Dentatorubral–pallidoluysian atrophy

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Dentatorubral–pallidoluysian atrophy
Dentatorubral–pallidoluysian atrophy is inherited in an autosomal dominant manner.
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Dentatorubral–pallidoluysian atrophy (DRPLA) is an

atrophin-1 protein.[1] 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.[citation needed
]

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.[citation needed]

Signs and 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

seizures and myoclonus. Juvenile-onset DRPLA presents with ataxia and symptoms consistent with progressive myoclonus epilepsy[2]
(myoclonus, multiple seizure types and dementia). Other symptoms that have been described include cervical
autism, and surgery-resistant obstructive sleep apnea.[5]

Genetics

The

atrophin-1 gene is 7–34, affected individuals display 49–93 repeats. DRPLA displays 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).[2]

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

atrophin-1 produce viable and fertile offspring and show no compensatory upregulation of atrophin-2.[9]

Transgenic mouse models

Mouse models of DRPLA have been successfully generated, which demonstrate the same intergenerational instability and severe phenotype as human DRPLA.[10][11][12] 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.[13] 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.[13][14]

Pathology

DRPLA is characterized by marked, generalized brain atrophy and the accumulation of

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.[citation needed
]

Brain atrophy

There is significant reduction in CNS tissue throughout the brain and spinal cord, with brain weights of DRPLA patients often becoming less than 1000g.[15] 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.[13]

dendrites.[14] 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.[citation needed
]

Morphometric analysis of DRPLA mouse brains has shown a loss of normal inter-microtubule spacing in neuronal axons. The

lamellipodia and filopodia.[16]

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

cerebellar cortex and dentate nucleus,[17] though the incidence of neurons with NIIs is low, roughly 1-3%.[13]

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.[18]

NIIs are immunopositive for several

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.[21]

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.[13][21] In similar polyQ diseases, the association of this PML shell has been shown to be size-dependent with larger NIIs being PML negative.[22][23] 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.[21]

Filementous,

amyotrophic lateral sclerosis.[24]

Diffuse accumulation in the nuclei

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.[citation needed
]

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.[7]

In both the juvenile and adult forms, regions in which more than 40% of neurons became immunoreactive to 1C2 (a

atrophin-1 are deformed with nuclear membrane indentations.[25]

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.[citation needed]

Other diseases in the

Unverricht-Lundborg, Neuroaxonal dystrophy, Gaucher's disease, Sialidosis, and Galactosialidosis should be considered.[citation needed
]

Management

To quantify the extent of the disease, an

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 careers and adaptation to the environment.[citation needed
]

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 lengths greater than 17 are significantly more frequent in the Japanese population.[26][27]

References

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  10. PMID 9887337
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  11. ^ Sato, T; et al. (1999). "Transgenic mice harboring a full-length human DRPLA gene with highly expanded CAG repeats exhibit severe disease phenotype". Am J Hum Genet. 65 (suppl): A30.
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External links
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