Margolis et al. (2001) described a large kindred with an autosomal dominant disorder that is clinically similar to Huntington disease (143100) but arose from a CAG expansion in a different gene. The disorder is characterized by onset in ... Margolis et al. (2001) described a large kindred with an autosomal dominant disorder that is clinically similar to Huntington disease (143100) but arose from a CAG expansion in a different gene. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movements, psychiatric symptoms, weight loss, dementia, and relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal-to-ventral gradient and occasional intranuclear inclusions. This family was of African American ethnicity, and the parents of the first known affected individual were from a semirural region of the southeastern United States. The disorder in this family, designated family W, fell well within the spectrum of HD. Other than a lower frequency of eye movement findings and the absence of seizures, the disease was similar to juvenile-onset HD (van Dijk et al., 1986) and the 'Westphal' variant of HD observed in some adult cases. Unlike the HDL1 (603218), seizures did not occur in affected members of pedigree W. However, in both pedigrees, rigidity was more prominent than chorea. Walker et al. (2002) reported a family in which 3 individuals were affected with what the authors thought was an autosomal dominant form of chorea-acanthocytosis (200150), but which was later found by Walker et al. (2003) to be HDL2. The proband was a 56-year-old man who had initially been diagnosed with Huntington disease. At age 34 years, he developed a slowly progressive deterioration in memory and personality, with involuntary movements of the face and hands. By age 54 years, he was unable to stand, had no spontaneous speech, and showed continuous choreiform movements. Postmortem examination of the brain showed severe, diffuse cortical atrophy and severe atrophy of the caudate and putamen, as well as ubiquitinated intranuclear inclusions with immunoreactivity for expanded polyglutamine repeats throughout the brain. His son, who had fragile X syndrome (300624), developed gait abnormalities, chorea, and dystonia in his late twenties. Head CT scan showed generalized cerebral and caudate atrophy. Walker et al. (2002) suspected that the fragile X was unrelated to the neurologic disorder. The third patient, the nephew of the proband, developed personality changes, primitive reflexes, hyperreflexia, and mild parkinsonism beginning at age 28 years. All 3 patients had 30 to 35% acanthocytosis on peripheral blood smear.
Margolis et al., (2001) found that in family W all tested affected individuals, and no tested unaffected individuals, had a CAG/CTG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests ... Margolis et al., (2001) found that in family W all tested affected individuals, and no tested unaffected individuals, had a CAG/CTG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other then-known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation was novel. Holmes et al. (2001) demonstrated that the expanded CAG/CTG repeat in the original pedigree was located in an alternatively spliced exon of the JPH3 gene (605268.0001). This exon has multiple splice acceptor sites. They found the same mutation in the JPH3 gene in other African American patients with a Huntington disease-like neurologic disorder. Among 74 patients with an HD-like phenotype but without CAG repeat expansions in the IT15 gene (143100.0001), Stevanin et al. (2002) identified 1 patient with a pure uninterrupted 50 CAG/CTG repeat in the JPH3 gene. The patient was a 44-year-old Moroccan woman with subcortical dementia, mild choreic movements, and atrophy of the cerebral cortex. In the study by Stevanin et al. (2002), the HDL2 locus accounted for only 2% of typical HD cases not caused by expansion in the IT15 gene, suggesting further genetic heterogeneity. In the family reported by Walker et al. (2002) as having choreoacanthocytosis, Walker et al. (2003) identified trinucleotide repeat expansions of 51, 58, and 57 triplets in the junctophilin-3 gene, confirming Huntington disease-like-2. Walker et al. (2003) also reported a Mexican family with HDL2, characterized by dementia, depression, chorea, and parkinsonism, in which affected members had 46, 49, and 46 triplet repeats. One of the patients also had acanthocytosis. Another unrelated affected African American patient, who did not have acanthocytosis, had 44 triplet repeats. The findings indicated that some, but not all, patients with the HDL2 mutation may develop acanthocytosis, and Walker et al. (2003) suggested that there may be reduced penetrance of this feature or that the acanthocytosis may vary over the course of the disease.
In 9 independent series of patients referred for HD testing in North America (538 patients) or Japan (44 patients), Margolis et al. (2004) found an HDL2 frequency of approximately 1% in North America and 0% in Japan. HDL2 ... In 9 independent series of patients referred for HD testing in North America (538 patients) or Japan (44 patients), Margolis et al. (2004) found an HDL2 frequency of approximately 1% in North America and 0% in Japan. HDL2 was identified predominantly in patients of African ancestry. One affected Mexican pedigree originated from a region of Mexico colonized by Africans. Repeat expansions in the junctophilin-3 gene ranged from 44 to 57 triplets, and a younger age at onset was correlated with a longer repeat length. Rudnicki et al. (2007) stated that at least 25 HDL2 pedigrees had been identified; all with known ancestry are of definite or probable African origin. Santos et al. (2008) reported a 48-year-old Brazilian man of European ancestry who presented with a phenotype very suggestive of HD with onset of symptoms at age 44 years. His deceased father was reportedly similarly affected from age 50 years. Genetic analysis in the proband identified a 47 CTG repeat expansion in the JPH3 gene. Although the family did not refer to any African ancestry, the haplotype with the repeat expansion has only been identified in individuals of African ancestry (16.3%), suggesting that there was remote African ancestry in this family. Rodrigues et al. (2008) reported 4 unrelated Brazilian patients with HDL2 associated with heterozygous expanded repeat expansions of 47, 59, 46, and 48, respectively, in the JPH3 gene. Age at onset ranged from 22 to 60 years, and was inversely correlated to the size of the repeat expansion. Three patients were black, consistent with African descent, and the fourth patient, who was white, was found to have a 'dark-skinned' grandmother, suggesting African ancestry. Rodrigues et al. (2008) noted that approximately 44.6% of the Brazilian population is of African descent.
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. ...
DiagnosisClinical DiagnosisThe 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 TestingGene. JPH3 is the only gene in which mutations are known to cause Huntington disease-like 2 (HDL2).Allele sizesNormal 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 spanFull-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 testingTargeted mutation analysis. A PCR assay determines within one to two repeats the length of the CTG trinucleotide repeat in JPH3. Table 1. Summary of Molecular Genetic Testing Used in Huntington Disease-Like 2View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityJPH3Targeted mutation analysisCTG repeat expansion Nearly 100%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated geneInterpretation 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.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyConfirming/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. Genetically Related (Allelic) DisordersMutations in JPH3 have not been associated with other phenotypes.
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....
Natural HistoryLike 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].
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....
Genotype-Phenotype CorrelationsLonger 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.
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. ...
Differential DiagnosisThe 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:Dentatorubral-pallidoluysian atrophy (DRPLA) (more common in Japan)Chorea-acanthocytosis (both autosomal dominant and autosomal recessive forms)Benign hereditary chorea (usually of childhood onset)Certain autosomal dominant spinocerebellar ataxias (particularly SCA2, SCA3, and SCA17)Hereditary forms of Creutzfeld-Jakob disease (see Genetic Prion Diseases)Wilson disease (exclusion is essential since Wilson disease is treatable)Neuronal ceroid-lipofuscinoses (usually autosomal recessive childhood onset, rarely dominant with adult onset)Pantothenate kinase-associated neurodegeneration (PKAN) (childhood onset, autosomal recessive)Fahr disease (familial idiopathic basal ganglia calcification)Mitochondrial diseases (see Mitochondrial Disease Overview) (maternal inheritance)McLeod neuroacanthocytosis syndrome (X-linked neuroacanthocytosis)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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).HDL2 – onset ~4th decadeHDL2 – onset ≥5th decade
To establish the extent of disease in an individual diagnosed with Huntington disease-like 2 (HDL2), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 symptomsStandardized 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 cognitionGenetics consultationTreatment of ManifestationsTreatment 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 ManifestationsNo known treatment stops or slows the progression of HDL2.Prevention of Secondary ComplicationsLoose 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 AvoidAny 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 RiskSee 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 InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDJPH316q24.2Junctophilin-3JPH3 homepage - Mendelian genesJPH3Data 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) View in own window 605268JUNCTOPHILIN 3; JPH3 606438HUNTINGTON DISEASE-LIKE 2; HDL2Normal 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.Pathologic allelic variants. The only pathologic allele detected in JPH3 to date is the repeat expansion. No attempt has yet been made to find other mutations 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].