Huntington’s Disease (HD) has become widely recognized by both physicians and patients alike, however, patients occasionally go to the doctor with HD symptoms and, surprisingly, genetic tests show that they do not have the HD gene mutation. These patients may have what recent investigations have unveiled as a new class of Huntington Disease-Like (HDL) syndromes. There are four types of HDL syndromes, termed HDL1, HDL2, HDL3 and HDL4, and, much like HD, they are extremely rare. Although HD primarily affects those of European descent, Huntington’s Disease-Like 2 (HDL2) has been found almost exclusively in people of African heritage (those who phenotypically show predominate African ancestry) or people of African descent (individuals that descend from an ancestor of African origin).
Background & History of HDL2^
In 2001, Dr. Russell Margolis’s research team at the Johns Hopkins University School of Medicine discovered HDL2, an autosomal dominant neurological disorder that clinically and pathologically resembles HD. Its symptoms usually begin in mid-life and are characterized by irregular voluntary and involuntary movements, psychiatric ailments, dementia, and an eventual progression to death (Margolis and Rudnicki, 2008). Over 25 HDL2 pedigrees have been identified thus far, all of which have definite or probable African ancestry (Greenstein et al., 2007). Like HD which is a polyglutamine (CAG) expansion disease, HDL2 involves a trinucleotide repeat expansion caused by a chromosomal mutation in which the number of CAG/CTG repeats is expanded in the JPH3 gene which encodes the junctophilin-3 protein. Junctophilin-3 is a component of complexes that facilitate communication between the cell surface and ion channels necessary to cause cells to be activated and is primarily expressed in the brain.
Repeat expansions range from 6 to 28 triplets in unaffected populations, and range from 40 to 58 triplets in the affected population. Expansions of 40 repeats or more have been shown to cause the disease (Greenstein et al., 2007). The trinucleotide mutation originates in the CTG direction of DNA, which causes corresponding malfunctions when proteins and other structures are made from the encoded information (Rodrigues et al., 2008). JPH3 is the only known gene that is associated with HDL2, therefore diagnosis requires molecular genetic testing on JPH3. Forty-one or more CTG trinucleotide repeats is considered sufficient diagnosis with HDL2. The normal full-length junctophilin-3, does not include exon 2A with the CTG/CAG repeat (Margolis, 2009). The complete involvement in JPH3 in HDL2 pathogenesis remains unknown (Santos et al., 2008). The pathology of HDL2 manifests in striatal and cortical atrophy, as well as intranuclear protein aggregates, again showing similarities to HD. Another symptom shown in some patients is acanthocytosis, or spiny protuberances on red blood cells. The mechanism for HDL2 pathogenesis has not yet been determined, but there are some outstanding hypothesis being considered, which will be discussed below (Margolis and Rudnicki, 2008).
Hypotheses for HDL2 Pathogenesis^
As mentioned above, the mechanism of HDL2 pathogenesis is currently unknown, however there are three pertinent hypotheses along these lines.
(1) Poly-Amino Acid Toxicity^
HDL2 has strong similarities to other diseases caused by abnormal polyglutamine (CAG) expansion, such as mid-life onset of symptoms, progressive neurodegeneration, disease onset threshold of about 40 triplets, length of expansion correlating to age onset and protein aggregates (Margolis and Rudnicki, 2008). Due to these similarities, researchers initially speculated that HDL2 would fall into the category of a polyglutamine disorder. However, given that the mutation is in the CTG coding region of JPH3 this speculation is doubtful. The disease would need to originate in the corresponding CAG direction which codes for glutamine in order to surely categorize HDL2 as a polyglutamine disease. Researchers indicate that it is possible that areas containing CAG-repeats could be expressed in low levels, however there is no evidence that indicates expression of a polyglutamine protein from HDL2.
Even with this notion, protein aggregates still appear, leading scientists to question why? There are two possible explanations for this mysterious result. Firstly, the test could be marking other aggregates aside from polyglutamine. Secondly, there could be a peptide containing such low levels of polyglutamine that it is below detection in the HDL2 locus. Due to this uncertainty, researchers hypothesize that polyglutamine expression at best plays a contributing role in HDL2 pathogenesis, and is unlikely in itself to fully explain HDL2 neurotoxicity. Alternatively, HDL2 neurotoxicity could arise from expression of long tracts of other amino acids such as alanine or leucine (Margolis and Rudnicki, 2008). Expansions of these amino acids are also known to be toxic in cell cultures. Furthermore, there is at least one known neurodegenerative disease caused by polyalanine.
(2) JPH3 Loss of Function^
The second possibility is that the CAG/CTG expansion mutation leads to a loss of JPH3 expression and consequently associated neuropathology due to its loss of function. At least a partial loss of expression in the JPH3 transcript and protein was detected by studying patient’s brains. However variability among the available brains makes this data difficult for researchers to interpret. Thus, the loss of JPH3 function is an unlikely explanation for HDL2 pathogenesis, however it could contribute to neurotoxicity (Margolis and Rudnicki, 2008).
(3) RNA Gain of Function and Toxicity^
In addition to HDL2, there are eleven known diseases caused by CAG/CTG expansions (Margolis et al., 2006). Eight of those diseases are thought to promote pathogenic polyglutamine expression. However, the remaining CAG/CTG diseases have myotonic dystrophy type 1 (DM1) disorder, which has a different physical appearance. DM1 is caused by a 3’ untranslated CTG repeat expansion from 60-2,000 triplets in the DMPK gene. The CTG region of DNA is transcribed to CUG repeats in RNA. The RNA transcript with the CUG expansion is thought to be toxic to cells. Interestingly, the DM1 RNA foci greatly resembles foci that have been detected in HDL2 brains. It is unclear whether RNA foci are fundamental to the disease pathogenesis, however they do serve as markers for potentially toxic transcripts. These findings have lead researchers to the hypothesis that at least a portion of the neuronal dysfunction and death in HDL2 may be derived from toxicity of the untranslated expanded CUG repeat (Margolis and Rudnicki, 2008; & Rudnicki et al., 2007).
Clinical Presentation of HDL2^
In the context of the clinical presentation of HD and HDL2, the two diseases cannot be distinguished. However, HDL2 patients tend to have more pronounced parkinsonism symptoms than in HD. Muscle weakness, lip and tongue biting and seizures are generally not part of the typical HDL2 clinical presentation (Margolis and Rudnicki, 2008). HDL2 has generally manifests in two types of ways, resembling: 1) juvenile-onset HD (Westphal variant) or 2) typical late-onset HD. The first HDL2 type typically correlates with longer CAG/CTG repeat expansions than the second one (Greenstein et al., 2007). Type 1 accounts for more than half of the HDL2 cases outside of South Africa and the initial reported case of HDL2 developed in the manner. In the type 1 cases, disease symptoms usually appear at 29-41 years of age. Neurological abnormalities could include parkinsonism (rigidity, bradykinesia, tremor), dysarthria, and hyperreflexia. Diminished coordination and weight loss are often observed, despite an increase in food intake. Individuals are often left in a bedridden, nonverbal state with significant dementia 10 to 15 years after disease onset. Dystonia and chorea occur in the majority of individuals and dementia and psychiatric disturbances are prominent (Margolis, 2009).
The second type of HDL2, is more variable, but generally corresponds to the typical progression of HD whereby the age of onset is generally in the 40s or beyond and the disease progresses more slowly. The definition of the phenotypical presentation of HDL2 may expand as more individuals are diagnosed and identified. In this HDL2 type, chorea may be more prominent, while dystonia, bradykinesia, tremors, hyperreflexia, and dysarthria are less prominent (Margolis, 2009).
Neuroimaging studies have consistently shown cortical and basal ganglia atrophy in individuals afflicted with HDL2. MRI images cannot be used to distinguish HD patients from HDL2 patients. The first patient family diagnosed with HDL2 showed mild frontal, temporal, mesial parietal and occipital atrophy with serve atrophy of the caudate and putamen. Conclusions from the preliminary findings lead researchers to conclude that HDL2 and HD cannot be distinguished pathologically or clinically; however the occipital lobe and potentially the substantia nigra may be affected more in HDL2 (Margolis and Rudnicki, 2008). Neuronal loss predominately occurs in the striatum and cerebral cortex (Margolis, 2009). A clearer distinction in the neuropathology of HD as compared to HDL2 and the degree of correlation will emerge as more cases are identified and analyzed (Greenstein et al., 2007).
Protein aggregates in HDL2 individuals have ranged from punctate to 5μm in size. The frequency of aggregates does not appear to have any correlation with neuronal degeneration. Unlike HD, aggregates have not been found outside of the nucleus. However in all cases the aggregates were round or oval in shape, which characteristically resembles HD (Margolis and Rudnicki, 2008).
Acanthocytosis has been identified in two unrelated families affected with HDL2. Researchers have concluded that the presence of acanthocytes in two unrelated pedigrees is unlikely coincidental. Acanthocytosis is a condition where red blood cells have many spiny cytoplasmic projections and may be caused by the JPH3 mutation, which could disrupt red blood cell membranes. Although the significance of acanthocytosis is uncertain, it appears that it may be a variable feature of HDL2 (Margolis and Rudnicki, 2008) .
Epidemiology & Association with African Ancestry^
HDL2 is very rare and thus far has been identified in about 1% of individuals with HDL disorders who tested negative for the HD mutation. There are 28 genetically documented cases of HDL2 in North America and these arise from 12 different ancestries (Margolis, et al., 2006). For geographic reference, no cases have been identified in Japan and there has been one pedigree detected in patients from Mexico. The data suggests a strong link between African ancestry and HDL2. HDL2 was first described in an African American pedigree from the southeastern region of the United States (Margolis et al., 2004). HDL2 has been found primarily in people with definite African ancestry. Even in cases where, at first, HDL2 individuals appear to have an ancestry other than African some link to Africa has later been discovered. For example, in one case in Mexico, a family identified with HDL2 originated from a region that was previously colonized by Africans, which suggests a link to African ancestry (Margolis et al., 2004). Furthermore, in a Brazilian pedigree HDL2 case where the person was presumed to be of European ancestry, a subsequent molecular analysis showed a haplotype containing an allele that has only been found in Africans. Given that JPH3 mutations may be a variable feature of HDL2, this case illustrates the importance of performing HDL2 analysis in HDL patients of ambiguous or mixed ethnic origin to account for the possibility of an indirect path to African ancestry (Rodrigues et al., 2008). The strong association with African ancestry suggests that HDL2 may have originated in Africa. In support of this, HDL2 was as common as HD in people of African descent in a South African population (Margolis and Rudnicki, 2008).
The diagnosis of HDL2 is typically suspected in individuals who present the general characteristics of HD, have a family history of an HDL disorder, but do not have the CAG repeat expansion mutation in the HD gene. To establish the diagnosis of HDL2, molecular genetic testing is required since clinical findings are not sufficient. PCR assay can determine the length of CTG trinucleotide repeats in JPH3 with an accuracy of within one to two repeats (Margolis, 2009).
Evaluations Following Initial Diagnosis^
The following evaluations are recommended by researchers to establish the extent of HDL2 once one is diagnosed. (1) Neuroimaging: this excludes other lesions or conditions which may be causing or contributing to symptoms. (2) Standardized rating instruments, such as the Unified Huntington’s Disease Rating Scale (UHDRS) or Quantitated Neurological Examination (QNE) for motor abnormalities and the Mini-Mental State Examination (MMSE) for cognition (Margolis, 2009).
Treatment and Prevention^
Like HD, there is currently no known treatment that stops or slows the progression of HDL2.
While HDL2 cannot yet be clinically or pathologically distinguished from HD, it is important to recognize it as a separate disease. Although the symptoms of HDL2 and HD may converge, they are caused by two different mutations on different genes. Even though HDL2 may be exclusively present in people of African ancestry, it is important to acknowledge the possibility that anyone with a clinical presentation of HD, familial history of an HDL disorder and who tests negative for the HD mutation could potentially have HDL2. This point is especially relevant for people of mixed and/or unknown heritage. Clinical diagnosis is insufficient to make such a diagnosis given the uncanny similarity to HD, therefore genetic molecular testing is necessary to make a definitive diagnosis.
For Further Reading^
Greenstein, Penny E., et al. “Huntington’s Disease Like-2 Neuropathology.” Movement Disorder Society 22.10 (2007): 1416-423. Wiley InterScience, 21 May 2007. Web. 30 Oct. 2011.
This quick and easy to read article describes the basis of the Huntington disease-like syndromes.
This newsletter explains the origins of the HDL2 discovery.
Margolis, Russell L. “Huntington Disease-Like 2.” Ed. Karen Stephens. et al. GeneReviews. U of Washington, Seattle, 13 Aug. 2009. Web. 30 Oct. 2011.
Margolis, R. L., and D. D. Rudnicki. “Huntington’s Disease-Like 2.” Neuroacanthocytosis Syndromes II. Ed. Ruth H. Walker, Shinji Saiki, and Adrian Danek. Springer-Verlag Berlin Heidelberg, 2008. 59-73. 1 Jan. 2008. Web. 30 Oct. 2011. <http://www.springerlink.com/content/g8k068gu6394335p/>.
Margolis, Russell L., Dobrilla D. Rdnicki, and Susan E. Holmes. “Huntington’s Disease Like-2: Review and Update.” Acta Neurologica Taiwanica 14.1 (2005): 1-8. 19 Jan. 2005. Web. 30 Oct. 2011.
Margolis, Russell L., et al. “Huntington’s Disease-Like 2 (HDL2) in North America and Japan.” Annals of Neurology 56.5 (2004): 670-74. Wiley-Liss, 4 Oct. 2004. Web. 30 Oct. 2011.
An easy to read article that explains the different components of HDL2
Rodrigues, Guilherme G. Riccioppo, et al. “Huntington’s Disease-Like 2 in Brazil-Report of 4 Patients.” Movement Disorders 23.15 (2008): 2244-247. Wiley InterScience, 24 Sept. 2008. Web. 30 Oct. 2011.
Santos, C., H. et el. “Huntington Disease-like 2: the First Patient with Apparent European Ancestry.” Clinical Genetics 73.5 (2008): 480-85. 28 Jan. 2008. Web. 30 Oct. 2011.
-B. Tatum, 8/21/12