HDL2 occurs at a median age of 41 years, range 12 to 66 years, and typically affects those of Southern African ethnicity 1. The highest reported number of affected individuals is 69, making HDL2 incredibly rare 1.
Presentation is similar to Huntington disease. Chorea and dystonia are present in the majority of cases 1,2. Bradykinesia, tremor and rigidity may also occur 2. Dementia and psychiatric disturbance, namely depression and aggression, are considered universal 1. Acanthocytosis is present in a small proportion patients affected by HDL2; due to the low prevalence of acanthocytosis, there is some debate as to whether HDL2 should be considered a neuroacanthocytosis syndrome 1,3.
A diagnosis of HLD2 is based on genetic profiling. Specifically, the absence of genetic alteration in the huntingtin gene and the presence of repeat expansions in the junctophilin 3 (JPH3) gene. JPH3 is a structural membrane protein that is highly expressed in the brain and has a role in cross-talk between ion channels and the cell surface 4. The exact pathogenesis of JPH3 alteration is unclear, but preliminary data suggest that loss of JPH3 causes a movement-disorder-like phenotype 5.
Magnetic resonance imaging demonstrates bilateral atrophy of the caudate, putamen and globus pallidus 6. This is particularly apparent in the caudate nucleus, which is most frequently affected. HDL2 differs from the other neuroacanthocytosis syndromes due to the occurrence of generalized cortical atropy 6.
Treatment and prognosis
Supportive treatment is at the center of patient care. HDL2 is often aggressive, rapidly progressing to death in 10-20 years 7.
- 1. Anderson DG, Walker RH, Connor M, Carr J, Margolis RL, Krause A. A Systematic Review of the Huntington Disease-Like 2 Phenotype. (2017) Journal of Huntington's Disease. 6 (1): 37. doi:10.3233/JHD-160232
- 2. Margolis RL. Huntington Disease-Like 2. 2004 Jan 30 [Updated 2012 Apr 26]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Pubmed
- 3. Anderson DG, Carmona S, Naidoo K, Coetzer TL, Carr J, Rudnicki DD, Walker RH, Margolis RL, Krause A. Absence of Acanthocytosis in Huntington's Disease-like 2: A Prospective Comparison with Huntington's Disease. (2017) Tremor and other hyperkinetic movements (New York, N.Y.). 7: 512. doi:10.7916/D81J9PDX - Pubmed
- 4. Takeshima H, Komazaki S, Nishi M, Iino M, Kangawa K. Junctophilins: a novel family of junctional membrane complex proteins. (2000) Molecular cell. 6 (1): 11-22. Pubmed
- 5. Nishi M, Hashimoto K, Kuriyama K, Komazaki S, Kano M, Shibata S, Takeshima H. Motor discoordination in mutant mice lacking junctophilin type 3. (2002) Biochemical and biophysical research communications. 292 (2): 318-24. doi:10.1006/bbrc.2002.6649 - Pubmed
- 6. Jung HH, Danek A, Walker RH. Neuroacanthocytosis syndromes. (2011) Orphanet journal of rare diseases. 6: 68. doi:10.1186/1750-1172-6-68 - Pubmed
- 7. Martino D, Stamelou M, Bhatia KP. The differential diagnosis of Huntington's disease-like syndromes: 'red flags' for the clinician. (2013) Journal of neurology, neurosurgery, and psychiatry. 84 (6): 650-6. doi:10.1136/jnnp-2012-302532 - Pubmed