Cerebellar ataxias according to main clinical features

Diseases Associated with Chorea

1. Ataxia-Telangiectasia and Related Conditions

   • ATX–ATM (Ataxia-Telangiectasia Mutated gene)
     A progressive condition involving cerebellar ataxia, oculomotor apraxia, immunodeficiency, and increased risk of malignancies. Chorea is a possible symptom.
   • ATX–APTX (Aprataxin gene mutation)
     Associated with Ataxia with Oculomotor Apraxia Type 1 (AOA1), presenting with ataxia, dystonia, and chorea.
   • ATX–SETX (Senataxin gene mutation)
     Found in Ataxia with Oculomotor Apraxia Type 2 (AOA2), with symptoms including ataxia and involuntary movements like chorea.
   • ATX–MRE11A (MRE11A gene mutation)
     Related to Ataxia-Telangiectasia-like disorder (ATLD), involving ataxia and chorea.
   • ATX–OPA3 (OPA3 gene mutation)
     Associated with 3-Methylglutaconic Aciduria Type III (Costeff syndrome), including ataxia, dystonia, and chorea.

2. Neurodegeneration with Brain Iron Accumulation (NBIA)

   • Includes dystonia, chorea, and parkinsonism. Specific NBIA subtypes can also involve chorea.

3. Dystonia/Parkinsonism (DYT/PARK-CP)

   • Some dystonia-parkinsonism conditions involve chorea, especially when associated with metabolic or genetic causes.

4. XFE/ERCC4 (Xeroderma Pigmentosum Complementation Group F/E)

   • Patients may develop neurodegeneration, including movement disorders such as chorea, along with progressive neurological symptoms.

5. Spinocerebellar Ataxias (SCAs)

   • SCA2/ATXN2 (large CAG expansion)
     Spinocerebellar Ataxia Type 2 can involve chorea in the advanced stages of the disease, along with ataxia and dysarthria.
   • SCA17/TBP (TATA-box binding protein gene mutation)
     Spinocerebellar Ataxia Type 17 often presents with chorea as a feature of progressive neurodegeneration.
   • SCA48/STUB1 (STIP1 Homology and U-Box Containing Protein 1 gene mutation)
     Chorea can emerge as part of a complex phenotype including ataxia and cognitive decline.

6. Dentatorubral-Pallidoluysian Atrophy (DRPLA/ATN1)

   • Caused by mutations in the ATN1 gene. Chorea occurs during disease progression alongside myoclonus, ataxia, and psychiatric symptoms.

Chorea is a key feature in multiple neurodegenerative and neurogenetic disorders, often overlapping with ataxia, dystonia, or other movement disorders. Each associated gene or syndrome contributes specific clinical and molecular nuances that guide diagnosis and management.

Diseases Associated with Myoclonus

1. Ataxia-Related Myoclonus Syndromes

   • ATX–ADCK3 (Coenzyme Q10 Deficiency 4)
     • Myoclonus occurs alongside progressive cerebellar ataxia. Mutations in the ADCK3 gene affect coenzyme Q10 biosynthesis, leading to mitochondrial dysfunction.
   • MYC/ATX–GOSR2 (GOSR2-Related Epilepsy and Ataxia)
     • Associated with Progressive Myoclonus Epilepsy (PME). Characterized by myoclonus, ataxia, and generalized seizures.
   • MYC–SCARB2 (SCARB2 Gene Mutation)
     • Related to Action Myoclonus-Renal Failure Syndrome (AMRF), with severe myoclonus, ataxia, and kidney involvement.
   • MYC/ATX–KCTD7 (KCTD7 Gene Mutation)
     • A form of PME presenting with myoclonus, ataxia, and epilepsy. Progressive in nature.
   • MYC/ATX–NEU1 (NEU1 Gene Mutation)
     • Found in Sialidosis Type I or II, characterized by myoclonus, ataxia, and visual impairment (cherry-red spots).

2. PRICKLE1 Gene Mutation

   • Linked to Myoclonic Epilepsy and Movement Disorder Syndrome. Presents with myoclonus, developmental delay, and ataxia.

3. Spinocerebellar Ataxias (SCAs) with Myoclonus

   • SCA2/ATXN2 (Large CAG Expansion)
     • Myoclonus is seen in advanced disease stages alongside ataxia, dystonia, and dysarthria.
   • DRPLA/ATN1 (Dentatorubral-Pallidoluysian Atrophy)
     • Myoclonus occurs during disease progression, along with ataxia, seizures, and psychiatric symptoms.
   • SCA13/KCNC3 (Potassium Channel Mutation)
     • Presents with cerebellar ataxia and, in some cases, myoclonus.
   • SCA14/PRKCG (Protein Kinase C Gamma Mutation)
     • Myoclonus and ataxia are prominent features.
   • SCA19/KCND3 (Potassium Voltage-Gated Channel Mutation)
     • Associated with ataxia, myoclonus, and cognitive decline.
   • SCA21/TMEM240 (TMEM240 Gene Mutation)
     • A rare SCA subtype with myoclonus, ataxia, and progressive neurodegeneration.Summary

Myoclonus is a clinical hallmark of various neurogenetic disorders, often co-occurring with ataxia, epilepsy, or other motor dysfunctions. The specific genetic mutation and associated pathophysiology help delineate the subtype, guiding diagnosis and tailored management. Each gene or syndrome adds unique features that distinguish the presentation of myoclonus.

Diseases Associated with Dystonia

1. Ataxia Syndromes (ATX) with Dystonia

   • ATX–ATM (Ataxia-Telangiectasia Mutated)
     • A neurodegenerative disorder involving ataxia, dystonia, oculomotor apraxia, and immunodeficiency.
   • ATX–APTX (Aprataxin Mutation)
     • Seen in Ataxia with Oculomotor Apraxia Type 1, involving dystonia, ataxia, and cerebellar symptoms.
   • ATX–SETX (Senataxin Mutation)
     • Found in Ataxia with Oculomotor Apraxia Type 2, presenting with dystonia alongside other movement disorders.
   • ATX–NPC (Niemann-Pick Disease Type C)
     • A lysosomal storage disorder involving dystonia, ataxia, and vertical gaze palsy.

2. Hereditary Spastic Paraplegia (HSP) with Dystonia

   • ATX/HSP–HEXA (Hexosaminidase A Mutation) and ATX/HSP–HEXB (Hexosaminidase B Mutation)
     • Associated with Sandhoff and Tay-Sachs diseases, featuring dystonia, spasticity, and progressive neurological decline.

3. Neurodegeneration with Brain Iron Accumulation (NBIA) and Dystonia

   • NBIA/DYT/PARK–PLA2G6 (PLA2G6 Mutation)
     • Found in PLAN (PLA2G6-associated Neurodegeneration), presenting with dystonia, parkinsonism, and ataxia.

4. Other Rare Genetic Syndromes with Dystonia

   • PNKP (Polynucleotide Kinase/Phosphatase Mutation)
     • Involves dystonia as part of progressive neurological decline, often with seizures.
   • MARS2 (Methionyl-tRNA Synthetase 2 Mutation)
     • A mitochondrial disorder presenting with dystonia, ataxia, and cognitive impairment.
   • HSP/ATX/NBIA–FA2H (Fatty Acid 2-Hydroxylase Mutation)
     • Associated with hereditary spastic paraplegia and NBIA, with dystonia as a hallmark feature.
   • DYT/ATX–ATP7B (Wilson’s Disease)
     • A disorder of copper metabolism where dystonia, parkinsonism, and ataxia are common neurological features.

5. Spinocerebellar Ataxias (SCAs) with Dystonia

   • SCA2/ATXN2, SCA3/ATXN3, SCA17/TBP (TATA-box Binding Protein Mutation)
     • These SCAs frequently include dystonia in the progression of ataxia and other motor dysfunctions.

6. Combined Dystonia and Parkinsonism Syndromes

   • DYT/PARK/NBIA–PLA2G6 (PLA2G6 Mutation)
     • Part of PLAN, showing an overlap of dystonia and parkinsonism.

7. Pol III-related Leukodystrophy (POLR3-related Disorders)

   • ATX–POLR3A/ATX–POLR3B (Polymerase III Mutations)
     • Disorders like 4H leukodystrophy can involve dystonia, ataxia, and hypomyelination.

Diseases Associated with Parkinsonism

Ataxia Syndromes (ATX) with Parkinsonism

• ATX–ATM (Ataxia-Telangiectasia Mutated gene)
  • A neurodegenerative disorder featuring cerebellar ataxia, dystonia, and parkinsonism in later stages due to progressive basal ganglia involvement.

  Mitochondrial Disorders

  • Found in Cerebrotendinous Xanthomatosis (CTX), a metabolic disorder causing parkinsonism, ataxia, and tendon xanthomas.

  Wilson’s Disease

  • POLG (DNA Polymerase Gamma Mutation)
    • POLG mutations cause mitochondrial diseases such as Progressive External Ophthalmoplegia (PEO), with parkinsonism as part of the phenotype in later stages.

    Neurodegeneration with Brain Iron Accumulation (NBIA)

    • DYT/ATX–ATP7B (ATP7B Mutation)
      • A disorder of copper metabolism leading to basal ganglia dysfunction and parkinsonism, along with dystonia, tremors, and psychiatric symptoms.

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