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MOTOR
NEURON
DISEASE
TESTING
SERVICES
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
Test Code
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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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