genetics of hereditary spastic paraplegia dr. arianna tucci · pathophysiology •degeneration of...

Genetics of Hereditary Spastic Paraplegia

Dr. Arianna Tucci

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Genetics of Hereditary

Spastic Paraplegia

Dr. Arianna Tucci

Clinical Research Fellow

Institute of Neurology

University College London

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• Clinical designation for neurologic syndromes

characterized by:

� Bilateral lower limb spasticity and weakness

(spastic paraparesis)

� Caused by a gene mutation

• First described by Strümpell in 1880

as an upper motor neuron syndrome

Hereditary spastic paraplegia: definition

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The motor system

1st Stage�

2nd Stage�


Dr. Arianna Tucci


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Pathophysiology

• Degeneration of the lateral corticospinal tracts

in the spinal cord (> at a thoracic level)

→Consistent with clinical findings: spasticity and weakness

in the lower limbs. Upper limbs usually not involved

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• Large group of inherited neurological disorders in which lower limbs

weakness and spasticity are the predominant symptoms

• Second most important group of motor neuron disorder

• Prevalence 1 – 10/100,000

• Genetically heterogeneous

• Usually gait impairment that begins after childhood

that worsens over many years

• Symptoms beginning at any age

• Can be associated to additional neurological abnormalities

Introduction

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Heterogeneity

• Genetic heterogeneity �� wide clinical variation:

�Variation in the severity of lower limb spasticity and weakness

�Variation in the onset and progression

�Variable presence of additional neurological features

• HSP = defines an inherited clinical syndrome characterized

by lower limbs weakness and spasticity of varying degree,

variable age at onset and variable degree of progression


Dr. Arianna Tucci


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Neuropathology

• Axon degeneration of the lateral corticospinal tracts

(> thoracic spinal cord)

• Axon degeneration of the fasciculus gracilis fibers

in the posterior columns (> cervical spinal cord)

�Most severe in the longest axons

�At the distal ends

� Little neuronal death

� Axonopathy

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The motor system

Corticospinal tracts

Posterior columns

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Classification

Clinical

A. Pure

B. Complex

Genetics

A. Autosomal dominant

B. Autosomal recessive

C. X-linked


Dr. Arianna Tucci


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Clinical features: pure forms

• Progressive walking difficulties of subtle onset

• Urinary urgency and incontinence

(occasionally a presenting feature)

• Many patients describe decreased sense of balance

• Age at onset: variable (early childhood to senescence)

• Progression: variable (functional plateau)

• In general, normal life expectancy

• Upper limbs and cranial nerves rarely involved

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Neurologic examination: pure forms

• Variable degrees of spasticity and weakness of the lower limbs

• Spasticity: hamstrings, quadriceps, adductor

and gastrocnemius-soleus muscle

• Weakness: ileopsoas, hamstring and tibialis anterior muscles

• Hyperreflexia, extensor plantar responses and ankle clonus

• Vibration sense in the toes impaired

• Mild upper limbs hyperreflexia or impaired dexterity

can be present

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Diagnosis and treatment: pure forms

• Diagnosis:

� Clinical symptoms of spastic gait impairment and neurologic

findings of lower extremity spasticity and weakness

� Often a family history of similarly affected first-degree relative(s)

� Exclusion of other disorders

� Genetic testing where possible

• Treatment: reducing symptoms and improving strength

and balance through physical therapy and rehabilitation,

devices to improve functional gait, medications and stretching

to reduce spasticity


Dr. Arianna Tucci


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Clinical classification: complex forms

• Rare

• Large number of conditions

• Lower limb weakness and spasticity combined with variable

presence of one or more complicating features:

� Cognitive impairment

� Ataxia

� Distal amyotrophy

� Peripheral neuropathy

� Neuroimaging abnormalities

(e.g. Thin corpus callosum)

� Extrapyramidal symptoms

� Optic atrophy

� Deafness

� Epilepsy

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Genetics: general features

• Genetics is a feature (Hereditary Spastic Paraplegia)

• 70 spastic paraplegia loci have been classified (Spastic Gait,

SPG1–70), with autosomal dominant, recessive and X-linked

mode of inheritance, each of which is genetically heterogeneous

• 50 causative genes

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19941994 SPG1 SPG2

19951995

19961996

19971997

19981998 SPG7

19991999

20002000

20012001

20022002 SPG10 SPG13 SPG20

20032003 SPG6 SPG21 SPG22

20042004 SPG17

20052005

20062006

SPG3A

SPG4

SPG31 SPG33

20072007 SPG8 SPG11

20082008 SPG5 SPG15 SPG35 SPG39 SPG42

20092009 SPG44 SPG50

20102010 SPG48

20112011 SPG18 SPG30 SPG47 SPG51 SPG52

20122012 SPG12 SPG28 SPG49 SPG53 SPG54 SPG55 SPG56

20132013 SPG26 SPG46 SPG57 SPG43

20142014 SPG45 SPG58 SPG59 SPG61 SPG60 to SPG70


Dr. Arianna Tucci


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Clinical heterogeneity

• Although some genetic types usually manifest as ‘pure’

(e.g. SPG4) and some as ‘complex’ (e.g. SPG11),

many genetic types are associated with both ‘pure’

and ‘complex’ HSP syndrome

• Sometimes the same mutation in a family

causes both pure and complex syndrome

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Genetics: autosomal dominant

• >70% pure forms

• Positive family history

• Incomplete penetrance

• Intrafamilial variability- Affected

- Non affected

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Genetics: autosomal dominant (2)

[CATEGORY

NAME], [VALUE]

[CATEGORY NAME],

[VALUE]

[CATEGORY NAME],

[VALUE]

[CATEGORY NAME],

[VALUE]

OTHERS, 42%

• 18 loci, 11 genes identified to date

• Relative frequencies of HSP genes in AD-HSP:

� SPG4 (SPAST), SPG3A (ATL1),

SPG31 (REEP1) up to 55%


Dr. Arianna Tucci


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• SPAST gene (spastin)

• 40-45% of AD HSP

• Phenotype: pure HSP

• Onset: from childhood to adult life (~30 yrs.)

• Progression: slow

• Incomplete penetrance (85% by age 45)

• Often complicated by cognitive decline by 60-80 yrs.

* Has been associated to cognitive impairment and dementia,

and ataxia

* MRI cerebellar atrophy and also thin corpus callosum (rare)


SPG4

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SPG4 - SPAST gene, Spastin

• 17 exons

• > 230 different mutations: missense, nonsense, splice site

mutations and insertions/deletions and large deletions

• No obvious genotype–phenotype correlations


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• ATL1 gene (atlastin)

• 10% of AD HSP (30-50% of AD HSP; onset < 10)

• Phenotype: pure

• Up to 90% penetrance

• Onset: childhood (average 4 years)

• Relatively non-progressive course

* Has been associated with motor sensory axonal neuropathy,

and/or distal amyotrophy with lower motor neuron involvement

(Silver syndrome phenotype)

* SPG3A is allelic with hereditary sensory neuropathy type 1D (HSN 1D)


SPG3A


Dr. Arianna Tucci


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SPG3A - ATL1 gene, Atlastin

• 14 exons

• Multimeric integral membrane GTPase (similar to dynamin superfamily)

• 65 mutations: > missense (1 del)

• Genotype–phenotype correlations: early-onset disease have point missense

mutations clustered around the GTPase binding domain


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• REEP1 gene (receptor expression-enhancing protein 1)

• 5% of AD HSP

• Phenotype: pure

• Onset: 1st -2nd decade (but 30% over 30 years)


• Complex phenotype has been described,

with Silver syndrome, dysarthria or tremor

* Mutations in REEP1 also cause distal hereditary

motor neuronopathy type 5B


SPG31

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• Involved in ER shaping (induction and stabilization of high curvature ER tubule)

• C-terminal domain that binds microtubules � interaction of the ER

with the cytoskeleton


SPG31 - REEP1 gene, receptor accessory protein 1


Dr. Arianna Tucci


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• Rare form of AD HSP

• BSCL2 gene (seipin)

• Seipinopathy

• Phenotype: complex, amyotrophy of small muscles of the hands

and feet (Silver syndrome)

• Onset: 2nd decade (but can be as late as 7th)


• Allelic to congenital generalized lipodystrophy type 2, Silver-syndrome,

CMT2, and distal hereditary motor neuropathy type 5


SPG17

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• 11 exons spanning at least 14 kb

• 3 mutations cause SPG31: missense (N88S, S90L and C36Y)

• Homozygous null mutations cause congenital generalized

lipodystrophy type 2

• Unknown function. Transmembrane protein (2 transmb. domains)

localized in the endoplasmic reticulum (ER)

• Mutations enhance ubiquitination,

form inclusion bodies, and appear

to be improperly folded,

leading to accumulation

of the mutant protein

in the endoplasmic reticulum (ER)


SPG17 - BSCL2 gene, Seipin

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• KIF5A gene

• 2-3% AD HSP

• Phenotype: pure and complex

• Onset: infancy to adulthood (3rd- 4th decade)

• Slowly progressive

• Complex form: sensory-motor neuropathy

most frequently associated feature

� Moreover complex cases with Silver-syndrome, mental impairment

and parkinsonism have been reported


SPG10


Dr. Arianna Tucci


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• 29 exons

• 15 mutations: > missense

• Neuronal kinesin heavy chain protein

• Kinesins are microtubule-based motor proteins

involved in the transport of organelles

in eukaryotic cells

• In neurons: transport of the proteins (cargoes)

from cell body down the axon

(anterograde transport)

• N-terminal motor domains and C-terminal

cargo-binding tail domains separated by hinge regions

• Mutations mostly in the motor domain:

impair kinesin velocity along microtubules

• Motor-based transport impairment

SPG10 - KIF5A gene, kinesin family member 5A


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• Rare (Less prevalent than autosomal dominant forms) ~<1/100,000

• > 90% complex forms

• Sporadic forms and consanguineous populations (e.g. Amish)

• Vast genetic heterogeneity and variability in the clinical phenotype

Genetics: autosomal recessive

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SPG11

45%

SPG7

6%

Others

[PERCENT

AGE]

• 44 loci

• 30 genes identified

• Thin corpus callosum: 9 loci

(most frequent SPG11 and SPG15)

Genetics: autosomal recessive (2)


Dr. Arianna Tucci


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• SPG11 gene (Spatacsin)

• ~45 % of AR HSP. Sporadic cases

• Phenotype: complex and pure

• Early onset (10 -30 years)

• Spastic paraparesis, cognitive decline (60%) (several years before

the recognition of motor dysfunction), peripheral nerve involvement

(25%). There may be upper limb involvement, ataxia and nystagmus

• Neuroradiological examination

� Thin corpus callosum (100%) (> anterior portion)

� White matter hyperintensity (100%) (> frontal horns)

� Mild enlargement lateral ventricles (80%)

Genetics: autosomal recessive (3)SPG11

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• 40 exons

• > 100 mutations: >> small indels but also missense and nonsense

• Protein of unknown function, located in axons and dendrites

• Involved in axonal maintenance and cargo trafficking

• The loss of function of spatacsin leads to axonal instability

Genetics: autosomal recessive (4)SPG11 - KIAA1840 gene, Spatacsin

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• Paraplegin protein

• 5% of AR HSP


• Onset: 11-70 years, mostly adulthood

• Associated features: Amyotrophy, peripheral neuropathy,

ataxia, optic atrophy and raised creatine kinase

Muscle biopsy: oxidative phosphorylation defect (ragged red fibers)

• Can have rapid progression (8-10 years from onset to severe disability)

* Bi-allelic SPG7 mutations also causes progressive external ophthalmoplegia

with spastic ataxia


SPG7


Dr. Arianna Tucci


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• 17 exons

• 30 mutations: > missense, (small indels)

• Nuclear-encoded mitochondrial AAA metalloprotease

• Located within the inner mitochondria membrane


SPG7 – SPG7 gene, Paraplegin

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• FA2H gene

• Rare cause of AR HSP (2nd most common AR HSP China)


• Childhood onset (6-11 years - and rapidly progressing)

• Most common associated phenotypes: extrapyramidal features,

progressive dysarthria, dementia, seizures

• MRI imaging: brain iron accumulation, white matter abnormalities,

thinning of corpus callosum


SPG35

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• 7 exons

• FA2H: Enzyme responsible for the hydroxylation of free fatty acids

prior to their incorporation into 2-hydroxylated sphingolipids

(major constituents of the myelin leaflet)

• A decrease in hydroxylated fatty acids

may lead to abnormal white matter

• Deficiency of hydroxylated fatty acids may also lead to an abnormal

increase in membrane fluidity, with implications for the regulation

of autophagy via the endosomal-lysosomal system

• A cell-cycle signaling role for FA2H has also been shown


SPG35 – FA2H gene, fatty acid 2-hydroxylase


Dr. Arianna Tucci


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• 5 loci, 3 genes:

1. SPG1 - L1CAM

2. SPG2 - PLP1

3. SPG22 – MCT8

• Mostly complex

• Affect male only

• No male to male transmission

Genetics: X-linked

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• L1CAM gene

• Most common form of X-linked HSP

• Phenotype: complex

� Part of L1 –syndrome: Involves a phenotypic spectrum ranging from severe to mild

o MASA Syndrome: Mental retardation, Aphasia, Spastic paraplegia, Adducted thumbs

o HSP + intellectual disability and corpus callosum dysplasia, hypoplasia, or aplasia

• Pathognomonic finding: bilateral absence of the pyramids

detected by MRI or autopsy

• Onset: hydrocephalus may be present prenatally, in most sever cases

• Females may manifest minor features such as adducted thumbs

and/or subnormal intelligence. Rarely do females manifest

the complete L1 syndrome phenotype

Genetics: X-linked (2)

SPG1

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• 29 exons

• L1 cell adhesion molecule

• ~250 mutations: > private, throughout the protein

• Cell surface glycoprotein

• Expressed in neurons

• On differentiated neurons, L1 is found at regions of contact between neighboring

axons and on the growth cones. The L1 protein mediates

cell-cell adhesion through interactions with other L1 protein molecules and with

various ligands

• Involved in migration and differentiation of neurons (axon pathfinding)

Genetics: X-linked (3)

SPG1 - L1CAM gene, neural cell adhesion molecule protein


Dr. Arianna Tucci


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Pathogenic mechanisms

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Conclusions

• Clinical and genetic heterogeneity

• Large group that includes many pure and complex forms

• Axonopathy

• 70 loci described, 50 genes identified

• Genetic discoveries are leading to a better understanding

of the molecular mechanisms

• Cellular pathways: ER morphology and membrane trafficking,

axonal transport, mitochondrial dysfunction, lipid metabolism

and neurodevelopmental processes

• Clarification of hereditary spastic paraplegia would bring us closer

to developing treatment for this group of disorders

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Thank you!


Dr. Arianna Tucci


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genetics of hereditary spastic paraplegia dr. arianna tucci · pathophysiology •degeneration of...

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