Download Important NEW Discoveries and the Latest Molecular Tests for ALS

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.
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