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MOTOR NEURON DISEASE TESTING SERVICES Important Gene Tests for Hereditary Spastic Paraplegia Hereditary Spastic Paraplegia (HSP) SPG3A SPG4 CYP7B1 SPG6 SPG7 SPG8 KIF5A SPG11 ZYFVE26 SPG17 REEP1
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Page 1: Important Gene Tests for Hereditary Spastic … NEURON DISEASE TESTING SERVICES Important Gene Tests for Hereditary Spastic Paraplegia Hereditary Spastic Paraplegia (HSP) SPG3A SPG4

M O T O R N E U R O N D I S E A S E T E S T I N G S E R V I C E S

Important Gene Tests for Hereditary Spastic Paraplegia

Hereditary Spastic Paraplegia (HSP)

SPG3ASPG4

CYP7B1SPG6SPG7SPG8

KIF5ASPG11

ZYFVE26SPG17REEP1

Page 2: Important Gene Tests for Hereditary Spastic … NEURON DISEASE TESTING SERVICES Important Gene Tests for Hereditary Spastic Paraplegia Hereditary Spastic Paraplegia (HSP) SPG3A SPG4

Clinical Symptoms OverlapHSP is characterized by insidiously progressive lower-extremity weaknessand spasticity often presenting in other motor neuron diseases. DiagnosingHSP can be a challenge.

Differential Diagnosis of HSP vs. Other Neurological DiseasesDefinitively rule out serious differential diagnoses for the patient and family.

The Differential Diagnosis of HSP includes:1

Patients with HSP Benefit from TreatmentManagement of spasticity can include:1

• Tropical spastic paraplegia (caused by HTLV1 infection)

• Dopa-responsive dystonia

• Primary Lateral Sclerosis (PLS)

• Arginase deficiency

• Friedreich’s ataxia

• Machado-Joseph disease (SCA3)

• Early-onset Alzheimer diseasewith a PS1mutation

• Amyotrophic Lateral Sclerosis(ALS)

• Structural abnormalities of the brain or spinal cord

• Adrenomyeloneuropathy and other leukodystrophies

• Spastic diplegic cerebral palsy

• Multiple Sclerosis (MS)

• Vitamin B12 deficiency

– Baclofen (in advanced cases,sometimes intrathecal baclofen)

– Tizanidine

– Dantrolene

– Botox injections to relieve muscle tightness

• Daily regimen of physical therapy

• Occupational therapy

• Drugs to reduce clonus andmuscle tightness:

– Benzodiazepines

HSP is a Subset ofMotor Neuron/Axon Disease

Clinical Evaluation(Medical and

neurological histories,physical exam)

Family History(Three-generation reviewvia direct exam, medical

records includingneuroimaging,

neuropathology, neurologicexam, results of molecular

genetic testing)

HSP

ALS

PLSSMA

MND

SBMA

Evaluation Strategy for Spastic Paraplegia1

To establish the cause of spasticparaplegia in an affected person, the evaluation strategy includes:

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.

Molecular testing services for

Hereditary Spastic Paraplegia (HSP)

Page 3: Important Gene Tests for Hereditary Spastic … NEURON DISEASE TESTING SERVICES Important Gene Tests for Hereditary Spastic Paraplegia Hereditary Spastic Paraplegia (HSP) SPG3A SPG4

Testing for Other Motor Neuron DiseasesIn 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.

HSP Evaluation Test Menu – Important Factors to Consider

Information referenced to GeneReviews,1 unless otherwise noted. †Data on file at Athena Diagnostics, Inc.

Clinical Manifestations Test Prevalence

Main Clinical Features Age of Onset/Range Inheritance Classification

May resemble spastic diplegic cerebral palsy. ~ 6 yrs, 2 – 50 yrs AD Uncomplicated/ Atlastin (SPG3A) 10% ADHSP†Children with very early onset may have relatively Complicated DNA Sequencingnon-progressive spastic gait.

Mainly pure HSP ~ 29 yrs, 0 – 74 yrs AD Uncomplicated/ Spastin (SPG4) 40 – 45%Complicated DNA Sequencing uncomplicated ADHSP

Spastin (SPG4) Detects additionalMPLA Deletion 18% ADHSP†

Peripheral neuropathy, severe upper limb amyotrophy Early and late AD Uncomplicated/ KIF5A 10% of complicated(Silver syndrome-like), mental impairment, onset reported2 Complicated (SPG10) HSP in France; ~ 2% parkinsonism, deafness and/or retinitis pigmentosa2 DNA Sequencing of ADHSP2

Pure spastic paraplegia3 Mean 18 yrs, AD Uncomplicated/ REEP1 (SPG31) 8.2% pure HSP3

range 1 – 78 yrs4 Complicated4 DNA Sequencing

REEP1 (SPG31) 4.5% in ADHSP5

MPLA Deletion

Part of BSCL2-related neurologic disorders, including Adolescence to AD Complicated BSCL2 (SPG17) Underdiagnosed unknown,Silver syndrome and variants of CMT type 2, distal early adulthood DNA Sequencing so far, 11 pedigrees haveHMN type V and spastic paraplegia 17. Features been identified†include slow disease progression, upper and lowermotor neuron involvement, abnormal vibration sense and pes cavus and other foot deformities.

Progresses insidiously and may become severe ~ 22 yrs, 12 – 35 yrs AD Uncomplicated NIPA1 (SPG6) ~ 1% ADHSP†DNA Sequencing

Severe spasticity, hyperreflexia, lower-limb ~ 37 yrs, 22 – 60 yrs AD Uncomplicated KIAA0196 (SPG8) ~ 8% ADHSP†weakness and decreased vibration sensation DNA Sequencing

Insidious progressive bilateral lower-limb weakness, 25 – 42 yrs AR Uncomplicated/ Paraplegin (SPG7) ~ 5% ARHSP†spasticity. Often proximal or generalized Complicated DNA Sequencingweakness in legs and impaired vibration sense.

Spastic paraplegia, variably associated with Childhood to AR Uncomplicated/ Spatacsin (SPG11) Most common ARHSP gene tocognitive decline, thin corpus callosum, adulthood Complicated DNA Sequencing date, estimated at ~ 21% ofupper extremity weakness, dysarthria all ARHSP8 and up to 77%and nystagmus of ARHSP, depending on

ethnicity9 and 40% of cHSPwith thin corpus callosum10

Severe spastic paraplegia; other features may Mean 20 yrs, AR Uncomplicated/ CYP7B1 Mutation frequency of 7.7% include mild cerebellar ataxia and optic atrophy6 range 1 – 40 yrs Complicated6 (SPG5A) in pure recessive cases

DNA Sequencing and 6.6% in complex forms6

Early onset spastic paraplegia, cognitive deficits, 13 – 23 yrs AR Complicated Spastizin/ZYFVE26 3 – 25% frequency reportedthin corpus callosum, peripheral neuropathy (SPG15) in complicated HSP, and mild cerebellar ataxia7 DNA Sequencing population dependent7

Page 4: Important Gene Tests for Hereditary Spastic … NEURON DISEASE TESTING SERVICES Important Gene Tests for Hereditary Spastic Paraplegia Hereditary Spastic Paraplegia (HSP) SPG3A SPG4

such as Spinal Muscular Atrophy (SMA), Kennedy’s Disease (Spinal-Bulbar Muscular Atrophy, SBMA) and

Complete Autosomal Dominant Autosomal RecessiveHSP Evaluation, 655 HSP Evaluation, 653 HSP Evaluation, 654 Single Tests

• Detect more cases of HSP including • Provides high detection rates • ARHSP accounts for Individual complicated, uncomplicated, recessive, > 75 percent ADHSP approximately 20 – 30 percent gene tests dominant, sporadic • When time is a factor and of HSP cases are available

• Mutations in the same family members family history is known • Detect up to 26 – 77 percent may present with different symptoms and • HSP symptoms are widely of autosomal recessive HSP,significant variability may exist between variable. Mutations in the depending upon ethnicity8,9,10families with the same genetic type of HSP2 same family members may • Unexplained gait disturbance

• When time is a factor. When your patient present with different with no known family historyneeds immediate answers to rule out other symptoms or go unnoticed.serious differential diagnoses such as ALS.

• Avoid unnecessary tests that are time consuming, costly and invasive

Test Code

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Page 5: Important Gene Tests for Hereditary Spastic … NEURON DISEASE TESTING SERVICES Important Gene Tests for Hereditary Spastic Paraplegia Hereditary Spastic Paraplegia (HSP) SPG3A SPG4

Why Athena Diagnostics®?

Gene Tests for HSPAs genes are discovered and assays are developed, Athena Diagnosticsbrings you additional tests to detect genetic forms of HSP, rule out othersignificant causes of spastic paraplegia including ALS and guide optimaltreatment for the patient.

The Complete HSP Evaluation from Athena Diagnostics includes DNAsequencing tests for CYP7B1 (SPG5A), KIF5A (SPG10) and ZFYVE26 (SPG15),and MPLA deletion for REEP1 (SPG31). Turn to Athena Diagnostics forcomprehensive HSP genetic testing services.

Athena InsightTM Complete VariantInvestigation ServicesAthena Insight is a powerful bioinformatic servicethat is included with every DNA sequencing testordered. Our technical comprehensive analysis of variants of unknown significance determinesthe likelihood of variants being benign orpathogenic. A complete synopsis of researchdata and findings is presented in clear andconcise clinical terms enabling the physician to utilize this enhanced report with patients and family members during discussionsrelative to diagnosis, treatment, patientmanagement 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 makinginformed medical and personal decisions.

Page 6: Important Gene Tests for Hereditary Spastic … NEURON DISEASE TESTING SERVICES Important Gene Tests for Hereditary Spastic Paraplegia Hereditary Spastic Paraplegia (HSP) SPG3A SPG4

References: 1. Fink J, Hereditary Spastic Paraplegia Overview. GeneReviews. 2000/2009. 2. Goizet C, Boukhris A, Mundwiller E, et al. Complicated forms of autosomal dominanthereditary 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. ADX426SG-12/14-REV05Athena Insight is a trademark of Athena Diagnostics, Inc. Any person depicted in this material is a model.

Comprehensive Services from Athena Diagnostics

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.

Specimen Volume Test (Whole Blood, Turnaround Code Test Name Lavender Top Tube) Time

655 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 BSCL2DNA 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 20 mL 28 – 56 days (C9orf72, SOD1, OPTN, VCP, UBQLN2, FUS, TARDBP, ANG, FIG4)

Test Ordering Information for Hereditary Spastic Paraplegia


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