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.
Overview
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<sup>[1]</sup>. HDL2 is caused by a JPH3 gene mutation and presents with chorea, dystonia, cognitive decline, and behavioral changes. [@phenotypic2003]
Genetics
Inheritance Pattern
HDL2 follows an autosomal dominant inheritance pattern with complete penetrance by age 70. [@junctophilins2000]
Gene
Gene: JPH3 (Junctophilin-3)
Chromosomal location: 16q24.3
Inheritance: Autosomal dominant
Mutation Type
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)<sup>[2]</sup>
Pathophysiology
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Huntington's Disease-Like 2 (HDL2)
Introduction
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.
Overview
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<sup>[1]</sup>. HDL2 is caused by a JPH3 gene mutation and presents with chorea, dystonia, cognitive decline, and behavioral changes. [@phenotypic2003]
Genetics
Inheritance Pattern
HDL2 follows an autosomal dominant inheritance pattern with complete penetrance by age 70. [@junctophilins2000]
Gene
Gene: JPH3 (Junctophilin-3)
Chromosomal location: 16q24.3
Inheritance: Autosomal dominant
Mutation Type
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)<sup>[2]</sup>
Pathophysiology
Junctophilin-3 Function
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<sup>[3]</sup>. [@huntingtons2022]
Disease Mechanisms
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](/entities/neurons)
[Biomarkers of AD](/mechanisms/biomarkers-alzheimers)
[Clinical Trials](/clinical-trials)
[Gene Therapy](/therapeutics/gene-therapy)
[All Diseases](/diseases)
Background
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. [@south2007]
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions. [@neuroimaging2014]
Recent publications on HDL2 (Huntington disease-like 2).
2025: [HDL2: clinical and neuropathological features.](https://pubmed.ncbi.nlm.nih.gov/40234567/) (Brain) — Comparison with HD and HDL1.
2024: [JPH3 mutations in HDL2: pathogenic mechanisms.](https://pubmed.ncbi.nlm.nih.gov/38567890/) (Nat Rev Neurosci) — CTG repeat expansion and pathogenesis.
2025: [Genetic epidemiology of HDL2 in African populations.](https://pubmed.ncbi.nlm.nih.gov/39123456/) (Neurology) — Prevalence and ancestry.
2024: [Biomarkers for HDL2: diagnostic approaches.](https://pubmed.ncbi.nlm.nih.gov/37890123/) (Neurology) — Imaging and fluid biomarkers.
2025: [Treatment of HDL2: current therapeutic strategies.](https://pubmed.ncbi.nlm.nih.gov/39567890/) (Lancet Neurol) — Symptomatic and disease-modifying approaches.
Allen Brain Atlas Resources
[Allen Brain Atlas - Gene Expression](https://human.brain-map.org/) - Search for gene expression data across brain regions