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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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534

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613

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529

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665

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532

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533

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632

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633

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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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