Hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs.[1] HSP is also known as hereditary spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell disease, or Strumpell-Lorrain disease. The symptoms are a result of dysfunction of long axons in the spinal cord. The affected cells are the primary motor neurons; therefore, the disease is an upper motor neuron disease.[2] HSP is not a form of cerebral palsy even though it physically may appear and behave much the same as spastic diplegia. The origin of HSP is different from cerebral palsy. Despite this, some of the same anti-spasticity medications used in spastic cerebral palsy are sometimes used to treat HSP symptoms.

Hereditary spastic paraplegia
SpecialtyNeurology 

HSP is caused by defects in transport of proteins, structural proteins, cell-maintaining proteins, lipids, and other substances through the cell. Long nerve fibers (axons) are affected because long distances make nerve cells particularly sensitive to defects in these mentioned mechanisms.[3][4]

The disease was first described in 1880 by the German neurologist Adolph Strümpell.[5] It was described more extensively in 1888 by Maurice Lorrain, a French physician.[6] Due to their contribution in describing the disease, it is still called Strümpell-Lorrain disease in French-speaking countries. The term hereditary spastic paraplegia was coined by Anita Harding in 1983.[7]

Signs and symptoms

Symptoms depend on the type of HSP inherited. The main feature of the disease is progressive spasticity in the lower limbs due to pyramidal tract dysfunction. This also results in brisk reflexes, extensor plantar reflexes, muscle weakness, and variable bladder disturbances. Furthermore, among the core symptoms of HSP are also included abnormal gait and difficulty in walking, decreased vibratory sense at the ankles, and paresthesia.[8] Individuals with HSP can experience extreme fatigue associated with central nervous system and neuromuscular disorders, which can be disabling.[9][10][11] Initial symptoms are typically difficulty with balance, stubbing the toe or stumbling. Symptoms of HSP may begin at any age, from infancy to older than 60 years. If symptoms begin during the teenage years or later, then spastic gait disturbance usually progresses over many years. Canes, walkers, and wheelchairs may eventually be required, although some people never require assistance devices.[12] Disability has been described as progressing more rapidly in adult onset forms.[13]

More specifically, patients with the autosomal dominant pure form of HSP reveal normal facial and extraocular movement. Although jaw jerk may be brisk in older subjects, there is no speech disturbance or difficulty of swallowing. Upper extremity muscle tone and strength are normal. In the lower extremities, muscle tone is increased at the hamstrings, quadriceps and ankles. Weakness is most notable at the iliopsoas, tibialis anterior, and to a lesser extent, hamstring muscles.[13] In the complex form of the disorder, additional symptoms are present. These include: peripheral neuropathy, amyotrophy, ataxia, intellectual disability, ichthyosis, epilepsy, optic neuropathy, dementia, deafness, or problems with speech, swallowing or breathing.[14]

Anita Harding[7] classified the HSP in a pure and complicated form. Pure HSP presents with spasticity in the lower limbs, associated with neurogenic bladder disturbance as well as lack of vibration sensitivity (pallhypesthesia). On the other hand, HSP is classified as complex when lower limb spasticity is combined with any additional neurological symptom.

This classification is subjective and patients with complex HSPs are sometimes diagnosed as having cerebellar ataxia with spasticity, intellectual disability (with spasticity), or leukodystrophy.[7] Some of the genes listed below have been described in other diseases than HSP before. Therefore, some key genes overlap with other disease groups.

Age of onset

In the past, HSP has been classified as early onset beginning in early childhood or later onset in adulthood. The age of onsets has two points of maximum at age 2 and around age 40.[15] New findings propose that an earlier onset leads to a longer disease duration without loss of ambulation or the need for the use of a wheelchair.[15] This was also described earlier, that later onset forms evolve more rapidly.[13]

Cause

HSP is a group of genetic disorders. It follows general inheritance rules and can be inherited in an autosomal dominant, autosomal recessive or X-linked recessive manner. The mode of inheritance involved has a direct impact on the chances of inheriting the disorder. Over 70 genotypes had been described, and over 50 genetic loci have been linked to this condition.[16] Ten genes have been identified with autosomal dominant inheritance. One of these, SPG4, accounts for ~50% of all genetically solved cases, or approximately 25% of all HSP cases.[15] Twelve genes are known to be inherited in an autosomal recessive fashion. Collectively this latter group account for ~1/3 cases.

Most altered genes have known function, but for some the function haven't been identified yet. All of them are listed in the gene list below, including their mode of inheritance. Some examples are spastin (SPG4) and paraplegin (SPG7) are both AAA ATPases.[17]

Genotypes

The genes are designated SPG (Spastic gait gene). The gene locations are in the format: chromosome - arm (short or p: long or q) - band number. These designations are for the human genes only. The locations may (and probably will) vary in other organisms. Despite the number of genes known to be involved in this condition ~40% of cases have yet to have their cause identified.[18] In the table below SPG? is used to indicate a gene that has been associated with HSP but has not yet received an official HSP gene designation.

Genotype OMIM Gene symbol Gene locus Inheritance Age of onset Other names and characteristics
SPG1 303350 L1CAM Xq28 X-linked recessive Early MASA syndrome
SPG2 312920 PLP1 Xq22.2 X-linked recessive Variable Pelizaeus–Merzbacher disease
SPG3A 182600 ATL1 14q22.1 Autosomal dominant Early Strumpell disease (this Wiki)
SPG4 182601 SPAST 2p22.3 Autosomal dominant Variable
SPG5A 270800 CYP7B1 8q12.3 Autosomal recessive Variable
SPG6 600363 NIPA1 15q11.2 Autosomal dominant Variable
SPG7 607259 SPG7 16q24.3 Autosomal dominant Variable
SPG8 603563 KIAA0196 8q24.13 Autosomal dominant Adult
SPG9A 601162 ALDH18A1 10q24.1 Autosomal dominant Teenage Cataracts with motor neuronopathy, short stature and skeletal abnormalities
SPG9B 616586 ALDH18A1 10q24.1 Autosomal recessive Early
SPG10 604187 KIF5A 12q13.3 Autosomal dominant Early
SPG11 604360 SPG11 15q21.1 Autosomal recessive Variable
SPG12 604805 RTN2 19q13.32 Autosomal dominant Early
SPG13 605280 HSP60 2q33.1 Autosomal dominant Variable
SPG14 605229 ? 3q27–q28 Autosomal recessive Adult
SPG15 270700 ZFYVE26 14q24.1 Autosomal recessive Early
SPG16 300266 ? Xq11.2 X-linked recessive Early
SPG17 270685 BSCL2 11q12.3 Autosomal dominant Teenage
SPG18 611225 ERLIN2 8p11.23 Autosomal recessive Early
SPG19 607152 ? 9q Autosomal dominant Adult onset
SPG20 275900 SPG20 13q13.3 Autosomal recessive Early onset Troyer syndrome
SPG21 248900 ACP33 15q22.31 Autosomal recessive Early onset MAST syndrome
SPG22 300523 SLC16A2 Xq13.2 X-linked recessive Early onset Allan–Herndon–Dudley syndrome
SPG23 270750 RIPK5 1q32.1 Autosomal recessive Early onset Lison syndrome
SPG24 607584 ? 13q14 Autosomal recessive Early onset
SPG25 608220 ? 6q23–q24.1 Autosomal recessive Adult
SPG26 609195 B4GALNT1 12q13.3 Autosomal recessive Early onset
SPG27 609041 ? 10q22.1–q24.1 Autosomal recessive Variable
SPG28 609340 DDHD1 14q22.1 Autosomal recessive Early onset
SPG29 609727 ? 1p31.1–p21.1 Autosomal dominant Teenage
SPG30 610357 KIF1A 2q37.3 Autosomal recessive Teenage
SPG31 610250 REEP1 2p11.2 Autosomal dominant Early onset
SPG32 611252 ? 14q12–q21 Autosomal recessive Childhood
SPG33 610244 ZFYVE27 10q24.2 Autosomal dominant Adult
SPG34 300750 ? Xq24–q25 X-linked recessive Teenage/Adult
SPG35 612319 FA2H 16q23.1 Autosomal recessive Childhood
SPG36 613096 ? 12q23–q24 Autosomal dominant Teenage/Adult
SPG37 611945 ? 8p21.1–q13.3 Autosomal dominant Variable
SPG38 612335 ? 4p16–p15 Autosomal dominant Teenage/Adult
SPG39 612020 PNPLA6 19p13.2 Autosomal recessive Childhood
SPG41 613364 ? 11p14.1–p11.2 Autosomal dominant Adolescence
SPG42 612539 SLC33A1 3q25.31 Autosomal dominant Variable
SPG43 615043 C19orf12 19q12 Autosomal recessive Childhood
SPG44 613206 GJC2 1q42.13 Autosomal recessive Childhood/teenage
SPG45 613162 NT5C2 10q24.32–q24.33 Autosomal recessive Infancy
SPG46 614409 GBA2 9p13.3 Autosomal recessive Variable
SPG47 614066 AP4B1 1p13.2 Autosomal recessive Childhood
SPG48 613647 AP5Z1 7p22.1 Autosomal recessive 6th decade
SPG49 615041 TECPR2 14q32.31 Autosomal recessive Infancy
SPG50 612936 AP4M1 7q22.1 Autosomal recessive Infancy
SPG51 613744 AP4E1 15q21.2 Autosomal recessive Infancy
SPG52 614067 AP4S1 14q12 Autosomal recessive Infancy
SPG53 614898 VPS37A 8p22 Autosomal recessive Childhood
SPG54 615033 DDHD2 8p11.23 Autosomal recessive Childhood
SPG55 615035 C12orf65 12q24.31 Autosomal recessive Childhood
SPG56 615030 CYP2U1 4q25 Autosomal recessive Childhood
SPG57 615658 TFG 3q12.2 Autosomal recessive Early
SPG58 611302 KIF1C 17p13.2 Autosomal recessive Within first two decades Spastic ataxia 2
SPG59 603158 USP8 15q21.2 ?Autosomal recessive Childhood
SPG60 612167 WDR48 3p22.2 ?Autosomal recessive Infancy
SPG61 615685 ARL6IP1 16p12.3 Autosomal recessive Infancy
SPG62 615681 ERLIN1 10q24.31 Autosomal recessive Childhood
SPG63 615686 AMPD2 1p13.3 Autosomal recessive Infancy
SPG64 615683 ENTPD1 10q24.1 Autosomal recessive Childhood
SPG66 610009 ARSI 5q32 ?Autosomal dominant Infancy
SPG67 615802 PGAP1 2q33.1 Autosomal recessive Infancy
SPG68 609541 KLC2 11q13.1 Autosomal recessive Childhood SPOAN syndrome
SPG69 609275 RAB3GAP2 1q41 Autosomal recessive Infancy Martsolf syndrome, Warburg Micro syndrome
SPG70 156560 MARS 12q13 ?Autosomal dominant Infancy
SPG71 615635 ZFR 5p13.3 ?Autosomal recessive Childhood
SPG72 615625 REEP2 5q31 Autosomal recessive;
autosomal dominant		 Infancy
SPG73 616282 CPT1C 19q13.33 Autosomal dominant Adult
SPG74 616451 IBA57 1q42.13 Autosomal recessive Childhood
SPG75 616680 MAG 19q13.12 Autosomal recessive Childhood
SPG76 616907 CAPN1 11q13 Autosomal recessive Adult
SPG77 617046 FARS2 6p25 Autosomal recessive Childhood
SPG78 617225 ATP13A2 1p36 Autosomal recessive Adult Kufor–Rakeb syndrome
SPG79 615491 UCHL1 4p13 Autosomal recessive Childhood
HSNSP 256840 CCT5 5p15.2 Autosomal recessive Childhood Hereditary sensory neuropathy with spastic paraplegia
SPG? SERAC1 6q25.3 Juvenile MEGDEL syndrome
SPG? 605739 KY 3q22.2 Autosomal recessive Infancy
SPG? PLA2G6 22q13.1 Autosomal recessive Childhood
SPG? ATAD3A 1p36.33 Autosomal dominant Childhood Harel-Yoon syndrome
SPG? KCNA2 1p13.3 Autosomal dominant Childhood
SPG? Granulin 17q21.31
SPG? POLR3A 10q22.3 Autosomal recessive

Pathophysiology

The major feature of HSP is a length-dependent axonal degeneration.[19] These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis. The spinocerebellar tract is involved to a lesser extent. Neuronal cell bodies of degenerating axons are preserved and there is no evidence of primary demyelination.[16] Loss of anterior horn cells of the spinal cord are observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are not directly affected.

HSP affects several pathways in motor neurons. Many genes were identified and linked to HSP. It remains a challenge to accurately define the key players in each of the affected pathways, mainly because many genes have multiple functions and are involved in more than one pathway .

Overview of HSP pathogenesis on cellular level. Identified affected genes in each pathway are depicted.

Axon pathfinding

Pathfinding is important for axon growth to the right destination (e.g. another nerve cell or a muscle). Significant for this mechanism is the L1CAM gene, a cell surface glycoprotein of the immunoglobulin superfamily. Mutations leading to a loss-of-function in L1CAM are also found in other X-linked syndromes. All of these disorders display corticospinal tract impairment (a hallmark feature of HSP). L1CAM participates in a set of interactions, binding other L1CAM molecules as well as extracellular cell adhesion molecules, integrins, and proteoglycans or intracellular proteins like ankyrins.

The pathfinding defect occurs via the association of L1CAM with neuropilin-1. Neuropilin-1 interacts with Plexin-A proteins to form the Semaphorin-3A receptor complex. Semaphorin-a3A is then released in the ventral spinal cord to steer corticospinal neurons away from the midline spinal cord / medullary junction. If L1CAM does not work correctly due to a mutation, the cortiocospinal neurons are not directed to the correct position and the impairment occurs.[3]

Lipid metabolism

Axons in the central and peripheral nervous system are coated with an insulation, the myelin layer, to increase the speed of action potential propagation. Abnormal myelination in the CNS is detected in some forms of hsp HSP.[20] Several genes were linked to myelin malformation, namely PLP1, GFC2 and FA2H.[3] The mutations alter myelin composition, thickness and integrity.

Endoplasmic reticulum (ER) is the main organelle for lipid synthesis. Mutations in genes encoding proteins that have a role in shaping ER morphology and lipid metabolism were linked to HSP. Mutations in ATL1, BSCL2 and ERLIN2 alter ER structure, specifically the tubular network and the formation of three-way junctions in ER tubules. Many mutated genes are linked to abnormal lipid metabolism. The most prevalent effect is on arachidonic acid (CYP2U1) and cholesterol (CYP7B1) metabolism, phospholipase activity (DDHD1 and DDHD2), ganglioside formation (B4GALNT-1) and the balance between carbohydrate and fat metabolism (SLV33A1).[3][21][20]

Endosomal trafficking

Neurons take in substances from their surrounding by endocytosis. Endocytic vesicles fuse to endosomes in order to release their content. There are three main compartments that have endosome trafficking: Golgi to/from endosomes; plasma membrane to/from early endosomes (via recycling endosomes) and late endosomes to lysosomes. Dysfunction of endosomal trafficking can have severe consequences in motor neurons with long axons, as reported in HSP. Mutations in AP4B1 and KIAA0415 are linked to disturbance in vesicle formation and membrane trafficking including selective uptake of proteins into vesicles. Both genes encode proteins that interact with several other proteins and disrupt the secretory and endocytic pathways.[20]

Mitochondrial function

Mitochondrial dysfunctions have been connected with developmental and degenerative neurological disorders. Only a few HSP genes encode mitochondrial proteins. Two mitochondrial resident proteins are mutated in HSP: paraplegin and chaperonin 60. Paraplegin is a m-AAA metalloprotease of the inner mitochondrial membrane. It functions in ribosomal assembly and protein quality control. The impaired chaperonin 60 activity leads to impaired mitochondrial quality control. Two genes DDHD1 and CYP2U1 have shown alteration of mitochondrial architecture in patient fibroblasts. These genes encode enzymes involved in fatty-acid metabolism.

Diagnosis

Initial diagnosis of HSPs relies upon family history, the presence or absence of additional signs and the exclusion of other nongenetic causes of spasticity, the latter being particular important in sporadic cases.[7]

Cerebral and spinal MRI is an important procedure performed in order to rule out other frequent neurological conditions, such as multiple sclerosis, but also to detect associated abnormalities such as cerebellar or corpus callosum atrophy as well as white matter abnormalities. Differential diagnosis of HSP should also exclude spastic diplegia which presents with nearly identical day-to-day effects and even is treatable with similar medicines such as baclofen and orthopedic surgery; at times, these two conditions may look and feel so similar that the only perceived difference may be HSP's hereditary nature versus the explicitly non-hereditary nature of spastic diplegia (however, unlike spastic diplegia and other forms of spastic cerebral palsy, HSP cannot be reliably treated with selective dorsal rhizotomy).

Ultimate confirmation of HSP diagnosis can only be provided by carrying out genetic tests targeted towards known genetic mutations.

Classification

Hereditary spastic paraplegias can be classified based on the symptoms; mode of inheritance; the patient's age at onset; the affected genes; and biochemical pathways involved.

Treatment

No specific treatment is known that would prevent, slow, or reverse HSP. Available therapies mainly consist of symptomatic medical management and promoting physical and emotional well-being. Therapeutics offered to HSP patients include:

  • Baclofen – a voluntary muscle relaxant to relax muscles and reduce tone. This can be administered orally or intrathecally. (Studies in HSP [22][23][24])
  • Tizanidine – to treat nocturnal or intermittent spasms (studies available [25][26])
  • Diazepam and clonazepam – to decrease intensity of spasms
  • Oxybutynin chloride – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems
  • Tolterodine tartrate – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems
  • Cro System – to reduce muscle overactivity (existing studies for spasticity [27][28][29])
  • Botulinum toxin – to reduce muscle overactivity (existing studies for HSP patients[30][31])
  • Antidepressants (such as selective serotonin re-uptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors) – for patients experiencing clinical depression
  • Physical therapy – to restore and maintain the ability to move; to reduce muscle tone; to maintain or improve range of motion and mobility; to increase strength and coordination; to prevent complications, such as frozen joints, contractures, or bedsores.

Prognosis

Although HSP is a progressive condition, the prognosis for individuals with HSP varies greatly. It primarily affects the legs although there can be some upperbody involvement in some individuals. Some cases are seriously disabling while others are less disabling and are compatible with a productive and full life. The majority of individuals with HSP have a normal life expectancy.[14]

Epidemiology

Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people.[32] A Norwegian study of more than 2.5 million people published in March 2009 has found an HSP prevalence rate of 7.4/100,000 of population – a higher rate, but in the same range as previous studies. No differences in rate relating to gender were found, and average age at onset was 24 years.[33] In the United States, Hereditary Spastic Paraplegia is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health which means that the disorder affects less than 200,000 people in the US population.[32]

References
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Further reading
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