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LEADING ALS GENETIC TESTING SERVICES C9orf72 OPTN UBQLN2 VCP SOD1 FUS TARDBP ANG FIG4 Important NEW Discoveries and the Latest Molecular Tests for ALS New Tests Now Available. Molecular testing services for Amyotrophic Lateral Sclerosis (ALS) The Challenge of Diagnosing ALS Every year, more than 5,600 people are diagnosed with amyotrophic lateral sclerosis by history, neurological exam and tests to rule out mimics. The interval between symptom onset and the ALS diagnosis averages around one year.1 During this period, it is not uncommon for patients to undergo unnecessary tests and even surgeries.2 By the time they receive their diagnosis many patients will have lost half their motor neuron pool and one-third to one-half of their remaining lives.3 Athena Diagnostics can give patients a head start with NEW genetic tests for mutations in C9orf72, OPTN, UBQLN2 and VCP. As a leader in genetic testing services, we have focused on helping ALS patients get the answers they need sooner. For those individuals who carry a genetic mutation, early knowledge is important to making decisions about family planning. “More than ever, I wanted to have a child, but it really was my wife’s decision, because if things ran their course with me, potentially she’d have to be taking care of and supporting two people.” —Steve Gleason, former NFL player, Diagnosed with ALS in 2011 New Genetic Tests from Athena Diagnostics for C9orf72, OPTN, UBQLN2 and VCP C9orf72: The most common identifiable cause of ALS and frontotemporal dementia (FTD) has recently been identified as a hexanucleotide repeat expansion in the gene C9orf72.4,5 In some populations, this mutation is present in more than 40 percent of individuals with a family history of ALS and more than 20 percent of those without a family history.4,5,6 UBQLN2: Mutations in UBQLN2, which encodes the ubiquitin-like protein ubiliquin 2, cause dominantly inherited chromosome-X-linked ALS and ALS dementia. This links abnormalities in ubiliquin 2 to the protein degradation pathway, indicating a common pathogenic mechanism that can be used to explore therapeutic intervention.10,11 Genetic testing for C9orf72 should be considered in patients presenting with an ALS and/or FTD phenotype.6 VCP: Mutations in the VCP (valosin-containing protein) gene have been identified which account for one to two percent of patients with autosomal dominant ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes.12 OPTN: Mutations in the gene encoding optineurin (OPTN) have been found in familial and sporadic ALS patients.7,8 Interestingly, OPTN mutations have not been identified recently in patients with FTD, which could represent a novel and important neurological hallmark for ALS. Research in this area continues.8,9 Genetic Testing can Detect up to 70 Percent of Familial ALS ALS Genetic Evaluation Test Menu—Important Facts to Consider Clinical Manifestations Notes on Phenotype Ethnicity Inheritance Characteristic phenotypes include behavioral variant FTD, ALS or FTD/ALS. Many with the behavioral variant FTD-predominant phenotype have evidence of upper and/or lower motor neuron involvement. Some with the ALS-predominant phenotype have features of behavioral variant FTD. Psychosis and appetite/eating changes are common.13 Varied4,5,6 AD13 Lower-limb onset and is characterized by a presence of upper motor neuron signs.8 Confirmed in Japanese,7 Italian8 subjects; rare in Caucasian subjects9 AD, AR7,8 Dementia10 Non-specific AD, X-linked10 Limb-onset motor neuron symptoms12 Italian confirmed so far12 AD12 Classical ALS, often LMN predominant. Genotype-phenotype correlations (for penetrance, site of onset and progression rate) exist for many mutations.14 Non-specific AD14 Proximal upper extremity weakness spreading to the lower extremities but not the bulbar region14 Non-specific Cape Verdean AD14 Phenotype is clinically indistinguishable from sporadic ALS and SOD1-positive FALS14 Non-specific AD14 Classical ALS with prominent UMN involvement (sometimes pure Primary Lateral Sclerosis). Compound heterozygosity is associated with CMT4J.* Non-specific AD Classical ALS with variable survival* Non-specific AD14 QUICK FACTS *Information on file. ALS Quick Facts • ALS has an incidence rate of one to three per 100,000.15 • The prevalence rate of ALS is four to eight per 100,000.14 • All clinical features reported in familial cases have also been observed in sporadic cases.15 • The clinical diagnosis of ALS can take a year from symptom onset, and along the way unnecessary tests and treatments including surgery are very common.1 • The prognosis of ALS is highly variable. Most patients die within three to five years of symptom onset, however, ten percent live ten years or more.16 While many patients remain cognitively intact, some develop severe cognitive and/or behavioral problems.17 • Patients receiving a timely ALS diagnosis can now benefit from more evidence-based interventions for preserving quality and length of life than ever before.18,19 • Results from a study by Srinivasan showed that almost one-third of ALS patients were previously misdiagnosed as having vascular pseudobulbar palsy or cervical myelopathy, which led to over 20 percent of patients undergoing unnecessary surgical procedures.2 Differential Diagnosis for ALS14 Gene/ Test Name Prevalence in FALS Test Code Complete ALS Evaluation Up to 70% 643 C9orf72 24 – 46% (4 – 20% reported in sporadic cases)4,5,6 670 OPTN 2%8 609 UBQLN2 1 – 2%10,11 611 VCP 1 – 2%12 610 SOD1 20% familial; 3% sporadic14 620 FUS 4% of SOD1 negative FALS14 619 TARDBP 1 – 4%14 621 FIG4 3% ANG Rare14 622 Diagnosing ALS can be difficult, and some patients have endured years of testing and misdiagnoses. Athena’s testing can help rule out other diseases that present with similar symptoms: Kennedy Disease (SBMA) DNA Test, 117 Spinal Bulbar Muscular Atrophy is an X-linked disease that typically occurs in males is characterized by bulbar and proximal muscle weakness, atrophy and fasciculations. Multifocal Motor Neuropathy Evaluation, 356 MMN is one of the most common conditions mistaken for ALS. Differentiating MMN from ALS is extremely important as patients with MMN may benefit from IVIg. These patients also tend to survive for longer periods.20 Complete Hereditary Spastic Paraplegia Evaluation, 655 HSP is an upper motor neuron disorder inherited in an autosomal dominant, autosomal recessive and X-linked manner and characterized by insidiously progressive lower weakness and spasticity. Uncomplicated forms of HSP do not result in shortened lifespan. HSP is caused by at least 13 different SPG genes. Complete SMA Evaluation, 215 Spinal Muscular Atrophy is an autosomal recessive disorder characterized by progressive degeneration and loss of anterior horn cells in the spinal cord and in some brain stem nuclei, resulting in proximal greater than distal symmetric muscle weakness and atrophy (LMN involvement only). FSHD DNA Test, 405 Facioscalpulohumeral muscular dystrophy typically presents with slowly progressive asymmetric wasting of muscles of the face, shoulder and upper arms.21 Huntington’s Disease DNA Test, 116 Huntington’s disease is inherited in an autosomal dominant manner. It’s a progressive, neurodegenerative disorder that presents with motor disturbances, psychiatric symptoms and cognitive decline.22 Five Reasons to Test for ALS A Physician’s Perspective—Richard Bedlack, M.D., Ph.D., M.Sc. 1 Helps Speed Diagnosis • The typical interval between symptom onset and an ALS diagnosis is one year.23,24 • This interval time can be a period of great anxiety for patients with ALS symptoms, their families and caregivers.2 • Over this period of time, patients with ALS symptoms may be subjected to unnecessary tests and surgeries. Furthermore, over this time period, up to 50 percent of the motor neuron pool may be lost which can limit response to eventual treatment.2 • In much the same way that antibody testing has revolutionized the diagnosis of myasthenia gravis, Athena’s Complete ALS Evaluation can sometimes dramatically speed an ALS diagnosis. 2 May Help Answer “Why did this Happen to Me?” • The cause of most ALS is unknown.25 • It is common for patients with ALS without a strong family history of ALS to wonder how they got their disease, and to create their own theory on an exposure that caused it. Sometimes these theories lead to exhausting and ineffective lawsuits. • Not all patients with ALS can provide an accurate family history.26 About Dr. Bedlack – Many of the mutations found in patients with a family history of ALS are also found in patients without a family history. For example, C9orf72 is found in 1 to 20 percent of those without a family history.4,5,6 3 Allows Risk Assessment to Offspring Dr. Richard Bedlack is Associate Professor of Neurology at Duke University, directs the Duke ALS Clinic in North Carolina, and is the Chairman of the North American ALS Research Group (ALSRG). He has participated in numerous ALS research studies and in 2009 he was the American Academy of Neurology’s National Patient Advocate of the Year. • Another common question of patients with ALS symptoms is “What are the chances that I can pass this onto my children?” • Without genetic testing, it can be difficult to qualify an inheritance pattern, which often varies within mutations of the same gene. In many cases, an inaccurate family history or a sporadic mutation can compound the challenge. The question is impossible to answer without the insight that genetic testing provides. 4 Helps Aid in Prognosis • The prognosis of ALS is highly variable. Variability includes the presence of dementia, the sequence of involved regions and the expected survival.25 • Genetic testing can help narrow these ranges, facilitating planning by patients with ALS symptoms, their families and their medical teams. – For example, patients with an Ala4Val mutation in their SOD1 gene typically have rapid progression and a survival of about one year. – On the other hand, patients with an His46Arg mutation in this same gene typically have very slow progression, with survival of more than a decade.27 – Patients with familial ALS due to SOD1 mutations are in general less likely to have cognitive deficits than patients with familial ALS due to mutations in other genes.28 5 Allows for More Informed Treatment • For more than 100 years, we have been treating and researching ALS as if it is one single disease. It is now clear that this is not true.25 • Proposed treatments come largely from animal studies of ALS, based on SOD1 mutations. While many treatments have prolonged survival in this model, only one has translated into humans with other forms of ALS (riluzole).29 • Studies are underway for patients with proven SOD1 mutations (see www.clinicaltrials.gov for a listing of open ALS trials). • It is only a matter of time before specific studies and hopefully treatments are available for patients with other genetic ALS subtypes. Comprehensive Services from Athena Diagnostics Athena InsightTM Athena Insight is a powerful result-reporting service that is included with every DNA sequencing test ordered. Our technical comprehensive review of variants of unknown significance determines the likelihood of variants being benign or pathogenic. A complete synopsis of research data and findings is presented in clear and concise clinical terms enabling the physician to utilize this enhanced report with patients and family members during discussions relative to diagnosis, treatment, patient management and family planning. Genetic Counselors at Your Service Genetic Counselors can provide information on the nature, inheritance and implications of genetic disorders to help the physician guide the patient and family in making informed medical and personal decisions. Athena’s Test Menu for ALS Test Code Test Name Specimen Volume Turnaround Time 643 Complete ALS Evaluation SOD1, FUS, TARDBP, ANG, FIG4, OPTN, VCP, UBQLN2, C9orf72 10 mL whole blood 21 – 28 days 620 SOD1 DNA Sequencing Test 10 mL whole blood 21 – 28 days 619 FUS DNA Sequencing Test 10 mL whole blood 21 – 28 days 621 TARDBP DNA Sequencing Test 10 mL whole blood 21 – 28 days 622 ANG DNA Sequencing Test 10 mL whole blood 21 – 28 days FIG4 DNA Sequencing Test 10 mL whole blood 21 – 28 days 609 OPTN DNA Sequencing Test 10 mL whole blood 21 – 28 days 610 VCP DNA Sequencing Test 10 mL whole blood 21 – 28 days 611 UBQLN2 DNA Sequencing Test 10 mL whole blood 21 – 28 days 670 C9orf72 DNA Test 10 mL whole blood 21 – 28 days Client Services Representatives are available from 8:30am to 6:30pm Eastern Time (U.S.). Customers in the U.S. and Canada please call toll free 800-394-4493 or visit us on our website at AthenaDiagnostics.com. References: 1. Cellura E, Spataro R, Taiello AC, et al, Factors affecting the diagnostic delay in amyotrophic lateral sclerosis. Clin Neuro Neurosurg 2011; doi:10.1016/j.clineuro.2011.11.026. 2. Srinivasan J, Scala H, Jones HR, Inappropriate Surgeries Resulting from Misdiagnosis of Early Amyotrophic Lateral Sclerosis. Muscle Nerve 2006; 34:359-360. 3. http://www.ncbi.nlm.nih.gov/pubmed/21989247. 4. Dejesus-Hernandez M, Mackenzie IR, Boeve BF, et al, Expanded GGGGCC hexanucleotide repeat in noncoding region of C9orf72 causes chromosome 9p-linked FTD and ALS. Neuron 2011; 72:245–56. 5. Renton AE, Majounie E, Waite A, et al, A hexanucleotide repeat expansion in C9orf72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011; 72:257–68. 6. Majounie E, Renton A, Mok K, et al, Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 2012; 11:323–30. 7. Maruyama H, Morino H, Ito H, et al, Mutations of optineurin in amyotrophic lateral sclerosis. Nature 2010; 465:223-227. 8. Del Bo R, Tiloca C, Pensato V, et al, Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2011; doi:10.1136/jnnp.2011.242313. 9. Sugihara K, Maruyama H, Kamada M, et al, Screening for OPTN mutations in amyotrophic lateral sclerosis in a mainly Caucasian population. Neuro of Aging 2011; doi:10.1016. 10. Deng HX, Chen W, Hong ST, et al, Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 2011; doi:10.1038/nature10353. 11. Daoud H, Rouleau GA, Nat Rev Neurol 7, 599–600 (2011); published online 11 October 2011; doi:10.1038/nrneurol. 2011.163. 12. Johnson J, Mandrioli J, Benatar M, et al, Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS. Neuron 2010; 68:857–864. 13. Boeve B, Boylan K, Graff-Radford NR, et al, Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012; 135:765–783. 14. Donkervoort S, Siddique T, Amyotrophic Lateral Sclerosis Overview. Gene Reviews. Last Update: July 28, 2009. 15. Andersen P, Al-Chalabi A, Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 2011; 7:603-615. 16. National Institute of Neurological Disorders and Stroke, What is the Prognosis? Page, accessed March 2012. http://www.ninds.nih.gov/disorders/amyotrophiclateralsclerosis/ALS.htm. 17. http://www.ncbi.nlm.nih.gov/pubmed/20953810. Accessed April 2012. 18. Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, Kalra S, Katz JS, Mitsumoto H, Rosenfeld J, Shoesmith C, Strong MJ, Woolley SC; Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009 Oct 13; 73(15):1227-33. Review. 19. Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, Kalra S, Katz JS, Mitsumoto H, Rosenfeld J, Shoesmith C, Strong MJ, Woolley SC; Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009 Oct 13; 73(15):1218-26. Review. Erratum in: Neurology. 2009 Dec 15; 73(24):2134. Neurology. 2010 Mar 2; 74(9):781. 20. Hardiman O, van den Berg LH, Kiernan MC, Clinical diagnosis and management of amyotrophic lateral sclerosis. Nat Rev Neurol 2011 Oct 11; 7(11):639-49. doi: 10.1038/nrneurol.2011.153. 21. http://www.ncbi.nlm.nih.gov/books/NBK1443/. Accessed April 2012. 22. http://www.ncbi.nlm.nih.gov/books/NBK1305/. Accessed April 2012. 23. Househam, E., et al., Diagnostic delay in amyotrophic lateral sclerosis: What scope for improvement? J Neurol Sci. 2000; 180:76-81. 24. Chió, A., Update on ISI Survey: Europe, North America and South America. Amyotroph Lateral Scler Other Motor Neuron Disord 2000; Suppl1:S9-11. 25. Bedlack, RS, et al., ALS Update: Signs of Progress, Reasons for Hope. Continuum 15: 2009. 26. Smith, R., Handbook of ALS, 1992. 27. Neuromuscular Disease Center of Washington University [Internet]. St. Louis; c1996-2010 [updated 2010 January; cited 2010 January]. Table showing ALS Syndromes: Correlations with specific SOD mutations; [about 2 screens]. Available from: http://neuromuscular.wustl.edu/synmot.html#halsclinmut 28. Wicks, P., et al., SOD1 and cognitive dysfunction in familial amyotrophic lateral sclerosis. J Neurol 2009; 256:234-241. 29. Benatar, M., Lost in translation: Treatment trials in the SOD1 mouse and in human ALS. Neurobiology of Disease 2007; 26(1):1-13. ©2012 Athena Diagnostics, the Athena Diagnostics logo and Recombx are registered trademarks of Athena Diagnostics, Inc. Athena Insight is a trademark of Athena Diagnostics, Inc. ADX440SG-9/12SR-REV00