      • Impotence
      • Bladder dysfunction

Differential Point between MSA and Late Cerebellar Ataxia

• Impotence or urinary urgency > for MSA
• Narrow > broad based gait favors MSA (impairment of postural reflexes)

Marie–Foix Alajouanine Syndrome

• General characteristics:
  • Midline cerebellar syndrome
  • Gait ataxia > appendicular
  • Minimal or absent dysarthria
  • Dementia can occur
• Pathology:
  • Vermian atrophy
  • Olivary atrophy; minimal long tract involvement
  • Pons spared
  • Minimal long tract involvement

Dyssynergia Cerebellaris Progressiva (Ramsay Hunt)

• General characteristics:
  • Small number of late onset patients
• Clinical features:
  • Onset fifth and sixth decade
  • Prominent resting or postural kinetic tremor
  • Intention tremor

Variants of Olivopontocerebellar atrophy

Old Classification:

• Type 1-Menzel variant
  • Cerebellar ataxia
  • Dorsal column involvement
• Fick–Hamacher Type II
  • Prominent cranial nerve involvement
  • Cerebellar ataxia
• Type III
  • AD
  • Pure cerebellar ataxia
• Type IV
  • Retinitis pigmentosa
  • Cerebellar ataxia

Unusual Genetic Ataxia

Cerebrotendinous Xanthomatosis

• General characteristics:
  • Sterol 27-hydroxylase (CYP27A1) deficiency
  • Slightly > female to male ratio
  • Treatable with chenodeoxycholic acid
• Clinical features:
  • Tendon xanthomas – 70%
  • Cataracts – 92%
  • Decreased cognitive function – 80%
  • Ataxia-approximately 100%
• Laboratory evaluation:
  • Elevated plasma cholestanol levels

Pelizaeus–Merzbacher Disease

• General characteristics:
  • X-linked; increased copies of the proteolipid protein gene (PLP1 gene) also arises from duplications, deletions and mutations
  • PLP 1-duplications usually have classical or transitional PMD
  • Defective CNS myelination
• Clinical features:
  • Usually childhood illness starting at 2.5 years of age; rare adolescent or adult onset patients.
  • Early nystagmus and hypotonia progressing to spasticity legs > arms
  • Cognitive deficiency
  • Expressive aphasia in some children