LOS PRIMEROS INTENTOS DE REGLAMENTACIÓN DE LA CARRERA

2. CAPÍTULO SEGUNDO: UNA EXPLICACION DEL PERFIL ENCONTRADO

2.3. LOS PRIMEROS INTENTOS DE REGLAMENTACIÓN DE LA CARRERA

• Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurologic

disorder. Age of onset ranges from one year of age to 62 years of age; the mean age of onset is 30 years of age.1

o In adults (over ~age 20), DRPLA presents as ataxia, choreoathetosis, and dementia or character changes. This is known as the non-progressive myoclonic epilepsy phenotype or (non-PME) phenotype.

o In people under ~age 20, DRPLA typically manifests with progressive intellectual deterioration, behavior changes, ataxia, myoclonus, and seizures. This is known as the progressive myoclonic epilepsy phenotype (PME) phenotype.

o Neuropathology demonstrates degeneration of the dentatorubral and pallidoluysian systems.2 In addition, white matter lesions have been described.1

• DRPLA is also known as Myoclonic Epilepsy with Choreoathetosis; Naito- Oyanagi Disease; Haw River Syndrome; Ataxia, Chorea, Seizures, and Dementia.1

• Although initially thought to be a disorder of the Japanese population, DRPLA has been diagnosed in people from a variety of other ethnic backgrounds. Its prevalence is estimated to be about 0.48 in 100,000 in the Japanese population based on a study conducted by Tsjuji et al in 2008.3

• The diagnosis of DRPLA is based on presenting findings, family history, and the results of molecular genetic testing demonstrating an expansion of the CAG trinucleotide/polyglutamine tract in ATN1.1

o Normal alleles typically have a repeat length of 6 to 35.

o Individuals with DRPLA have a full penetrance allele with repeat length > 48 repeats, usually 48-93.1

o So-called ‘mutable normal’ alleles may exist, i.e., alleles with repeats between 36 and 47. Mutable normal alleles do not result in symptoms for the individual, but they are unstable and may increase in size when transmitted to offspring.1

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• The age of onset and clinical presentation is indirectly correlated with the size of the expansion. On average, people with large expansions have earlier onset (and the PME phenotype) than those with a smaller number of repeats.1,2

o Although the size of the trinucleotide repeat is inversely correlated with the age of onset, the number of repeats cannot be used for specific prediction of symptoms or age of onset in an asymptomatic person. Repeat length is estimated to account for 50-68% of the variability in age of onset, the other contributing factors are not known.4

• DRPLA is inherited in an autosomal dominant manner. Males and females are equally likely to be affected. A person with DRPLA has a 50% chance of passing the ATN1 mutation to each of his/her children.

o Most individuals with DRPLA have inherited the mutation from a parent. The parent may not have had signs of DRPLA because the number of repeats he or she had were below the ‘threshold’ for manifesting symptoms (‘mutable normal’ or ‘intermediate’ alleles) or the number of repeats was within the disease-causing range, but small in number thus the parent with the abnormal allele has not yet developed symptoms. o Unaffected persons with mutable normal or intermediate alleles may pass

this allele to offspring and the allele may undergo intergenerational expansion to a disease-causing range. The amount that of expansion depends upon the size of the repeat and gender of the transmitting parent. When the expansion is inherited from the father, increase in size of the expansion tends to be larger than when the disease-causing allele is inherited from the mother.1 As a result, individuals who inherit the mutation from their father tend to have onset of disease 26-29 years earlier than their affected parent; when inheritance is from the mother, the onset of disease is about 14-15 years earlier.1

Test Information

• DRPLA molecular genetic testing identifies the number of CAG

trinucleotide/polyglutamine repeats in ATN1. A repeat length of >48 confirms the diagnosis of disease. Testing is >99% accurate. Once the diagnosis is confirmed in an affected relative, pre-symptomatic/predictive testing, prenatal diagnosis, and preimplantation genetic diagnosis are available to at-risk family members.

Guidelines and Evidence

• No U.S. guidelines exist for genetic testing for DRPLA. • A 2010 expert-authored review states:1

o "The diagnosis of dentatorubral-pallidoluysian atrophy (DRPLA) is established in individuals with disease-causing CAG trinucleotide expansions in ATN1 (DRPLA) who are:

 Under age 20 years and have ataxia, myoclonus, seizures, and progressive intellectual deterioration;

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 Over age 20 years and have ataxia, choreoathetosis, dementia, and psychiatric disturbance."

o "Most individuals diagnosed with DRPLA have an affected parent. It is appropriate to evaluate both parents of an affected individual with molecular genetic testing even if they are asymptomatic."

o "Testing of asymptomatic at-risk adults for DRPLA in the presence of nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. When testing at-risk individuals for DRPLA, it is helpful to test for the CAG expansion in an affected family member to confirm the molecular diagnosis in the family."

o "At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of DRPLA, the possible impact of positive and negative test results, and neurologic status are assessed."

o "Requests from parents for testing of asymptomatic at-risk individuals during childhood require sensitive and understanding counseling. Consensus holds that individuals under age 18 at risk for adult-onset disorders should not have testing in the absence of symptoms."

o "If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation)."

Criteria

• Clinical Consultation & Genetic Counseling:

o Examination by a geneticist or physician familiar with hereditary neurological disease and

• Pre and post-test genetic counseling by an appropriate provider (as deemed by the Health Plan policy), AND

• Previous Testing:

o No previous ATN1 testing for DRPLA, AND • Diagnostic Testing for Symptomatic Individuals:

o < 20 years of age and 2 or more of the following:

 Ataxia

 Myoclonus

 Seizures

 Progressive intellectual deterioration/behavior changes

 Affected 1st degree biologic relative or Japanese/Haw River descent, OR

o ≥ 20 years of age and 2 or more of the following:

 Ataxia

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 Choreoathetosis

 Affected 1st degree biologic relative or Japanese/Haw River descent, OR

• Predisposition Testing for Presymptomatic/Asymptomatic Individuals:

o ATN1 CAG trinucleotide expansion detected in 1st degree biologic relative, or

o Suspected DRPLA in a deceased 1st, 2nd, or 3rd degree biologic relative who was not genetically diagnosed

References

1. Tsuji S. (Updated June 2010). DRPLA. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Available at

http://www.ncbi.nlm.nih.gov/books/NBK1491/.

2. Wardle M, Majounie E, Williams NM, Rosser AE, Morris HR, Robertson NP. Dentatorubral pallidoluysian atrophy in South Wales. J Neurol Neurosurg Psychiatry. 2008;79(7):804-7. 3. Tsuji S, Onodera O, Goto J, Nishizawa M. Sporadic ataxias in Japan--a population-based

epidemiological study. Cerebellum. 2008;7(2):189-97.

4. Potter NT. The relationship between (CAG)n repeat number and age of onset in a family with dentatorubral-pallidoluysian atrophy (DRPLA): diagnostic implications of confirmatory and predictive testing. J Med Genet. Feb 1996;33(2):168-70.

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