Drpla

Clinical characteristics.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive disorder of ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children and ataxia, choreoathetosis, and dementia or character changes in adults. Onset ranges from before age one year to age 72 years; mean age of onset is 31.5 years. The clinical presentation varies depending on the age of onset. The cardinal features in adults are ataxia, choreoathetosis, and dementia. Cardinal features in children are progressive intellectual deterioration, behavioral changes, myoclonus, and epilepsy.

Diagnosis/testing.

The diagnosis of DRPLA is established in a proband with suggestive clinical findings and a family history of DRPLA or by the identification of a heterozygous pathogenic CAG trinucleotide expansion in ATN1 by molecular genetic testing. The CAG repeat length in individuals with DRPLA ranges from 48 to 93.

Management.

Treatment of manifestations: Standard antiepileptic drugs (AEDs) for seizures; appropriate psychotropic medications for psychiatric manifestations; symptomatic treatment of ataxia with riluzole and rehabilitation therapy; adaptation of environment and care to the level of dementia; appropriate educational programs for children.

Agents/circumstances to avoid. General anesthesia can increase the risk of intra- and postoperative seizures.

Pregnancy management. The use of antiepileptic medication during pregnancy may have an effect on the fetus. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception; transition to a lower-risk medication may be possible. The use of riluzole during pregnancy has not been well studied in humans.

Genetic counseling.

DRPLA is inherited in an autosomal dominant manner. The risk to the offspring of an affected individual of inheriting an expanded CAG repeat is 50%. The size of the repeat transmitted to the offspring depends on the size of the parent's repeat and the gender of the transmitting parent. Prenatal testing for pregnancies at increased risk is possible using molecular genetic testing if the diagnosis in the family has been confirmed.

Suggestive Findings

Dentatorubral-pallidoluysian atrophy (DRPLA) should be suspected in individuals with the following clinical features (by age), brain MRI findings, and family history:

• Clinical features (by age)
  • Age <20 years. Ataxia, myoclonus, seizures, progressive intellectual deterioration
  • Age >20 years. Ataxia, choreoathetosis, dementia, psychiatric disturbance
• Brain MRI findings. Cerebellar and brain stem atrophy [Tsuji 2012]
• Family history. Consistent with autosomal dominant inheritance and Asiatic (mainly Japanese) familial origin

Note: (1) Absence of a family history of DRPLA does not preclude the diagnosis. (2) DRPLA is extremely rare outside of Asiatic populations [Tsuji 2012].

Establishing the Diagnosis

The diagnosis of DRPLA is established in a proband with suggestive clinical findings and a family history of DRPLA or by the identification of a heterozygous pathogenic CAG trinucleotide expansion in ATN1 by molecular genetic testing (see Table 1).

Note: Comprehensive testing strategies for the diagnosis of ataxic disorders can be found in van de Warrenburg et al [2014] and the Hereditary Ataxia Overview.

Allele sizes

• Normal alleles. 6-35 CAG repeats
• Mutable normal alleles. Mutable normal alleles are not associated with symptoms but are unstable and can expand on transmission resulting in occurrence of symptoms in the next generation; this is a very rare event. The normal Japanese population has a greater number of individuals with 20-35 CAG repeats than are found in populations of European origin [Takano et al 1998].
• Full-penetrance alleles. ≥48 CAG repeats. The largest full-penetrance allele reported to date is 93 [Shimojo et al 2001, Maruyama et al 2012].

Molecular testing approaches typically involve targeted testing. Testing is typically performed by PCR amplification of the ATN1 trinucleotide repeat region followed by gel or capillary electrophoresis.

Note: (1) In CAG repeat disorders in general, highly expanded alleles (usually >100 CAG repeats) may not be detectable by the PCR-based assay, and additional testing (e.g., Southern blot analysis or triplet repeat primed [TP] PCR [Warner et al 1996]) is indicated to detect a highly expanded allele in individuals who are apparently homozygotes by PCR analysis. (2) Variants detectable by sequencing analysis have not been associated with DRPLA.

Clinical Description

Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive disorder of ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children and ataxia, choreoathetosis, and dementia or character changes in adults. The onset of DRPLA ranges from infancy to late adulthood (range: 0-72 years; mean: 31.5 years) [Hasegawa et al 2010]. Disease duration is on average eight years (range 0-35 years) and age at death is on average 49 years (range 18-80 years) [Hasegawa et al 2010]. The clinical presentation varies depending on the age of onset. The cardinal features in children are ataxia, intellectual disability, behavioral changes, myoclonus, and epilepsy; cardinal features in adults are ataxia, choreoathetosis, and dementia [Tsuji 2012].

Studies have shown that ataxia and cognitive impairment are cardinal features irrespective of the age of onset [Ikeuchi et al 1995b].

Individuals with onset before age 20 years usually have a progressive myoclonus epilepsy (PME) phenotype characterized by myoclonus, seizures, ataxia, and progressive intellectual deterioration [Naito & Oyanagi 1982, Ikeuchi et al 1995b, Tsuji 2012]. Various forms of generalized seizures (including tonic, atonic, clonic, or tonic-clonic seizures) are also observed [Tsuji 2012].

Seizures are less frequent in individuals with onset between ages 20 and 40 years. Seizures are rare in individuals with onset after age 40 years and a CAG repeat size lower than 65 [Hasegawa et al 2010, Tsuji 2012].

Individuals with onset of DRPLA after age 20 years tend to develop cerebellar ataxia, choreoathetosis, dementia, and psychiatric disturbances (non-PME phenotype). In some individuals, involuntary movements and dementia mask the presence of ataxia. Psychosis may sometimes be a presenting feature [Adachi et al 2001].

Cervical dystonia was the presenting feature in one family [Hatano et al 2003].

Neuroimaging. Atrophic changes in the cerebellum and brain stem, in particular the pontine tegmentum, are the typical MRI findings of DRPLA. Quantitative analyses revealed that both the age at MRI and the size of the expanded CAG repeat correlate with the atrophic changes.

Diffuse high-intensity areas deep in the white matter are often observed on T₂-weighted MRI in individuals with adult-onset DRPLA of long duration [Koide et al 1997].

Using ¹⁸F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET), bistriatal glucose hypometabolism was reported in two affected individuals with preadolescent-onset disease; this was not present in individuals with later-onset disease [Sone et al 2016].

Neuropathology. The major neuropathologic changes are relatively simple and consist of combined degeneration of the dentatorubral and pallidoluysian systems. Cerebral white matter damage, including diffuse myelin pallor, axonal preservation, and reactive astrogliosis with only mild atherosclerotic changes, has been described at autopsy [Muñoz et al 2004]. Histologically, as in other polyglutamine diseases, neurons show intranuclear inclusions [Mori et al 2012a, Mori et al 2012b].

See Molecular Pathogenesis for further information on the pathogenesis of DRPLA.

Genotype-Phenotype Correlations

Heterozygotes. In general, an inverse correlation exists between the age at onset and the size of the expanded ATN1 CAG repeat [Koide et al 1994, Ikeuchi et al 1995b] (see Table 2).

Note: ATN1 CAG repeat ranges overlap and the distinctions are not clearly defined.

Because onset before age 20 years is associated with the progressive myoclonus epilepsy (PME) phenotype and an older age of onset with the non-PME phenotype, the clinical presentation is strongly correlated with the size of expanded CAG repeats. The frequency of signs and symptoms in affected individuals with fewer than 65 CAG repeats and those with 65 or more CAG repeats are summarized in Hasegawa et al [2010].

Severe infantile onset with an allele with an extreme ATN1 CAG expansion of 90-93 CAG repeats [c.1462CAG(90-93)] has been reported [Shimojo et al 2001].

Homozygotes. A single individual who had relatively small biallelic expanded ATN1 CAG repeat alleles is reported to have had symptom onset at 14 years, indicating a possible dosage effect [Sato et al 1995].

Penetrance

Expanded alleles are fully penetrant except for one individual with a mildly expanded number of CAG repeats (51 repeats) who was asmptomatic at age 81 years [Hattori et al 1999].

Anticipation

The marked expansion of the CAG repeat during transmission of pathogenic ATN1 alleles from parent to child results in prominent anticipation. Affected offspring typically have symptoms 26 to 29 years earlier than affected fathers and 14 to 15 years earlier than affected mothers [Koide et al 1994, Nagafuchi et al 1994, Ikeuchi et al 1995a, Ikeuchi et al 1995b, Ikeuchi et al 1995c, Hattori et al 1999, Vinton et al 2005].

Nomenclature

DRPLA may also be referred to as Naito-Oyanagi disease, after the individuals who first observed the age-dependent onset of symptoms and the robust heritability of the condition [Kanazawa 1998]. DRPLA in a large African American family in North Carolina was referred to as Haw River syndrome [Burke et al 1994a, Burke et al 1994b].

Prevalence

The prevalence of DRPLA in the Japanese population is estimated at 0.48:100,000 based on the nationwide study [Tsuji et al 2008]. Analysis of the distribution of normal ATN1 alleles by size has demonstrated that CAG repeats larger than 17 repeats are significantly more frequent in the Japanese population than in populations of European origin, which is in accordance with the observation that DRPLA is relatively more common among the Japanese than other ethnic populations [Takano et al 1998].

Although DRPLA has been reported to occur predominantly in the Japanese, individuals with molecularly confirmed DRPLA have been identified in other populations including European and North and South American [Burke et al 1994b, Le Ber et al 2003, Martins et al 2003, Wardle et al 2009, Paradisi et al 2016]. Analyses of some Italian families with DRPLA show that the haplotype associated with DRPLA is very similar to the Japanese and Portuguese haplotype, suggesting a founder effect [Veneziano et al 2014].

Although rare in the US, DRPLA has been identified in a large African American family in North Carolina [Burke et al 1994a, Burke et al 1994b] and in a second African American family [Licht & Lynch 2002].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with dentatorubral-pallidoluysian atrophy (DRPLA), the following evaluations are recommended:

• EEG in the presence of seizures
• Head MRI to monitor progression of the disease
• Neuropsychological testing for evidence of dementia and psychiatric disturbance
• Consultation with a clinical geneticist and/or genetic counselor
• Consultation with a rehabilitation therapist

Treatment of Manifestations

The following are appropriate:

• Treatment of seizures with antiepileptic drugs (AEDs) in a standard manner
• Treatment of psychiatric problems with appropriate psychotropic medications
• Symptomatic treatment of ataxia using riluzole and rehabilitation therapy [van de Warrenburg et al 2014, Romano et al 2015]
• Adaptation of environment and care to the level of dementia
• For affected children, adaptation of educational programming to abilities

Surveillance

Surveillance is individualized based on disease progression.

Agents/Circumstances to Avoid

General anesthesia can increase the risk of intra- and postoperative seizures [Takayama et al 2002].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

The use of riluzole during pregnancy has not been well studied in humans. One woman took riluzole throughout her pregnancy and delivered a healthy term infant whereas another woman delivered an infant with growth restriction [Kawamichi et al 2010, Scalco et al 2012].

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

Therapies Under Investigation

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