The Inherited Ataxias

The Inherited Ataxias

Friday, November 05, 2004

Genetic Classification

Abbreviations used are seen at bottom of this page

Dominant - progressive

i) expanded polyglutamine tract disorders

typical (unstable) SCA’s 1, 2, 3, 7, 17

atypical (stable) SCA 6

ii) non-coding repeat amplification promotor region triplet repeat

SCA 12

intronic pentanucleotide repeat expansion SCA 10

intronic triplet repeat expansion

iii) gene unknown (locus defined)

SCA’s 4, 5, 11, 13, 14, 15, 16

B.Dominant - episodic

EA1 - KCNA1 gene (K+ channel)

EA2 - allelic with SCA 6 (Ca2+ channel)

Recessive

Friedreich’s ataxia

intronic triplet repeat expansion

carrier rate ~1 in 100

Ataxia telangiectasia

various mutations in ATM gene

ARSACS

(at least) 2 truncating mutations in sacsin

AVED

numerous single base mutations in a-tocopherol transferase protein (a-TTP)

Mitochondrial Inheritance

NARP (ATP-synthase 6 subunit)

MELAS, (tRNAleu, etc.

(Note: KSS - sporadic)

Implications

diseases with single defined mutations(FA, SCA’s 1, 2, 3, 6, 7, 10, 12, 17, ??8) are easy to test for genetically

diseases with numerous different mutations in large genes (e.g. EA1 and 2, A-T) do not have routine genetic testing available, and must usually be diagnosed clinically. (Occasionally, the relevant overseas researcher can be persuaded to analyse a sample.)

diseases where only the locus is known can only be diagnosed in informative (large) pedigrees. Typically, 8-10 informative meioses needed, so diagnosisis nearly always clinical.

Pathogenetic Mechanisms

CAG repeat disorders

unstable (role of non-CAG intrusion)

expansion from premutation zone

anticipation, and relationship to repeat number

“true dominance”

gain of (novel) function

possible mechanisms of neurotoxicity

product insufficiency

point mutations

relationship of severity to smaller expanded allele

mitochondrial iron regulation and oxidative damage - idebenone

SCA’s - Making the Diagnosis

ADCA’s I, II and III, but becoming obsolete

i) Presence of family history - BUT

new mutation: SCA 2 especially

non-penetrance: SCA 6 especially

extreme anticipation: SCA 7 especially

plus all the usual traps

ii) Ethnic origin - founder effects

SCA 1: Angloceltic, Siberian

SCA 2: Italian (especially Southern), Indian

SCA 3: Portuguese, German, (French), Chinese

SCA 6: everywhere but France

SCA 7: uncommon everywhere

SCA 10: Mexican

SCA 12: very rare in USA & UK (not found elsewhere yet)

SCA 17: ?may be common (Germany & Japan)

DRPLA: very rare outside Japan (Haw River Syndrome in USA)

FA: rare in blacks, absent in orientals

AT: common everywhere (different mutations)

ARSACS: French Canadians, North Africans

AVED: North Africans

(Frequencies of locus-defined SCA’s are unknown)

Australian Figures: SCA 1 = SCA 6>SCA 3>SCA 2 >SCA 7

These together account for just under half of all dominant pedigrees.

iii) Distinctive clinical features

(Note: often none, and can be very hard to assign in individual. Easier with a whole pedigree - average phenotype)

SCA 7: tritanopia ® visual loss (especially with younger onset)

SCA 2: viscous saccades, hypo/areflexia, ± dementia

MRI: severe pontocerebellar atrophy

SCA 3: may present with parkinsonian features

most have horizontal gaze-evoked nystagmus

may have convergence insufficiency

MRI: enlargement of 4th ventricle but preserved cerebellar cortex

SCA 6: “pure” ataxia (± minor pyramidal signs)

slow progression (20+ years) ± episodic onset

virtually all have nystagmus - often with vertical eye movement abnormalities

MRI: pure cerebellar cortical atrophy

SCA 1: often spasticity (prolonged MEP’s common)

hypermetric saccades, but only 10% have nystagmus

may have optic atrophy

(Others:)

SCA 4: sensory neuropathy? (not in Japan!)

SCA 10: epilepsy in most - (seems robust)

SCA 12: tremor first symptoms by 10-20 years

SCA 13: early childhood onset, intellectual impairment, slowly progressive

SCA 14: axial action myoclonus first

SCA 15: extremely slow progression (50+ years - still ambulant without aids)

SCA 17: cognitive decline, parkinsonism, marked pyramidal features(eventually). Eye movements normal

SCA’s 5, 8, 11, 16: ADCA’s type III - no particular distinguishing characteristics

Friedreich’s Ataxia

classically, onset 5-25 with gait ataxia/scoliosis/cardiomyopathy; areflexia (and absent sural SNAP’s), extensor plantars within 5 years; dysarthria within 10

phenotype much more variable than classically thought (onset can be 2-50, reflexes need not be lost, can present with chorea, etc.!)

Frequency of classical features:

axonal neuropathy ~97%

lower limb hypo/areflexia ~90%

cardiomyopathy ~85%

extensor plantars ~80%

scoliosis ~60%

foot deformity ~55%

Other features:

nystagmus ~40% only

diabetes/impaired glucose ~30% tolerance

dysphagia ~30%

visual loss ~15%

(optic atrophy ~3%)

hearing loss ~15%

Note: MRI - cervical cord atrophy. Cerebellum is normal in early-mid disease.

Variants:

FARR, LOFA, (Acadian)

Differential diagnosis:

AVED, Bassen-Kornzweig, NARP, (“Roussy-Levy”)

Care:

multidisciplinary

Treatment:

idebeonone (French ECb10 study)

Ataxia-telangiectasia

Most diagnosed before adulthood, but variants

without telangiectasia

without immune compromise

exist and may be diagnosed later.

Pointers:

i) progressive ataxia, with

ocular motor apraxia; OKN absent

chorea/dystonia common (especially dystonia in adolescent/adult patients)

peripheral neuropathy/areflexia common

elevated aFP (after age 10)

ii) oculocutaneous features

iii) radiosensitivity (and heterozygotes?)

iv) immune compromise (humoral/cellular - variable)

v) susceptibility to malignancy (and heterozygotes?)

Note: neurological features may resemble isolated case of SCA 2

Non-Genetic Ataxias

Sporadic OPCA variant of MSA

clue - autonomic dysfunction

Sporadic CCA

no clues (some are actually SCA 6)

Paraneoplastic (and imitators)

clue - acute - subacute course with subsequent stability, pancerebellar syndrome

(Arnold-Chiari malformation!)

Episodic Ataxias

Distinctive story (always ask for this specifically)

EA1

brief (£5 minute) attacks

typically, childhood onset easing in adulthood

dysarthria/incoordination, ± tremor

myokymia (often EMG only) interictally, but little else

precipitation by startle/sudden movement/intercurrent infection

Differential diagnosis:

PKC, “epilepsy”

treatment - may respond to acetazolamide, carbamazepine

EA2

onset 2-30 years - some non-penetrance

longer attacks (hours)

ataxia, with vertigo/nausea/vomiting in over 50% of patients

gaze-evoked nystagmus + rebound common interictally (some also have spontaneous vertical nystagmus); may evolve to fixed truncal ataxia

precipitation by emotional upset/exercise/caffeine/alcohol

treatment - responds reliably to acetazolamide

Note: Some patients with FHM1 (allelic with EA2 and SCA 6) show later, progressive ataxia, especially of gait (and sparing speech)

Inherited ataxia abbreviations

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is an early onset neurodegenerative disease with high prevalence (carrier frequency 1/22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec.

Ataxia with vitamin E (Vit E) defciency (AVED) is an autosomal recessive disorder caused by mutations of the alpha tocopherol transfer protein gene. The Friedreich ataxia phenotype is the most frequent clinical presentation.

NARP: neuropathy, ataxia and retinitis pigmentosa

MELAS: mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes

Kearns-Sayre syndrome (KSS) is a sporadic multisystem disorder due to a defect of oxidative phosphorylation and associated with clonally-expanded rearrangements of mitochondrial DNA (mtDNA) deletions (Delta-mtDNAs) and/or duplications (dup-mtDNAs).