Dentatorubral-pallidoluysian atrophy
Encyclopedia
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar degeneration caused by an expansion of a CAG repeat encoding a polyglutamine tract
in the atrophin-1
protein. 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.
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
.
, 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
(myoclonus, multiple seizure types and dementia). Other symptoms that have been described include cervical dystonia
, corneal endothelial degeneration autism
, and surgery-resistant obstructive sleep apnea
.
contains two atrophin genes; DRPLA has been correlated to the expansion of the polyglutamine region of the atrophin-1
gene on chromosome 12p13.3. A normal number of CAG repeats in the atrophin-1
gene is 7-34, affected individuals display 49-93 repeats. DRPLA displays anticipation
, 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 to 15 years).
in the N-terminus of the protein and a putative nuclear export signal
in the C-terminus. 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. Atrophin-1 may be a dispensable or redundant protein as mice bred with a null allele
for atrophin-1
produce viable and fertile offspring and show no compensatory upregulation of atrophin-2.
as human DRPLA. 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. 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.
with expanded glutamine
stretches. Mutant 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.
, with brain weights of DRPLA patients often becoming less than 1000g. 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.
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. 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
mice.
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. In humans, atrophin-1
interacts with IRSp53, which interacts with Rho GTPases
to regulate the organization of the actin cytoskeleton
and the pathways that regulate lamellipodia
and filopodia
.
s in the striatum
, pontine nuclei
, inferior olive, cerebellar cortex and dentate nucleus
, though the incidence of neurons with NIIs is low, roughly 1-3%.
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.
NIIs are immunopositive for several transcription factors such as TATA binding protein
(TBP), TBP-associated factor (TAFII130), Sp1, camp-responsive element-binding protein (CREB
) and CREB-binding protein (CBP). It has been proposed that recruitment of transcription factors into NIIs may induce transcriptional abnormalities that contribute to progressive neuronal degeneration. Other polyQ
disorders, such as 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.
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. In similar polyQ diseases, the association of this PML shell has been shown to be size-dependent with larger NIIs being PML negative. 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.
Filementous, 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
.
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
.
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.
In both the juvenile and adult forms, regions in which more than 40% of neurons became immunoreactive to 1C2 (a 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 raphe 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. Nuclei containing accumulations of mutant atrophin-1
are deformed with nuclear membrane indentations.
. 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
and the spinocerebellar ataxias. For juvenile-onset, familial essential myoclonus and epilepsy (FEME), Lafora
, Unverricht-Lundborg
, Neuroaxonal dystrophy, Gaucher's disease
, Sialidosis
, and Galactosialidosis.
and neuropsychological testing are recommended. Seizures are treated with anticonvulsants and psychiatric disturbances with psychotropic medications.
alleles has demonstrated that CAG repeat length greater than 17 are significantly more frequent in the Japanese population.
Polyglutamine tract
A polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units....
in the atrophin-1
ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
protein. 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.
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
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
.
Symptoms
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 ataxiaAtaxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, choreoathetosis
Choreoathetosis
Choreoathetosis is the occurrence of involuntary movements in a combination of chorea and athetosis ....
and dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
. Early adult-onset DRPLA also includes seizures and myoclonus
Myoclonus
Myoclonus is brief, involuntary twitching of a muscle or a group of muscles. It describes a medical sign and, generally, is not a diagnosis of a disease. Brief twitches are perfectly normal. The myoclonic twitches are usually caused by sudden muscle contractions; they also can result from brief...
. Juvenile-onset DRPLA presents with ataxia and symptoms consistent with progressive myoclonus epilepsy
(myoclonus, multiple seizure types and dementia). Other symptoms that have been described include cervical dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
, corneal endothelial degeneration autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
, and surgery-resistant obstructive sleep apnea
Obstructive sleep apnea
Obstructive sleep apnea or obstructive sleep apnea syndrome is the most common type of sleep apnea and is caused by obstruction of the upper airway. It is characterized by repetitive pauses in breathing during sleep, despite the effort to breathe, and is usually associated with a reduction in...
.
Genetics
The human genomeHuman genome
The human genome is the genome of Homo sapiens, which is stored on 23 chromosome pairs plus the small mitochondrial DNA. 22 of the 23 chromosomes are autosomal chromosome pairs, while the remaining pair is sex-determining...
contains two atrophin genes; DRPLA has been correlated to the expansion of the polyglutamine region of the atrophin-1
ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
gene on chromosome 12p13.3. A normal number of CAG repeats in the atrophin-1
ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
gene is 7-34, affected individuals display 49-93 repeats. DRPLA displays anticipation
Anticipation (genetics)
In genetics, anticipation is a phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders such as...
, 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 to 15 years).
Atrophin-1
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 signalNuclear localization signal
A nuclear localization signal or sequence is an amino acid sequence which 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different...
in the N-terminus of the protein and a putative nuclear export signal
Nuclear export signal
A nuclear export signal is a short amino acid sequence of 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite effect of a nuclear localization signal, which targets a...
in the C-terminus. ATN1 is ubiquitously expressed in all tissues, but proteolytically cleaved in neuronal cells. The function of ATN1
ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
is not clear, however it is believed to be a transcriptional co-repressor. ATN1
ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
and atrophin-2 can be co-immunoprecipitated, indicating that they may carry out some functions together in a molecular complex. Atrophin-1 may be a dispensable or redundant protein as mice bred with a null allele
Null allele
A null allele is a mutant copy of a gene that completely lacks that gene's normal function. This can be the result of the complete absence of the gene product at the molecular level, or the expression of a non-functional gene product...
for atrophin-1
ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
produce viable and fertile offspring and show no compensatory upregulation of atrophin-2.
Transgenic mouse models
Mouse models of DRPLA have been successfully generated, which demonstrate the same intergenerational instability and severe phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
as human DRPLA. 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. 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.
Pathology
DRPLA is characterized by marked, generalized brain atrophy and the accumulation of atrophin-1ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
with expanded glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
stretches. Mutant atrophin-1
ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
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
There is significant reduction in CNS tissue throughout the brain and spinal cordSpinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, with brain weights of DRPLA patients often becoming less than 1000g. In regions lacking obvious neuronal depletion, atrophy of the neuropil
Neuropil
In neuroanatomy, a neuropil, which is sometimes referred to as a neuropile, is a region between neuronal cell bodies in the gray matter of the brain and blood-brain barrier . It consists of a dense tangle of axon terminals, dendrites and glial cell processes...
is noted. The globus pallidus
Globus pallidus
The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...
(lateral greater than medial segment) and subthalamic nucleus
Subthalamic nucleus
The subthalamic nucleus is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. Anatomically, it is the major part of subthalamus. As suggested by its name, the subthalamic nucleus is located ventral to the thalamus. It is also...
demonstrate consistent neuronal loss and astrocytic gliosis
Gliosis
Gliosis is a proliferation of astrocytes in damaged areas of the central nervous system . This proliferation usually leads to the formation of a glial scar....
. The dentate nucleus
Dentate nucleus
The dentate nucleus is located within the deep white matter of each cerebellar hemisphere, and it is the largest single structure linking the cerebellum to the rest of the brain. It is the largest and most lateral, or farthest from the midline, of the four pairs of deep cerebellar nuclei, the...
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.
Transgenic DRPLA mice demonstrated several neuronal abnormalities including a reduction in the number and size of dendritic spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...
s as well as in the area of perikarya and diameter of dendrites. Spine morphology and density have been linked to learning and memory functions as well as epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. The stubby-type spines seen in DRPLA mice are morphologically different from the thin and mushroom-type spines seen in Huntington’s
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
mice.
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. In humans, atrophin-1
ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
interacts with IRSp53, which interacts with Rho GTPases
Rho family of GTPases
The Rho family of GTPases is a family of small signaling G protein , and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic organisms including yeasts and some plants...
to regulate the organization of the actin cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
and the pathways that regulate lamellipodia
Lamellipodia
The lamellipodium is a cytoskeletal protein actin projection on the mobile edge of the cell. It contains a quasi-two-dimensional actin mesh; the whole structure propels the cell across a substrate...
and filopodia
Filopodia
Filopodia are slender cytoplasmic projections that extend beyond the leading edge of lamellipodia in migrating cells. They contain actin filaments cross-linked into bundles by actin-binding proteins, e.g. fascin and fimbrin. Filopodia form focal adhesions with the substratum, linking it to the...
.
Neuronal intranuclear inclusions
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 cellGlial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
, pontine nuclei
Pontine nuclei
The pontine nuclei are a part of the pons involved in motor activity. Corticopontine fibres carry information from the primary motor cortex to the ipsilateral pontine nucleus in the ventral pons, and the pontocerebellar projection then carries that information to the contralateral cerebellum via...
, inferior olive, cerebellar cortex and dentate nucleus
Dentate nucleus
The dentate nucleus is located within the deep white matter of each cerebellar hemisphere, and it is the largest single structure linking the cerebellum to the rest of the brain. It is the largest and most lateral, or farthest from the midline, of the four pairs of deep cerebellar nuclei, the...
, though the incidence of neurons with NIIs is low, roughly 1-3%.
In DRPLA, the NIIs are spherical, eosinophilic
Eosinophilic
Eosinophilic refers to the staining of certain tissues, cells, or organelles after they have been washed with eosin, a dye.Eosin is an acidic dye; thus, the structure being stained is basic....
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.
NIIs are immunopositive for several transcription factors such as TATA binding protein
TATA Binding Protein
The TATA-binding protein is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 35 base pairs upstream of the transcription start site in some eukaryotic gene promoters...
(TBP), TBP-associated factor (TAFII130), Sp1, camp-responsive element-binding protein (CREB
CREB
CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....
) and CREB-binding protein (CBP). It has been proposed that recruitment of transcription factors into NIIs may induce transcriptional abnormalities that contribute to progressive neuronal degeneration. Other polyQ
Trinucleotide repeat disorders
Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes exceeding the normal, stable, threshold, which differs per gene...
disorders, such as Huntington’s
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
and spinocerebellar ataxia
Spinocerebellar ataxia
Spinocerebellar ataxia is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a disease in its own right.-Classification:...
(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.
NIIs have also been demonstrated to alter the distribution of the intranuclear structures, such as promyelocytic leukemia protein
Promyelocytic leukemia protein
Probable transcription factor PML is a tumor suppressor protein that in humans is encoded by the PML gene.-Interactions:Promyelocytic leukemia protein has been shown to interact with Retinoic acid receptor alpha, HDAC1, Nerve Growth factor IB, SKI protein, Zinc finger and BTB domain-containing...
(PML) nuclear bodies. Although the role of PML bodies is unclear, they are believed to be involved in apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. In neurons with NII, PML bodies in DRPLA patients form a shell or ring around the ubiquitinated core. In similar polyQ diseases, the association of this PML shell has been shown to be size-dependent with larger NIIs being PML negative. 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.
Filementous, atrophin-1
ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
positive, inclusions are also observed exclusively in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
of the dentate nucleus
Dentate nucleus
The dentate nucleus is located within the deep white matter of each cerebellar hemisphere, and it is the largest single structure linking the cerebellum to the rest of the brain. It is the largest and most lateral, or farthest from the midline, of the four pairs of deep cerebellar nuclei, the...
, which are extremely similar to the inclusions observed in the motor neuron
Motor neuron
In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
s in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
.
Diffuse accumulation in the nuclei
In DRPLA, diffuse accumulation of mutant ATN1ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
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
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
and epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
.
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.
In both the juvenile and adult forms, regions in which more than 40% of neurons became immunoreactive to 1C2 (a monoclonal antibody
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
against expanded polyglutamine stretches) included: the nucleus basalis of Meynert, large striatal neurons, globus pallidus
Globus pallidus
The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...
, subthalamic nucleus
Subthalamic nucleus
The subthalamic nucleus is a small lens-shaped nucleus in the brain where it is, from a functional point of view, part of the basal ganglia system. Anatomically, it is the major part of subthalamus. As suggested by its name, the subthalamic nucleus is located ventral to the thalamus. It is also...
, thalamic intralaminar nucleus
Intralaminar nucleus
The intralaminar nucleus is a nucleus of the thalamus that contains the following nuclei:* central lateral* centromedian * paracentral* parafascicular.Some sources also include a "central dorsal" nucleus....
, lateral geniculate body, oculomotor nucleus
Oculomotor nucleus
The fibers of the oculomotor nerve arise from a nucleus in the midbrain, which lies in the gray substance of the floor of the cerebral aqueduct and extends in front of the aqueduct for a short distance into the floor of the third ventricle...
, red nucleus
Red nucleus
The red nucleus is a structure in the rostral midbrain involved in motor coordination. It comprises a caudal magnocellular and a rostral parvocellular part.-Function:...
, substantia nigra
Substantia nigra
The substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
, trigeminal motor nucleus
Trigeminal motor nucleus
The trigeminal motor nucleus contains motor neurons that innervate muscles of the first branchial arch, namely the muscles of mastication, the tensor tympani, tensor veli palatini, mylohyoid, and anterior belly of the digastric.-External links:*...
, nucleus raphe pontis, pontine nuclei
Pontine nuclei
The pontine nuclei are a part of the pons involved in motor activity. Corticopontine fibres carry information from the primary motor cortex to the ipsilateral pontine nucleus in the ventral pons, and the pontocerebellar projection then carries that information to the contralateral cerebellum via...
, vestibular nucleus, inferior olive and the cerebellar dentate nucleus
Dentate nucleus
The dentate nucleus is located within the deep white matter of each cerebellar hemisphere, and it is the largest single structure linking the cerebellum to the rest of the brain. It is the largest and most lateral, or farthest from the midline, of the four pairs of deep cerebellar nuclei, the...
. The juvenile type also shows reactivity in the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
, hippocampal CA1 area, and the reticular formation
Reticular formation
The reticular formation is a part of the brain that is involved in actions such as awaking/sleeping cycle, and filtering incoming stimuli to discriminate irrelevant background stimuli...
of the brainstem. Nuclei containing accumulations of mutant atrophin-1
ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
are deformed with nuclear membrane indentations.
Diagnosis
Diagnosis of DRPLA rests of positive family history, clinical findings, and genetic testingGenetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
. 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
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
of adult-onset DRPLA include Huntington's
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
and the spinocerebellar ataxias. For juvenile-onset, familial essential myoclonus and epilepsy (FEME), Lafora
Lafora disease
Lafora disease, also called Lafora progressive myoclonic epilepsy or MELF , is a fatal autosomal recessive genetic disorder characterized by the presence of inclusion bodies, known as Lafora bodies, within neurons and the cells of the heart, liver, muscle, and skin.Most patients with this disease...
, Unverricht-Lundborg
Unverricht-Lundborg disease
Unverricht-Lundborg disease is the most common form of an uncommon group of genetic epilepsy disorders called progressive myoclonic epilepsy. It is caused due to a mutation in the cystatin B gene...
, Neuroaxonal dystrophy, Gaucher's disease
Gaucher's disease
Gaucher's disease is a genetic disease in which a fatty substance accumulates in cells and certain organs.Gaucher's disease is the most common of the lysosomal storage diseases. It is caused by a hereditary deficiency of the enzyme glucosylceramidase. The enzyme acts on the fatty acid...
, Sialidosis
Sialidosis
Mucolipidosis type I or sialidosis is an inherited lysosomal storage disease that results from a deficiency of the enzyme sialidase. The lack of this enzyme results in an abnormal accumulation of complex carbohydrates known as mucopolysaccharides, and of fatty substances known as mucolipids...
, and Galactosialidosis.
Management
To quantify the extent of the disease, an MRI, EEGEEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
and neuropsychological testing are recommended. Seizures are treated with anticonvulsants and psychiatric disturbances with psychotropic medications.
Epidemiology
The prevalence of DRPLA in the Japanese population is believed to be 0.2-0.7 in 100,000. DRPLA is observed relatively less frequently in other ethnic populations and an analysis of normal ATN1ATN1
ATN1 is a protein found in nervous tissue.It is associated with a form of trinucleotide repeat disorder known as "dentatorubral-pallidoluysian atrophy" or "dentatorubropallidoluysian atrophy".-Interactions:...
alleles has demonstrated that CAG repeat length greater than 17 are significantly more frequent in the Japanese population.