Cerebellar disorders Flashcards
What are the 2 most important features of cerebellar disorders
Age of onset
1. Early = congenital, autosomal recessive
2. Adult = ADCA, alcohol, paraneoplasia, vascular
Course
1. Acute = vascular
2. Subacute = paraneoplasia, infection
3. Chronic = ILOCA, ADCA, MSA
What are the associated signs ?
Neurological
- pyramidal
- neuropathic
- ocular (retinitis pigmentosa, maculopathy, optic atrophy)
Outside the nervous system
- telangiectasia
- hepatosplenomegaly (Neimann- pick)
- any skeletal deformity - scoliosis
What are the investigation methods used ?
Imaging
(To refine the phenotype)
Neurophysiology
- demyelinating versus axonal neuropathy?
Blood tests
- genetic testing
What are the different types of inheritance for ataxia
Early onset <20yrs
- autosomal recessive
Late onset >25yrs
- autosomal dominant
X linked
- very rare
What are the core and additional features of Friedreichs ataxia ?
Early onset
Autosomal recessive inheritance
- absent reflexes and extensor plantars
- skeletal abnormalities: skoliosis, pes cavus
- cardiomyopathy
Progressive gait and limb ataxia
Additional features
- nystagmaus (rhythmic, repetitive, involuntary movement of the eye)
- optic atrophy
- diabetes
- deafness
What are rare types of recessive ataxia
(Defects in DNA repair)
Double strand breaks
Ataxia telangiectasia
Gene - ATM
Ataxia telangiectasia-like disease ATLD
Gene - MRE11
Single strand breaks
Spinocerebellar ataxia with axonal neuropathy (SCAN1)
Gene - TDP1
Ataxia with oculomotor apraxia 2 (AOA2)
Gene - SETX
What are the clinical pointers of autosomal recessive ataxia ?
Early onset
Complicated
- neuropathy, predominantly sensory
Oculomotor abnormalities
- apraxia/ supeanuclear
Cancer risk increased
Vitamin E deficiency
What is ADCA and its clinical classification
ADCA is autosomal dominant cerebellar ataxia
ADCA 1 - ataxia plus
- extrapyramidal
- supranuclear opthalmoplegia
- neuropathy
- dementia
- psychiatric disorder
ADCA 2 - pigmented macular dystrophy
ADCA 3 - “pure” cerebellar ataxia
What are the genetics of ADCA
ADCA 1
- SCA 1, 2, 3
ADCA 2
- SCA 7
ADCA 3
- SCA 6
Trinucleotide repeats and their related disorders
CAG repeats
- HD
- DRPLA
- SCA 1 2 3 6 7
-SBMA
Other
- Fragile X
- myotonic dystrophy
- Fra 16
- Friedreichs ataxia
What are the similarities of polyglutamine
- modest expansions of CAG
- in coding region
- neurodegenerative
- paternal transmission effects
- variable prevalence
What are the genetically tested ataxia’s ?
SCA(s)
FRDA
FXTAS
A few rare types
Gene panels and related genes
Stage 1
Hereditary ataxia (107 genes)
Ex; SETX, AAAS
Stage 2
Hereditary ataxia (52 genes)
Ex; ATP7B , C5orf72
Dystonia and Parkinsonism (28 gene panel)
Ex; LRRK2, MAPT
What is CANVAS
CANVAS (cerebellar ataxia sensory neuropathy, vestibular areflexia syndrome)
It is an adult onset slowly progressive syndrome
What is the frequency and spectrum of RFC1
500 individuals identified with bialellic expanded RFC1 alleles
It was identified in 32% of idiopathic sensory neuropathies
What are the requirements of translation
Finding genetic variants
(Clinical diagnosis or proving causality then clinical diagnosis)
Proving causality
Determining biological function
Influencing that function
What are the recent successes in gene therapy
- spinal muscular atrophy
- Hexosaminidase A
- Metachromatic leukodystrophy
- SOD1
Rapid sequencing- based diagnosis of thiamine metabolic dysfunction syndrome
24-48 hrs
Clinical course:
Emergency room —> biotin and thiamine.
administered
instability & feeding
started, Sent home
Diagnostic course:
Genomics, medical —> genomics, med
Genetics + neonate genetics, neonatal
team personnel to discuss
diagnosis and treat
