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Show NANOS SYMPOSIUM 2002 Practical Approaches to Neurogenetic Disease David R. Lynch, MD, PhD, and Jennifer Farmer, MS, CGC Over the past 15 years, molecular genetic advances have led to new approaches for evaluation of neurogenetic disease. New diagnostic tests are available, and in some cases new diseases have been defined. However, effective use of these new tests still relies on solid clinical assessment to prioritize testing and interpret results. This review presents applications of genetic advances to a series of neurogenetic disorders, emphasizing the specific uses of genetic testing and the clinical questions that may arise. The rapid expansion in molecular diagnostics and genomics has fundamentally changed the approach to neurogenetic illnesses. Use of molecular biologic techniques has elucidated new disease mechanisms and allowed the application of genetic concepts to classically nongenetic illnesses. This has led to a wealth of new clinical information and created new dilemmas in patient care. In addition, it has brought into common usage a series of clinical genetic terms, such as variable expressivity ( the range of pheno-typic features in which the same disease can manifest) and anticipation ( the progressively earlier age of onset of a specific disease in a family). This review provides a practical approach for neurogenetic evaluation of individuals who are likely to present in neuro- ophthalmologic practices with inherited ataxias, myotonic dystrophy, oculopharyngeal dystrophy, and Parkinson disease. ( JNeuro- Ophthalmol 2002; 22: 297- 304) AUTOSOMAL DOMINANT ATAXIAS Inherited ataxias are a series of disorders united by specific symptoms ( balance difficulty, lack of coordination, tremor) in conjunction with a family history showing specific patterns of inheritance ( 1). For the neuro-ophthalmologist, the most common reasons for referral Assistant Professor, Departments of Neurology and Pediatrics ( DRL), and Genetic Counselor Division of Medical Genetics, Department of Medicine ( JF), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Address correspondence to David R. Lynch, MD, PhD, Department of Neuroscience Research, Children's Hospital of Philadelphia, 502 Abramson Building, Philadelphia, PA 19104- 4318, USA; E- mail: lynch@ pharm. med. upenn. edu Peer reviewed and modified from an oral presentation at the 28th Annual Meeting of the North American Neuro- Ophfhalmology Society, Copper Mountain, Colorado, February 9- 14, 2002. result from dysfunction in the efferent visual system, although afferent visual function may be subclinically or clinically involved in some patients ( 2). The genetic classification of ataxic disorders is by pattern of inheritance: autosomal dominant, autosomal recessive, X- linked, and maternal ( mitochondrial). Maternally transmitted and X- linked ataxias are far less common than autosomal dominant or autosomal recessive ataxias. Most autosomal dominant cerebellar ataxias are now designated by the term " spinocerebellar ataxia" ( SCA), reflecting the fact that the pathology affects the spinal cord and cerebellar pathways in most of these disorders. There are now at least 16 different genetic loci for SCAs ( 3,4). Although originally defined as clinical entities within specific families, they are now defined by the genetic loci and specific mutations in these families. The original name for the disease locus has become the name of the disease ( SCA1 to SCA 17). The combination of SCA1, 2, 3, 6, and 7 comprises roughly 80% of autosomal dominant ataxias; SCA13, 14, 15, and 16 have each been reported in two families or fewer ( 5). Many SCAs are caused by genetic mutations involving the expansion of a cytosine- adenine- guanine ( CAG) trinucleotide repeat in the protein coding sequences of specific genes ( Table 1). When translated into protein, this CAG repeat gives rise to a series of glutamines. In each of these disorders, the expansion arises from a naturally occurring CAG repeat within these genes. The expanded CAG repeat is inherited in an autosomal dominant fashion, and can become larger with each successive generation. This causes anticipation, in which the disorder occurs at a younger age in each generation. Longer trinucleotide repeats are also associated with increased severity of the disease. Onset later in life is classic among these disorders; however, due to anticipation, the disease can affect patients at progressively younger ages over many generations, and eventually have onset in children or even neonates ( with SCA7) in cases of huge expansions of the CAG repeat. Longer expansions are usually inherited from the father; in some situations, a child may be diagnosed with the condition before the parent, particularly if the affected parent is the father. Clinically, the SCAs are characterized by many signs and symptoms attributable to cerebellar degeneration as Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. J Neuro- Ophthalmol, Vol. 22, No. 4, 2002 297 JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 NANOS SYMPOSIUM 2002 TABLE 1. Neurologic triplet repeat diseases CAG CTG GAA GCG Huntington disease [ 4p] Myotonic dystrophy [ 19q] Friedreich ataxia [ 9q] Oculopharyngeal dystrophy [ 14q] Spinocerebellar ataxias ( SCAs) SCA 1 [ 6p] SCA8 [ 13q] SCA2 [ 12q] SCA3 [ 14q] SCA6 [ 19p] SCA7 [ 3p] SCA12 [ 5q] Dentatorubro- pallidoluysian atrophy ( DRPLA) [ 12p] X- linked spinobulbar muscular atrophy ( Kennedy syndrome) [ X] Chromosomal locations of disease are given in brackets. well as neurologic dysfunction based on damage outside the cerebellum. The unifying pathologic feature of these disorders is a loss of neurons in the CNS, particularly in the cerebellum. The distinct genetic diseases overlap clinically, so that few characteristics define a particular type ( Table 2) ( 3,4). However, there are exceptions to this phenotypic overlap, some of which involve neuro- ophthamiological features. For example, SCA7 is essentially the only SCA associated with pigmentary retinal degeneration. Slow saccades and areflexia early in the disease are characteristic of SCA2, but not exclusive to it. Other disease- selective features are non- neuro- ophthamiologic, such as L- DOPA responsive Parkinsonism in SCA3 ( Machado- Joseph disease) ( 6,7). Data from Subramony and Filla [ 3] and Tan and Ashizawa [ 4]. * Single families with SCA3 or SCA2 and retinopathy have been reported. Diagnostic Testing and Genetic Counseling Genetic testing is now commercially available for SCA1, 2, 3, 6, 7, 8, 10, 12,17 and dentatorubropallidoluy-sian atrophy ( DRPLA). Each test is specific for that SCA. Because clinical phenotypes overlap, genetic testing, usually sent as a panel, is usually needed to define particular forms. The rationale for genetic testing must reflect the clinical utility of the test to provide proper genetic counseling. New mutations are uncommon- accounting for only 10% of cases of SCA6 and much lower levels of other forms of SCA ( 8)- so that when a reliable family history is available and there are no other affected family members, commercial genetic testing for autosomal dominant ataxias TABLE 2. Clinical characteristics of spinocerebellar ataxias ( SCAs) All SCAs Most SCAs A few SCAs A single SCA Ataxia Loss of coordination Dysarthria Anticipation Upper motor neuron features Slow saccades ( mainly SCA2,7) Downbeat nystagmus ( SCA6) Parkinsonism ( mainly SCA3) Postural tremor ( SCA12,16) Chorea ( DRPLA, SCA2) Areflexia ( SCA2, 3,4) Seizures ( mainly SCA10, DRPLA; children with SCA7, DRPLA) Myoclonus ( SCA2, 14, DRPLA) Cognitive change ( DRPLA, SCA13, occasionally SCA2,7) Pigmentary retinopathy ( SCA7)* Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 298 © 2002 Lippincott Williams & Wilkins NANOS SYMPOSIUM 2002 JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 is unlikely to provide a conclusive diagnosis. In cases with no family history, the crucial diagnostic maneuver is ruling out treatable causes of ataxia ( Table 3). However, one must also consider late- onset variants of early- onset, autosomal recessive ataxias in patients with apparently sporadic ataxia ( 9). Genetic testing for SCAs is thus most useful for confirming diagnoses in families with likely autosomal dominant disease, particularly in patients early in the course of illness when clinical signs raise the question of a condition that is not yet fully established. The molecular diagnosis allows the clinician to provide more precise prognostic information and information on recurrence risk. In patients with no relevant family history, genetic testing is unlikely to provide a diagnosis and can be costly and time consuming. In such cases, it is appropriate to rule out treatable causes of disease before consideration of genetic testing. If no treatable causes are found, then genetic testing can be performed if it aids in the management of the patients or addresses specific questions the patient may have. Commercial testing for SCAs directly measures the length of the CAG repeat in the disease- associated gene for each specific disease. Thus it is highly sensitive and specific. Although commercial tests provide the exact CAG repeat length, they are not perfect for predicting age of onset. The relation of CAG repeat length and age of onset provides an excellent correlation over many patients, but many exceptions arise at the level of individual patients. Predictions of age of onset are also confounded by the variable presentations of disease. For example, SCA7 may present with retinopathy or ataxia. As individuals are extraordinarily sensitive to visual changes, and frequently undergo screening vision exams, individuals with primarily retinopathy may present at an earlier stage of the disease than those having primarily balance dysfunction. Testing can also be used for at- risk, pres-ymptomatic individuals as described below. Genetic test results for each CAG- repeat disease are reported such that CAG- repeat lengths in the patient are compared with the normal ranges for each specific disease. TABLE 3. Potentially treatable causes of apparently sporadic ataxia Wilson disease Connective tissue disease Paraneoplastic disorder ( including lymphoma) B12 deficiency Celiac disease Vitamin E deficiency Hyperammonemia Ataxia with coenzyme Q deficiency Cerebellar, brainstem mass lesions, or ischemia The normal range is unique for each SCA and gene. Disease occurs when the repeat expands into the abnormal range. Alleles in the intermediate range are uncommon. In some cases, individuals with intermediate repeat lengths are destined to develop disease if they live to extremely old ages, or if other modifying events occur ( 10). However, exact predictions as to whether individuals carrying repeats in the intermediate range will develop disease are extremely difficult and should be approached with care. Several topics are particularly important in genetic counseling for SCAs: 1. There are currently no specific therapeutic options so that diagnosis does not change medical management. 2. The risk for family members is definitively revealed only when a genetic diagnosis is established. 3. Molecular results do not always predict the phenotype. 4. Even if testing with the SCA panel is negative, the patient may still have an undescribed hereditary ataxia. 5. Presymptomatic testing issues: The genetic test can predict the disease years before clinical features appear. This can provide many benefits to patients but also comes with many risks. These are outlined below in the section on Huntington disease ( HD), for which defined procedures for predictive testing are well established. Pathophysiology and Treatment The demonstration of expanded CAG repeats in most SCAs unites their pathophysiology with disorders like HD, another disorder characterized by slowly progressive neuronal degeneration. The SCAs share an accumulation of intranuclear and/ or intracytoplasmic inclusions that are analogous to the Lewy bodies or senile plaques of Parkinson disease ( PD) and Alzheimer disease, respectively ( 11). The inclusions contain the specific glutamine repeat-containing protein of each disorder, bound to ubiquitin ( a protein mediating the cellular turnover of proteins). Thus, these disorders appear to involve neuronal mishandling of protein turnover, which could then lead to cell death and apoptosis. However, in some disease models, accumulation of these intraneuronal inclusions can be pathologically separated from disease progression. This suggests that inclusion formation represents an epiphenomenon, and not a cause of disease. In addition, how each abnormal protein gives rise to the specific features of that disease is unclear. Thus, while significant strides have been made in understanding the pathophysiology of these disorders, many questions still remain. Treatments for the SCAs remain speculative. In HD, which may have a similar pathophysiology, animal studies have suggested that minocycline may slow the speed of apoptosis. Antioxidants have been used in an attempt to slow the development of oxidation reactions that may Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 299 JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 NANOS SYMPOSIUM 2002 TABLE 4. Clinical features of Friedreich ataxia Classical phenotypic requirements Other features Occasional features Variant features confirmed by genetic definition Onset before age 25 Upper and lower extremity dysfunction Absent LE reflexes Babinski signs Dysarthria Loss of vibration/ proprioception Scoliosis Cardiomyopathy Abnormal electrocardiogram Complete areflexia Pyramidal weakness of the legs Optic neuropathy Hearing loss Diabetes Onset at age > 25 Chorea Spasticity Retained reflexes propagate the disease ( 12,13), but results in humans have been unimpressive. AUTOSOMAL RECESSIVE ATAXIAS: FRIEDREICH ATAXIA Autosomal recessive ataxic disorders are typically of early onset. However, understanding the molecular causes of these disorders has allowed the phenotype to expand greatly, so that less severe, later- onset forms of disease have been recognized for the two major forms of early onset recessive ataxia: Friedreich ataxia ( FRDA) and ataxia telangiectasia. FRDA is a distinct autosomal recessive disorder that is readily distinguished clinically and pathologically from the autosomal dominant SCAs ( 14). In contrast to the SCAs, FRDA is largely a disorder of the afferent cerebellar pathways. Degeneration of the large sensory neurons concerned with position sense and the afferent spinocerebellar tracts causes a sensory ataxia ( 15). Classically, FRDA progresses slowly over 20 to 30 years and is associated with cardiomyopathy, diabetes, scoliosis, and occasionally hearing loss. Up to 80% of patients are clinically or sub-clinically affected with afferent visual dysfunction ( usually optic neuropathy), and many patients have fixation or gaze abnormalities ( 16- 19). The genetic abnormality of FRDA is an expansion of a naturally occurring guanine- adenine- adenine ( GAA) repeat in intron 1 of a novel gene ( FRDA/ X25) that codes for the protein now known as frataxin ( 20). The GAA repeat probably disrupts RNA transcription, leading to markedly decreased levels of frataxin ( 21). About 5% of patients carry point mutations in the gene on one allele in association with a GAA expansion of the other allele. These point mutations are believed to create abnormal or unstable frataxin ( 22). Carriers of a single abnormal allele are phe-notypically normal. Genetic testing has expanded the phenotype of FRDA ( 23). Before introduction of genetic testing, the disease was characterized clinically by progressive upper and lower extremity ataxia beginning before age 25, loss of reflexes, and extensor plantar responses. However, by identification of affected individuals with molecular testing, new manifestations of the phenotype of FRDA include spastic paraparesis, chorea, isolated sensory neuropathy, isolated cardiomyopathy before onset of ataxia, and onset of disease at much later ages (> 40 years)( 24- 26). Patients with atypical manifestations more frequently carry point mutations ( rather than an expanded GAA repeat) or have GAA repeats at the shorter ( more normal) end of the pathologic range ( 19,25,27- 29). Diagnostic Testing and Genetic Counseling The clinical phenotype of FRDA overlaps with other acquired and genetic disorders. As FRDA is an autosomal recessive disease, there may be no affected members in the immediate family. FRDA is thus distinguishable from autosomal dominant SCAs based both on family history and the location of the lesion ( afferent cerebellar pathways in FRDA versus cerebellum in SCAs). Thus, the crucial clinical differentiation is from sporadic forms of cerebellar, peripheral nerve, and spinal cord disease, many of which imitate FRDA or its atypical forms ( 30). Vitamin E deficiency, particularly the inherited form resulting from lack of alpha- tocopherol transfer protein, can match FRDA exactly in clinical features and mode of inheritance ( 31). Other disorders frequently confused with FRDA include mitochondrial illnesses, early- onset ataxia with retained reflexes ( a heterogeneous syndrome likely including many disorders), and adult onset hexosaminidase A deficiency. These possibilities can be differentiated with genetic testing for FRDA based on the expanded GAA repeat. Testing for the expanded GAA repeat alone will identify 95% of patients with FRDA. A few commercial labs also offer sequencing of the FRDA gene in conjunction with GAA expansion testing, which can identify the remaining individuals. The carrier frequency for the expanded GAA repeat is roughly 1 in 100. Carrier testing is available for at risk relatives, as well as spouses/ partners of known carriers and affected individuals. This testing allows assessment of recurrence risk and family planning counseling. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 300 © 2002 Lippincott Williams & Wilkins NANOS SYMPOSIUM 2002 JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 Neuro- ophthalmologic Features FRDA may be encountered by neuro- ophthalmolo-gists in the context of afferent visual symptoms in an individual with suspected or known FRDA ( 16- 19). The afferent visual loss is usually mild ( optic disc pallor with no loss of visual acuity), but may be more severe in up to 20% of patients. ( 14). Visual loss is more frequent among the 5% of patients with a single expanded GAA repeat in association with a point mutation in the FRDA gene ( 28). However, rarely is visual loss the dominant clinical abnormality; in fact, visual loss has never been reported without ataxia. These observations have two implications: 1) patients with visual loss more prominent than ataxia are unlikely to have FRDA; 2) patients with confirmed FRDA and visual loss should have an evaluation for other causes of visual dysfunction. Pathophysiology and Future Therapy Identification of the genetic abnormality has led to significant advances in the understanding of the pathophysiology of FRDA. Frataxin is a mitochondrial protein that appears to regulate iron levels in the mitochondria ( 32- 36). Its absence is associated with mitochondrial iron overload, leading to production of reactive oxygen species and cell death over the course of time. The reason for selective death of afferent cerebellar pathways, cardiac tissue, and pancreatic islet tissue, however, is not known. This pathophysiology suggests possible therapies based on treatment of mitochondrial illnesses. Idebenone ( a coenzyme Q analog) and high doses of coenzyme Q have reversed surrogate markers of disease activity, but have not been fully assessed for effects in humans ( 37- 40). MYOTONIC DYSTROPHY Myotonic dystrophy is an autosomal dominant disease with a prevalence of 1 in 20,000 that is characterized by progressive myopathy, cataracts, cardiomyopathy with conduction defects, and diabetes ( 41,42). Frontal balding, in association with ptosis and facial weakness, gives rise to a typical facial appearance. Cognitive and psychiatric dysfunction are also components of myotonic dystrophy. The myopathy is characterized by the presence of true myotonia on physical examination and electromyography ( EMG). Myotonic dystrophy has three treatable components: diabetes, cardiac arrhythmias, and cataracts. Cataracts occur in nearly all individuals with myotonic dystrophy and can be the presenting sign, particularly among individuals with mild phenotypes. Bilateral iridescent lens opacities and posterior lens opacities are highly specific for myotonic dystrophy ( 43). Myotonic dystrophy is inherited as an autosomal dominant condition through passage of a pathologic CTG repeat in the DMPK gene. As with the repeat found in SCA8, it lies outside the protein- coding region of the mRNA. As with the CAG repeat of the SCAs, this CTG repeat is unstable and expands with successive generations, giving rise to anticipation. The clinical presentation of myotonic dystrophy is extraordinarily variable, ranging from isolated cataracts or cardiomyopathy to the full spectrum of disease with effects on multiple organ systems. As seen with other autosomal dominant triplet repeat diseases, anticipation leads to progressively earlier onset of disease in each generation and a severe neonatal form. The neonatal form of myotonic dystrophy is most commonly seen with maternal rather than paternal transmission. This phenomenon most likely reflects a lack of viability of male gametes with hugely expanded repeats, while oocytes with similar large repeats remain viable. Clinical Testing and Genetic Counseling Clinical genetic testing is useful for diagnosis of myotonic dystrophy in families. It is also useful in screening individuals who present with a disease resembling myotonic dystrophy and whose family history reveals many individuals with relatively common disorders such as heart disease, diabetes, or cataracts, but without features specific for myotonic dystrophy. Genetic testing in myotonic dystrophy cannot answer all clinical questions. There can be a substantial difference in the length of the CTG repeat in leukocytes compared with other tissues. This does not usually prevent diagnosis in affected individuals, but makes prediction of the age of onset and specific organ system involvement difficult. The repeat length can be generally used to predict severity within broad ranges. Genetic testing in myotonic dystrophy has also identified new sets of patients. One group of patients has a phenotype similar to myotonic dystrophy, but lacks the CTG repeat of typical myotonic dystrophy. This variant is autosomal dominant but shows no evidence of anticipation. Affected patients also have predominantly proximal weakness and are referred to as having " proximal myotonic myopathy" ( PROMM). A second variant has a phenotype similar to classic myotonic dystrophy with distal weakness, but is genetically linked to a distinct locus ( DM2) on chromosome 3. How closely DM2 relates to PROMM has yet to be determined. Genetic counseling in myotonic dystrophy is particularly important in these situations: 1. Congenital onset, in which the infant may be diagnosed before the parent. 2. Counseling of affected women and men of child- bearing age, so that the risk of neonatal myotonic dystrophy is realized and options of prenatal testing can be discussed. 3. Extended families in which complicated medical histories and the common nature of some of the symptoms of myotonic dystrophy leave questions as to who is affected. 4. Presymptomatic testing, particularly given some of the treatable aspects of myotonic dystrophy. Genetic coun- Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 301 JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 NANOS SYMPOSIUM 2002 seling in this situation must also include a discussion of the risk and limitations of presymptomatic testing ( see below). 5. Allele length in the intermediate range, which is broader than for other disorders. Pathophysiology and Therapy The location of the CTG repeat in myotonic dystrophy differs from that of the CAG- repeat diseases. In myotonic dystrophy, the CTG repeat is located in the 3' untranslated region of the myotonin protein kinase gene ( DMPK). However, the mechanism of disease production is unknown. Loss of the myotonin protein kinase is not sufficient for disease, but can produce some myopathic changes in mice. Other proposed mechanisms for production of myotonic dystrophy include effects of the expanded CTG repeat on regulation of other genes at the same region of the chromosome, as well as diffuse mRNA processing changes from the long CTG repeat. OCULOPHARYNGEAL DYSTROPHY Oculopharyngeal dystrophy ( OPD) is an autosomal dominant and autosomal recessive disorder that becomes evident in the fifth or sixth decade of life with ptosis and dysphagia. Resulting from yet another form of triplet repeat ( 42), it is most common in the French Canadian population ( 1: 1000). With time, it may affect extraocular, extremity, and rarely cardiac muscle ( 44). Pathologically, rimmed vacuoles, as well as intranuclear inclusions, characterize the disorder. Genetically, the disorder is caused by expansion of a GCG repeat in the gene ( PABPN1) coding for a nuclear polyA- binding protein. The normal sequence of the protein contains 10 sequential alanines, 6 of which are coded by a naturally occurring GCG repeat. Autosomal dominant OPD results when the GCG sequence expands to include 8 to 13 repeats. This mutation has been found in multiple ethnic groups. Autosomal recessive OPD is caused by inheritance of 2 alleles containing 7 GCG repeats. Genetic testing is available for diagnostic confirmation as well as genetic counseling. Obligate heterozygotes for the recessive forms have a 1% chance of being affected. The mechanism by which this expanded repeat causes myopathy is unknown. The pathologic hallmark of intranuclear inclusions is similar to that of other CAG repeat diseases, while the presence of rimmed vacuoles mimics inclusion body myositis. PARKINSON DISEASE Molecular biologic approaches have been useful not only for identification of the mutations of specific diseases, but also in understanding pathophysiological mechanisms in traditionally non- genetic neurodegenerative disorders. Although typically viewed as a sporadic disease, PD has familial components ( 45,46). Epidemiological studies have noted clustering within families ( most likely of a multifactorial nature), and a few families have been found with specific forms of inherited PD. PD is thus like amyotrophic lateral sclerosis ( ALS), Alzheimer disease, and Creutzfeldt- Jakob Disease, in which a small number ( 10% or less) of cases are inherited while the majority show no strict Men-delian pattern of inheritance. While these inherited forms may not represent a significant percentage of the overall population of patients with PD, they can be instructive from a pathophysiological point of view. Approximately 10 families have been characterized with autosomal dominant PD; several have alterations in a protein called alpha synuclein. This protein is a component of Lewy bodies, the pathologic hallmark of PD. The mutant forms aggregate in vitro in a manner that could lead to protein accumulation such as that seen in Lewy bodies in vivo ( 47) ( 48). This could theoretically be the initiating step in an inability to remove alpha- synuclein from dopaminergic neurons ( 11). Other individuals inherit PD in an autosomal recessive form ( AR- PD). Most of these families have mutations in a protein now called parkin ( 49). These mutations presumably result in diminished or loss of function of parkin, believed to function as a regulator of protein turnover in cells by its ability to ligate proteins to ubiquitin ( 50). How this process causes PD is unclear. Most patients with AR-PD present early in life ( age 10- 20), although patients who are homozygous for mutations of parkin have now been found with older age at onset. Maternal ( mitochondrial) inheritance has also been proposed in PD, based on biochemical evidence linking PD and mitochondrial function ( 51). However, at this point there is minimal genetic evidence. The high mutation rate of mtDNA and the large number of benign polymorphisms in mtDNA make it difficult to find any truly causative mtDNA mutations in a common disease such as PD. Clinical Implications of the Genetics of Parkinson Disease The discovery of genetic forms of PD has been crucial in recent advances in understanding the pathophysiology of PD. However, the direct clinical utility of these discoveries is at present limited. There are no commercially available tests for genetic forms of PD, and application of these tests on a research basis has found no causative mutations of alpha- synuclein in individuals outside the original families. Parkin mutations may have a wider phenotype and are present in some patients with apparently sporadic PD. In addition, a nonpathogenic polymorphism of alpha- synuclein may be a risk factor for development of PD ( 52). However, it is also not available as a clinical test, and the interpretation of such risk factors in patient counseling is complex. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 302 © 2002 Lippincott Williams & Wilkins NANOS SYMPOSIUM 2002 JNeuro- Ophthalmol, Vol. 22, No. 4, 2002 Thus, the crucial step in clinical evaluation of a patient with a possible genetic form of PD is to rule out other diseases that resemble PD. SCA3/ Machado Joseph Disease can appear identical to PD clinically, including the response to L- DOPA ( 6). Thus, in families with apparently autosomal dominant inheritance of PD, a genetic test for SCA3 is needed. In addition, L- DOPA- responsive dystonia ( resulting from a mutation in GTP cyclohydrolase I) can present with Parkinsonism in adults ( 53). This autosomal dominant disease typically causes treatable dystonia in children, but men frequently manifest no features until later in life. For clinical diagnosis, these individuals should be tested for neopterin/ biopterin levels, looking for evidence of decreased biopterin synthesis. Predictive Presymptomatic Testing Molecular testing can be a valuable tool in diagnosis and counseling when applied to defined questions. However, in some cases the value of genetic testing must be balanced against the risks of identifying affected individuals before they would normally come to medical attention. These are issues in the testing of all presymptomatic individuals, but particularly those with untreatable illnesses. The appropriate considerations for presymptomatic testing have been best characterized for HD ( 54). HD is an autosomal dominant disease characterized by chorea, dementia, and psychosis as well as genetic anticipation. Because of the wide variability in symptoms associated with HD ( including depression), the genetic test for HD is crucial in firmly making a diagnosis in many patients. The availability of genetic testing for HD, SCAs, and many other hereditary conditions has made presymptomatic diagnosis possible, even though these potentially devastating disorders have no therapy. This situation requires careful consideration of the individual's motives for testing and of the risks and benefits associated with firm diagnosis. Experience with genetic testing for HD has been used as the prototype for predictive testing of adult- onset neurologic diseases. The principles involved are not based on the psychologic features of HD, although the nature of HD makes them most notable there. Instead, they are based on the clinical approach to individuals at risk for a genetic disorder. All individuals have the right not to know if they are affected with an incurable disorder, or to live as long as possible without such knowledge if they so choose. This gives rise to a variety of psychologic issues regarding being at risk. In addition, there are good reasons not to know. For example, knowing the diagnosis may change insurability of patients in some situations, as once a test is performed it becomes part of a person's medical record. Conversely, there are good reasons for knowing, including the need for making decisions about having children and other life planning issues. Balancing the possible outcomes is difficult and requires careful genetic counseling and informed consent before pursuing predictive testing ( 55). Children should not be presymptomatically tested for untreatable conditions, as they cannot give informed consent. At present, presymptomatic testing for HD typically requires at least three visits for evaluation. The first visit consists of genetic counseling with an appropriately trained genetic counselor ( to discuss inheritance testing motivations, risks, benefits and limitations, consent and adverse reactions) and a trained psychologist ( for an initial psychologic evaluation and assessment of support system). The second visit includes further discussions of informed consent and the drawing of a blood sample. A final disclosure visit also occurs with the psychologist and genetic counsel or, in which the patient is told the test results, the psychologic reaction to the results is discussed, and the support system is reassessed. Many institutions also require evaluation by a neurologist before testing, as well as detailed follow- up visits after disclosure. This protocol is designed to ensure that a person understands the issues and is independently deciding to proceed. It should also diminish the psychologic stress associated with the testing itself, and provide a team of individuals who can counsel the patient should psychologic difficulties arise. Only 10% to 20% of people proceed with testing after pretest counseling and fully exploring the issues. The specific rules for predictive testing of HD do not necessarily apply to all disorders or all situations. When a new preventive therapy becomes available, presymptomatic testing becomes free of many of its caveats. Moreover, the rules do not apply to testing of already symptomatic patients. One must still be sure that they comprehend the issues involved in genetic confirmation, but there is now a medical obligation to explain symptoms and rule out treatable disorders. Finally, there are situations in which the disease as a whole is not treatable, but some of its manifestations are. 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