Hereditary Spastic Paraplegias. Clinical Spectrum and Growing … · or spastic paraplegia (SPGs)...

1Neurodegenerative Diseases | www.smgebooks.comCopyright Aleem AA.This book chapter is open access distributed under the Creative Commons Attribution 4.0 International License, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited.

Gr upSMHereditary Spastic Paraplegias. Clinical

Spectrum and Growing List of Genes

ABSTRACTHereditary spastic paraplegias (HSPs) constitute a large growing group of genetically

determined neurodegenerative disorders. The basic pathology in HSPs is degeneration of axons of the corticospinal tract, the long tract connecting cerebral cortical neurons to spinal cord ones. Axonal degenerative process is length dependent and starting most distally, the reason for the given designation of “distal axonopathy “or “retrograde degeneration”. Typically, HSPs are characterized by lower limbs progressive spasticity, muscle weakness, pyramidal signs of brisk deep tendon reflex, hypertonia, and extensor planter response, as well as associated urinary sphincter disturbance. HSPs group of disorders are one of the most clinically and genetically heterogeneous human genetic disorders. The several molecular complex mechanisms involved in axonal transport, membrane and organelle trafficking, organelle morphogenesis and distribution,

Alice K Abdel Aleem, MB, B.Ch., MDDepartment of Neurology, Weill Cornell Medical College Qatar, Qatar

*Corresponding author: Alice Abdel Aleem, Department of Neurology, Neurogenetics program, Research Division, Weill Cornell Medical College Qatar, Education City, Doha, Qatar, Email: [email protected]

This work was funded by Qatar Foundation National Priority Fund, Grant NPRP5-448-3-118.

Published Date: March 11, 2017


maintenance of healthy environments of corticospinal tract’s axons, as well as the lipid/sphingolipid/phosphatases/ and nucleotide metabolisms are the basics for the extensive genetic heterogeneity and the evolving list of genes that are expanding and discovered in relation to HSPs. This genetic heterogeneity is projected on the occurrence of various inheritance patterns; autosomal recessive, dominant, X-linked, sporadic, or mitochondrial and the association of a diverse of clinical presentations, as well as the notable phenotypic overlaps. Clinical heterogeneity in HSPs displayed marked intra- and inter-familial variability in disease age of onset, presentations spectrum, progression severity, and importantly is the association of severe neurodevelopmental, cerebellar ataxia, lower motor neuron, or neuropathy signs. In the light of such genotype and phenotype complexity, whole exome sequencing (WES) or whole genome sequencing (WGS) has progressively increasing the ability of identification of causative genes. Clinical WES is currently evolved into a mandatory diagnostic genetic tool to uncover the genetic defects in familial or sporadic HSPs.

Keywords: Hereditary spastic paraplegia; HSPs; Clinical and genetic heterogeneity; Axonal degeneration; Corticospinal tract degenration; HSPs’ molecular mechanisms; Spastic gait differential diagnosis

HSP OVERVIEWHereditary spastic paraplegias (HSPs) or spastic paraplegia (SPGs) describes a huge,

extensively heterogeneous group of inherited neurodegenerative disorders characterized mainly by spasticity and weakness (Paraparesis) of the lower limbs [1,2]. Inheritance of HSPs involves the three modes of Mendelian inheritance; Autosomal dominant, Autosomal recessive and X-linked, in addition to the non-Mendelian mitochondrial transmission [2-6]. There are several molecular and pathophysiological mechanisms described as HSPs’ causal [7-10]. However, the main pathology underlies the typical HSPs’ disease features of lower limb spasticity and muscle weakness is the retrograde degeneration of the descending motor fibers “axons” of the corticospinal tract and degeneration of the posterior column of the spinal cord [9,11,12]. Corticospinal tract is the main motor pathway controlling voluntary movements, connecting upper motor neuronal cells in cerebral cortex grey matter to lower motor neuronal cells in spinal cord grey matter. Axons of the lower motor neurons (spinal cord grey matter neuronal cells) synapse with the motor end plate at the neuromuscular junctions mediating motor voluntary movements. HSPs is a kind of upper motor neuron involvements, however, the upper motor neuron axonopathy is a rather specific designation.

In HSPs, axonal degeneration started at the most distal ends and progress further cranially toward the neuronal cells. Interestingly, there is little neuronal death in HSPs. High throughput sequencing tools, WES and WGS enabled the identification of an expanding list of genes contributing to SPGs causality [13,14]. Investigators’ efforts were, to a great extent, successful in gathering or relating different SPGs’ genes, to intersecting functional pathways or to particular molecular


mechanisms. Membrane trafficking/axonal transport related cell biological process involves the ER and Endosomal morohogenesis, ER membrane proteins, Endosomal traffic, ER-Golgi traffic, Cytoskeletal (microtubules and motor molecules) regulation, Lipid droplet biogenesis, and mitochondrial related functions [2,8,9,11,15]. Such complex machineries function in establishing a proper intracellular sorting, distribution, and transport of proteins and organelles, anterograde and retrograde, along the long corticospinal tract’s axons as well as proper maintenance of axonal myelination. Understanding these mechanisms contributing to either axonal maintenance or degeneration is of a great clinical relevance to better understanding of the rather common neurological disorders mainly those due to axonopathies, like neuropathies or multiple sclerosis.

Up to date, more than 70 Spastic paraplegias (SPGs) with identified genes or assigned loci were described encompassing 19 AD-SPGs, 48 AR –SPGs, 5 X-linked SPGs,4 mitochondrial genome associated SPGs (maternal inheritance) (Table 1).

HSPs overall prevalence was estimated, in an updated study, around 1.8/100.000. Other studies estimated a range of HSPs’ prevalence between 4.3-9.8 in100.00 [16,17].

HSPS PHENOTYPESTypical HSPs Presentations

There are standard SPG’s characteristics with or without variable association of neurological and non-neurological symptoms and signs.

The main clinical features that points out a case with a provisional clinical diagnosis of HSP involve: (i) bilateral lower limbs spasticity and weakness with repeated falling and tip-toe walking or spastic gait; (ii) signs of pyramidal involvements; exaggerated/brisk deep tendon reflexes (DTRs) with ankle clonus in some cases, spasticity in the form of limited ankle dorsiflexion, limited hips’ abduction, and up-going planter reflex “positive Babinski”; (iii) upper limbs are spared with normal tone and DTRs, in almost most of the cases; (iv) urinary urgency is of the HSPs’ primary presentation, however not in all cases; (v) familial or sporadic; the proband can be the first case in the family or has multiple affected family members with or without remote positive family history.

HSPs Clinical Classification {Clinical heterogeneity}

HSPs diagnosis should be primarily preceded by imaging of spines, spinal cord and brain to exclude structural causes of myelopathies or cerebral palsy.

HSPs is known to be largely clinically heterogeneous with a wide spectrum of presentations ranging from pure HSP of only the standard features of LL spasticity and weakness to HSP’s features associated with mental and cognitive involvements, ataxia, optic atrophy, and brain imaging abnormalities among other features [8,18,19].


· Pure forms of HSPs are described in patients who presented with rather a pure presentation of progressive pyramidal signs [brisk DTR, spasticity, hypertonia, and positive Babinski] and symptoms [tip toe gait, delayed crawling and/or walking, lower limbs weakness and frequent falling] with the common association of urinary bladder urgency. Motor development, muscle power, cognition, speech, and sensation are described as normal in pure forms of HSPs. Pure HSPs is the predominant presentation among most of the AD-HSPs, whereas it is not frequently encountered in AR forms.

· Complex HSPs (Table 1) characterized by the combined presentations of typical HSP pyramidal signs and symptoms together with the variable association of other neurologic and non-neurologic features. Associated neurological manifestations in complex forms involve cerebellar ataxia, nystagmus, a spectrum of cognitive impairments [ranging from intellectual disability to variable degrees of mental retardation up to dementia], delay in developmental milestones including speech delay and dysarthria, peripheral neuropathy, myopathic changes including muscles of the eye [ptosis and external ophthalmoplegias], convulsions, extrapyramidal manifestations [dystonia, involuntary movements, tremors or parkinsonism], brain imaging abnormalities [leukodytrophy, cerebellar hypoplasia/atrophy, small brain stem, thin/dysgenic/hypoplastic corpus callosum, brain iron accumulation, or hydrocephalus]. Other manifestations involved strabismus, optic atrophy, macular degeneration, icthyosis, facial dysmorphism, micro- or macro-cephaly, adducted thumb, Talebus deformities, congenital hip dislocation, or kyphosis/scoliosis/kyphoscoliosis.

· Pure HSPs’ phenotype is more commonly seen in families with AD-HSPs. Pure autosomal dominant HSPs described as the prevalent forms in specific population of Northern Europe, North America, and Japan [20-22]. Complicated HSPs’ phenotypes are mostly inherited as Autosomal Recessive group of disorders [10,23], which signifies the growing list of newly discovered HSP-related genes. AR-HSPs are more prevalent in Arab, Mediterranean, and non-European countries, the population with high rate of consanguineous marriages. The prevalence rate was estimated in Tunisia as 5.75/100.000 versus 0.6/100.000 in Norway [24,25].

Neuroimaging Features in HSPs’ Phenotypes

Brain MRI imaging in patients with HSPs are variable and mostly nonspecific describing white matter (WM) lesions or signal intensities abnormalities involving high signal intensity of the posterior limb of the internal capsule in T2 images, where the corticospinal tracts are routing in their way to the brain stem and spinal cord [26].

· Interesting brain MRI studies in HSPs’ patients, involving a quantitative MRI of brain volume reported a notable brain atrophy of both the grey and white matters in complex HSPs’ patients compared to age matched controls. Studies applied single-photon emission CT (SPECT) in HSPs revealed progressively metabolism of thalamus and cerebral cortex; frontal, temporal


and parietal regions [26-29]. Several other studies reported a significant atrophy of the spinal cord at the cervical and thoracic levels in AD and AR HSPs patients compared to controls [30-32].

· Thin Corpus Callosum (TCC), Brain Iron Accumulation (BIA), cerebellar hypoplasia/atrophy (CH/CA) are of the particulars seen in brain imaging of patients with certain HSPs subgroups.TCC in HSPs patients is documented to be frequently accompanied with the presentation of intellectual disability or cognitive involvements [33,34]. SPG11 and SPG 15 are the most common ARHSPs found to be associated with TCC [35,36], however; TCC was variably reported in other subtypes that were collectively labeled as “HSPs with TCC subgroup”.

· Neurodegeneration with Brain Iron Accumulation (NBIA), particularly in basal ganglion,is a group of rare autosomal recessive neurodegenerative diseases that involves a spectrum of distinguished clinical disorders of which SPG35 with mutations in FA2H has been reported [37].

· Association of cerebellar atrophy (CA) or hypoplasia (CH) in brain imaging of HSPs is commonly associated with clinical presentation of cerebellar signs [7] involving dysarthric speech (the most common associated sign in patients with complex HSP), ataxia that can be a prominent feature or only an associated presentation, coordination involvements, and nystagmus.

Rare subgroups of complex HSPs classified on the basis of particular neuroimaging characteristics

(i) “Thin Corpus Callosum SPG’s subgroup (TCC-SPG)”: SPGs with a notably thin or dysgenic corpus callosum seen in brain imaging of patients, mostly with complex forms of AR-HSP. (Figure 1 and Figure 2). TCC-SPG subgroup involves SPG11 (SPG11) [33], SPG15 (ZFYVE26) [35], SPG 7 (SpG7) [38,39], SPG21 (ACP33) [40], SPGs 44 (GJC2) [41], SPG 46 (GBA2) [42], SPG 47 (AP4B1) [43], SPG56 (CYP2U1) [44], SPG 54(DDHD2) [45], SPG45/65(NT5C2) [13].

(ii) “Brain iron accumulation SPG’s subgroup (NBIA-SPG)”: SPG characterized by the association of progressive extra pyramidal and/or parkinsonian manifestations (dystonia, choreoathetosis, rigidity) with brain imaging of iron accumulation, predominantly in the basal ganglia (figure 2). SPG35 with mutations in FA2H falls under this rare group of NBIA [46].

(iii) Cerebellar Hypoplasia/Cerebellar Atrophy, CH/CA is a brain imaging finding seen in a number of complex HSPs, in SPG46 (GBA2) [42,47] and SPG58 (KIF1C) [13,48], in particular, ataxia is of the prominent phenotypic presentations. Meanwhile, the CH in brain imaging of other SPGs forms seems rather as an associated sign [7,8]: SPG1 (L1CAM), SPG7 (SPG7), SPG11 (SPG11), SPG15 (ZFYVE26), SPG26 (B4GALNT1), SPG30 (KIF1A), SPG31 (REEP1), SPG44 (GJC2), SPG49/SPG56 (CYP2U1), SPG50 (AP4M1), SPG54 (DDHD2), SPG66 (ARSI), and SPG67 (PGAP1).


Figure 1: Brain MRI scan of two identical Egyptian twins with SPG11 from Abdel Aleem et al. [33]. Images A and B, feature TCC in both twins (black arrows), C and F, white matter hyper intensities (white arrow head). Cerebellar arachnoid cyst was present only in one of the twin,

image E (large black arrow).

Figure 2: Brain MRI of a case with FA2H mutation from Krueret al. [46].

Fig. 2A: Shows hypointense “black” signal in the globus Palidus [basal ganglion] consistent with iron accumulation [blue arrow head]. Fig 2B: Shows white matter hyper intensities. Fig 2C: Reveals TCC [pink arrow] and brain stem, spinal cord, and cerebellar atrophy (pontocerebellar atrophy) [yellow arrows].


Table 1: Inheritance, genetics, and phenotypic features of hereditary spastic paraplegias (HSPs).

Genetic Inheri-tance

SPG subtype/ chr. number/ gene name

Protein Putative protein function/molecular mechanisms

Clinical phenotype Ref

AD SPG3A /14q/ ATL1

Atlastin1. Dynamin related GTPase/ Golgi transmembrane protein

Neurite outgrowth, interact with Spastin functions in membrane trafficking, ER& Golgi morphology and trafficking, BMP signaling

Main typical presentation is pure HSP with urinary sphincter disturbance. Variable age of onset and disease progression. Atypical complex presentation of mild ID, TCC (present or absent)

8, 49,50

SPG4/2p/ SPAST

Spastin Microtubule disassembly & dynamics, axonal transport, membrane trafficking, ER morphogenesis, BMP signaling

Typical presentation of Pure HSP, variability in severity and age of onset. Atypical complex cases with nystagmus, ID, behavioral abnormalities, neuroimaging abnormalities.

15, 51, 52

SPG6/ 15q/ NIPA1 [non- imprinted gene in Prader-Willi/Angelman chromosome region]

NIPA neural protein

Endosomal/ER morphogenesis, protein folding, magnesium ion metabolism in the cell., BMP signaling

Pure and complex [seizures, ID, neuropathies] HSP’s phenotypes.

53,54

SPG8/ 8q/

KIAA0196

Strumpellin Ubiquitously expressed in cytoplasm and ER. Endosomal morphogenesis, protein folding

Phenotypes of pure (with severe spasticity) and complex [dysphagia] HSP

3, 55, 56

SPG9/10q/ ALDH18A1 [Aldehyde dehydrogenase18A1]

Glutamate semialdehyde synthetase

Denovo biosynthesis of Ornithine, proline, & arginine.

SPG9A, a dominant complicated HSP, slowly progressive, associated with dysarthria , motor neuropathy, gastro-esophageal reflux (vomiting), bones dysplasia [dysplastic hips, carpal bones], cataract, short stature, amyotrophy. SPG9B, a recessive, complicated HSP seen in Spanish and Portuguese families with sever ID, psychomotor retardation, microcephaly, dysmorphic, generalized amyotrophy.

7,8, 57

SPG10/12q/ KIF5A

Kinesin heavy chain 5A.

Axonal transport anterograde-microtubule related motor protein molecules’ transport

Pure and complex [parkinsonism, ID, ataxia, PN, distal amyotrophy, scoliosis.

3, 58, 59, 60

SPG12/ 19q/ Reticulon2 ER morphogenesis, A typical pure HSP of variable 61,


RTN2

interacts with spastin age of onset 62

SPG13/ 2q/ HSPD1/ HSPD60

Chaperonin [mt-heat shock 60KD protein 1

Protein folding and assembly in mitochondria

Pure HSP with severe spasticity 7, 63, 64

SPG17/ 11q/ BSCL2 “Silver syndrome”

Seipin ER protein Lipid metabolism, adipogenesis, ER stress response

HSP associated with distal lower limb amyotrophy, wasting of hand muscles [then arms & dorsal interossei]

65-68

SPG19/9q/

{locus}

- - Typical HSP associated with motor neuropathy

3, 69

SPG29/1p/

{locus}

- - HSP associated with hiatal & esophageal hernia, hearing loss

70

SPG31/ 2p/ REEP1 Receptor expression enhancing protein1

ER morphogenesis , mito-chondrial chaperon like activity

Pure HSP , association with distal amyotrophy , &/or dysphagia was reported. Rarely, few patients showed complicated forms.

71-73

SPG33/10q / ZFYVE27

Protrudin Spastin binding protein Pure HSP 74

SPG36/ 12q {locus}

- - Pure HSP, association with PN. 75

SPG37/ 8P {locus}

- - Pure HSP with urinary sphincter disturbance, slowly progressive course and variable age of onset

76

SPG38 /4P {locus}

- - Pure HSP associated with distal amyotrophy , lower motor neuron phenotype, similar to HSP17.

77

SPG41 /11P {locus}

- - Pure HSP, urinary sphincter disturbance, slowly progressive course.

78

SPG42/3q/ SLC33A1

Acetyl-coenzyme A transporter1 in Golgi

Transport acetyl-CoA into lumen of Golgi apparatus

Pure HSP, variable age of onset, slowly progressive course, pes cavus.

79

SPG73/19q/ CPT1C

Carnitine palmitoyl

Neuronal isoform localized to ER, not to mitochondria,

Reported in a large Italian family as adult onset slowly

80


(Carnitine Palmitoyl Transferase 1C)

transferase in the soma, dendrites, and projections of axons of motor neuron. Little activity in B-oxidation of long chain fatty acids (LCFA) compared to CPT1A & B that transport LCFA from cytoplasm to mitochondrial matrix. CPT1C Interacts with atlastin1. A role in altered lipid mediated signal transduction.

progressive pure HSP associated with mild proximal muscle wasting and atrophy, urinary dysfunction, feet deformities.

AR SPG5A/8q/

CYP7B1 [Cytochrome P450 Family7 , sub-family B1]

25-hydroxy-cholesterol 7-alpha-hydroxylase

Steroid/lipid metabolism, generation of neuroprotective steroids

Pure HSP forms of variable age of onset & slow progression course. Complex forms with spastic, cerebellar ataxia, optic atrophy. NI: cerebellar &spinal cord atrophy, WM changes.

3, 81, 82

SPG7/16q/ SPG7 (PNG) {rarely of AD or sporadic inheritance}

Paraplegin Mitochondrial protease Involved in degradation of misfolded proteins and regulation of ribosomes association at the inner mitochondrial membrane ATP-proteolytic complex.

Phenotypes either of rather pure forms, however with dysarthria, pes cavus, cerebellar ataxia or complex forms with optic atrophy, ID, ophthalmoparesis, nystagmus, scoliosis. NI: cerebral and cerebellar atrophy with WM lesions. SPG7 causative in sporadic or AR pure cerebellar ataxia.

39, 83 84

SPG11/15q/ SPG11

Spatacsin Neuronal growth, vesicles sorting and transport, intracellular cargo trafficking.

Typical HSP associated with cerebellar ataxia, ID, PN, distal amyotrophy, dysphagia, parkinsonism, macular degeneration over years. NI: TCC, mild VD, periventricular WM changes, cortical atrophy, sign of ears of the lynx.

7, 85,33,86

SPG14/3q/{locus}

- - Complex form of HSP with slowly progressive course, ID, distal motor neuropathy

87

SPG15/ 14q / ZFYVE26

Spastizin

Spinal motor neuronal axons outgrowth, lysosomal tubulation, lysosomal autophagic

Complex slowly progressive HSP phenotype with cerebellar ataxia, distal amyotrophy, demyelinating and axonal

35, 36, 88, 89


reformation. Secretory vesicles maturation, endosomal trafficking , cytokinesis

polyneuropathy, seizures, pes cavus, hearing loss, variable degrees of mental involvements, retinal degeneration [reduced visual acuity] sometimes macular degeneration, psychosis, parkinsonism. NI: cortical atrophy , TCC, WM changes

SPG18/8p/ ERLIN

Erlin2/SPFH2 ERAD pathway regulator. Modulate the ER-associated degradation pathway [ERAD] of inositol triphosphate receptors [IP3Rs] involved in intracellular cholesterol homeostasis.

Severe progressive complex HSP with marked psychomotor and mental retardation, seizures, multiple joints contractures, scoliosis.

90, 91

SPG20/13q/ SPG20 [Troyer syndrome]

Spartin Co-localize with mitochondria, partially co-localize with microtubule

Involved in lipid droplets turn over. Intracellular trafficking of epidermal growth factor receptor [EGFR], endosomal trafficking, mitochondrial function, microtubule dynamics.

Childhood onset HSP with distal, hands and feet muscle wasting, kyphoscoliosis, multiple joint contractures, hands’ joints hyperextensibility, clinodactyly, camptodacyly, pes cavus, developmental delay, cerebellar signs, dysmorphic features of hypertelorism & maxillary overgrowth, short stature. NI: cortical and cerebellar atrophy, WM changes.

8, 92, 93

SPG21/15q/ SPG21 or ACP33 [Acidic Cluster Protein 33KD] ” Mast syndrome”

Maspardin Endocytoplasmic trafficking, vesicles sorting and protein transport in trans-golgi.

Slowly progressive complex HSP with extrapyramidal &cerebellar signs, bulbar dysfunction, PN, MR, severe dementia, NI: TCC, cortical frontotemporal atrophy

8, 94

SPG23/1q DSTYK (RIP5)

DSTYK [Dusty protein kinase] or RIP5 [receptor interacting protein 5]

Dual serine-threonine and tyrosine protein kinase. A role in regulating cell death.

HSP complex phenotype with progressive loss of skin and hair pigmentation [general or patchy dyspigmentation] Peripheral neuropathy/ epilepsy, mild MR, early graying of hair, urinary developmental defects, thin face, micrognathia & microcephaly.

95- 97


SPG24/13q

/{locus}

- - Early onset pure HSP phenotype.

98

SPG25/6q /{locus}

- - Pure HSP with characteristic intervertebral cervical and lumber disk herniation, pain radiating to upper and lower limbs.

99

SPG26/12q/

B4GALNT1

Beta 1,4 N - Acetyl-galactosaminyl-transferase 1

Lipid metabolism/ ganglioside biosynthesis

Slowly progressive, variable onset complex HSP with distal amyotrophy, PN, pes cavus, scoliosis, mild MR, extrapyramidal dystonia, & dyskinesais, cerebellar ataxia, nystagmus, cataracts

100

SPG27/10q/ {locus}

- - Pure HSP phenotype 101

SPG28/14q/ DDHD1

Phosphatidic acid PhospholipaseA1 [PAPLA1]

Lipid/phospholipid/fatty acid metabolism. Maintenance of organelle ER/Golgi membrane and intracellular trafficking.

Slowly progressive, variable age of onset HSP with scoliosis, pes cavus, cerebellar oculomotor disturbance, axonal PN. Brain & skeletal muscles reduced energy metabolism in magnetic resonance spectroscopy

44

SPG30/2q /KIF1A

Kinesin-like protein KIF1A

Motor proteins, anterograde axonal transport of synaptic vesicles.

HSP with mild cerebellar ataxia & distal axonal neuropathy. NI: mild cerebellar atrophy.

8, 102

SPG32/14q /{locus}

- - Slowly progressive complex HSP with mild MR. NI: TCC, cortical & cerebellar atrophy.

3, 7, 8

SPG35/16q/ FA2H

Fatty acid 2 hydroxylase

Lipid /sphingolipid metabolism

Early onset complex HSP with mild MR, cerebellar ataxia, nystagmus, dysarthria, strabismus, optic atrophy, external ophthalmoplegia, dystonia. NI: TCC, periventricular WM hyperintensities, iron deposition in BG, mild cortical & pontocerebellar atrophy.

103104 37 46

SPG39/19p/ PNPLA6

Neuropathy target esterase [NTE]. NTE-motor neuron disease

De-esterification of membrane phosphatidyl-choline. Phospholipid homeostasis, motor neuron membrane integrity.

Slowly progressive rather pure HSP with notable upper & lower limbs distal amyotrophy, axonal neuropathy. NI: cerebellar & spinal cord

105 106


thoracic atrophy SPG43/19p/

C19ORF12

Protein C19ORF12, mitochondrial & ER protein.

- HSP associated with dysarthria, marked muscle atrophy of limbs, disuse-joints contractures.

107 108

SPG44/1q/ GJC2

Gap junction gamma-2 Protein, connexin 47 protein.

Gap junctions formation, cell to cell interactions , facilitate diffusion of ions and small molecules

HSP with cerebellar ataxia, dysarthria, pes cavus, lumber lordosis, scoliosis, seizures, hearing loss. NI: TCC, WM hypomyelination

41

SPG45 / 10q/ NT5C2 [designated also as SPG65]

Nucleotidase cytosolic 2

Cytoplasmic Hydrolase specific to IMP releasing adenosine. Functions in nucleotide purine metabolism

Early onset slowly progressive complex HSP associated with mild ID, DD. NI: TCC and WM changes.

13, 109

SPG46/9p/ GBA2

Non-lysosomal Glucosyl-ceramidase

Lipid/ganglioside metabolism

Slowly progressive HSP, urinary incontinence, cerebellar ataxia, kyphoscoliosis, pes cavus, +/- MR, head tremor, dysarthria, dementia, congenital cataracts, hearing loss, small testicles with infertility. NI: TCC, cerebral & cerebellar atrophy

42, 101

SPG47/1p/ AP4B1

AP-4 complex subunit beta-1

Endosome Cargo transport, Vesicles formation and trafficking

Neonatal hypotonia, spastic paraplegia, MR, lack of speech, dysmorphisms (microcephaly, short philtrum, wide nasal bridge with bulbous nose, bitemporal narrowing, wide mouth), short stature, acetabular dysplasia, stereotypic movements, spastic tongue protrusion, dystonia, seizures. NI: TCC, WM changes, ventricular dilatation.

43, 111

SPG48/7p/ AP-5Z1

AP-5 complex subunit zeta-1

Endosomal transport interacting with spatacsin and spastizin , DNA (double stranded) repair helicase

HSP pure or complex with urinary incontinence, MR. NI: cervical spinal cord hyperintensities.

112

SPG49/14q/ TECPR2

Tectonin B-propeller repeat-containing protein2.

Intracellular lysosomal autophagy pathway

Complex HSP with DD, ID, cerebellar ataxia, recurrent episodes of central apnoea, recurrent chest infections 2ry to gasteroesophageal reflux, dysmorphic features, microcephaly. NI: TCC, cerebral and cerebellar atrophy.

113

175

110


SPG50/7q/ AP4M1 [cerebral palsy, spastic quadriplegic type 3]

AP-4 complex subunit mu-1

Cell Cargo transport, Vesicles formation and trafficking

Neurodevelopmental phenotype of slowly progressive HSP associated with neonatal hypotonia evolved into spastic quadriplegia, lack of speech, severe MR, lack of sphincter control, strabismus, mild dysmorphic features, microcephaly. NI: TCC, cerebellar atrophy, WM changes, ventriculomegaly.

111 114

SPG51/15q/ AP4E1 cerebral palsy, spastic quadriplegic type 4]

AP-4 complex subunit epsilon 1


Clinical and imaging picture is largely similar to SPG50 with additional findings of seizures, stereotypic laughter, nystagmus

43, 115

SPG52/ 14q/ AP4S1 Cerebral Palsy, Spastic quadri-plegia type 6

AP-4 complex subunit sigma 1


HSP clinical phenotype similar to SPG50 & SPG51

43

SPG53/8p/ VPS37A

Vacuolar protein sorting 37 homolo.A

Vesicular traffecking and ubiquitination

Complex HSP with developmental and speech delay, ID, kyphosis, sternum abnormalities, dystonia.

116

SPG54/8p/ DDHD2

Phospholipase DDHD2

Lipid/phospholipid metabolism

Neurodevelopmental HSP phenotype with sychomotor and DD, ID, dysphagia, strabismus, optic nerve hypo-plasia. NI: WM changes, TCC.

45

SPG55/ 12q/ C12ORF65

Mitochondrial pr. Peptide release factor c12orf65

Mitochondrial peptide translational machinery

Progressive complex HSP, progressive visual loss- related optic atrophy, psychomotor and MR, PN, arthrogryposis.

117 118

SPG56/4q/ CYP2U1

Cytochrome P450 2U1

Fatty acid hydroxylation, lipid/fatty acid metabolism

Early onset HSP pure or complex forms with upper limbs dystonia, MR, axonal neuropathy “subclinical”. NI: TCC, WM changes.

44

SPG57/3q/ TFG

TFG protein vesicles formation and trafficking

Early onset Complex HSP with early onset optic atrophy, axonal and demyelinating sensory-motor neuropathy.

119

SPG58/17p/ Kinesin protein Retrograde motor transport Variable onset complex HSP 13


KIF1C

1C Golgi to ER with cerebellar ataxia, dysarthria, MR, microcephaly, hypodontia, extrapyramidal involuntary movements “chorea”.

SPG59/15q/ USP8

Ubiquitin speci�c protease “hydrolase” 8

Maintain the morphology of the endosome by ubiquitination of its proteins & involved in the early stage of endosomal membrane trafficking.

HSP with borderline intelligence.

13

SPG60/3p /WDR48

WDrepeat-containing protein 48

Protein regulator, regulator of deubiquitination

Infantile onset HSP with nystagmus, PN, ID.

13

SPG61/16p/ ARL6IP1

ADP-ribosylation-like protein 6-interacting protein1

Protein transport, membrane trafficking

Complex HSP with severe sensory& motor polyneuro-pathy, loss of terminal digits “severe acropathy”.

13

SPG62/10q/ ERLIN1

Erlin 1 [ER lipid RAFT associated 1]

ER associated lipid degradation

Complex HSP, cerebellar ataxia, amyotrophy

13

SPG63/1p/ AMPD2

AMP deaminase 2

Purine nucleotide metabolism, AMP into IMP deamination

Pure HSP, very slowly progressive, short stature. NI: WMC, TCC

13, 120

SPG64/10q/ ENTPD1

Ectonucleosidase triphosphate diphosphorilase 1

Hydrolase regulating Purinergic transmission

HSP slowly progressive, ID, microcephaly, delayed puberty, cerebellar signs, amyotrophy. NI: WM changes.

13

SPG66/5q/ ARSI

Arylsulphatase I Hydrolysis of sulphates esters

Very early manifested HSP, severe sensory & motor polyneuropathy. NI: TCC, cerebellar hypoplasia

13

SPG67/2q/ PGAP1

Inositol deacylase

Inositol deactylation , nucleotide metabolism

HSP with global developmental delay, hand and feet deformities.NI: cortical atrophy, cerebellar hypoplasia, hypomyelination, CC agenesis.

13

SPG68/11q/ FLRT1

Leucine-rich Transmembrane protein

Cell adhesions and receptor signaling

Typical HSP with mild spasticity, mild amyotrophy, nystagmus, optic atrophy.

13

SPG69/ 1q/ RAB3GAP2

Rab3GTPase-activating Protein 2-non-catalytic unit

Non-catalytic GTPase activating protein with RAB3 specificity generates RAB3GDP required while brain and eye development. Rab3GAP2. Golgi-ER retrograde

Complex HSP with Early onset spasticity, developmental delay, ID, dysarthria, cataracts, deafness.

13


transport, vesicles mediated transport, and Ca-dependent exocytosis of neurotransmitters is of the related pathways.

SPG70/ 12q/ MARS

Methionine-tRNA ligase

Protein biosynthesis through its aminoacyl-tRNA activity

Infantile onset HSP with marked spasticity and contractures of tendo-Achilles, Borderline IQ, rarely associated with nephrotic syndrome.

13

SPG71/5p/ ZFR

Zinc �nger RNA binding protein

RNA-binding protein with ZF domain. Involved in nucleo-cytoplasmic shuttling of another RNA-binding protein “STAU2” in neurons. Related pathways of Diurnally regulated genes.

Pure HSP with TCC. 13

SPG72/5q /REEP2

Receptor expression enhancing protein2

Involved in ER network formation, remodelling and shaping.

Presented as AD or AR pure HSP with urinary sphincter disturbance, pes cavus and rarely mild postural tremors.

121

SPG74/1q/ IBA57

IBA57 protein Iron-Sulfur cluster assembly mitochondrial protein

Involved in mitochondrial heme biosynthesis, as a part of the iron– sulfur cluster machinery in mitochondria

Early onset slowly progressive HSP associated with axonal PN, pes cavus, visual field defects, optic atrophy. Reduced activity of mitochondrial respiratory chain complexes I and II.

122

X Linked

SPG1/ Xq28/ L1CAM [L1 cell adhesion molecule]

Neural cell adhesion molecule (NCAM)

It is an axonal glycoprotein of the immunoglobulin superfamily. Cell adhesion molecule involved in neurite outgrowth, neuron to neuron adhesion, neuronal survival, & development of cerebral cortex.

Infantile onset neuro-developmental HSP. Phenotypic manifestations described under acronyms “MASA” syndrome [Mental retardation, Adducted thumbs, Shuffling gait, Aphasia] or “CRASH” syndrome (Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spastic paraplegia, and Hydrocephalus). HSP severe spasticity, dysmorphic features, pes cavus, kypho-scoliosis. NI: TCC, dilated ventricles

3,7123 124


SPG2/Xq22/ PLP1

Myelin proteolipid protein1 (MPLP1)

Myelin formation, maintenance of myelin sheath and axonal survival

HSP with marked progressive spasticity, scissoring resembling CP, MR, cerebellar ataxia signs, nystagmus, optic atrophy. NI: severe lack of myelination.

3, 125

SPG22/Xq13/ SLC16A2 (MCT8)

Mono-carboxylase transporter 8

A membrane protein involved in thyroid hormones transport and assumed to have an important role in central nervous system development.

HSP associated with neonatal hypotonia evolved into spasticity, MR, cerebellar ataxia, microcephaly, dysmorphic features including marfanoid habitus & pectus excavatum, multiple joints contractures, dystonia, amyotrophy, thyroid hormones disturbances. NI: mild hypomyelination.

126 127

SPG16/Xq11/ {locus}

- -

Very early onset complex HSP with MR, developmental delay, transient nystagmus, short and thick phalanges, maxillary hypoplasia.

8, 128

SPG34/ Xq24-25/ {locus}

- - Pure phenotype of HSPs with late childhood onset.

129

Mitochondrial {MT} MT-TI gene

mutation (m.4284G-A)

mtRNA-isolucine transfer [RNA-mitochondrial isoleucine]

transfer RNA function in mitochondria

Complex HSP with progressive ophthalmoplegia, cerebellar ataxia, MR, associated cardiomyopathy, hearing loss, diabetes.

130

MT-ATP6 gene mutation (m.9176T>C)

Complex V, ATP synthase subunit

Synthesis of ATP 6 subunit of MT-complex V

Dominant HSP with axonal neuropathy, normal lactate, reduced ATP synthesis, cerebellar signs, associated cardiomyopathy

131

MT—ND4 gene mutation (m.G11778A)

NADH ubiquinone oxidoreductase

Functions in ND4 subunit of MT-complex I

Adult onset HSP, painful spasticity, associated with visual loss and sphincter disturbance.

132

MT-CO3 gene mutation (9537insC)

Cytochrome C Oxidase (COX), Subunit III

Functions in COX complex IV

Childhood onset HSP with MR, ophthalmoplegia, severe lactic acidosis, enzyme (COX) deficient activity measured in skin or muscle biopsy.

133


Unclassi�ed syndromic HSPs AR Cerebral Palsy

spastic paraplegia Type 1 GAD1 gene/2q [L glutamate decarboxylase 1],

Glutamate decarboxylase 67-KD [GAD67] brain isoform

Conversion of glutamic acid into gamma-aminobutyric acid

Complex HSPS with marked spasticity, MR, microcephaly, scoliosis, multiple contractures, seizures.

134 135

AD Spastic Paraplegia with DNM2 mutation DNM2 gene/19p

Dynamin 2, large GTPase

functions in centrosome, intracellular membrane trafficking, endocytosis, interacts with actin and microtubules, involved in retrograde motor transport

Variable onset, slowly progressive HSP with pes cavus. Rarely with dysarthria, urinary urgency and mild MR.

136

AR FARS2 gene associated HSP/ FARS2 gene/6p

Mitochomdrial phenylalanyl-tRNA synthetase

Functions in attachment of mt-phenylalanine to its tRNA

Pure phenotype HSP 137

AD TUBB4A gene associated HSP/TUBB4A gene/19p

Beta tubulin Formation of brain specific microtubule.

Complex slowly progressive HSPs associated with cerebellar ataxia. NI: hypo-myelination

138

AR MAG gene associated HSP (SPG75)/MAG gene/19q

Myelin associated glycoprotein

Myelin formation Complex HSP with cerebellar ataxia, ID, amyotrophy.

13

AR KLC4 gene associated HSPs/KLC4 gene/6p

Kinesin light chain 4

Microtubule association as a motor transport molecule

Complex HSP with joints contractures and remarkable NI abnormalities: TCC, global cortical and cerebellar atrophy, periventricular excessive WM lesions, marked high signal at corticospinal tracts bilaterally.

139

AR Spastic paraparesis, optic atrophy, polyneuropathy syndrome (SPOAN)/KLC2 gene/11q

Kinesin light chain 2

Microtubule association as a motor transport molecule

Complex infantile onset progressive HSP with non-progressive optic atrophy, fixation nystagmus, hyperhidrosis, scoliosis, joint contracures, distal amyotrophy and sensorimotor polyneuropathy [later onset].

140 141

AR Infantile Ascending spastic paralysis (IAHSP)/ALS gene/2q

Alsin protein Small GTPase Rab5

Intracellular endoplasmic trafficking. NI: variable cortical atrophy.

Infantile complex HSP progressed into quadriplegia with dysphagia, pes cavus, abnormal eye movements,

142 143


AR Spastic paraplegia with EXOSC3 gene mutations/ Exosome gene/9p

Exosome component 3, part of the protein complex RNA exosome

Degradation of un-needed RAN molecules. Important for normal development of the cerebellum and spinal cord motor neurons

Complex HSP with mild MR, cerebellar ataxia, strabismus, distal amyotrophy, adducted thumb, atrophy of tongue, short stature. NI: cortical atrophy, vermal cerebellar hypoplasia, enlarged cisterna magna

144

AR Spastic paraplegia associated LYST gene mutations/ LYST gene/1q

Lysosomal transport protein regulator

Lysosomal trafficking and vesicular transport protein regulator

Complex HSP with cerebellar ataxia, demyelinating sensorimotor neuropathy. NI: cerebellar and spinal cord atrophy.

145

AR Spatic paraplegia associated with BICD2 gene mutations/ BICD cargo adaptor2 gene/9q

Motor adaptor protein

Involved in dynein mediated vesicular and mRNA transport

Infantile onset complex HSP associated with amyotrophy.

146

ER: Endoplasmic reticulum; ERAD: ER associated degradation; NI: Neuroimaging; ID: Intellectual disabilities; MR: Mental retardation; PN: Peripheral neuropathy; CP: Cerebellar palsy; IQ: Intellectual quotient; DD: Developmental delay, TCC: Thin corpus callosum; WM: White matter. Colored circles with number: chromosome number for each gene or locus.

Symbol: “amyotrophy” phenotypic association.

Differential Diagnosis of HSPs

The particular diseases, acquired or inherited, with a clinical picture that resembles the HSPs of lower limbs spasticity, brisk reflexes, hypertonia, with or without ataxia should be excluded (Table 2). In clinical practice, CNS and spinal cord structural, neurodegenerative, and autoimmune causes (see Table 2) usually are taking the first place of exclusion. The metabolic diseases are usually associated with particular clinical findings that can ease the clinical exclusion.


Table 2: Differential diagnosis of HSPs.Acquired Myelopathies Inherited

Structural changes Neuroinfectious& autoimmune Metabolic Disorders Other neurodegenerative

diseases

- Cerebral palsy- Cervical spine degeneration- Atlanto-axial subluxation- Chiari malformation- CNS tumor- Vascular causes; spinal cord infarction, duralarteriovenous malformation

- Myelitis- HIV- Syphilis- HTLV1- Multiple sclerosis

- Peroxisomal disorders(Adrenoleukodystrophy)

- Lysosomal diseases(GM1/GM2 gangliosidosis, Krabbe disease, Gaucher’s disease, metachromatic leukodystrophy)

- Urea cycle disorders(Arginase deficiency)

- Homocysteineremethylationdefects (Methylene-tetrahydrofolatereductase (MTHFR) deficiency, cobalamin Cdeficiency)

- Dobamine synthesis defects

- Abetalipoproteinaemia

- Biotinidase deficiency

- Vitamine B12 (subacute spinal cord degeneration) & E deficiency

- Spastic ataxias- Motor neuron disease (Primary lateral sclerosis, familial amyotrophic lateral sclerosis)-Recessive Spinocerebellar ataxias.- Inherited dementias (PSEN1-related disorders).

Table references [147-152].

Clinical investigations

Brain and spinal cord imaging should be done as a routine to exclude neuro-structural causes or specific leukodystrophies. Brain imaging is also very important to reveal HSPs associated CNS anomalies. Plasma amino acids, extended metabolic screening, very long chain fatty acids, lipoprotein profile, serum copper, vitamin E, cobalamin and homocystine are of the clinical investigations recommended in the differential diagnosis, particularly in sporadic cases. Lumber puncture and CSF analysis should be considered (suspect viral infection or to exclude multiple sclerosis).

HSPS GENETICS HETEROGENEITYHSPs comprise a markedly genetically heterogeneous group of disorders. This heterogeneity

is accounted for in different ways:

· HSPs inheritance pattern can be Mendelian, sporadic, or rarely of maternal trait. The three modes of Mendelian inheritance were observed among the various SPGs subgroup; for autosomal recessive inheritance 49 forms of AR-SPGs for the dominant, up to date 20 forms of AD-SPGs and HSPs 5 SPGs of the X-linked HSPs, were described in the literatures.

· Recent reports showed that mutations in same SPGs’ gene can produce a particular SPG subgroup segregated in different modes of inheritance, examples; SPG3A is known to be of AD inheritance, due to heterozygous mutations in ATL1, was also found to show in a recessive mode with mutations in the same gene [8,50]; SPG30 with KIF1A mutations described both in a recessive pure SPG30 and in a de-novo complex dominant SPG30 [8,102]; SPG72 described with dominant mutations in REEP2 (causing dominant negative effect on the wild encoded protein) as well as with recessive mutations leading to protein loss of functions [8,122].


· On the other side mutations in the same gene can produce two different phenotypes, even in the same family, suggesting a phenotypic spectrum of the same gene when mutated. Example; KIF5A mutation in a patient clinically presented by axonal CMT peripheral neuropathy was found to be a member of an HSP family (SPG10). This anticipated that SPG10 and CMT may present a phenotypic spectrum resulting from KIF1A mutations [153].

· Complexity of HSPs’ genetics is not only due to different genetic inheritance patterns that are impacting the recurrence rate or the anticipated disease progression, but also it is the HSPs’ contributing genes, which constitute a long and still growing list. These genes are heterogeneous both in their functions and metabolic impacts, however might interact on a similar or networking, pathways [13].

· Sporadic HSP case might presents either a de-novo mutation happens in the germ-line of the affected patient or it is actually a paternal inherited case, however with a negative family history. When the family has only carriers of recessive alleles or harboring dominant alleles of reduced penetrance then inherited Sporadic cases can possibly encountered. The SPGs genes frequently encountered in sporadic HSPs’ cases, however as well as in familial cases involve SPG 11, KIF5A, SPG7, SPAST, CYP7B1, and to less extent REEP1 and ATL1 [8,2].

Genetic Diagnosis/Genomic Testing

Exclusion of HSPs differential diagnosis is the first line in HSPs professional diagnosis.

• Taking into consideration the extensive clinical and genetic heterogeneity of various HSPs subgroups and the reported association of lower motor neuron signs, cerebellar ataxia, and even head circumference’s abnormalities; microcephaly or macrocephaly, which evolved as prominent findings in some SPGs (Table1), consequently the HSPs phenotype delineation is rather difficult. Therefore, the genetic testing tools constitute a mandatory requirement in the diagnosis of HSPs.

• Genetic testing using HSPs panel for known genes of AD and AR SPGs can be used as a first approach to genetic testing. However, the need of continuous update of this panel with the newly discovered genesas well as the progressive price reduction of the large-scale clinical whole exome sequencing (WES) places WES as the first choice when considering HSPs genetic testing. WES sequencing enables the identification of pathogenic, likely pathogenic variants in coding regions of all the human genes. The proportion of intronic, non-coding genetic mutations contribution to HSPs’ phenotypes remain to be considered, however it can be worked out only through research studies applying Whole Genomic Sequencing (WGS).

• HSPs due to mitochondrial genome related mutations; MT-ATP6 or MT-TI could account for some cases, even few, with pure or complex forms of SPGs. These cases can be overlooked, particularly with the notable intra-familial variability in clinical presentations depending on the tissues affected or rate of heteroplasmy. Paying attention to presentations indicating


mitochondrial involvements is of value in directing the genetic testing to involve mitochondrial genome.

MOLECULAR AND POTENTIAL PATHOPHYSIOLOGY MECHANISMS LEADING TO HSP’S GROUP OF DISORDERS

Degeneration of axons of the long corticospinal tract, the main pathology in HSPs starts at the most distal parts of the axons (distal axonopathy) in a retrograde fashion toward the cell body. HSPs is branded as a clinically and genetically heterogeneous group of diseases for which a large and growing list of genes is expanding. Those genes when mutated, encoding altered proteins that contributing to corticospinal tract “degeneration” and leading to a wide range of associated abnormal clinical and neuroimaging features. Proteins encoded by such list of genes are found either to interact on different molecular pathways, or act under the same functional category or involved in multiple functions such as the “Spastin”.

Maintenance of corticospinal tract’s axonal’s integrity requires multiple-functioning and interacting complex machineries to achieve the following:

- Maintain adequate levels of mitochondrial ATPase produced energy,

- Protect axonal environment against excessive oxidative stress,

- Keep normal shaping and morphogenesis of organelles (ER and Golgi) to enable their active functions in clearance of unwanted cargos,

- Act in severing/disassembly of microtubules; the axonal cytoskeleton structure, to facilitate its organization and dynamic functions in axonal transport. Microtubule dynamics is coupled to the moving motor molecules; kinesin, dynein , & actin in transporting protein cargos and vesicles along the long corticospinal tract axons in anterograde and retrograde directions,

- Maintain proper myelination process with maintenance of myelin sheath,

- Promote axonal development, and to

- promote autophagy (removing of unwanted cellular components).

Based on the above, SPGs’ proteins were grouped into a number of functioning categories or pathways, which were assumed to interact or networking together. The main functional groups, listed below, form the basis of the updated pathophysiological mechanisms underlying HSPs subgroups:

Axonal Development

X linked SPG1 and SPG22 are of the known SPGs to play a crucial role in central nervous system and axonal development.

NCAM (L1CAM), involved in X-linked SPG1, is a glycol-transmembrane protein that is expressed mainly in neurons and Schwann cells. It plays an important role in the development of


the nervous system through its interactions with other cell adhesions molecules (CAM) partners, promoting neuron-neuron adhesion and axon outgrowth [154].

SLC16A or MCT8 gene (clinical disease’s name Allan-Herndon syndrome or X-linked SPG22), MCT8 encoded protein, monocarboxylase transporter 8 is expressed in cerebral microvesels and neurons. It functions in shuttling thyroid hormones from blood- cerebrospinal fluid (CSF)-blood and in efflux of thyroid hormones’ inactive metabolites from CSF to blood and is described to lead to axons impairment when mutated [155].

Myelination Impairments

PLP1gene (X-linked SPG2) encodes the myelin proteolipid protein (MPLP). This protein comprises the major myelin protein that is responsible for stabilization and maintenance of the myelin sheath [3,125].

FA2Hgene, (SPG35) encodes an NADPH-dependent mono-oxygenase, which is involved in synthesizing 2-hydroxy fatty acids, which is further incorporated in the biosynthesis of sphingolipids and ceramide. Ceramide is of the major consitutents of myelin. FA2H encoded protein is highly expressed in oligodendrocytes [37,156] and have a role in maintaining interactions between sphingolipids and cells membrane to membrane interactions [157].

SPG42/SLC33A1 encodes the “acetyl-CoA transporter”, a multiple trans-membrane protein in the ER. It carries acetyl-CoA into the lumen of Golgi apparatus, where it is transferred to the gangliosides and glycoproteins. This gangliosides and glycoprotein modification presumed to play a critical role in motor neurons’ axons maintenance and outgrowth. Inadequate supply of acetyl-CoA, caused by a reduced flow of acetyl-CoA into the Golgi apparatus, can result in misprocessing of gangliosides and glycoproteins [79].

GJC2 (SPG44) encoded protein plays an important role in central and peripheral nervous system myelination. Gene mutations disrupt the junction channels between astrocytes and oligodendrocytes causing cells communication impairment and impaired myelin maintenance [41].

Axonal Transport

SPG10 (KIF5A), SPG30 (KIF1A) and SPG58 (KIF1C) is three HSPs associated with kinesin defects. Kinesin are motor molecules involved in anterograde transport of neurofilaments subunits, membrane vesicles, and other anterograde cellular cargos along its interaction with microtubules cytoskeleton [9,158,159].

SPG4 (SPAST) acts to severing (breaking) the microtubules promoting their dynamics in axonal transport. Spastin has multiple isoforms with rather complex subcellular localizations and hence its functions. Spastin localization at the ER, ER-Golgi compartment, cytosolic pool movable to the endosomes, in the nucleus, and to microtubules was described. Spastin interacts with protrudin promoting neurite extenstion [9,160].


Membrane and Endosome Trafficking/ Organelle Shaping

SPG3 (ATL1), SPG31 (REEP1), SPG12 (RTN2) and the interacting protein Spastin performing in shaping/morphogenesis of ER tubules membrane structures and Golgi apparatus and in formation of ER networks. Atlastin, in particular regulates ER-tubules fusion. In general, ER morphology is determined by microtubules dynamic which is dependent on spastin, interaction between spastin REEP1 and altastin promote ER-networks formation. Vesicles trafficking across ER and Golgi is altered when mutations occur in these genes [9,161,162] SPG11 (Spatacsin) and SPG15 (Spastizin ) interacting together and colocalize with the proteins functioning in trafficking vesicles, ER-shaping and in microtubules dynamics [163].

Adaptor protein (AP) complexes are ubiquitously expressed in tissues. SPG48 (AP5Z1) and AP4 complex subunits; SPG 47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1), SPG52 (AP4S1) mediate secretory vesicles formation and trafficking across Golgi compartment and endosome-lysosome system. The AP4-mediated endosomal trafficking presumed to be involved in brain development and functioning [43,164].

Bone Morphologic Protein (BMP) Signaling

Atlastin-1 (SPG3), NIPA1 (SPG6), spastin (SPG4) and spartin (SPG20) act to inhibit the bone morphogenetic protein (BMP) signaling [165]. Loss of function of these proteins leads to up-regulation of BMP pathway, which derive the assumption that the regulation of BMP signaling might be a common pathogenic mechanism in these proteins related HSPs. Interestingly, in zebrafish development, it was found that Atalstin1 regulates the axons architecture by down-regulating the BMP, loss of function mutation in Atlastin1 leads to severe axonal defects [166]. NIPA1 is expressed in early endosomes and cell surface and found to be a direct binding partner with Atlastin1 [165,167].

Oxidative Stress/Mitochondrial Related Functions

Oxidative stress as a contributing mechanism in HSPs pathogenesis was primarily identified in SPG7 mutations. Paraplegin (encoded by SPG7) was found to form a complex with AFG3L2, which is mAAA protease important for mitochondrial functions. Paraplegin forms a complex with AFG3L2 at the inner mitochondrial membrane [168]. This complex plays a key role on the oxidative-phosphorylation pathway and forms a kind of quality control over the inner mitochondrial membrane’s proteins [169,170]. Increased sensitivity to oxidative stress and impaired function of respiratory chain complex I were reported in SPG7 patients [171].

REEP1 (SPG31), localized to mitochondria and suggested to have a role in protecting the cells against oxidative stress. When mutated, mitochondrial chain complexes I and IV dysfunctions was described in SPG31 patients [172].


ATP synthase (MT-ATP6), when mutated causes dysfunctions and instability of chain complex V which is critically contributing for energy of the cells. Clinical features of HSP’s patients with MT-ATP6 was described to mimic that of patients with mt-DNA mutations [131].

Lipid Metabolism

One can anticipate how alterations in genes those encode proteins, which are related to lipids and fatty acids metabolismforms an important contributorto the pathogenesis of HSPs. Lipids, in addition to its action in cellular metabolism and as a source of energy, have a critical role in membrane’s composition.Hence,are having active roles in axonal maintenance through cell membrane integrity, permeability,intracellular membrane/organelle trafficking, and cell to cell interactions. Enzymes or proteins, which act in hydroxylation or phosphorylation of lipidsor synthesis of sterols, sphingolipids, or long chain fatty acids are constituting a list of targeted HSPs’ causative genes.The HSPs categorized under lipid metabolism pathogenesis involve SPG5 (CYP7B1), SPG49/56 (CYP2U1), SPG28(DDHD1), SPG54 (DDHD2), SPG35 (FA2H), SPG46 (GBA2), SPG44 (PNPLA6), and SPG26 (B4GALNT1). The molecular mechanism by which each one or a small related-group (the cytochromes CYP7B1 and CYP2U1) of these genes/proteins is causing the disease phenotype when mutated is not well known, however; speculation were presumed for some of them. Examples; CYP7B1 hydroxylates specific sterol compounds (Dehydroepianderosterone) in the body converting it into neurosteroids, which is presumed to have a neuro-protective activity [173]. PNPLA6 is a phospholipase that functions to maintain cell membrane integrity through its role in phospholipid homeostasis and hence its suggested role in axonal maintenance [174].

Nucleotide Metabolism

Purines and pyrimidine are known for their role in DNA synthesis and repair. AMPD2 [13], ENTPD1 [13], and NT5C2 [13,175] have critical roles in maintaining the balance of purines, nucleotides, nucleosides, and free bases in brain and spinal cord. Additionally, NT5C2 [175] when its two copies are mutated leads to striking involvements of central white matter structures, presumed to be due to its role on oligodendrocytes maturation and differentiation [175].

CONCLUSIONHereditary spastic paraplegiasisa group of “rare” neurodegenerative diseases affecting a

particular axonal tract, the corticospinal tract, which descends from the cortical upper motor neurons and synapsis with the lower motor neurons of the spinal cord. That is, theoretically, no involvements of upper motor neuronal cells or of lower motor neurons is anticipated. However, a quite number of HSPs are described to be associated with amyotrophy or motor neuropathies which constitute interesting findings that require further experimental investigations. Detection of the convergent/ interacting pathways or molecules that eventually leads to lower motor neuron involvements has the great potential to better understanding of the diseases pathophysiology and the clinical spectrum and its anticipated progression.


In countries with a high rate of consanguineous marriages, HSPs are not that rare; multiple affected members and several affected branches of the same core family is the usual presentation.

Large scale sequencing technologies, WES, next generation sequencing or WGS are evolving as the most important laboratory tools to diagnose HSPs. Gene identification in HSPs is essential to provide genetic counseling to families with HSPs, to enable primary prevention through carrier detection, prenatal diagnosis, and preimplentation genetics.

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