ICAs are a group of rare, complex neurodegenerative diseases primarily affecting the cerebellum

Introduction and Overview

• Definition: ICAs are a group of rare, complex neurodegenerative diseases primarily affecting the cerebellum
• Additional involvement: Often affects spinal cord and peripheral nerves
• Primary clinical feature: Progressive cerebellar syndrome leading to significant disability
• Genetic basis: Over 100 new entities described in the past 25 years, with up to 500 genes related to ataxias

Diagnosis and Initial Approach

Patient Assessment

• Collect detailed family medical history (three generations minimum)
• Perform thorough physical examination
• Exclude acquired causes of cerebellar ataxia

Key Clinical Features

• Gait and balance difficulties
• Cerebellar dysarthria
• Dysmetria (nose-finger and heel-shin tests)
• Hypotonia
• Cerebellar eye signs (often earliest clinical features)

Diagnostic Algorithm

• Determine age at onset and disease progression speed
• Assess functional disability
• Look for associated symptoms and signs

Genetic Testing

• Initial screening for most frequent expansions
• Next-Generation Sequencing (NGS) for comprehensive genetic analysis

Classification and Types of ICAs

Inheritance Patterns

• Autosomal Recessive Cerebellar Ataxias (ARCAs)
• Autosomal Dominant Cerebellar Ataxias (ADCAs)
• X-linked ataxias

Key ICA Types

• Friedreich Ataxia (FA)
  • Most common ARCA
  • Gene: FXN (GAA repeat expansion)
  • Classic onset: 7-25 years
  • Late-onset (LOFA): 25-40 years
  • Very late-onset (VLOFA): >40 years
• Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS)
  • Gene: RFC1 (AAGGG repeat expansion)
  • Onset: Usually adult (mean 54 years)
• Spinocerebellar Ataxias (SCAs)
  • Most common ADCAs
  • Several types (SCA1, SCA2, SCA3, etc.)
  • Often due to CAG repeat expansions
• Fragile X-associated Tremor/Ataxia Syndrome (FXTAS)
  • Gene: FMR1 (CGG repeat expansion)
  • X-linked inheritance
  • Late-onset (typically >50 years)

Clinical Features and Associated Symptoms

• Peripheral neuropathy
• Chorea, myoclonus, Dystonia, Spastic Paraplegia, Parkinsonism, Pyramidal signs
• Cognitive impairment, intellectual deficiency
• Oculoomotor apraxia, strabismus, Square wave jerks, hypometric slow saccades, vertical supranuclear saccades palsy

Cerebellar ataxias according to main clinical features

Cerebellar Cognitive Affective Syndrome (CCAS)

• Also known as Schmahmann’s syndrome
• Includes executive deficits, language difficulties, visual-spatial impairment
• Common in some ICA subtypes (e.g., SCA48)

Specific Clinical Clues

• Telangiectasias and oculomotor apraxia: Consider Ataxia-Telangiectasia
• Sensory neuropathy with areflexia: Consider Friedreich Ataxia
• Visual loss (cone-rod dystrophy): Consider SCA7

Diagnostic Investigations

• Brain Imaging
  • MRI: Assess cerebellar atrophy and other structural changes
  • Specific patterns may suggest certain ICA types
• Electrophysiology
  • Electroneuromyography: Categorize ARCAs based on neuropathy type
• Laboratory Tests
  • Serum alpha-fetoprotein (AFP): Elevated in Ataxia-Telangiectasia
  • Vitamin E levels: Low in Ataxia with Vitamin E Deficiency
• Genetic Testing Strategies
  • Screen for common repeat expansions first
  • Use targeted gene panels or whole exome/genome sequencing
  • Consider trio analysis for improved variant interpretation

Treatment and Management

Current Treatment Options

• Most ICAs lack specific disease-modifying treatments
• Focus on supportive care and symptom management

Supportive Therapies

• Physical therapy: Improves balance and coordination
• Speech therapy: Manages dysarthria and swallowing difficulties
• Occupational therapy: Enhances daily living activities

Disease-Specific Treatments

• ATX–TTP (Ataxia with vitamin E deficiency)
  • α-Tocopherol (vitamin E) supplementation.
• ATX–CYP27A1 (Cerebrotendinous Xanthomatosis)
  • Chenodeoxycholic acid, ursodeoxycholic acid, cholic acid, and taurocholic acid.
• ATX–PHYH (Refsum’s disease)
  • Diet with phytanic acid restriction; plasmapheresis for acute presentations.
• ATX–NPC1 (Niemann–Pick disease type C1)
  • Miglustat.
• ATX–ADCK3 (ARCA2/SCAR9)
  • Oral supplementation of coenzyme Q10.
• ATX–ATM (Ataxia–telangiectasia)
  • Supportive care; minimize radiation exposure, especially X-rays.
• ERCC4 (XFE progeroid syndrome)
  • Avoid exposure to sun and radiation; supportive measures.
• DYT/ATX–ATP7B (Wilson’s disease)
  • D-penicillamine, trientine, zinc acetate/sulfate; liver transplantation in acute forms.
• MTTP (Abetalipoproteinemia)
  • Fat-soluble vitamins (A, E, D, K) and a low-fat diet.
• PxMD–SLC2A1 (GLUT1 deficiency)
  • Ketogenic diet and triheptanoin.
• PxMD–KCNA1 (Episodic ataxia type 1)
  • Carbamazepine.
• PxMD–CACNA1A (Episodic ataxia type 2)
  • Acetazolamide; 4-aminopyridine or baclofen (for downbeat nystagmus treatment).

Recent Advances and Future Directions

Gene Therapies in Development

• Antisense Oligonucleotides (ASOs)
  • Promising results for SCA1, SCA2, SCA3, and SCA7 in animal models
  • First clinical trial for SCA3 began in early 2022
• Viral Gene Therapy
  • AAV-mediated frataxin delivery shows promise in Friedreich Ataxia animal models

• RNA interference (RNAi)Micro RNA (miRNA)
• CRISPR/Cas9 gene editing

Clinical Trials

• Omaveloxolone: Showed neurological improvement in Friedreich Ataxia phase 2 trial

Genetic Counseling and Ethical Considerations

• Discuss inheritance patterns and recurrence risks
• Address presymptomatic testing options
• Consider prenatal and preimplantation genetic diagnosis
• Provide psychological support for patients and families

Conclusion

• ICAs represent a complex group of neurodegenerative disorders
• Advances in genetic understanding have improved diagnosis and classification
• Management currently focuses on supportive care, but gene-targeted therapies show promise
• Continued research is needed to develop effective treatments for various ICA subtypes