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Huntington Disease-Like 2

, MD
Professor of Psychiatry and Neurology, Laboratory of Genetic Neurobiology
Department of Psychiatry
Johns Hopkins University School of Medicine
Baltimore, Maryland

Initial Posting: ; Last Update: April 26, 2012.

Summary

Disease characteristics. Huntington disease-like 2 (HDL2) typically presents in midlife with a relentless progressive triad of movement, emotional, and cognitive abnormalities progressing to death over ten to 20 years. In some individuals the presentation resembles juvenile-onset Huntington disease (HD) or the Westphal variant of HD, usually presenting in the fourth decade (ages 29 to 41 years) with diminished coordination and weight loss despite increase in food intake. Neurologic abnormalities include parkinsonism (rigidity, bradykinesia, tremor), dysarthria, and hyperreflexia. In others the presentation is more variable but, in general, corresponds to typical HD.

Diagnosis/testing. The diagnosis of HDL2 requires molecular genetic testing of JPH3, the only gene in which mutations are known to cause HDL2. In the presence of a clinical syndrome consistent with HDL2 (findings and family history typical of Huntington disease), 41 or more CTG trinucleotide repeats in JPH3 are considered diagnostic of HDL2.

Management. Treatment of manifestations: Treatment is symptomatic and is presumably similar to that for HD and other neurodegenerative disorders, though this must be considered speculative pending objective data. Pharmacologic agents that may suppress abnormal movements include low-dose neuroleptic agents such as fluphenazine and haloperidol, and potentially tetrabenazine. Antidepressants, antipsychotics, mood stabilizers (lithium, valproic acid, carbamazepine, and lamotragine), and occasionally stimulants may treat psychiatric manifestations. Education about the course of disease and environmental interventions (regular schedules, use of lists to assist memory, removing clutter so that things are easier to find) benefit affected individuals and family members.

Prevention of secondary complications: Remove loose rugs and clutter from the individual's home to help prevent falls and other injuries; driving may need to be curtailed or limited to prevent risk of accidents; food should be prepared in such a manner as to prevent choking.

Surveillance: Monitor nutrition and swallowing in order to implement feeding changes when necessary to minimize risk of aspiration; gait should be monitored, with use of appropriate strategies or devices to minimize falls; monitor driving to assure that the affected individual does not present a danger to themselves or others; monitor mood and irritability, such that measures to decrease the risk of suicide, other behavioral abnormalities, and distress may be implemented.

Agents/circumstances to avoid: Any agents that increase ataxia should be used with caution; avoid polypharmacy, which may exacerbate delirium.

Genetic counseling. HDL2 is inherited in an autosomal dominant manner. De novo mutations causing HDL2 have not been reported. If a parent of the proband is affected or has the JPH3 expansion, the risk to each sib of a proband is 50%. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family has been identified.

Diagnosis

Clinical Diagnosis

The diagnosis of Huntington disease-like 2 (HDL2) is usually suspected in individuals who present with findings typical of Huntington disease (HD) and a family history of an HD-like disorder, but who do not have a disease-causing CAG expansion (i.e., reduced-penetrance allele or full-penetrance allele) in HTT.

Clinical findings are not sufficient to establish the diagnosis of HDL2: molecular genetic testing is required.

Molecular Genetic Testing

Gene. JPH3 is the only gene in which mutations are known to cause Huntington disease-like 2 (HDL2).

Allele sizes

  • Normal alleles. Six to 28 CTG repeats [Holmes et al 2001]. The diagnosis can be excluded if neither allele has a repeat length greater than 28 CTG repeats.
  • Alleles of questionable significance. 29 to 39 CTG repeats; the pathogenicity of alleles in this range is unknown. Repeats in this range could be either of the following:
    • Mutable normal alleles that do not have a phenotypic effect in the individual but are unstable in vertical transmission

      Note: (1) A 48-year-old woman with an atypical cerebellar disorder (rapid onset following hospitalization for out-of-control diabetes mellitus, little or no progression) had a JPH3 CTG repeat length of 33 in one allele. Her 30-year-old son had developed Cogan's syndrome, an autoimmune disease resulting in complete hearing loss, at age 25 years. He complained of tinnitus, occasional lapses of concentration, and difficulty with balance, all associated with the onset of Cogan's syndrome. Examination suggested possible cerebellar involvement. He had a CTG repeat length of 35, suggesting repeat length instability at this range. (2) An individual with molecularly diagnosed Huntington disease coincidentally also had a JPH3 allele of 34 CTG repeats [Author, personal observation].
    • Reduced-penetrance alleles that result in very late-onset disease and/or a different phenotype and/or no occurrence of clinical disease in a normal life span
  • Full-penetrance (disease-causing) alleles. 41 CTG repeats or greater. In the presence of a clinical syndrome consistent with HDL2, an allele with 41 or more CTG repeats is considered diagnostic of HDL2. The longest repeat expansion detected so far is 58 triplets.

    Note: Apparently unaffected individuals with repeat lengths in the pathogenic range may eventually develop the disease. One individual (in a family with a proband with clinically, neuropathologically, and molecularly defined HDL2) had an expanded allele of 44 CTG repeats without clear evidence of clinical HDL2 at age 65 years. It is possible that the effects of a mild stroke several years prior to examination masked signs of HDL2.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Huntington Disease-Like 2

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
JPH3Targeted mutation analysisCTG repeat expansion Nearly 100%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

Interpretation of test results. The test should detect nearly all expanded alleles; however, it is theoretically possible that expanded repeats may not be detected because of a polymorphism at the primer site or an unusually long repeat.

Testing Strategy

Confirming/establishing the diagnosis in a proband requires molecular genetic testing.

Predictive testing for at-risk asymptomatic adult family members requires prior confirmation of the diagnosis of HDL2 through identification of a disease-causing JPH3 expansion in the family.

  • If genetic confirmation of the diagnosis is not available, a negative HDL2 test in the asymptomatic adult may mean that the familial disease is not HDL2.
  • A positive test in the asymptomatic adult, however, would still be predictive.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Like Huntington disease [Ross et al 1997, Bates et al 2002], HDL2 typically presents in midlife with a relentless progressive triad of movement, emotional, and cognitive abnormalities progressing to death over ten to 20 years.

The course of HDL2 appears to fall into two presentations that probably reflect opposite ends of a spectrum [Holmes et al 2001, Margolis et al 2001, Walker et al 2002, Stevanin et al 2003, Walker et al 2003a, Walker et al 2003b, Margolis et al 2004]. The two presentations are: (1) weight loss and poor coordination, with fairly rapid development of rigidity and dystonia; and (2) chorea with a somewhat less rapidly progressive course. This phenotypic range may broaden as additional individuals with HDL2 are identified.

The first HDL2 presentation, similar to juvenile-onset Huntington disease (HD) or the Westphal variant of HD, was observed in the index family, which with its many branches and suspected branches accounts for a sizeable proportion of cases outside of South Africa [Krause et al 2002]. Onset is usually from age 29 to 41 years with diminished coordination and weight loss, which is often striking despite an increase in food intake. The disorder culminates in a bedridden, nonverbal state with profound dementia ten to 15 years after onset.

Neurologic abnormalities include: rigidity, bradykinesia, tremor, dysarthria, and hyperreflexia with no clear cerebellar signs and little or no clinically detectable abnormalities of eye movements. Although dystonia and chorea occur in a majority of individuals, the chorea may be mild. Dementia and psychiatric disturbances are universal. Depression, apathy, and irritability are the most common forms of psychiatric disturbance. Death usually follows ten to 20 years after disease onset.

The second presentation is more variable but, in general, corresponds to typical HD. Onset is generally in the fifth decade and beyond. Chorea is more prominent and abnormal eye movements (jerky saccades) may be present, while dystonia, bradykinesia, tremor, hyperreflexia, and dysarthria are less prominent. Psychiatric and cognitive disturbances may be milder, and the disease progresses more slowly.

Acanthocytosis has been reported in affected members of one family with HDL2 and in some affected members of a second family. The significance of acanthocytosis remains uncertain [Walker et al 2002, Walker et al 2003b].

Brain MRI shows the typical features of HD: prominent atrophy of the caudate and cerebral cortex with sparing of the brain stem and cerebellum [Margolis et al 2001]. Findings may be quite modest early in the clinical course of the disease.

Neuropathology. Neuronal loss is most prominent in the striatum and the cerebral cortex. Striatal loss appears limited to medium spiny neurons and occurs in a dorsal to ventral gradient as in HD. Intranuclear inclusions that stain with antibodies against polyglutamine, ubiquitin [Margolis et al 2001, Walker et al 2002], torsinA [Walker et al 2002], and TBP have been detected, predominantly in the cortex [Rudnicki et al 2008].

Genotype-Phenotype Correlations

Longer CTG repeat length correlates with an earlier age of onset, with a relationship similar to that observed in Huntington disease [Margolis et al 2004]. It is possible that longer repeat length (~50 CTG repeats or longer) may be associated with the more virulent course observed in the first subtype of HDL2. However, this association is derived primarily from the large index family [Margolis et al 2001] and could alternatively be explained by other genetic or environmental factors. Thus, until further data have been collected, caution must be employed in interpreting the clinical implications of a CTG repeat expansion of a given length. Disease course in the other family members of the individual requesting information may be valuable as a clinical guide in the interim.

Penetrance

For ethical reasons, only a few unaffected individuals from families with HDL2 have been tested; therefore, the penetrance is unknown.

Anticipation

Limited evidence from the large index pedigree suggests that anticipation may occur [Margolis et al 2001].

Nomenclature

The disease is occasionally (and incorrectly) referred to as HD2.

Prevalence

HDL2 is rare. Information about HDL2 is limited by the small number of affected individuals so far identified (fewer than 25 pedigrees and 40 affected individuals).

Most individuals with HDL2 have been of definite or likely African ancestry, including a Mexican family (from a region originally colonized by survivors of a wrecked African slave ship), and five unrelated cases detected in Brazil. HDL2 has also been found in an individual from Morocco [Holmes et al 2001] and an individual identified as being of Mid-Eastern origin [Wild & Tabrizi 2007].

In South Africa, individuals of African ethnicity with an HD-like phenotype are almost as likely to have HDL2 as HD [Krause et al 2002].

Outside of South Africa, HDL2 has been identified in as few as 1% of individuals with clinically or pathologically defined HD who do not have an HTT disease-causing mutation [Rosenblatt et al 1998, Stevanin et al 2003, Margolis et al 2004]. In Brazil, where an estimated 44% of the population is of African descent, as many as 10% of cases with an HD-like disorder may have HDL2 [Rodrigues et al 2011].

  • Two individuals with HDL2 were detected out of 300 individuals referred to a large commercial diagnostic laboratory in the United States for HD testing. None of the 300 individuals showed evidence of an HTT disease-causing gene expansion.
  • In 74 individuals (60 of French origin) with a variety of movement disorders with and without dementia, and an autosomal dominant inheritance pattern in 36% [Stevanin et al 2002], only one case of HDL2 was detected (in an individual from North Africa).
  • In 1600 individuals who had no evidence of an HTT disease-causing mutation (including 147 individuals with a family history of chorea) referred by neurologists in Germany and Austria, no JPH3 expansions were found [Bauer et al 2002].
  • If the cases under consideration are narrowly defined, the frequency of HDL2 is much higher. For instance, of four individuals identified by Rosenblatt et al [1998] with HD-like autosomal dominant disorders, two ultimately proved to have HDL2.
  • No cases of HDL2 have yet been detected in Japan, though only a small number of individuals have been tested.

Differential Diagnosis

The differential diagnosis of Huntington disease-like 2 (HDL2) is the same as for Huntington disease (HD), and is based on the co-occurrence of: (1) movement abnormalities (chorea, dystonia, and/or parkinsonism) reflecting basal ganglia dysfunction, dementia, and psychiatric disturbances; and (2) autosomal dominant inheritance.

The most obvious diagnosis to exclude is HD itself. Also to be considered is neuroferritinopathy (ferritin-associated basal ganglia disease).

Other possibilities:

Nonfamilial disorders that may present like HDL2 include: tardive dyskinesia (common), Sydenham's chorea, systemic lupus erythematosus (SLE), neurosyphilis, hyperglycemia, acquired forms of Creutzfeld-Jakob disease, pregnancy, multisystem atrophy, and thyroid disease.

HD-like symptoms can also arise from drugs, including: antipsychotics, anticonvulsants, oral contraceptives, lithium, and stimulants.

A variety of parkinsonian conditions may also be considered, including: Parkinson disease, progressive supranuclear palsy, corticobasal ganglia degeneration, dopa-responsive dystonia, and frontotemporal dementia with parkinsonism-17.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Huntington disease-like 2 (HDL2), the following evaluations are recommended:

  • Neuroimaging studies to exclude other lesions, such as subdural hematomas secondary to falls, which may be contributing to signs or symptoms
  • 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
  • Genetics consultation

Treatment of Manifestations

Treatment is symptomatic and based on the treatment for HD and other neurodegenerative disorders.

  • Pharmacologic agents may suppress abnormal movements. The most common choices are low-dose neuroleptic agents, such as fluphenazine or haloperidol.
  • Tremor in one individual was suppressed with clonazepam. However, clonazepam, levodopa/carbidopa, anticholinergics, and typical and atypical neuroleptics were not found helpful in treating the abnormal movements of other affected individuals.
  • Based on experience with Huntington disease, antidepressants, antipsychotics, mood stabilizers (lithium, valproic acid, carbamazepine, and lamotragine), and occasionally stimulants may be effective in treating the psychiatric manifestations of HDL2.
  • In the only report specifically related to HDL2, depression partially responded to sertaline in one individual and to nortriptyline in another individual [Walker et al 2003b].
  • The affected individual, other family members, and care providers should be educated regarding the likely course of the disease. Assurance that cognitive decline, depression, apathy, and irritability are manifestations of the disease rather than the "fault" of the individual can decrease stress and guilt.
  • Environmental interventions (establishing regular schedules, easing of expectations to maintain the family finances, encouraging the use of lists to assist with memory) may help.
  • Families often need help in obtaining social services (see Resources).

Prevention of Primary Manifestations

No known treatment stops or slows the progression of HDL2.

Prevention of Secondary Complications

Loose rugs and clutter should be removed from the individual's home to help prevent falls and other injuries. Driving may need to be curtailed or limited to prevent risk of accidents. Food preparation may need to be altered to prevent choking.

Surveillance

Nutrition and swallowing should be monitored. Feeding changes should be implemented when necessary to minimize the risk of aspiration.

Gait should be monitored, with consultation as needed from physical therapists to provide the most appropriate strategies or devices to minimize falls.

Driving safety should be monitored, with consideration of formal driving safety evaluations if safety is uncertain.

Monitor mood and irritability so that measures to decrease the risk of suicide, other behavioral abnormalities, and distress may be implemented.

Agents/Circumstances to Avoid

Any agents that increase ataxia should be used with caution.

Individuals with HDL2, like others with neurodegenerative disorders, are vulnerable to delirium from medical illnesses and medicines, especially polypharmacy.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There is no specific information available about disease management during pregnancy. Prudence suggests close attention to prevention of falls and monitoring for swallowing difficulties. Medications should be reviewed to assess their safety during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Huntington disease-like 2 is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals with HDL2 have an affected parent.
  • De novo mutations causing HDL2 have not been reported, but family information is lacking in several cases.
  • It is possible that CTG repeat expansion of a mutable normal allele/reduced-penetrance allele into the affected range may occur, as it does in HD; such an event has never been documented.
  • It is appropriate to offer molecular genetic testing to an asymptomatic parent.

Note: Although most individuals diagnosed with HDL2 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has the JPH3 expansion, the risk to the sibs is 50%.
  • It is conceivable that an affected parent with a repeat length just at the disease threshold could transmit an expanded allele to one sib and an unexpanded allele to another sib; such a case has not yet been detected.

Offspring of a proband. Each child of an individual with HDL2 has a 50% chance of inheriting the mutation.

Other family members of a proband

  • The risk to other family members depends on the genetic status of the proband's parents.
  • If a parent is affected or has the JPH3 expansion, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing expansion, it is possible that the proband has a de novo mutation. Alternative explanations include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

Testing of at-risk asymptomatic adults. Testing for the expansion in the absence of definite symptoms of the disease is predictive testing. Testing of at-risk asymptomatic adults for Huntington disease-like 2 is possible using the techniques described in Molecular Genetic Testing. When testing at-risk individuals for HDL2, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Whether an asymptomatic adult will develop HDL2 can be predicted by the length of the repeat in JPH3, although this prediction must be qualified by the fact that the correlation between repeat length and disease has been examined in relatively few individuals. In particular, the penetrance of repeat lengths near the disease threshold and the association between age of onset and repeat length have not been well established. As additional persons with HDL2 are reported, the reliability of clinical predictions based on the length of the HDL2 expansion mutation will increase. One approach could be to assign at-risk individuals with an expansion of 41 or more triplets a status of "high probability."

At-risk, asymptomatic, adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic, at-risk, adult family members involves pre-test counseling in which the motives for requesting the test, the individual's knowledge of HDL2, the possible impact of positive and negative test results, and neurologic status are discussed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members, and the limited information available about HDL2. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations. The best model for HDL2 predictive testing is Huntington disease predictive testing. Prudence suggests following the same genetic testing guidelines used for Huntington’s disease, including counseling prior to testing, a confidant to serve as a social support, and availability of counseling following the disclosure of genetic results.

Testing of at-risk individuals younger than 18 years of age. Consensus holds that asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders should not have testing. The principal arguments against testing asymptomatic individuals during childhood:

  • It removes the individuals choice to know or not know this information.
  • It raises the possibility of stigmatization within the family and in other social settings.
  • It could have serious educational and career implications.
  • No preventive treatment is available for this disorder.

Individuals younger than 18 years of age who are symptomatic usually benefit from having a specific diagnosis established.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Hereditary Disease Foundation
    3960 Broadway
    6th Floor
    New York NY 10032
    Phone: 212-928-2121
    Fax: 212-928-2172
    Email: cures@hdfoundation.org
  • Huntington Society of Canada
    151 Frederick Street
    Suite 400
    Kitchener Ontario N2H 2M2
    Canada
    Phone: 800-998-7398 (toll-free); 519-749-7063
    Fax: 519-749-8965
    Email: info@huntingtonsociety.ca
  • Huntington's Disease Society of America (HDSA)
    505 Eighth Avenue
    Suite 902
    New York NY 10018
    Phone: 800-345-4372 (toll-free); 212-242-1968
    Fax: 212-239-3430
    Email: hdsainfo@hdsa.org
  • International Huntington Association
    Callunahof 8
    Harfsen 7217 ST
    Netherlands
    Phone: +31 573 431 595
    Fax: +31 573 431 719
    Email: iha@huntington-assoc.com
  • National Library of Medicine Genetics Home Reference
  • Neuroacanthocytosis Database (Registry)
    Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
    Königstrasse 46
    Stuttgart D-70173
    Germany
    Phone: 49 731 500 63100
    Fax: 49 731 500 63082
    Email: benedikt.bader@med.uni-muenchen.de

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Huntington Disease-Like 2: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
JPH316q24​.2Junctophilin-3JPH3 homepage - Mendelian genesJPH3

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Huntington Disease-Like 2 (View All in OMIM)

605268JUNCTOPHILIN 3; JPH3
606438HUNTINGTON DISEASE-LIKE 2; HDL2

Benign allelic variants. The CTG repeat expansion occurs in a variably spliced exon of JPH3 denoted as exon 2A [Holmes et al 2001]. There is now evidence that in humans a transcript from the reverse complementary strand containing the CAG repeat is expressed, but that expression of the transcript and its protein product is low or nonexistent if the repeat is expanded [Seixas et al 2012]. See Abnormal gene product.

Pathogenic allelic variants. The only pathogenic allele detected in JPH3 to date is the repeat expansion. No attempt has yet been made to find other pathogenic variants in JPH3. The longest repeat expansion detected so far is 58 triplets.

Normal gene product. The normal full-length JPH3 product, junctophilin-3, does not include the exon with the repeat [Holmes et al 2001]. The protein, which is primarily expressed in the brain, appears to help establish the junctional complex between the cytoplasmic membrane and the endoplasmic reticulum (ER). This may serve to link voltage-gated calcium channels with calcium release channels in the ER [Nishi et al 2000, Takeshima et al 2000, Ito et al 2001]. Exon 2A, containing the repeat, is the terminal exon of a truncated transcript. Because alternate splice acceptor sites occur between exon 1 and exon 2A in this transcript, the repeat may fall into any of three possible reading frames, such that it is in-frame to encode polyalanine, or polyleucine, or it falls in the 3' untranslated region. The pattern of expression and the function of the exon 1 - exon 2A transcript variants are not known, although this short transcript contains the plasma membrane recognition motif, but not the ER insertion domain, present in the full-length transcript.

Abnormal gene product. It appears that the repeat expansion results in a decrease in expression of JPH3 protein product, through sequestration or a loss of expression of the JPH3 transcript [Seixas et al 2012]. RNA transcripts with an expanded repeat may have a toxic effect on neurons, similar to the effect of toxic RNA repeat expansions in myotonic dystrophy type 1 and myotonic dystrophy type 2 [Rudnicki et al 2007]. A mouse model has raised the possibility that a transcript on the reverse complementary strand to JPH3, containing the repeat in the CAG orientation, could contribute to disease pathogenesis by encoding a polyglutamine tract [Wilburn et al 2011]. As noted above, in humans this antisense transcript can be detected when the repeat is of normal length. However, expression becomes undetectable if the repeat is expanded [Seixas et al 2012].

References

Literature Cited

  1. Bates G, Harper PS, Jones L, eds. Huntington's Disease. Oxford, UK: Oxford University Press; 2002.
  2. Bauer I, Gencik M, Laccone F, Peters H, Weber BH, Feder EH, Weirich H, Morris-Rosendahl DJ, Rolfs A, Gencikova A, Bauer P, Wenning GK, Epplen JT, Holmes SE, Margolis RL, Ross CA, Riess O. Trinucleotide repeat expansions in the junctophilin-3 gene are not found in Caucasian patients with a Huntington's disease-like phenotype. Ann Neurol. 2002;51:662. [PubMed: 12112122]
  3. Holmes SE, O'Hearn E, Rosenblatt A, Callahan C, Hwang HS, Ingersoll-Ashworth RG, Fleisher A, Stevanin G, Brice A, Potter NT, Ross CA, Margolis RL. A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2. Nat Genet. 2001;29:377–8. [PubMed: 11694876]
  4. Ito K, Komazaki S, Sasamoto K, Yoshida M, Nishi M, Kitamura K, Takeshima H. Deficiency of triad junction and contraction in mutant skeletal muscle lacking junctophilin type 1. J Cell Biol. 2001;154:1059–67. [PMC free article: PMC2196186] [PubMed: 11535622]
  5. Krause A, Temlett J, Van der Meyden K, Ross CA, Callahan C, Margolis RL. CAG/CTG repeat expansions at the HDL2 locus are a common cause of Huntington disease in black South Africans. Am J Hum Genet. 2002;71:528S.
  6. Margolis RL, Holmes SE, Rosenblatt A, Gourley L, O'Hearn E, Ross CA, Seltzer WK, Walker RH, Ashizawa T, Rasmussen A, Hayden M, Almqvist EW, Harris J, Fahn S, MacDonald ME, Mysore J, Shimohata T, Tsuji S, Potter N, Nakaso K, Adachi Y, Nakashima K, Bird T, Krause A, Greenstein P. Huntington's Disease-like 2 (HDL2) in North America and Japan. Ann Neurol. 2004;56:670–4. [PubMed: 15468075]
  7. Margolis RL, O'Hearn E, Rosenblatt A, Willour V, Holmes SE, Franz ML, Callahan C, Hwang HS, Troncoso JC, Ross CA. A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion. Ann Neurol. 2001;50:373–80. [PubMed: 11558794]
  8. Nishi M, Mizushima A, Nakagawara K, Takeshima H. Characterization of human junctophilin subtype genes. Biochem Biophys Res Commun. 2000;273:920–7. [PubMed: 10891348]
  9. Rodrigues GR, Walker RH, Bader B, Danek A, Brice A, Cazeneuve C, Russaouen O, Lopes-Cendes I, Marques Jr W, Tumas V. Clinical and genetic analysis of 29 Brazilian patients with Huntington's disease-like phenotype. Arq Neuropsiquiatr. 2011;69:419–23. [PubMed: 21755114]
  10. Rosenblatt A, Ranen NG, Rubinsztein DC, Stine OC, Margolis RL, Wagster MV, Becher MW, Rosser AE, Leggo J, Hodges JR. Patients with features similar to Huntington's disease, without CAG expansion in huntingtin. Neurology. 1998;51:215–20. [PubMed: 9674805]
  11. Ross CA, Margolis RL, Rosenblatt A, Ranen NG, Becher MW, Aylward E. Huntington disease and the related disorder, dentatorubral-pallidoluysian atrophy (DRPLA). Medicine (Baltimore) 1997;76:305–38. [PubMed: 9352736]
  12. Rudnicki DD, Holmes SE, Lin M, Thorton CA, Ross CA, Margolis RL. Huntington’s disease-like 2 is associated with CUG repeat containing RNA foci. Ann Neurol. 2007;61:272–82. [PubMed: 17387722]
  13. Rudnicki DD, Pletnikova O, Vansattel JP, Ross CA, Margolis RL. A comparison of Huntington’s disease and Huntington’s disease-like 2 neuropathology. J Neuropathol Exp Neurol. 2008;67:366–74. [PubMed: 18379432]
  14. Seixas AI, Holmes SE, Takeshima H, Pavlovich A, Sachs N, Pruitt JL, Silveira I, Ross CA, Margolis RL, Rudnicki DD. Loss of junctophilin-3 contributes to Huntington disease-like 2 pathogenesis. Ann Neurol. 2012;71:245–57. [PubMed: 22367996]
  15. Stevanin G, Camuzat A, Holmes SE, Julien C, Sahloul R, Dode C, Hahn-Barma V, Ross CA, Margolis RL, Durr A, Brice A. CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients. Neurology. 2002;58:965–7. [PubMed: 11914418]
  16. Stevanin G, Fujigasaki H, Lebre AS, Camuzat A, Jeannequin C, Dode C, Takahashi J, San C, Bellance R, Brice A, Durr A. Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes. Brain. 2003;126:1599–603. [PubMed: 12805114]
  17. Takeshima H, Komazaki S, Nishi M, Iino M, Kangawa K. Junctophilins: a novel family of junctional membrane complex proteins. Mol Cell. 2000;6:11–22. [PubMed: 10949023]
  18. Walker RH, Jankovic J, O'Hearn E, Margolis RL. Phenotypic features of Huntington's disease-like 2. Mov Disord. 2003a;18:1527–30. [PubMed: 14673892]
  19. Walker RH, Morgello S, Davidoff-Feldman B, Melnick A, Walsh MJ, Shashidharan P, Brin MF. Autosomal dominant chorea-acanthocytosis with polyglutamine-containing neuronal inclusions. Neurology. 2002;58:1031–7. [PubMed: 11940688]
  20. Walker RH, Rasmussen A, Rudnicki D, Holmes SE, Alonso E, Matsuura T, Ashizawa T, Davidoff-Feldman B, Margolis RL. Huntington's disease-like 2 can present as chorea-acanthocytosis. Neurology. 2003b;61:1002–4. [PubMed: 14557581]
  21. Wilburn B, Rudnicki DD, Zhao J, Weitz TM, Cheng Y, Gu X, Greiner E, Park CS, Wang N, Sopher BL, La Spada AR, Osmand A, Margolis RL, Sun YE, Yang XW. An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington's disease-like 2 mice. Neuron. 2011;70:427–40. [PMC free article: PMC3107122] [PubMed: 21555070]
  22. Wild EJ, Tabrizi SJ. Huntington's disease phenocopy syndromes. Curr Opin Neurol. 2007;20:681–7. [PubMed: 17992089]

Chapter Notes

Author Notes

The laboratory of Dr Russell L Margolis, which identified the first known family with HDL2 and found the causative mutation of HDL2, is actively investigating the phenotype and pathogenesis of HDL2 and welcomes questions about possible HDL2 patients. The laboratory will arrange for free genetic testing for the HDL2 mutation in appropriate patients (DNA, blood, or brain samples). For information, contact Ms. Nadine Yoritomo, 410-955-2398 or nyorito1@jhmi.edu. Additional information is available online.

Revision History

  • 26 April 2012 (me) Comprehensive update posted live
  • 13 August 2009 (me) Comprehensive update posted live
  • 10 March 2006 (me) Comprehensive update review posted to live Web site
  • 30 January 2004 (me) Review posted to live Web site
  • 15 September 2003 (rm) Original submission
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