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.
• ATX–CYP27A1 (CYP27A1 Mutation)
  • Found in Cerebrotendinous Xanthomatosis (CTX), a metabolic disorder causing parkinsonism, ataxia, and tendon xanthomas.

Mitochondrial Disorders

• 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.

Wilson’s Disease

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

Neurodegeneration with Brain Iron Accumulation (NBIA)

• NBIA/DYT/PARK–PLA2G6 (PLA2G6 Mutation)
  • Known as PLAN (PLA2G6-associated Neurodegeneration), this subtype involves parkinsonism, dystonia, and cognitive decline due to abnormal iron deposition in the basal ganglia.

Fragile X-associated Tremor Ataxia Syndrome (FXTAS)

• A late-onset condition in carriers of the FMR1 premutation, characterized by tremor, ataxia, and parkinsonism, often co-occurring with cognitive and behavioral issues.

Spinocerebellar Ataxias (SCAs) with Parkinsonism

• SCA2/ATXN2 (Large CAG Repeat Expansion)
  • Parkinsonism develops in later stages, alongside ataxia and dysarthria.
• SCA3/ATXN3 (Machado-Joseph Disease)
  • Parkinsonism is a common manifestation in addition to ataxia, dystonia, and spasticity.
• SCA17/TBP (TATA-box Binding Protein Mutation)
  • Parkinsonism often accompanies ataxia, cognitive decline, and dystonia in advanced stages.

Combined Dystonia-Parkinsonism Syndromes

• DYT/PARK/NBIA–PLA2G6 (PLA2G6 Mutation)
  • Overlaps parkinsonism and dystonia in the context of NBIA, leading to significant motor impairment.

Diseases Associated with Spastic Paraplegia

Ataxia-Related Spastic Paraplegia (ATX/HSP)

• ATX–CYP27A1 (CYP27A1 Mutation)

  • Found in Cerebrotendinous Xanthomatosis (CTX), a metabolic disorder with spastic paraplegia, cerebellar ataxia, tendon xanthomas, and progressive neurological symptoms.

• ATX/HSP–SACS (SACS Mutation)

  • Associated with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS). Presents with spasticity, ataxia, and peripheral neuropathy.

• ATX/HSP–SPG7 (SPG7 Mutation)

  • Found in Spastic Paraplegia 7 (SPG7). Characterized by progressive spasticity, weakness in the lower limbs, and ataxia.

• ATX/HSP–POLR3A (POLR3A Mutation)

  • Related to 4H Leukodystrophy (Hypomyelination, Hypogonadotropic Hypogonadism, and Hypodontia). Spasticity and ataxia are common neurological symptoms.

• ATX/HSP–CLCN2 (CLCN2 Mutation)

  • Associated with spasticity, ataxia, and epilepsy due to disrupted chloride channel function.

Combined Syndromes with Spastic Paraplegia

• HSP/ATX/NBIA–FA2H (FA2H Mutation)
  • Found in disorders involving hereditary spastic paraplegia and neurodegeneration with brain iron accumulation (NBIA). Features include spasticity, ataxia, and dystonia.

Mitochondrial and Metabolic Disorders

• MARS2 (Methionyl-tRNA Synthetase 2 Mutation)

  • A mitochondrial disorder presenting with spastic paraplegia, ataxia, and other neurological impairments.

• GBE1 (Glycogen Branching Enzyme Mutation)

  • Associated with Adult Polyglucosan Body Disease (APBD). Symptoms include spasticity, neuropathy, and urinary dysfunction.

• MTPAP (Mitochondrial Poly(A) Polymerase Mutation)

  • Found in Spastic Ataxia 4, which combines features of spastic paraplegia and cerebellar ataxia.

• ATX/HSP–DARS2 (DARS2 Mutation)

  • Associated with Leukoencephalopathy with Brainstem and Spinal Cord Involvement and Lactate Elevation (LBSL). Presents with spasticity, ataxia, and brainstem dysfunction.

• HSD17B4 (Hydroxysteroid Dehydrogenase 4 Mutation)

  • Found in Peroxisomal Disorders. Progressive spasticity and ataxia are hallmarks of this group of diseases.

Neurodegeneration with Brain Iron Accumulation (NBIA)

• DYT/PARK/NBIA–PLA2G6 (PLA2G6 Mutation)
  • Known as PLAN (PLA2G6-Associated Neurodegeneration). Includes spastic paraplegia, dystonia, parkinsonism, and other neurological impairments due to iron deposition in the basal ganglia.

Pyramidal Signs

• ATX–ANO10 (Anoctamin-10 Mutation)
  • Associated with Autosomal Recessive Spinocerebellar Ataxia Type 10 (SCAR10), featuring pyramidal signs and ataxia.
• Spinocerebellar Ataxias (SCAs):
  • SCA1/ATXN1, SCA3/ATXN3, SCA7/ATXN7, SCA17/TBP (TATA-box Binding Protein)
    • Progressive conditions with cerebellar ataxia, pyramidal signs, and additional features like dystonia or cognitive decline.
  • SCA8/ATXN8, SCA10/ATXN10, SCA14/PRKCG, SCA15/ITPR1, SCA35/TGM6, SCA40/CCDC88C, SCA43/MME
    • Rare SCAs presenting with combinations of cerebellar ataxia, pyramidal signs, and other neurological impairments.
• ATX–POLR3A/ATX–POLR3B (RNA Polymerase III Mutations)
  • Found in Pol III-related leukodystrophy, often featuring hypomyelination, spasticity, and pyramidal signs.

Oculomotor Apraxia

• ATX–ATM (Ataxia-Telangiectasia Mutated)
  • Characterized by difficulty initiating eye movements (oculomotor apraxia), ataxia, and immunodeficiency.
• ATX–APTX (Aprataxin Mutation)
  • Seen in Ataxia with Oculomotor Apraxia Type 1, with similar symptoms.
• ATX–SETX (Senataxin Mutation)
  • Found in Ataxia with Oculomotor Apraxia Type 2, including apraxia and ataxia.
• ATX–MRE11 (MRE11 Mutation)
  • Associated with Ataxia-Telangiectasia-Like Disorder (ATLD), involving oculomotor apraxia.
• AOA4/PNKP (Polynucleotide Kinase Phosphatase Mutation)
  • Found in AOA4, with progressive oculomotor apraxia and neurological decline.

Strabismus or Diplopia

• ATX–SETX (Senataxin Mutation)
  • Often associated with ataxia and ocular movement abnormalities.
• SCA3/ATXN3 (Machado-Joseph Disease)
  • Strabismus or diplopia occurs due to oculomotor dysfunction.

Square Wave Jerks

• ATX–FXN (Frataxin Mutation)
  • Found in Friedreich Ataxia, presenting with cerebellar signs and involuntary ocular movements.
• POLG (Polymerase Gamma Mutation)
  • Associated with mitochondrial disorders with abnormal saccades and square wave jerks.
• FXTAS (Fragile X-associated Tremor Ataxia Syndrome)
  • Square wave jerks and tremors are prominent features.
• SCA3/ATXN3 (Machado-Joseph Disease)
  • Ocular abnormalities, including square wave jerks, are common.

Hypometric, Slow Saccades

• SCA2/ATXN2 (Spinocerebellar Ataxia Type 2)
  • Hypometric and slow saccades are key features due to cerebellar and brainstem involvement.

Vertical Supranuclear Saccades Palsy

• ATX–NPC (Niemann-Pick Disease Type C)
  • Vertical supranuclear gaze palsy is a hallmark feature alongside ataxia and cognitive impairment.
• ATX/HSP–SACS (SACS Mutation)
  • Seen in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay, with combined features of spasticity and eye movement abnormalities.
• ATX–STUB1 (STIP1 Homology and U-Box Containing Protein 1 Mutation)
  • Found in SCAR16, characterized by ataxia, eye movement abnormalities, and cognitive decline.

Diseases Associated with Intellectual Deficiency

Ataxia Syndromes with Intellectual Deficiency (ATX)

• ATX–GRID2 (Glutamate Receptor Delta-2 Mutation)
  • Causes cerebellar ataxia and intellectual deficiency due to disrupted glutamatergic signaling.
• ATX–L2HGDH (L-2-Hydroxyglutarate Dehydrogenase Mutation)
  • Found in L-2-Hydroxyglutaric Aciduria, causing developmental delay, intellectual deficiency, and cerebellar ataxia.
• ATX–POLR3A (RNA Polymerase III Mutation)
  • Associated with hypomyelinating leukodystrophies, presenting with intellectual disability and motor impairments.
• ATX–APTX (Aprataxin Mutation)
  • Causes Ataxia with Oculomotor Apraxia Type 1 (AOA1), often accompanied by mild intellectual deficiency.

Spastic Ataxia and Related Disorders

• SCAR12/WWOX (WW Domain-Containing Oxidoreductase Mutation)
  • Found in SCAR12, with intellectual disability, seizures, and ataxia.
• SCAR22/VWA3B (Von Willebrand Factor A Domain-Containing 3B Mutation)
  • Associated with autosomal recessive cerebellar ataxia, intellectual deficiency, and neurodevelopmental delay.
• SCAR23/TDP2 (Tyrosyl-DNA Phosphodiesterase 2 Mutation)
  • A form of spastic ataxia with intellectual deficiency and other neurological symptoms.
• ATX–SNX14 (Sorting Nexin 14 Mutation)
  • Involves cerebellar atrophy, ataxia, and intellectual deficiency.
• SCAR5/WDR73 (WD Repeat Domain 73 Mutation)
  • Associated with Galloway-Mowat Syndrome, involving intellectual disability and cerebellar atrophy.

Lysosomal and Peroxisomal Disorders

• ATX–PEX10 (PEX10 Mutation)
  • Found in Zellweger Spectrum Disorders, presenting with intellectual deficiency and other systemic abnormalities.
• ATX/MYC–TPP1 (Tripeptidyl Peptidase 1 Mutation)
  • Causes CLN2 Batten Disease, featuring intellectual deficiency, seizures, and vision loss.

Mitochondrial and Metabolic Disorders

• MARS2 (Methionyl-tRNA Synthetase 2 Mutation)
  • Presents with intellectual deficiency, ataxia, and metabolic dysfunction.
• ACO2 (Aconitase 2 Mutation)
  • Associated with Infantile Cerebellar-Retinal Degeneration, including intellectual deficiency.
• ATX–WDR73 (WD Repeat Domain 73 Mutation)
  • Causes intellectual deficiency alongside cerebellar atrophy.

Ion Channel and Synaptic-Related Disorders

• ATX–KCNJ10 (Potassium Channel Mutation)
  • Found in EAST Syndrome (Epilepsy, Ataxia, Sensorineural Deafness, and Tubulopathy) with intellectual deficiency.
• SCA13/KCNC3 (Potassium Channel Mutation)
  • Includes cerebellar ataxia and cognitive impairments.
• SCA19–22/KCND3 (Voltage-Gated Potassium Channel Mutation)
  • Causes intellectual deficiency and ataxia.
• SCA21/TMEM240 (TMEM240 Mutation)
  • A rare spinocerebellar ataxia with intellectual and motor deficits.

Miscellaneous Conditions

• MYC/ATX–KCTD7 (KCTD7 Mutation)
  • Causes Progressive Myoclonic Epilepsy with ataxia and intellectual disability.
• ATX–CA8 (Carbonic Anhydrase 8 Mutation)
  • Causes developmental delay and intellectual disability.
• ATX–BTD (Biotinidase Deficiency Mutation)
  • Results in developmental delay and intellectual deficiency, treatable with biotin supplementation.
• NBIA/DYT/PARK–PLA2G6 (PLA2G6 Mutation)
  • Found in PLAN (PLA2G6-associated Neurodegeneration), with intellectual and motor impairments.

Cognitive Decline and Associated Diseases

Ataxia-Related Disorders

• ATX–NPC: Niemann-Pick disease type C, characterized by progressive neurodegeneration and lipid accumulation.
• ATX–CYP27A1: Cerebrotendinous xanthomatosis, a disorder involving cholesterol metabolism.
• ATX–ANO10: An autosomal recessive ataxia with associated cerebellar atrophy.
• ATX/HSP–PNPLA6: Neurodegeneration with brain iron accumulation and hereditary spastic paraplegia overlap.
• ATX–ADCK3: Coenzyme Q10 deficiency leading to ataxia and cerebellar atrophy.

Neurodegenerative and Systemic Disorders

• NBIA/DYT/PARK–CP: Neurodegeneration with brain iron accumulation, associated with movement disorders such as dystonia and parkinsonism.
• MYC/ATX–KCTD7: Myoclonic epilepsy with cognitive decline.
• GRM1: Associated with glutamate receptor dysfunction contributing to cerebellar atrophy.
• NBIA/DYT/PARK–PLA2G6: Linked to phospholipase A2 group VI mutations, causing parkinsonism, dystonia, and neurodegeneration.

Spinocerebellar Ataxias

• SCA2/ATXN2: Progressive ataxia with large CAG repeat expansions, leading to cognitive impairment in later stages.
• SCA17/TBP: Caused by mutations in the TATA-box binding protein, associated with ataxia, dystonia, and dementia.
• DRPLA/ATN1: Dentatorubral-pallidoluysian atrophy, involving myoclonus, ataxia, and cognitive decline.
• SCA48/STUB1: Rare ataxia associated with cerebellar degeneration and cognitive deterioration.

Fragile X-Associated Syndrome

• FXTAS: Fragile X-associated tremor/ataxia syndrome, a late-onset neurodegenerative disorder with tremor, ataxia, and cognitive decline.