Important Gene Tests for Hereditary Spastic Paraplegia Hereditary Spastic ... • Multiple Sclerosis (MS) ... Genetic Testing*
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Hereditary Spastic Paraplegia (HSP) SPG3A SPG4 CYP7B1 SPG6 SPG7 SPG8 KIF5A SPG11 ZYFVE26 SPG17 REEP1
Important Gene Tests for Hereditary Spastic Paraplegia
Molecular testing services for
Hereditary Spastic Paraplegia (HSP)
HSP is a Subset of Motor Neuron/Axon Disease
Clinical Symptoms Overlap HSP is characterized by insidiously progressive lower-extremity weakness and spasticity often presenting in other motor neuron diseases. Diagnosing HSP can be a challenge.
Differential Diagnosis of HSP vs. Other Neurological Diseases Definitively rule out serious differential diagnoses for the patient and family. The Differential Diagnosis of HSP includes: • Amyotrophic Lateral Sclerosis (ALS)
• Tropical spastic paraplegia (caused by HTLV1 infection)
• Structural abnormalities of the brain or spinal cord
• Dopa-responsive dystonia
• Adrenomyeloneuropathy and other leukodystrophies
• Arginase deficiency
• Multiple Sclerosis (MS) • Vitamin B12 deficiency
SBMA
ALS
SMA PLS
1
• Spastic diplegic cerebral palsy
MND
HSP
• Primary Lateral Sclerosis (PLS) • Friedreich’s ataxia • Machado-Joseph disease (SCA3) • Early-onset Alzheimer disease with a PS1 mutation
Patients with HSP Benefit from Treatment
Evaluation Strategy for Spastic Paraplegia1 To establish the cause of spastic paraplegia in an affected person, the evaluation strategy includes: Clinical Evaluation (Medical and neurological histories, physical exam)
Management of spasticity can include:1 • Daily regimen of physical therapy
– Baclofen (in advanced cases, sometimes intrathecal baclofen)
• Occupational therapy
– Tizanidine
• Drugs to reduce clonus and muscle tightness:
– Dantrolene
– Benzodiazepines
– Botox injections to relieve muscle tightness
Family History (Three-generation review via direct exam, medical records including neuroimaging, neuropathology, neurologic exam, results of molecular genetic testing)
Molecular Genetic Testing*
*Genetic loci for HSP are designated “SPG” (spastic gait) followed consecutively by the locus number assigned in order of discovery—the first locus identified was named SPG1.
HSP Evaluation Test Menu – Important Factors to Consider
Clinical Manifestations Main Clinical Features
Test
Prevalence
Age of Onset/Range
Inheritance
Classification
May resemble spastic diplegic cerebral palsy. Children with very early onset may have relatively non-progressive spastic gait.
~ 6 yrs, 2 – 50 yrs
AD
Uncomplicated/ Complicated
Atlastin (SPG3A) DNA Sequencing
Mainly pure HSP
~ 29 yrs, 0 – 74 yrs
AD
Uncomplicated/ Complicated
Spastin (SPG4) DNA Sequencing
40 – 45% uncomplicated ADHSP
Spastin (SPG4) MPLA Deletion
Detects additional 18% ADHSP†
10% ADHSP†
Peripheral neuropathy, severe upper limb amyotrophy (Silver syndrome-like), mental impairment, parkinsonism, deafness and/or retinitis pigmentosa2
Early and late onset reported2
AD
Uncomplicated/ Complicated
KIF5A (SPG10) DNA Sequencing
10% of complicated HSP in France; ~ 2% of ADHSP2
Pure spastic paraplegia3
Mean 18 yrs, range 1 – 78 yrs4
AD
Uncomplicated/ Complicated4
REEP1 (SPG31) DNA Sequencing
8.2% pure HSP3
REEP1 (SPG31) MPLA Deletion
4.5% in ADHSP5 Underdiagnosed unknown, so far, 11 pedigrees have been identified†
Part of BSCL2-related neurologic disorders, including Silver syndrome and variants of CMT type 2, distal HMN type V and spastic paraplegia 17. Features include slow disease progression, upper and lower motor neuron involvement, abnormal vibration sense and pes cavus and other foot deformities.
Adolescence to early adulthood
AD
Complicated
BSCL2 (SPG17) DNA Sequencing
Progresses insidiously and may become severe
~ 22 yrs, 12 – 35 yrs
AD
Uncomplicated
NIPA1 (SPG6) DNA Sequencing
Severe spasticity, hyperreflexia, lower-limb weakness and decreased vibration sensation
~ 37 yrs, 22 – 60 yrs
AD
Uncomplicated
KIAA0196 (SPG8) DNA Sequencing
25 – 42 yrs
AR
Uncomplicated/ Paraplegin (SPG7) Complicated DNA Sequencing
Childhood to adulthood
AR
Uncomplicated/ Complicated
Spatacsin (SPG11) Most common ARHSP gene to DNA Sequencing date, estimated at ~ 21% of all ARHSP8 and up to 77% of ARHSP, depending on ethnicity9 and 40% of cHSP with thin corpus callosum10
Severe spastic paraplegia; other features may include mild cerebellar ataxia and optic atrophy6
Mean 20 yrs, range 1 – 40 yrs
AR
Uncomplicated/ Complicated6
CYP7B1 (SPG5A) DNA Sequencing
Early onset spastic paraplegia, cognitive deficits, thin corpus callosum, peripheral neuropathy and mild cerebellar ataxia7
13 – 23 yrs
AR
Complicated
Insidious progressive bilateral lower-limb weakness, spasticity. Often proximal or generalized weakness in legs and impaired vibration sense. Spastic paraplegia, variably associated with cognitive decline, thin corpus callosum, upper extremity weakness, dysarthria and nystagmus
~ 1% ADHSP† ~ 8% ADHSP† ~ 5% ARHSP†
Mutation frequency of 7.7% in pure recessive cases and 6.6% in complex forms6
Spastizin/ZYFVE26 3 – 25% frequency reported (SPG15) in complicated HSP, DNA Sequencing population dependent7
Information referenced to GeneReviews,1 unless otherwise noted. †Data on file at Athena Diagnostics, Inc.
Testing for Other Motor Neuron Diseases In addition to a full menu of HSP genetic assays, Athena Diagnostics offers additional tests for the detection of other Motor Neuron Diseases Amyotrophic Lateral Sclerosis (ALS). Please refer to Athena Diagnostics comprehensive test menu on the back page.
Complete HSP Evaluation, 655
Autosomal Dominant HSP Evaluation, 653
• Detect more cases of HSP including complicated, uncomplicated, recessive, dominant, sporadic • Mutations in the same family members may present with different symptoms and significant variability may exist between families with the same genetic type of HSP2 • When time is a factor. When your patient needs immediate answers to rule out other serious differential diagnoses such as ALS. • Avoid unnecessary tests that are time consuming, costly and invasive
• Provides high detection rates > 75 percent ADHSP • When time is a factor and family history is known • HSP symptoms are widely variable. Mutations in the same family members may present with different symptoms or go unnoticed.
Autosomal Recessive HSP Evaluation, 654 • ARHSP accounts for approximately 20 – 30 percent of HSP cases • Detect up to 26 – 77 percent of autosomal recessive HSP, depending upon ethnicity8,9,10 • Unexplained gait disturbance with no known family history
Single Tests Individual gene tests are available
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531
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530
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534
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613
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529
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665
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631
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532
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533
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632
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633
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612
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614
such as Spinal Muscular Atrophy (SMA), Kennedy’s Disease (Spinal-Bulbar Muscular Atrophy, SBMA) and
Why Athena Diagnostics®?
Gene Tests for HSP As genes are discovered and assays are developed, Athena Diagnostics brings you additional tests to detect genetic forms of HSP, rule out other significant causes of spastic paraplegia including ALS and guide optimal treatment for the patient. The Complete HSP Evaluation from Athena Diagnostics includes DNA sequencing tests for CYP7B1 (SPG5A), KIF5A (SPG10) and ZFYVE26 (SPG15), and MPLA deletion for REEP1 (SPG31). Turn to Athena Diagnostics for comprehensive HSP genetic testing services.
Athena InsightTM Complete Variant Investigation Services Athena Insight is a powerful bioinformatic service that is included with every DNA sequencing test ordered. Our technical comprehensive analysis 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.
A Team of Genetic Counselors 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.
Comprehensive Services from Athena Diagnostics Test Ordering Information for Hereditary Spastic Paraplegia Specimen Volume (Whole Blood, Lavender Top Tube)
Turnaround Time
Complete Hereditary Spastic Paraplegia Evaluation
20 mL
28 – 56 days
653
Autosomal Dominant Hereditary Spastic Paraplegia Evaluation
20 mL
28 – 56 days
654
Autosomal Recessive Hereditary Spastic Paraplegia Evaluation
10 mL
28 – 56 days
531
Atlastin (SPG3A) DNA Sequencing Test
10 mL
28 – 56 days
530
Spastin (SPG4) DNA Sequencing Test
10 mL
28 – 56 days
534
Spastin (SPG4) Deletion Test
10 mL
28 – 56 days
612
CYP7B1 (SPG5A) DNA Sequencing Test
10 mL
28 – 56 days
532
NIPA1 (SPG6) DNA Sequencing Test
10 mL
28 – 56 days
632
Paraplegin (SPG7) DNA Sequencing Test
10 mL
28 – 56 days
533
KIAA0196 (SPG8) DNA Sequencing Test
10 mL
28 – 56 days
613
KIF5A (SPG10) DNA Sequencing Test
10 mL
28 – 56 days
633
Spatacsin (SPG11) DNA Sequencing Test
10 mL
28 – 56 days
614
Spastizin (ZYFVE26) DNA Sequencing Test (SPG15)
10 mL
28 – 56 days
631
BSCL2 DNA Sequencing Test
10 mL
28 – 56 days
529
REEP1 (SPG31) DNA Sequencing Test
10 mL
28 – 56 days
665
REEP1 (SPG31) Deletion Analysis
10 mL
28 – 56 days
111D
Spinal Muscular Atrophy Diagnostic Test
2 – 4 mL
7 days
117
Kennedy’s Disease (SBMA) DNA Test
10 mL
28 – 56 days
643
Complete ALS Evaluation (C9orf72, SOD1, OPTN, VCP, UBQLN2, FUS, TARDBP, ANG, FIG4)
20 mL
28 – 56 days
Test Code
Test Name
655
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. Fink J, Hereditary Spastic Paraplegia Overview. GeneReviews. 2000/2009. 2. Goizet C, Boukhris A, Mundwiller E, et al. Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. Mutation in Brief 2008; 1038, 30:E376-E385. 3. Beetz C, SchuÅsle R, Deconinck T, et al. REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31. Brain 2008; 10.1093/awn026. 4. Goizet C, Depienne C, Benard G, REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction. Human Mutation, 2011; 10.1002/humu.21542 5. Battini R, Fogli A, Borghetti D, et al. Clinical and genetic findings in a series of Italian children with pure hereditary spastic paraplegia. Eur J Neurol 2011; 18:150-157. 6. Arnoldi A, Crimella C, Tenderini E, et al. Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations. Clin Genet 2011; 1399-0004.2011.01624.x. 7. Schüle R, Schlipf N, Synofzik M, Frequency and phenotype of SGG11 and SPG15 in complicated hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 2009; 80:1401-1404. 8. Stevanin G, et al. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus collosum, cognitive decline and lower motor neuron degeneration. Brain, 2008; 131:772-784. 9. Boukhris A, et al. Hereditary spastic paraplegia with mental impairment and thin corpus collosum in Tunisia, Arch Neurol. 2008; 65(3):393-402. 10. Crimella C, et al. Point mutations and a large intragenic deletion in SPG11 in complicated spastic paraplegia without thin corpus collosum, J. Med Genet, 2009; 46:345-356. ©2014 Athena Diagnostics, Inc. Athena Diagnostics and the Athena Diagnostics logo are registered trademarks of Athena Diagnostics, Inc. Athena Insight is a trademark of Athena Diagnostics, Inc. Any person depicted in this material is a model.
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