Dentatorubral–pallidoluysian atrophy: Difference between revisions

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{{short description|Congenital disorder of nervous system}}
 
{{Short description|Congenital neurodegenerative disorder}}
{{Infobox medical condition (new)
{{Infobox medical condition (new)
| name            =
| name            = Dentatorubral–pallidoluysian atrophy
| synonyms        =
| synonyms        = Haw River syndrome, Naito–Oyanagi disease
| image          = Autosomal dominant - en.svg
| image          = Autosomal dominant - en.svg
| caption        = Dentatorubral–pallidoluysian atrophy is inherited in an autosomal dominant manner.
| caption        = DRPLA is inherited in an [[autosomal dominant]] manner.
| pronounce      =
| field          = [[Neurology]], [[Genetics]]
| field          =
| symptoms        = [[Ataxia]], [[choreoathetosis]], [[myoclonus]], [[seizures]], [[dementia]]
| symptoms        =
| complications  = Progressive neurodegeneration, [[epilepsy]], loss of mobility
| complications  =
| onset          = Childhood or adulthood (varies by CAG repeat length)
| onset          =
| duration        = Lifelong
| duration        =
| types          = Juvenile-onset, early adult-onset, late adult-onset
| types          =
| causes          = Mutation in the [[ATN1]] gene
| causes          =
| risks          = [[Family history]] of DRPLA
| risks          =
| diagnosis      = [[Genetic testing]], [[neuroimaging]], clinical evaluation
| diagnosis      =
| differential    = [[Huntington's disease]], [[spinocerebellar ataxia]], [[Lafora disease]], [[sialidosis]]
| differential    =
| prevention      = None
| prevention      =
| treatment      = Symptomatic management
| treatment      =
| medication      = [[Anticonvulsants]], [[psychotropic medications]]
| medication      =
| prognosis      = Progressive and variable
| prognosis      =
| frequency      = Rare, more common in Japan
| frequency      =
| deaths          = Progressive neurodegeneration may lead to early death
| deaths          =
}}
}}
'''Dentatorubral–pallidoluysian atrophy (DRPLA)''' is an [[autosomal dominant]] spinocerebellar degeneration caused by an expansion of a CAG repeat encoding a [[polyglutamine tract]] in the [[ATN1|atrophin-1]] protein.<ref>{{cite journal |author=Kanazawa I |title=Molecular pathology of dentatorubral–pallidoluysian atrophy |journal=Philos. Trans. R. Soc. Lond. B Biol. Sci. |volume=354 |issue=1386 |pages=1069–74 |date=June 1999 |pmid=10434307 |pmc=1692599 |doi=10.1098/rstb.1999.0460 }}</ref> It is also known as '''Haw River Syndrome''' and '''Naito–Oyanagi disease'''. Although this condition was perhaps first described by Smith et al. in 1958, and several sporadic cases have been reported from Western countries, this disorder seems to be very rare except in Japan.
'''Dentatorubral–pallidoluysian atrophy (DRPLA)''' is a rare [[neurodegenerative disorder]] inherited in an [[autosomal dominant]] pattern. It is caused by a [[trinucleotide repeat disorder|CAG repeat expansion]] in the [[ATN1]] gene, which encodes the protein [[atrophin-1]]. The condition leads to progressive [[spinocerebellar degeneration]] and affects various parts of the [[central nervous system]], including the [[dentate nucleus]], [[red nucleus]], [[globus pallidus]], and [[subthalamic nucleus]].


There are at least eight neurodegenerative diseases that are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches (see: [[Trinucleotide repeat disorder]]). The expanded CAG repeats create an adverse gain-of-function mutation in the gene products. Of these diseases, DRPLA is most similar to [[Huntington's disease]].
DRPLA is also known as '''Haw River syndrome''' or '''Naito–Oyanagi disease'''. It is most commonly found in individuals of Japanese descent but has been reported in other populations.


==Signs and symptoms==
== Clinical presentation ==
DRPLA can be juvenile-onset (<20 years), early adult-onset (20–40 years), or late adult-onset (>40 years). Late adult-onset DRPLA is characterized by [[ataxia]], [[choreoathetosis]] and [[dementia]]. Early adult-onset DRPLA also includes [[seizures]] and [[myoclonus]]. Juvenile-onset DRPLA presents with ataxia and symptoms consistent with [[progressive myoclonus epilepsy]] <ref name=Tsuji1999>{{
DRPLA has variable onset, categorized into three types:
cite journal
|author    = Tsuji, S.
|year      = 1999
|title      = Dentatorubral–pallidoluysian atrophy: Clinical features and molecular genetics
|journal    = Adv Neurol
|volume    = 79
|pages      = 399–409
|pmid      = 10514829
}}</ref>
(myoclonus, multiple seizure types and dementia). Other symptoms that have been described include cervical [[dystonia]],<ref name=Hatano2003>{{
cite journal
|author    = Hatano, T.
|year      = 2003
|title      = Cervical dystonia in dentatorubral–pallidoluysian atrophy
|journal    = Acta Neurol Scand
|volume    = 108
|pages      = 287–9
|pmid      = 12956864
|doi    = 10.1034/j.1600-0404.2003.00150.x
|issue    = 4 
|display-authors=etal}}</ref> corneal endothelial degeneration<ref name=Ito2002>{{
cite journal
|author    = Ito, D.
|year      = 2002
|title      = Corneal endothelial degeneration in dentatorubral–pallidoluysian atrophy
|journal    = Arch Neurol
|volume    = 59
|pages      = 289–91
|pmid      = 11843701
|doi    = 10.1001/archneur.59.2.289
|issue    = 2
|display-authors=etal|doi-access= free
}}</ref> [[autism]], and surgery-resistant [[obstructive sleep apnea]].<ref name=Licht2002>{{
cite journal
|vauthors=Licht D, Lynch D
|year      = 2002
|title      = Juvenile Dentatorubral–Pallidoluysian Atrophy: New Clinical Features
|journal    = Pediatr Neurol
|volume    = 26
|pages      = 51–4
|pmid      = 11814736
|doi    = 10.1016/S0887-8994(01)00346-0
|issue    = 1
}}</ref>


==Genetics==
* '''Juvenile-onset''' (before age 20): Presents with [[myoclonus]], [[epilepsy]], [[ataxia]], and [[cognitive decline]] resembling [[progressive myoclonus epilepsy]].
The [[human genome]] contains two atrophin genes; DRPLA has been correlated to the expansion of the polyglutamine region of the [[ATN1|atrophin-1]] gene on chromosome 12p13.3.<ref name=Yazawa1995>{{
* '''Early adult-onset''' (age 20–40): Characterized by [[ataxia]], [[seizures]], and [[dementia]].
cite journal
* '''Late adult-onset''' (after age 40): Symptoms include [[choreoathetosis]], [[ataxia]], and [[cognitive impairment]].
|author    = Yazawa, I
|year      = 1995
|title      = Abnormal Gene Product Identified in Hereditary DRPLA Brain
|journal    = Nat Genet
|volume    = 10
|issue      = 1
|pages      = 99–103
|pmid      = 7647802
|doi    = 10.1038/ng0595-99
|display-authors=etal}}</ref> A normal number of CAG repeats in the [[ATN1|atrophin-1]] gene is 7–34, affected individuals display 49–93 repeats. DRPLA displays [[anticipation (genetics)|anticipation]] (earlier age of onset for subsequent generations) and an inverse correlation between the size of the expanded CAG repeat and the age of symptom onset. Paternal transmission results in more prominent anticipation (26–29 years) than maternal transmission (14–15 years).<ref name=Tsuji1999/>


===Atrophin-1===
Additional features may include [[dystonia]], [[sleep apnea]], [[autism spectrum disorders]], and [[corneal degeneration]].
Atrophin-1 (ATN1) encodes a hydrophilic 1184 amino acid protein with several repetitive motifs including a serine-rich region, a variable length polyglutamine tract, a polyproline tract, and a region of alternating acidic and basic residues. It contains a putative [[nuclear localization signal]] in the [[N-terminus]] of the protein and a putative [[nuclear export signal]] in the [[C-terminus]].<ref name=Nucifora2003>{{
cite journal
|author    = Nucifora, F
|year      = 2003
|title      = Nuclear localization of a Non-caspase Truncation Product of Atrophin-1, with an Expanded Polyglutamine Repeat, Increases Cellular Toxicity
|journal    = J Biol Chem
|volume    = 278
|issue      = 15
|pages      = 13047–55
|pmid      = 12464607
|doi    = 10.1074/jbc.M211224200
|display-authors=etal|doi-access= free
}}</ref> ATN1 is ubiquitously expressed in all tissues, but proteolytically cleaved in neuronal cells. The function of [[ATN1]] is not clear, however it is believed to be a transcriptional co-repressor. [[ATN1]] and atrophin-2 can be co-immunoprecipitated, indicating that they may carry out some functions together in a molecular complex.<ref name=Zoltewicz2004>{{
cite journal
|author    = Zoltewicz, J
|year      = 2004
|title      = Atrophin-2 recruits histone deacetylase and is required for the function of multiple signaling centers during mouse embryogenesis
|journal    = Development
|volume    = 131
|issue      = 1
|pages      = 3–14
|pmid      = 14645126
|doi    = 10.1242/dev.00908
|display-authors=etal|doi-access= free
}}</ref> Atrophin-1 may be a dispensable or redundant protein as mice bred with a [[null allele]] for [[ATN1|atrophin-1]] produce viable and fertile offspring and show no compensatory upregulation of atrophin-2.<ref name=Shen2007>{{
cite journal
|author    = Shen, Y
|year      = 2007
|title      = Functional Architecture of Atrophins
|journal    = J Biol Chem
|volume    = 282
|issue      = 7
|pages      = 5037–44
|pmid      = 17150957
|doi    = 10.1074/jbc.M610274200
|display-authors=etal|doi-access= free
}}</ref>


===Transgenic mouse models===
== Genetics ==
Mouse models of DRPLA have been successfully generated, which demonstrate the same intergenerational instability and severe [[phenotype]] as human DRPLA.<ref name=Sato1999>{{
The disorder is caused by a pathogenic expansion of the CAG trinucleotide repeat in the [[ATN1]] gene on [[chromosome 12]]. Normal individuals have fewer than 35 repeats; those with DRPLA typically have more than 49. The expansion leads to an abnormally long [[polyglutamine tract]] in the [[atrophin-1]] protein.
cite journal
|author    = Sato, T
|year      = 1999
|title      = Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients
|journal    = Hum Mol Genet
|volume    = 8
|pages      = 99–106
|pmid      = 9887337
|doi    = 10.1093/hmg/8.1.99
|issue    = 1
|display-authors=etal|doi-access= free
}}</ref><ref name=Sato2>{{
cite journal
|author    = Sato, T
|year      = 1999
|title      = Transgenic mice harboring a full-length human DRPLA gene with highly expanded CAG repeats exhibit severe disease phenotype
|journal    = Am J Hum Genet
|volume    = 65
|issue      = suppl
|pages      = A30
|display-authors=etal}}</ref><ref name=schilling>{{
cite journal
|author    = Schilling, G
|year      = 1999
|title      = Nuclear accumulation of truncated atrophin-1 fragments in a transgenic mouse model of DRPLA
|journal    = Neuron
|volume    = 24
|pages      = 275–86
|doi    = 10.1016/S0896-6273(00)80839-9
|pmid    = 10677044
|issue    = 1
|display-authors=etal}}</ref> The Schilling mice express full-length human atrophin-1 with 65 CAG repeats under transcriptional control of the mouse prion protein promoter. The mice demonstrated progressive ataxia, tremors, abnormal movements, seizures and premature death. Like in human brains, nuclear accumulation was demonstrated and occasional NIIs were visualised, but the NIIs did not stain for ubiquitin and no neuronal loss was seen.<ref name=Yamada2008/> The Sato mice harbored a single copy of full-length human atrophin-1 with 76 or 129 CAG repeats. The hemizygous transgenic offspring of the Q129 mice exhibited symptoms similar to juvenile-type DRPLA, such as myoclonus and seizures. Again, neuronal atrophy was noted, but no neuronal loss (until death). Diffuse accumulation in the nuclei began on post-natal day 4 and ubiquitinated NII formation was detectable at 9 weeks of age. No PML bodies were found to be associated with the NIIs, which were morphologically mildly altered from those seen in human neural cells.<ref name=Yamada2008>{{
cite journal
|author    = Yamada, M
|year      = 2008
|title      = CAG repeat disorder models and human neuropathology: similarities and differences
|journal    = Acta Neuropathol
|volume    = 115
|pages      = 71–86
|pmid      = 17786457
|doi    = 10.1007/s00401-007-0287-5
|issue    = 1
|display-authors=etal}}</ref><ref name=Sakai2006>{{
cite journal
|author    = Sakai, K
|year      = 2006
|title      = Neuronal Atrophy and Synaptic Alteration in a Mouse Model of Dentatorubral–pallidoluysian Atrophy
|journal    = Brain
|volume    = 129
|pages      = 2353–62
|pmid      = 16891319
|doi    = 10.1093/brain/awl182
|issue    = Pt 9
|display-authors=etal|url= https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=38500&item_no=1&attribute_id=26&file_no=1
|doi-access= free
}}</ref>


==Pathology==
DRPLA shows [[genetic anticipation]], where symptoms appear earlier and more severely in subsequent generations, particularly with paternal transmission.
DRPLA is characterized by marked, generalized brain atrophy and the accumulation of [[ATN1|atrophin-1]] with expanded [[glutamine]] stretches. Mutant [[ATN1|atrophin-1]] proteins have been found in neuronal intranuclear inclusions (NII) and diffusely accumulated in the neuronal nuclei. While the role of NIIs (pathologic or protective) is unclear, the diffuse accumulation of mutant protein is regarded as toxic.


===Brain atrophy===
== Pathophysiology ==
There is significant reduction in CNS tissue throughout the brain and [[spinal cord]], with brain weights of DRPLA patients often becoming less than 1000g.<ref name=Naito1982>{{
The mutant atrophin-1 protein accumulates in [[neuronal nuclei]] and forms [[neuronal intranuclear inclusions]] (NIIs), which are associated with neurotoxicity. The inclusions are found throughout the brain, especially in the [[basal ganglia]], [[cerebellum]], and [[brainstem]]. The disease is marked by progressive [[brain atrophy]] and loss of [[neuronal function]].
cite journal
|vauthors=Naito H, Oyanagi S
|year      = 1982
|title      = Familial myoclonus epilepsy and choreoathetosis: hereditary dentatorubral–pallidoluysian atrophy
|journal    = Neurology
|volume    = 32
|issue      = 8
|pages      = 798–807
|pmid      = 6808417
|doi=10.1212/wnl.32.8.798
}}</ref> In regions lacking obvious neuronal depletion, atrophy of the [[neuropil]] is noted. The [[globus pallidus]] (lateral greater than medial segment) and [[subthalamic nucleus]] demonstrate consistent neuronal loss and astrocytic [[gliosis]]. The [[dentate nucleus]] shows neuronal loss with the remaining atrophic neurons exhibiting grumose degeneration. In general, the pallidoluysian degeneration is more severe than the dentatorubral degeneration in juvenile-onset and the reverse is true for the late adult-onset.<ref name=Yamada2008/>


[[Transgenic]] DRPLA mice demonstrated several neuronal abnormalities including a reduction in the number and size of [[dendritic spine]]s as well as in the area of [[perikarya]] and diameter of [[dendrites]].<ref name=Sakai2006/> Spine morphology and density have been linked to learning and memory functions as well as [[epilepsy]]. The stubby-type spines seen in DRPLA mice are morphologically different from the thin and mushroom-type spines seen in [[Huntington's disease|Huntington’s]] mice.
== Diagnosis ==
Diagnosis is based on:


Morphometric analysis of DRPLA mouse brains has shown a loss of normal inter-microtubule spacing in neuronal axons. The [[microtubules]] were relatively compacted, suggesting abnormalities in protein transport may play a role in neuronal degeneration.<ref name=Sakai2006/> In humans, [[ATN1|atrophin-1]] interacts with IRSp53, which interacts with [[Rho family of GTPases|Rho GTPases]] to regulate the organization of the actin [[cytoskeleton]] and the pathways that regulate [[lamellipodia]] and [[filopodia]].<ref name=Mackie2005>{{
* Family history and clinical symptoms
cite journal
* [[Genetic testing]] to confirm CAG repeat expansion in [[ATN1]]
|vauthors=Mackie S, Aitken A
* [[MRI]] to detect [[cerebral atrophy]]
|year      = 2005
* [[EEG]] to assess seizure activity
|title      = Novel brain 14-3-3 interacting proteins involved in neurodegenerative disease
* Neuropsychological testing for [[cognitive decline]]
|journal    = FEBS
|volume    = 272
|issue      = 16
|pages      = 4202–10
|pmid      = 16098201
|doi    = 10.1111/j.1742-4658.2005.04832.x
}}</ref>


===Neuronal intranuclear inclusions===
== Differential diagnosis ==
NIIs are not exclusive to DRPLA; they have been found in a variety of neurodegenerative disorders. In DRPLA, NIIs have been demonstrated in both neurons and [[glial cell]]s in the [[striatum]], [[pontine nuclei]], [[inferior olive]], [[cerebellar cortex]] and [[dentate nucleus]],<ref name=Hayashi1998>{{
Conditions that may mimic DRPLA include:
cite journal
|author    = Hayashi, Y
|year      = 1998
|title      = Hereditary dentatorubral–pallidoluysian atrophy: Detection of widespread ubiquitinated neuronal and glial intranuclear inclusions in the brain
|journal    = Acta Neuropathol
|volume    = 96
|issue      = 6
|pages      = 547–52
|pmid      = 9845282
|doi    = 10.1007/s004010050933
|display-authors=etal}}</ref> though the incidence of neurons with NIIs is low, roughly 1-3%.<ref name=Yamada2008/>


In DRPLA, the NIIs are spherical, [[eosinophilic]] structures of various sizes. They are non-membrane-bound and are composed of both granular and filamentous structures. They are ubiquitinated and may be paired or in doublet form within the nucleus.<ref name=Yamada2001>{{
* [[Huntington's disease]]
cite journal
* [[Spinocerebellar ataxias]]
|author    = Yamada, M
* [[Lafora disease]]
|year      = 2001
* [[Neuronal ceroid lipofuscinosis]]
|title      = Interaction between Neuronal Intranuclear Inclusions and Promyelocytic Leukemia Protein Nuclear and Coiled Bodies in CAG Repeat Diseases
* [[Sialidosis]]
|journal    = Am J Pathol
* [[Unverricht–Lundborg disease]]
|volume    = 159
|issue      = 5
|pages      = 1785–95
|pmid      = 11696439
|pmc    = 1867069
|doi    = 10.1016/S0002-9440(10)63025-8
|display-authors=etal}}</ref>


NIIs are immunopositive for several [[transcription factors]] such as [[TATA binding protein]] (TBP), TBP-associated factor (TAF<sub>II</sub>130), [[Sp1 transcription factor|Sp1]], camp-responsive element-binding protein ([[CREB]]) and CREB-binding protein (CBP).<ref name=Yamada2001p2>{{
== Management ==
cite journal
There is no cure for DRPLA. Management includes:
|author    = Yamada, M
|year      = 2001
|title      = Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with dentatorubral–pallidoluysian atrophy
|journal    = Ann Neurol
|volume    = 49
|issue      = 1
|pages      = 14–23
|pmid      = 11198291
|doi    = 10.1002/1531-8249(200101)49:1<14::AID-ANA5>3.0.CO;2-X
|display-authors=etal}}</ref><ref name=Shimohata2000>{{
cite journal
|author    = Shimohata, T
|year      = 2000
|title      = Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription
|journal    = Nat Genet
|volume    = 26
|issue      = 1
|pages      = 29–36
|pmid      = 10973244
|doi    = 10.1038/79139
|display-authors=etal}}</ref> It has been proposed that recruitment of [[transcription factors]] into NIIs may induce transcriptional abnormalities that contribute to progressive neuronal degeneration.<ref name=Yamada2008/> Other [[trinucleotide repeat disorders|polyQ]] disorders, such as [[Huntington's disease|Huntington’s]] and [[spinocerebellar ataxia]] (types 3 and 7), have been demonstrated to sequester some of the same transcriptions factors. That different gene products sequester the same transcription factors may contribute to the overlapping symptoms of genetically different diseases.<ref name=Woulfe2007>{{
cite journal
|author    = Woulfe, JM
|year      = 2007
|title      = Abnormalities of the nucleus and nuclear inclusions in neurodegenerative disease: a work in progress
|journal    = Neuropathol Appl Neurobiol
|volume    = 33
|issue      = 1
|pages      = 2–42
|pmid      = 17239006
|doi    = 10.1111/j.1365-2990.2006.00819.x
}}</ref>


NIIs have also been demonstrated to alter the distribution of the intranuclear structures, such as [[promyelocytic leukemia protein]] (PML) nuclear bodies. Although the role of PML bodies is unclear, they are believed to be involved in [[apoptosis]]. In neurons with NII, PML bodies in DRPLA patients form a shell or ring around the ubiquitinated core.<ref name=Yamada2008/><ref name=Woulfe2007/> In similar polyQ diseases, the association of this PML shell has been shown to be size-dependent with larger NIIs being PML negative.<ref name=Takahashi2006>{{
* [[Anticonvulsants]] for seizure control
cite journal
* [[Psychotropic drugs]] for mood or psychotic symptoms
|author    = Takahashi-Fujigasaki, J
* [[Physical therapy]] and [[occupational therapy]]
|year      = 2006
* Supportive care for mobility and [[activities of daily living]]
|title      = SUMOylation substrates in neuronal intranuclear inclusion disease
|journal    = Neuropathol Appl Neurobiol
|volume    = 32
|issue      = 1
|pages      = 92–100
|pmid      = 16409557
|doi    = 10.1111/j.1365-2990.2005.00705.x
|display-authors=etal}}</ref><ref name=Takahashi2002>{{
cite journal
|author    = Takahashi, J
|year      = 2002
|title      = Two populations of neuronal intranuclear inclusions in SCA7 differ in size and promyelocytic leukaemia protein content
|journal    = Brain
|volume    = 125
|issue      = 7
|pages      = 1534–43
|pmid      = 12077003
|doi    = 10.1093/brain/awf154
|display-authors=etal|doi-access= free
}}</ref> This has led to two models, one in which PML bodies represent sites for NII formation and a second in which PML bodies are involved in degradation and proteolysis of NIIs.<ref name=Woulfe2007/>


Filementous, [[ATN1|atrophin-1]] positive, inclusions are also observed exclusively in the [[cytoplasm]] of the [[dentate nucleus]], which are extremely similar to the inclusions observed in the [[motor neuron]]s in [[amyotrophic lateral sclerosis]].<ref name=Yamada2000>{{
== Prognosis ==
cite journal
DRPLA is progressive and leads to increasing neurological impairment. The rate of progression varies by age of onset and size of the CAG repeat expansion. Juvenile-onset cases generally have a more rapid and severe course.
|author    = Yamada, M
|year      = 2000
|title      = Ubiquitinated filamentous inclusions in cerebellar dentate nucleus neurons in dentatorubral–pallidoluysian atrophy contain expanded polyglutamine stretches
|journal    = Acta Neuropathol
|volume    = 99
|issue      = 6
|pages      = 615–8
|pmid      = 10867794
|doi    = 10.1007/s004010051171
|display-authors=etal}}</ref>


===Diffuse accumulation in the nuclei===
== Epidemiology ==
In DRPLA, diffuse accumulation of mutant [[ATN1]] occurs far more extensively than NII formation. The extent and frequency of neurons showing the diffuse nuclear accumulations changes depending on CAG repeat length. It is believed that the diffuse nuclear accumulations contribute to the clinical features such as [[dementia]] and [[epilepsy]].
DRPLA is rare worldwide but more prevalent in [[Japan]], with an estimated frequency of 2–7 per million people. The disorder is much less common in Western populations.


ATN1 contains both a nuclear localization sequence and a nuclear export sequence. Cleavage of ATN1 to an N terminal fragment relieves ATN1 of its nuclear export signal and concentrates it in the nucleus. Increased nuclear concentrations have been demonstrated via transfection assay to enhance cellular toxicity.<ref name=Nucifora2003/>
== Related topics ==
 
* [[Trinucleotide repeat disorder]]
In both the juvenile and adult forms, regions in which more than 40% of neurons became immunoreactive to 1C2 (a [[Monoclonal antibodies|monoclonal antibody]] against expanded polyglutamine stretches) included: the nucleus basalis of Meynert, large striatal neurons, [[globus pallidus]], [[subthalamic nucleus]], thalamic [[intralaminar nucleus]], [[lateral geniculate body]], [[oculomotor nucleus]], [[red nucleus]], [[substantia nigra]], [[trigeminal motor nucleus]], [[nucleus raphes pontis]], [[pontine nuclei]], [[vestibular nucleus]], [[inferior olive]] and the cerebellar [[dentate nucleus]]. The juvenile type also shows reactivity in the [[cerebral cortex]], [[hippocampal]] CA1 area, and the [[reticular formation]] of the brainstem.<ref name=Yamada2008/> Nuclei containing accumulations of mutant [[ATN1|atrophin-1]] are deformed with nuclear membrane indentations.<ref name=Takahashi2001>{{
* [[Huntington's disease]]
cite journal
* [[Spinocerebellar ataxia]]
|author    = Takahashi, J
* [[Neurodegeneration]]
|year      = 2001
* [[Ataxia]]
|title      = Neuronal nuclear alterations in dentatorubral–pallidoluysian atrophy: ultrastructural and morphometric studies of the cerebellar granule cells
* [[Epilepsy]]
|journal    = Brain Res
|volume    = 919
|issue      = 1
|pages      = 12–9
|pmid      = 11689158
|doi    = 10.1016/S0006-8993(01)02986-9
|display-authors=etal}}</ref>
 
==Diagnosis==
Diagnosis of DRPLA rests on positive family history, clinical findings, and [[genetic testing]]. Family history can be difficult to obtain if a relative was misdiagnosed, died young, or experiences late onset of symptoms.
 
Other diseases in the [[differential diagnosis]] of adult-onset DRPLA include [[Huntington's disease|Huntington's]] and the [[spinocerebellar ataxias]]. For juvenile-onset disease, familial essential myoclonus and epilepsy (FEME), [[Lafora disease|Lafora]], [[Unverricht-Lundborg disease|Unverricht-Lundborg]], Neuroaxonal dystrophy, [[Gaucher's disease]], [[Sialidosis]], and Galactosialidosis should be considered.
 
==Management==
To quantify the extent of the disease, an [[MRI]], [[EEG]] and neuropsychological testing are recommended. Seizures are treated with anticonvulsants and psychiatric disturbances with psychotropic medications. Physical therapy has also been recommended to maintain function as the condition progresses and occupational therapy to focus on activities of daily living, advice for carers and adaptation to the environment.
 
==Epidemiology==
The prevalence of DRPLA in the Japanese population is believed to be 2–7 in 1,000,000. DRPLA is observed relatively less frequently in other ethnic populations and an analysis of normal [[ATN1]] alleles has demonstrated that CAG repeat length greater than 17 are significantly more frequent in the Japanese population.<ref name=Burke1994>{{
cite journal
|author    = Burke, JR
|year      = 1994
|title      = Dentatorubral–pallidoluysian atrophy and Haw River Syndrome
|journal    = Lancet
|volume    = 344
|issue      = 8938
|pages      = 1711–2
|pmid      = 7996992
|doi    = 10.1016/S0140-6736(94)90497-9
|display-authors=etal}}</ref><ref name=Takano1998>{{
cite journal
|author    = Takano, H
|year      = 1998
|title      = Close associations between prevalences of dominantly inherited spinocerebellar ataxias with CAG-repeat expansions and frequencies of large normal CAG alleles in Japanese and Caucasian populations
|journal    = Am J Hum Genet
|volume    = 63
|issue      = 4
|pages      = 1060–6
|pmid      = 9758625
|doi    = 10.1086/302067
|pmc    = 1377499
|display-authors=etal}}</ref>
 
==References==
{{Reflist}}
== External links ==
{{Medical resources
|  DiseasesDB      = 32909 
|  OMIM            = 125370 
|  MeshID          = D020191
|  GeneReviewsNBK  = 1491
|  GeneReviewsName = DRPLA
}}
{{Seizures and epilepsy}}
{{Seizures and epilepsy}}
{{Trinucleotide repeat disorders}}
{{Trinucleotide repeat disorders}}
{{DEFAULTSORT:Dentatorubral-pallidoluysian atrophy}}
{{DEFAULTSORT:Dentatorubral-pallidoluysian atrophy}}
[[Category:Central nervous system disorders]]
[[Category:Central nervous system disorders]]
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[[Category:Neurogenetic disorders]]
[[Category:Neurogenetic disorders]]
[[Category:Trinucleotide repeat disorders]]
[[Category:Trinucleotide repeat disorders]]
{{dictionary-stub1}}
<gallery>
File:Autosomal_dominant_-_en.svg
</gallery>

Latest revision as of 23:52, 26 March 2025


Congenital neurodegenerative disorder


Dentatorubral–pallidoluysian atrophy
Synonyms Haw River syndrome, Naito–Oyanagi disease
Pronounce N/A
Field Neurology, Genetics
Symptoms Ataxia, choreoathetosis, myoclonus, seizures, dementia
Complications Progressive neurodegeneration, epilepsy, loss of mobility
Onset Childhood or adulthood (varies by CAG repeat length)
Duration Lifelong
Types Juvenile-onset, early adult-onset, late adult-onset
Causes Mutation in the ATN1 gene
Risks Family history of DRPLA
Diagnosis Genetic testing, neuroimaging, clinical evaluation
Differential diagnosis Huntington's disease, spinocerebellar ataxia, Lafora disease, sialidosis
Prevention None
Treatment Symptomatic management
Medication Anticonvulsants, psychotropic medications
Prognosis Progressive and variable
Frequency Rare, more common in Japan
Deaths Progressive neurodegeneration may lead to early death


Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder inherited in an autosomal dominant pattern. It is caused by a CAG repeat expansion in the ATN1 gene, which encodes the protein atrophin-1. The condition leads to progressive spinocerebellar degeneration and affects various parts of the central nervous system, including the dentate nucleus, red nucleus, globus pallidus, and subthalamic nucleus.

DRPLA is also known as Haw River syndrome or Naito–Oyanagi disease. It is most commonly found in individuals of Japanese descent but has been reported in other populations.

Clinical presentation[edit]

DRPLA has variable onset, categorized into three types:

Additional features may include dystonia, sleep apnea, autism spectrum disorders, and corneal degeneration.

Genetics[edit]

The disorder is caused by a pathogenic expansion of the CAG trinucleotide repeat in the ATN1 gene on chromosome 12. Normal individuals have fewer than 35 repeats; those with DRPLA typically have more than 49. The expansion leads to an abnormally long polyglutamine tract in the atrophin-1 protein.

DRPLA shows genetic anticipation, where symptoms appear earlier and more severely in subsequent generations, particularly with paternal transmission.

Pathophysiology[edit]

The mutant atrophin-1 protein accumulates in neuronal nuclei and forms neuronal intranuclear inclusions (NIIs), which are associated with neurotoxicity. The inclusions are found throughout the brain, especially in the basal ganglia, cerebellum, and brainstem. The disease is marked by progressive brain atrophy and loss of neuronal function.

Diagnosis[edit]

Diagnosis is based on:

Differential diagnosis[edit]

Conditions that may mimic DRPLA include:

Management[edit]

There is no cure for DRPLA. Management includes:

Prognosis[edit]

DRPLA is progressive and leads to increasing neurological impairment. The rate of progression varies by age of onset and size of the CAG repeat expansion. Juvenile-onset cases generally have a more rapid and severe course.

Epidemiology[edit]

DRPLA is rare worldwide but more prevalent in Japan, with an estimated frequency of 2–7 per million people. The disorder is much less common in Western populations.

Related topics[edit]

Seizures and epilepsy
Basics
Management
Personal issues
Seizure types
Related disorders


Non-Mendelian inheritance: anticipation
Trinucleotide
Tetranucleotide
Pentanucleotide
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