Clinical characteristics.

Huntington disease-like 2 (HDL2) typically presents in midlife with a relentless progressive triad of movement, emotional, and cognitive abnormalities that lead to death within ten to 20 years. HDL2 cannot be differentiated from Huntington disease (HD) clinically. Neurologic abnormalities include chorea, hypokinesia (rigidity, bradykinesia), dysarthria, abnormalities of eye movements and gait, and hyperreflexia in the later stages of the disease. There is a strong correlation between the duration of the disease and the progression of motor and cognitive signs and symptoms.

Diagnosis/testing.

The diagnosis of HDL2 is established in a proband with characteristic clinical findings and heterozygous expansion of 40 or more CTG trinucleotide repeats in JPH3 identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is symptomatic and is presumably similar to that for HD and other neurodegenerative disorders – although this must be considered speculative pending objective data. Pharmacologic agents that may suppress abnormal movements include tetrabenazine and its derivatives or low-dose neuroleptic agents such as fluphenazine and haloperidol. Remove loose rugs and clutter from the individual's home and minimize or eliminate the need for stairs to help prevent falls and other injuries; physical therapy evaluation and treatment for mobility issues; speech therapy, communication devices, and environmental modifications for dysarthria; speech-language pathology and nutrition referrals for dysphagia; food should be prepared in such a manner as to prevent choking; feeding changes when needed to minimize risk of aspiration; driving may need to be curtailed or limited to prevent risk of accidents; planning for financial matters; environmental interventions for cognitive issues; antidepressants, antipsychotics, mood stabilizers (lithium, valproic acid, carbamazepine, and lamotrigine), electroconvulsive therapy, and occasionally stimulants may improve psychiatric manifestations. Education about the course of disease; social work and care coordination support.

Surveillance: Annual evaluation or more frequently as needed to assess motor skills including gait and abnormal movements; physical therapy assessment of mobility and appropriate strategies or devices to minimize falls; assess cognitive skills and driving safety to assure that affected individuals do not present a danger to themselves or others; assess weight, nutrition, swallowing, and risk of aspiration in order to implement feeding changes when necessary; assess for psychiatric manifestations, including mood, suicidality, anxiety, irritability, and apathy; assess sleep and sexual concerns; assess family needs; assess planning for future (financial, legal issues).

Agents/circumstances to avoid: Any agents that increase ataxia should be used with caution; begin psychoactive medicines at lower doses and increase doses carefully; minimize polypharmacy, which may increase the risk of delirium.

Genetic counseling.

HDL2 is inherited in an autosomal dominant manner. Most individuals with HDL2 have an affected parent. At conception, each child of an individual with HDL2 has a 50% chance of inheriting the HDL2-causing allele. Offspring who inherit a pathogenic (full-penetrance) HDL2-causing allele (≥40 CTG repeats) are considered at risk of developing HDL2 in their lifetime; offspring who inherit an allele of questionable significance (29-39 CTG repeats) may or may not develop manifestations of HDL2. Testing of asymptomatic adults at risk for HDL2 is possible once a heterozygous expansion of a CTG repeat in JPH3 has been identified in an affected family member. Testing for the JPH3 CTG repeat expansion in the absence of definite manifestations of the disease is predictive testing. Prudence suggests following the same genetic testing guidelines used for HD, including counseling prior to testing, a confidant to serve as a social support, and availability of counseling following the disclosure of genetic results. If the presence of an HDL2-causing allele has been confirmed in the affected parent or in an affected relative of the at-risk parent, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Huntington disease-like 2 (HDL2) should be suspected in individuals – particularly of African descent or with African ancestry (even if distant) – who present with the following clinical and imaging features and family history typical of Huntington disease (HD) but do not have a disease-causing CAG expansion (i.e., reduced-penetrance allele or full-penetrance allele) in HTT.

Clinical features

• Progressive motor disability featuring involuntary movements (especially chorea) and affecting voluntary movement (e.g., gait, speech, swallowing). Rigidity and bradykinesia may predominate in the later stages of the disease.
• Psychiatric disturbances including changes in personality and depression
• Progressive dementia

Imaging findings on brain MRI. Prominent atrophy of the caudate and cerebral cortex with sparing of the brain stem and cerebellum [Margolis et al 2001]. Note: A comparison of brain volumes in individuals with HDL2 and HD using semiautomated MRI image analysis confirmed similar cortical and striatal volume loss with greater thalamic atrophy in individuals with HDL2 [Anderson et al 2019b].

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis as family history may be unavailable or inaccurate.

Establishing the Diagnosis

The diagnosis of HDL2 is established in a proband with suggestive findings and a heterozygous expansion of a CTG trinucleotide repeat in JPH3 identified by molecular genetic testing (see Table 1).

CTG repeat sizes

• Normal. 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 woman age 48 years with an atypical cerebellar disorder (rapid onset following hospitalization for out-of-control diabetes mellitus with little or no progression) had a JPH3 CTG repeat length of 33 in one allele. Her son, age 30 years, had developed Cogan syndrome, an autoimmune disease resulting in complete hearing loss, at age 25 years. He reported tinnitus, occasional lapses of concentration, and difficulty with balance, all associated with the onset of Cogan 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 HD coincidentally also had a JPH3 allele of 34 CTG repeats [Authors, personal observation].
  • Reduced-penetrance alleles that result in very late-onset disease, a different phenotype, and/or no occurrence of clinical disease in a normal life span. Whether this occurs is unknown.
• Pathogenic (full-penetrance) HDL2-causing alleles. 40 or more CTG repeats. Persons who have an HDL2-causing allele are considered at risk of developing HDL2 in their lifetime.
  Notes: (1) 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. (2) PCR-based assays, standard in genetic laboratories, are typically accurate to within ~±1 triplet, complicating interpretation of alleles of borderline length. (3) An allele with 39 CTG repeats has been reported in an individual with an HDL2 phenotype. (4) The longest repeat expansion detected to date is 63 CTG repeats.

Molecular genetic testing relies on targeted analysis to characterize the number of JPH3 CTG repeats.

Clinical Description

Like Huntington disease (HD), Huntington disease-like 2 (HDL2) typically presents in midlife with a relentless progressive triad of movement, emotional, and cognitive abnormalities. However, unlike HD, HDL2 has been described exclusively in individuals with confirmed or likely African ancestry. More than half of individuals with HDL2 have been reported from South Africa; most of the remaining individuals are from North and South America and the Caribbean [Anderson et al 2017, Walker et al 2018]. With longer disease duration, there is progression to marked dementia and a rigid and bradykinetic state with worsening dystonia. HDL2 is indistinguishable from HD in the clinical setting [Anderson et al 2019a]. In some individuals, especially with repeat expansions in the upper end of the range detected to date (i.e., ~58-63 triplets), cognitive deficits are more severe than motor deficits, and dystonia, rigidity, and parkinsonism are more severe than chorea [Margolis et al 2001, Narotam-Jeena et al 2024].

Onset. The average age of onset is 41 years (standard deviation [SD] = 11.1 years), although the range in onset has been reported to be wide (12-66 years) [Anderson et al 2017]. The length of the CTG expansion has an inverse correlation with age of onset.

Movement disorder. Chorea and oculomotor abnormalities are the initial motor manifestations in most individuals. Chorea is the most common movement abnormality, followed by rigidity, bradykinesia, dysarthria, and dystonia. Some individuals present with a more rigid, dystonic form of the illness with relatively less chorea. Clumsiness and gait issues are common, as are decreased motor speed and fine motor control. Oculomotor dysfunction (difficulty initiating saccades, slow and hypometric saccades, and problems in gaze fixation) is common and worsens with longer disease duration [Anderson et al 2019a]. Dysarthria may become evident within a few years of disease onset and, as in HD, worsens with time. Dysarthria and dystonia may be somewhat more severe for a given period of disease duration in HDL2 than in HD. Dysphagia is also common, though the course has not been determined [Anderson et al 2019a]. Hyperreflexia is a late feature of the disease [Anderson et al 2017].

Psychiatric disturbances / depression. Depression, personality changes, irritability, agitation, and aggression are the most commonly reported forms of psychiatric disturbance, and may be the presenting features of HDL2, though the literature is sparse. Social withdrawal, sleep disruptions, apathy, hallucinations, and delusions have also been reported, though less frequently [Krause et al 2024, Narotam-Jeena et al 2024]. Suicide has not been reported. Overall, the range of psychiatric symptoms and syndromes is quite similar to that observed in HD, and the expectation is that any of the psychiatric disorders that have been observed in HD, including suicide and sexual dysfunction, may also arise in HDL2.

Cognitive manifestations. Progressive dementia is a universal feature of HDL2 and is similar to the dementia profile seen in HD [Anderson et al 2017]. Deterioration of specific domains of cognition is somewhat heterogeneous. At a given point in disease progression, psychomotor speed and dexterity are the most severely affected domains, followed by executive function, some forms of memory, learning, attention, and concentration, with deficits in working memory less prominent. However, function in all domains deteriorates over time [Ferreira-Correia et al 2020].

Prognosis. Death usually follows ten to 20 years after disease onset [Margolis et al 2001]. While the typical causes of death have not been described, it is likely that death is largely a consequence of the effects of inanition, lack of movement, and dysphagia, as in HD.

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 TATA-binding protein (TBP) have been detected, predominantly in the cortex [Rudnicki et al 2008].

Genotype-Phenotype Correlations

As in HD, longer CTG repeat length correlates with an earlier age of onset in HDL2 [Margolis et al 2004, Anderson et al 2017], with an estimate of 1.2-2.9 years earlier onset for each increase of one triplet [Krause et al 2024; Sanfeliz et al, unpublished data]. It is possible that longer repeat length (~≥50 CTG repeats) may be associated with a more aggressive course (less chorea; more dystonia, rigidity, and weight loss), observed primarily in a large index family [Margolis et al 2001], although alternative genetic or environmental factors may be relevant.

Penetrance

For ethical reasons, only a few unaffected individuals from families with HDL2 have been tested; therefore, the penetrance is unknown. One individual with a repeat of 44 triplets did not have evidence of HDL2 at age 65 years, suggesting the possibility of reduced penetrance in some individuals.

Anticipation

Limited evidence from a large index pedigree suggests that anticipation may occur [Margolis et al 2001]. An example of anticipation through paternal inheritance has been described [Greenstein et al 2007]. So far, no large changes in allele size have been detected in either maternal or paternal transmission. However, in a large Caribbean pedigree, seven affected first cousins had allele lengths ranging from 43 to 57 triplets, and one father with 54 triplets transmitted an expansion of 58 triplets.

Nomenclature

HDL2 is occasionally (and incorrectly) referred to as HD2.

Prevalence

Although rare, HDL2 appears to be the most common HD phenocopy in populations with African ancestry, and overall the most prevalent HD-like disorder. These populations include France [Mariani et al 2016], parts of the Americas [Margolis et al 2004, Walker et al 2018], and South Africa [Krause et al 2015]. Individuals with HDL2 share a common haplotype that originated in Africa [Krause et al 2015].

• The highest number of affected individuals are from South Africa [Anderson et al 2017]. An analysis of blood samples from individuals with an HD-like phenotype referred for HD testing [Krause et al 2015] found that 15% of Black South Africans and no White individuals were found to have HDL2, while 62% of Whites and 36% of Blacks were found to have HD. Therefore, for every two Black individuals diagnosed with HD there was approximately one Black individual diagnosed with HDL2.
• 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 pathogenic variant [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 individuals with an HD-like disorder may have HDL2 [Rodrigues et al 2011].
  • In Venezuela, of 260 unrelated individuals referred for testing based on an HD-like phenotype, 11 (4.2%) had an expanded allele at the JPH3 locus [Paradisi et al 2024].
  • Of 300 individuals referred to a large commercial diagnostic laboratory in the United States for HD testing who had tested negative for the HD-causing expansion, two were found to have the HDL2-causing expansion.
  • A male age 47 years was the first individual with HDL2 described from Botswana [Ocampo et al 2018].
  • A family with HDL2 consisting of a proband and his two children were diagnosed in Mali, the first individuals identified with HDL2 in West Africa [Bocoum et al 2024].
  • Among 74 individuals (60 of French origin) with a variety of movement disorders with and without dementia, 36% of whom had an autosomal dominant inheritance pattern [Stevanin et al 2002], only one individual was had HDL2; the individual was from North Africa. One individual with HDL2 has been identified in Italy; the individual was originally from Brazil, and African ancestry was considered likely [Ruscitti et al 2022].
  • Among 1,600 individuals with movement disorders referred for genetic testing by neurologists in Germany and Austria who did not have an expanded HD allele (including 147 individuals with a family history of chorea), no HDL2-related expansions were found [Bauer et al 2002].
  If the cases described above are narrowly defined, the frequency of HDL2 is much higher than indicated. For instance, of four individuals identified by Rosenblatt et al [1998] with HD-like autosomal dominant disorders, two ultimately proved to have HDL2.
• HDL2 has not been identified in any individuals in Japan, though only a small number of individuals have been tested.
• HDL2 has been identified in affected individuals from multiple families in the Caribbean.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HDL2, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is based on the treatment for HD and other neurodegenerative disorders. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Any agents that increase ataxia should be used with caution.

Individuals with HDL2, like those with other neurodegenerative disorders, are vulnerable to delirium from medical illnesses and medicines. Particular caution is necessary to minimize polypharmacy, high doses, or rapid dose increases of medicines.

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. See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Huntington disease-like 2 (HDL2) is inherited in an autosomal dominant manner.

Note: HDL2 and Huntington disease (HD) cannot be clinically distinguished [Anderson et al 2019a], complicating genetic counseling in families in which a diagnosis has not been confirmed with molecular genetic testing (see Diagnosis); this distinction is critical for predictive testing and may be of relevance if treatments specific for HD emerge from ongoing clinical trials.

Risk to Family Members

Parents of a proband

• Most individuals with HDL2 have an affected parent.
• The family history of some individuals diagnosed with HDL2 may appear to be negative for one of the following reasons:
  • Failure to recognize the disorder in family members
  • Early death of the parent before the onset of symptoms
  • Late onset of the disease in the affected parent
  • Adoption, misidentified paternity, alternate maternity (via fertility interventions)
  • Expansion of a mutable normal allele / reduced-penetrance allele (29-39 CTG repeats in JPH3) in an asymptomatic parent into the pathogenic range (≥40 CTG repeats) in the proband. Expansion of a trinucleotide repeat from an intermediate to a pathogenic range occurs in HD; however, such an event has not been documented to date in HDL2.
• It is appropriate to offer molecular genetic testing to asymptomatic parents of a proband who appears to represent a simplex case (i.e., a single occurrence in a family). Note: Testing for the expansion in the absence of manifestations of the disease is predictive testing and genetic counseling, both before and after testing, is essential.

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 has a JPH3 allele with ≥40 CTG repeats, the risk to the sibs of inheriting a pathogenic (full-penetrance) HDL2-causing allele is 50%. Sibs who inherit a full-penetrance HDL2-causing allele are considered at risk of developing HDL2 in their lifetime.
• If a parent of the proband has a CTG repeat size close to 40 CTG repeats, the risk to sibs of inheriting an HDL2-causing allele is predicted to be significant, though not yet quantifiable. Theoretically, a parent with a CTG repeat size close to 40 CTG repeats could transmit an expanded allele to one sib and an unexpanded allele to another sib; however, this has not been reported to date.
• A sib who inherits a JPH3 allele of questionable significance (approximately 29-39 CTG repeats) may possibly develop manifestations of HDL2, though development of HDL2 in an individual with fewer than 40 CTG triplets has not yet been reported. As more families are ascertained, the threshold of repeat length leading to disease may clarify.
• Limited evidence from a large index pedigree suggests that anticipation may occur [Margolis et al 2001] (see Anticipation).

Offspring of a proband. At conception, each child of an individual with HDL2 has a 50% chance of inheriting the HDL2-causing allele. Offspring who inherit a:

• Pathogenic (full-penetrance) HDL2-causing allele (≥40 CTG repeats) are considered at risk of developing HDL2 in their lifetime.
• Offspring who inherit an allele of questionable significance (29-39 CTG repeats) may or may not develop manifestations of HDL2 (as described in Sibs of a proband).

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected and/or heterozygous for a CTG repeat expansion in JPH3, the parent's family members may be at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults (predictive testing). Testing of asymptomatic adults at risk for HDL2 is possible once a heterozygous expansion of a CTG repeat in JPH3 has been identified in an affected family member. Testing for the JPH3 CTG repeat expansion in the absence of definite manifestations of the disease is predictive testing. Persons who have an HDL2-causing allele are considered at risk of developing HDL2 in their lifetime, 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-causing expansion will increase.

• 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 HD predictive testing. Prudence suggests following the same genetic testing guidelines used for HD, including counseling prior to testing, a confidant to serve as a social support, and availability of counseling following the disclosure of genetic results.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years). For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive testing should be discussed in the context of formal genetic counseling. The autonomy of the minor is a primary concern, and consideration should be given to delay of predictive genetic testing until the at-risk individual is capable of informed decision making.

In a family with an established diagnosis of HDL2, it is appropriate to consider testing of symptomatic individuals regardless of age.

Considerations in families with an apparent de novo expansion. When neither parent of a proband has a pathogenic HDL2-causing allele (≥40 CTG repeats) or an allele of questionable significance (29-39 CTG repeats), nonmedical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption may need to be explored, as the information could have implications for other potentially at-risk family members.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

For fetuses at 50% risk. If the presence of an HDL2-causing allele has been confirmed in the affected parent or in an affected relative of the at-risk parent, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing (PGT) are possible.

A PGT exclusion protocol may be an option for testing of the embryo of couples in an at-risk family who do not wish to undergo predictive testing for the HDL2-causing allele themselves. While there is no known example of PGT applied to HDL2, the concepts and procedures would be nearly identical to those of HD.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate.

Molecular Pathogenesis

HDL2 is caused by a CTG expansion on chromosome 16q24.2, which is located on the sense strand in exon 2A of JPH3, and on the antisense strand in the CAG orientation in JPH3-AS. The primary JPH3 transcript does not contain exon 2A with the repeat [Holmes et al 2001]. The antisense strand appears to encode a short transcript that does contain the repeat in an exon.

JPH3 encodes junctophilin-3, which is primarily expressed in the brain and 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]. Other possible functions of the protein have not been systematically investigated; however, the closely related protein junctophilin-2 may function as a transcriptional regulator factor [Guo et al 2018].

A JPH3 transcript containing exon 1 and exon 2A is also expressed. Because alternate splice acceptor sites occur between exon 1 and exon 2A in this transcript, the repeat may exist in three alternate reading frames in which it could encode polyalanine or polyleucine or fall in the 3' untranslated region.

The expression pattern and function of the exon 1 to exon 2A transcript variants are not known. This short transcript contains the plasma membrane recognition motif but not the ER insertion domain present in the full-length transcript.

In the antisense strand in JPH3-AS, the repeat consists of CAG triplets predicted to encode a polyglutamine tract. The antisense gene is transcribed, and is suspected [Wilburn et al 2011], though not proven [Seixas et al 2012], to encode a short protein containing polyglutamine.

Mechanism of disease causation. The molecular pathogenesis of HDL2 appears to be complicated, and derived from at least three non-mutually exclusive mechanisms [Krause et al 2024]:

• Loss of expression of junctophilin-3, potentially by sequestration and loss of translation of JPH3 RNA carrying the expanded repeat. Loss of junctophilin-3 appears to lead to abnormal neurologic function based on cell and animal models and on mutations in JPH3 in humans [Seixas et al 2012, Seeley et al 2014, Bourinaris et al 2021, Steel et al 2023].
• Toxic properties of JPH3 transcripts containing an expanded repeat [Rudnicki et al 2007]
• Toxic gain of function from the expression of protein containing an expanded polyglutamine tract from JPH3-AS [Wilburn et al 2011]

JPH3-specific laboratory technical considerations. Laboratory testing is similar to that performed for other repeat expansion diseases. As such, unknown variations in sequence that affect PCR efficiency, or very long repeat lengths, could lead to a failure to detect a repeat expansion. Therefore, detection of a single allele should not automatically lead to the conclusion that an individual is homozygous for a repeat of that length; repeat length in other family members, or additional testing, may be necessary to prove that a long expansion is not present.

Author Notes

The laboratory of Dr Russell L Margolis at Johns Hopkins School of Medicine, Baltimore, MD, USA, which identified the first known family with HDL2 as well as the genetic cause, is actively investigating the phenotype and pathogenesis of HDL2 and welcomes questions regarding individuals possibly affected with HDL2. Contact Dr Margolis at ude.imhj@ilogramr with questions or additional information about HDL2.

The Division of Human Genetics, at the National Health Laboratory Services and the School of Pathology, the University of the Witwatersrand, Johannesburg, South Africa, is studying the detailed molecular genetics of the HDL2 locus and its association with clinical manifestations of HDL2. The laboratory will offer diagnostic testing for HDL2 for individuals from outside of South Africa. For further details, contact Professor Amanda Krause at az.ca.stiw@esuark.adnama.

Clinical expertise in the UK: Dr David Anderson, Consultant Neurologist at the Queen Elizabeth University Hospital and Honorary Senior Lecturer, University of Glasgow: ku.ca.wogsalg@2.nosredna.evad

Clinical expertise in Brazil: Dr Vitor Tumas, Universidade de São Paulo, Ribeirão Preto: rb.psu.prmf@vsamut :otliam

Clinical expertise in the Caribbean: Dr Remi Ballance, Centre de Référence Caribéen des maladies neuromusculaires rares, Centre Hospitalier de Martinique: rf.euqinitram-uhc@ecnalleb.imer

Genetic expertise in Venezuela: Dr Irene Paradisi, Human Genetics Laboratory, Venezuelan Institute for Scientific Research: moc.liamtoh@isidarapeneri

The authors would like to be informed of all newly diagnosed individuals with HDL2 to expand information about this rare disease.

Acknowledgments

The authors would like to acknowledge individuals with HDL2 and their families who have made progress in understanding HDL2 possible. We also acknowledge funding from the National Institute of Neurological Diseases and Stroke (USA), the South African Medical Research Council, and the ABCD Charitable Trust. Many scientists and clinicians have contributed to the understanding of HDL2, including Dr Susan E Holmes, Dr Christopher A Ross, Dr Aline Ferreira-Correia, Dr Dobrila D Rudnicki, Dr Anna I Seixas, Dr X William Yang, Dr Brian Wilburn, Dr Juan C Troncoso, Dr Olga Pletnikova, Dr Vitor Tumas, Dr Irene Paradisi, Dr Ruth Walker, and Dr Peggy E Greenstein. Many others listed in the references have also made significant contributions; our apologies for not naming them all.

Revision History

• 10 April 2025 (sw) Comprehensive update posted live
• 27 June 2019 (sw) Comprehensive update posted live
• 26 April 2012 (me) Comprehensive update posted live
• 13 August 2009 (me) Comprehensive update posted live
• 10 March 2006 (me) Comprehensive update review posted live
• 30 January 2004 (me) Review posted live
• 15 September 2003 (rm) Original submission

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