Genetics of Hereditary Spastic Paraplegia Dr. Arianna Tucci

Transcription

1 Genetics of Hereditary Spastic Paraplegia 1 Clinical Research Fellow Institute of Neurology University College London Hereditary spastic paraplegia: definition Clinical designation for neurologic syndromes characterized by: Bilateral lower limb spasticityand weakness (spastic paraparesis) Caused by a gene mutation First described by Strümpell in 1880 as an upper motor neuron syndrome 2 The motor system 1 st Stage 2 nd Stage 3 1

2 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 4 Introduction 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 5 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 6 2

3 Neuropathology Axon degeneration of the lateral corticospinaltracts (> thoracic spinal cord) Axon degeneration of the fasciculus gracilisfibers in the posterior columns (> cervical spinal cord) Most severe in the longest axons At the distal ends Little neuronal death 7 Axonopathy The motor system Posteriorcolumns 8 Corticospinaltracts Classification Clinical A.Pure B. Complex Genetics A. Autosomal dominant B. Autosomal recessive C. X-linked 9 3

4 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 10 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 11 Diagnosis and treatment: pure forms Diagnosis: 12 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 4

5 Rare 13 Clinical classification: complex forms 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 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 SPG1 SPG SPG SPG4 SPG3A SPG10 SPG13 SPG SPG6 SPG21 SPG SPG SPG31 SPG SPG8 SPG SPG5 SPG15 SPG35 SPG39 SPG SPG44 SPG SPG SPG18 SPG30 SPG47 SPG51 SPG SPG12 SPG28 SPG49 SPG53 SPG54 SPG55 SPG SPG26 SPG46 SPG57 SPG SPG45 SPG58 SPG59 SPG61 SPG60 to SPG70 5

6 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 16 Genetics: autosomal dominant >70% pure forms Positive family history Incomplete penetrance Intrafamilial variability -Affected - Non affected 17 Genetics: autosomal dominant (2) 18 loci, 11 genes identified to date Relative frequencies of HSP genes in AD-HSP: SPG4 (SPAST), SPG3A (ATL1), SPG31 (REEP1) up to 55% OTHERS, 42% [CATEGORY NAME], [VALUE] 18 [CATEGORY NAME], [VALUE] [CATEGORY NAME], [CATEGORY NAME], [VALUE] [VALUE] 6

7 SPAST gene (spastin) 40-45% of AD HSP Phenotype: pure HSP Onset: from childhood to adult life (~30 yrs.) Progression: slow 19 Genetics: autosomal dominant (3) SPG4 Incomplete penetrance (85% by age 45) Often complicated by cognitive decline by yrs. * Has been associated to cognitive impairment and dementia, and ataxia * MRI cerebellar atrophy and also thin corpus callosum (rare) 17 exons Genetics: autosomal dominant (4) SPG4- SPAST gene, Spastin > 230 different mutations: missense, nonsense, splice site mutations and insertions/deletions and large deletions No obvious genotype phenotype correlations 20 ATL1 gene (atlastin) 10% of AD HSP (30-50% of AD HSP; onset < 10) Phenotype: pure Up to 90% penetrance 21 Genetics: autosomal dominant (5) SPG3A Onset: childhood(average 4 years) Relatively non-progressive course * Has been associated with motor sensory axonal neuropathy, and/or distal amyotrophywith lower motor neuron involvement (Silver syndrome phenotype) * SPG3A is allelic with hereditary sensory neuropathy type 1D (HSN 1D) 7

8 14 exons Genetics: autosomal dominant (6) SPG3A- ATL1 gene, Atlastin 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 22 REEP1 gene (receptor expression-enhancing protein 1) 5% of AD HSP Phenotype: pure 23 Genetics: autosomal dominant (7) Onset: 1 st -2 nd decade (but 30% over 30 years) Incomplete penetrance SPG31 Complexphenotype has been described, with Silver syndrome, dysarthria or tremor * Mutations in REEP1also cause distal hereditary motor neuronopathytype 5B Genetics: autosomal dominant (8) SPG31- REEP1 gene, receptor accessory protein 1 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 24 8

9 Rare form of AD HSP BSCL2 gene (seipin) Seipinopathy 25 Genetics: autosomal dominant (9) Phenotype: complex, amyotrophy of small muscles of the hands and feet (Silver syndrome) Onset: 2 nd decade (but can be as late as 7 th ) Incomplete penetrance SPG17 Allelic to congenital generalized lipodystrophy type 2, Silver-syndrome, CMT2, and distal hereditary motor neuropathy type 5 26 Genetics: autosomal dominant (10) SPG17 - BSCL2 gene, Seipin 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) KIF5Agene 2-3% AD HSP Phenotype: pure and complex Onset: infancy to adulthood (3 rd -4 th decade) Slowly progressive 27 Genetics: autosomal dominant (11) SPG10 Complex form: sensory-motor neuropathy most frequently associated feature Moreover complex cases with Silver-syndrome, mental impairment and parkinsonism have been reported 9

10 SPG10 -KIF5Agene, kinesin family member 5A 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 28 Genetics: autosomal dominant (12) Motor-based transport impairment Genetics: autosomal recessive 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 loci 30 genes identified Genetics: autosomal recessive (2) Thin corpus callosum: 9 loci (most frequent SPG11 and SPG15) Others [PERCENT AGE] SPG11 45% 30 SPG7 6% 10

11 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 31 Genetics: autosomal recessive (3) SPG11 Thin corpus callosum (100%) (> anterior portion) White matter hyperintensity (100%) (> frontal horns) Mild enlargement lateral ventricles (80%) Genetics: autosomal recessive (4) SPG11 - KIAA1840 gene, Spatacsin 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 32 Paraplegin protein 5% of AR HSP 33 Genetics: autosomal recessive (5) Phenotype: pure and complex SPG7 Onset: 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 11

12 Genetics: autosomal recessive (6) SPG7 SPG7gene, Paraplegin 17 exons 30 mutations: > missense, (small indels) Nuclear-encoded mitochondrial AAA metalloprotease Located within the inner mitochondria membrane 34 FA2H gene Genetics: autosomal recessive (7) Rare cause of AR HSP (2 nd most common AR HSP China) Phenotype: pure and complex SPG35 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 35 7 exons 36 Genetics: autosomal recessive (8) SPG35 FA2H gene, fatty acid 2-hydroxylase 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 12

13 Genetics: X-linked 5 loci, 3 genes: 1. SPG1 -L1CAM 2. SPG2 -PLP1 3. SPG22 MCT8 Mostly complex Affect male only No male to male transmission 37 L1CAM gene Most common form of X-linked HSP Phenotype: complex 38 Genetics: X-linked (2) SPG1 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 SPG1 -L1CAMgene, neural cell adhesion molecule protein 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) 39 Genetics: X-linked (3) 13

14 Pathogenic mechanisms 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 Thank you! 42 14

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