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. 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. 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, they are very common in people with epilepsy, starting at age 40.

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.

The disease was first described in 1880 by the German neurologist Adolph Strümpell. It was described more extensively in 1888 by Maurice Lorrain, a French physician.Lorrain, Maurice. Contribution à l'étude de la paraplégie spasmodique familiale: travail de la clinique des maladies du système nerveux à la Salpêtrière. G. Steinheil, 1898. 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.

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. Individuals with HSP can experience extreme fatigue associated with central nervous system and neuromuscular disorders, which can be disabling. 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. Disability has been described as progressing more rapidly in adult onset forms.

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. 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.

Anita Harding 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. 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. 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. This was also described earlier, that later onset forms evolve more rapidly. However, this is not always the case as De Novo Early Onset SPG4, a form of infantile HSP, involves loss of ambulation and other motor skills.

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.Schüle R, Schöls L (2011) Genetics of hereditary spastic paraplegias. Semin Neurol 31(5):484-493 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. 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.Wang YG, Shen L (2009) AAA ATPases and hereditary spastic paraplegia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 26(3):298-301

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.Helbig KL, Hedrich UB, Shinde DN, Krey I, Teichmann AC, Hentschel J, Schubert J, Chamberlin AC, Huether R, Lu HM4, Alcaraz WA, Tang S, Jungbluth C, Dugan SL, Vainionpää L, Karle KN, Synofzik M, Schöls L, Schüle R, Lehesjoki AE, Helbig I, Lerche H, Lemke JR (2016) A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia. Ann Neurol 80(4) 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 L1CAM Xq28 X-linked recessive Early MASA syndrome SPG2 PLP1 Xq22.2 X-linked recessive VariablePelizaeus–Merzbacher disease SPG3A ATL1 14q22.1 Autosomal dominant EarlyStrumpell disease (this Wiki) SPG4 SPAST 2p22.3 Autosomal dominant Variable SPG5A CYP7B1 8q12.3 Autosomal recessive Variable SPG6 NIPA1 15q11.2 Autosomal dominantVariable SPG7 SPG7 16q24.3 Autosomal recessive Variable SPG8 KIAA0196 8q24.13 Autosomal dominant Adult SPG9A ALDH18A1 10q24.1 Autosomal dominant Teenage Cataracts with motor neuronopathy, short stature and skeletal abnormalities SPG9B ALDH18A1 10q24.1 Autosomal recessive Early SPG10 KIF5A 12q13.3 Autosomal dominant Early SPG11 SPG11 15q21.1 Autosomal recessive Variable SPG12 RTN2 19q13.32 Autosomal dominant Early SPG13 HSP60 2q33.1 Autosomal dominant Variable SPG14 3q27–q28 Autosomal recessive Adult SPG15 ZFYVE26 14q24.1 Autosomal recessive Early SPG16 Xq11.2 X-linked recessive Early SPG17 BSCL2 11q12.3 Autosomal dominant Teenage SPG18 ERLIN2 8p11.23 Autosomal recessive Early SPG19 9q Autosomal dominant Adult onset SPG20 SPG20 13q13.3 Autosomal recessive Early onset Troyer syndrome SPG21 ACP33 15q22.31 Autosomal recessive Early onset MAST syndrome SPG22 SLC16A2 Xq13.2 X-linked recessive Early onset Allan–Herndon–Dudley syndrome SPG23 RIPK5 1q32.1 Autosomal recessive Early onset Lison syndrome SPG24 13q14 Autosomal recessive Early onset SPG25 6q23–q24.1 Autosomal recessive Adult SPG26 B4GALNT1 12q13.3 Autosomal recessive Early onset SPG27 10q22.1–q24.1 Autosomal recessive Variable SPG28 DDHD1 14q22.1 Autosomal recessive Early onset SPG29 1p31.1–p21.1 Autosomal dominant Teenage SPG30 KIF1A 2q37.3 Autosomal recessive Teenage SPG31 REEP1 2p11.2 Autosomal dominant Early onset SPG32 14q12–q21 Autosomal recessive Childhood SPG33 ZFYVE27 10q24.2 Autosomal dominant Adult SPG34 Xq24–q25 X-linked recessive Teenage/Adult SPG35 FA2H 16q23.1 Autosomal recessive Childhood SPG36 12q23–q24 Autosomal dominant Teenage/Adult SPG37 8p21.1–q13.3 Autosomal dominant Variable SPG38 4p16–p15 Autosomal dominant Teenage/Adult SPG39 PNPLA6 19p13.2 Autosomal recessive Childhood SPG41 11p14.1–p11.2 Autosomal dominant Adolescence SPG42 SLC33A1 3q25.31 Autosomal dominant Variable SPG43 C19orf12 19q12 Autosomal recessive Childhood SPG44 GJC2 1q42.13 Autosomal recessive Childhood/teenage SPG45 NT5C2 10q24.32–q24.33 Autosomal recessive Infancy SPG46 GBA2 9p13.3 Autosomal recessive Variable SPG47 AP4B1 1p13.2 Autosomal recessive Childhood SPG48 AP5Z1 7p22.1 Autosomal recessive 6th decade SPG49 TECPR2 14q32.31 Autosomal recessive Infancy SPG50 AP4M1 7q22.1 Autosomal recessive Infancy SPG51 AP4E1 15q21.2 Autosomal recessive Infancy SPG52 AP4S1 14q12 Autosomal recessive Infancy SPG53 VPS37A 8p22 Autosomal recessive Childhood SPG54 DDHD2 8p11.23 Autosomal recessive Childhood SPG55 C12orf65 12q24.31 Autosomal recessive Childhood SPG56 CYP2U1 4q25 Autosomal recessive Childhood SPG57 TFG 3q12.2 Autosomal recessive Early SPG58 KIF1C 17p13.2 Autosomal recessive Within first two decades Spastic ataxia 2 SPG59 USP8 15q21.2 ?Autosomal recessive Childhood SPG60 WDR48 3p22.2 ?Autosomal recessive Infancy SPG61 ARL6IP1 16p12.3 Autosomal recessive Infancy SPG62 ERLIN1 10q24.31 Autosomal recessive Childhood SPG63 AMPD2 1p13.3 Autosomal recessive Infancy SPG64 ENTPD1 10q24.1 Autosomal recessive Childhood SPG66 ARSI 5q32 ?Autosomal dominant Infancy SPG67 PGAP1 2q33.1 Autosomal recessive Infancy SPG68 KLC2 11q13.1 Autosomal recessive Childhood SPOAN syndrome SPG69 RAB3GAP2 1q41 Autosomal recessive Infancy Martsolf syndrome, Warburg Micro syndrome SPG70 MARS 12q13 ?Autosomal dominant Infancy SPG71 ZFR 5p13.3 ?Autosomal recessive Childhood SPG72 REEP2 5q31 Autosomal recessive;autosomal dominant Infancy SPG73 CPT1C 19q13.33 Autosomal dominant Adult SPG74 IBA57 1q42.13 Autosomal recessive Childhood SPG75 MAG 19q13.12 Autosomal recessive Childhood SPG76 CAPN1 11q13 Autosomal recessive Adult SPG77 FARS2 6p25 Autosomal recessive Childhood SPG78 ATP13A2 1p36 Autosomal recessive AdultKufor–Rakeb syndrome SPG79 UCHL1 4p13 Autosomal recessive ChildhoodHSNSP CCT5 5p15.2 Autosomal recessive ChildhoodHereditary sensory neuropathy with spastic paraplegiaSPG? SERAC1 6q25.3 Juvenile MEGDEL syndromeSPG? KY 3q22.2 Autosomal recessive InfancySPG? PLA2G6 22q13.1 Autosomal recessive ChildhoodSPG? ATAD3A 1p36.33 Autosomal dominant Childhood Harel-Yoon syndromeSPG? KCNA2 1p13.3 Autosomal dominant ChildhoodKCNA2-related disordersSPG? Granulin 17q21.31SPG? POLR3A 10q22.3 Autosomal recessive

Pathophysiology