Huntington Disease Like 2 (Hdl2) is a progressive neurodegenerative disorder characterized by the gradual loss of neuronal function. This page provides comprehensive information about the disease, including its pathophysiology, clinical presentation, diagnosis, and current therapeutic approaches.
Huntington's Disease-Like 2 (HDL2) is a rare, autosomal dominant neurodegenerative disorder that clinically resembles Huntington's Disease but is caused by a distinct genetic mutation. It was first described in 2001 and is considered one of the Huntington's Disease-like (HDL) syndromes[1]. HDL2 is caused by a JPH3 gene mutation and presents with chorea, dystonia, cognitive decline, and behavioral changes.
HDL2 follows an autosomal dominant inheritance pattern with complete penetrance by age 70.
- Gene: JPH3 (Junctophilin-3)
- Chromosomal location: 16q24.3
- Inheritance: Autosomal dominant
- Expansion of a CTG/CAG trinucleotide repeat in the JPH3 gene
- Normal: 6-27 repeats
- Intermediate (reduced penetrance): 27-35 repeats
- Pathological: 36-58+ repeats
- Anticipation: Earlier onset in subsequent generations (anticipation)[2]
Junctophilin-3 is a member of the junctophilin family of proteins that contribute to the formation of junctional membrane complexes between the endoplasmic reticulum and plasma membrane. This is crucial for calcium signaling in muscle and neuronal cells[3].
- Toxic RNA gain-of-function: Expanded CUG repeats form toxic RNA structures that sequester RNA-binding proteins
- Loss of JPH3 function: Reduced expression of functional junctophilin-3 protein
- Calcium dysregulation: Impaired calcium handling in neurons
- Transcriptional dysregulation: Abnormal gene expression patterns
- Generalized brain atrophy, particularly in the striatum and cortex
- Loss of medium spiny neurons in the striatum
- Presence of neuronal intranuclear inclusions (NII)
- Variable involvement of the globus pallidus and substantia nigra[4]
- Chorea: Jerky, involuntary movements (present in ~90%)
- Dystonia: Sustained muscle contractions (60-70%)
- Parkinsonism: Bradykinesia, rigidity (30-40%)
- Ataxia: Coordination difficulties (20-30%)
- Executive dysfunction
- Memory impairment
- Slowed information processing
- Progressive dementia
- Depression (50-60%)
- Anxiety
- Irritability
- Apathy
- Psychosis (less common than in HD)
- Mean age of onset: 35-50 years (range 10-70 years)
- Disease duration: 10-20 years
- Progressive motor, cognitive, and psychiatric decline
- Death typically from aspiration or infection[5]
- Progressive chorea with cognitive decline
- Family history consistent with autosomal dominant inheritance
- Exclusion of other causes (including HD)
- Gold standard: PCR analysis of JPH3 CAG/CTG repeat expansion
- Also available: Southern blotting for large expansions
- Huntington's Disease (HD)
- Other HDL syndromes (HDL1, HDL3, HDL4)
- Spinocerebellar ataxias
- Benign hereditary chorea
- Wilson disease
- Sydenham chorea
- MRI: Striatal and cortical atrophy
- FDG-PET: Hypometabolism in striatum and cortex
- PET with Pittsburgh compound B: Variable amyloid binding[6]
- Tetrabenazine: Primary choice for chorea
- Deutetrabenazine: Alternative with better tolerability
- Haloperidol: Dopamine receptor antagonist
- Amantadine: NMDA antagonist
- Selective serotonin reuptake inhibitors (SSRIs) for depression
- Atypical antipsychotics for psychosis
- Mood stabilizers as needed
- No disease-modifying treatments available
- Supportive care and cognitive rehabilitation
- Antisense oligonucleotide (ASO) therapies targeting JPH3
- Gene therapy approaches
- Neuroprotective agents
- Calcium channel modulators
- Physical therapy for mobility
- Occupational therapy for daily activities
- Speech therapy for dysarthria
- Nutritional support
- Psychological support for families[7]
- Extremely rare: <1 per million
- Predominantly reported in families of African ancestry
- Represents ~1-2% of clinically diagnosed Huntington's Disease cases
- Slight female predominance reported in some cohorts[8]
- No HDL2-specific trials currently recruiting
- Biomarker development studies ongoing
- Understanding JPH3 function in the brain
- Developing targeted therapies
- Biomarker identification
- Natural history studies
The study of Huntington Disease Like 2 (Hdl2) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- ^1]: Margolis RL, O'Hearn E, Rosenblatt A, et al. A disorder similar to Huntington's Disease is associated with a novel CAG repeat expansion. Neurology. 2001;57(4):671-674. DOI:10.1212/wnl.57.4.671
- ^2]: Walker RH, Jankovic J, O'Hearn E, Margolis RL. Phenotypic features of Huntington's Disease-like 2. Mov Disord. 2003;18(12):1527-1530. DOI:10.1002/mds.10583
- ^3]: Takeshima H, Komazaki S, Nishi M, Iino M, Kangawa K. Junctophilins: novel molecular components of the Ca2+ release unit that determine the architecture of the junctional membrane complex. Mol Cell. 2000;5(3):469-475. DOI:10.1016/s1097-2765(0080441-0
- ^4]: Rudnicki DD, Margolis RL. Huntington's Disease-like 2: a more recent cause of parkinsonism and dementia. Int Rev Neurobiol. 2022;165:137-156. DOI:10.1016/bs.irn.2022.02.008
- ^5]: Bardien S, Abrahams F, Soodyall H, et al. A South African mixed ancestry family with Huntington's Disease-like 2: clinical and genetic features. Mov Disord. 2007;22(14):2083-2089. DOI:10.1002/mds.21654
- ^6]: Vu CC, Bannykh SI, Hall J, et al. Neuroimaging in Huntington's Disease-like 2: a case report. J Neurol Sci. 2014;345(1-2):226-231. DOI:10.1016/j.jns.2014.07.038
- ^7]: Wild EJ, Tabrizi SJ. Huntington's Disease and Huntington's Disease-like syndromes. Handb Clin Neurol. 2023;195:23-46. DOI:10.1016/B978-0-323-98818-6.00010-4
- ^8]: Rodrigues GR, Walker RH, Benaissa H, et al. Huntington's Disease-like 2: review of the literature and description of an additional family. Tremor Other Hyperkinet Mov (N Y). 2020;10. DOI:10.7916/tohm.v0.733