Hereditary spastic paraplegia
Hereditary spastic paraplegia is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness 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.
HSP is caused by defects in transport of proteins, structural proteins, cell-maintaining proteins, lipids, and other substances through the cell. Long nerve fibers 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. 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. 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, 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. 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 and paraplegin are both AAA ATPases.
Genotypes
The genes are designated SPG. The gene locations are in the format: chromosome - arm - band number. These designations are for the human genes only. The locations may 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. 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 | Variable | Pelizaeus–Merzbacher disease | |
| SPG3A | ATL1 | 14q22.1 | Autosomal dominant | Early | Strumpell disease | |
| SPG4 | SPAST | 2p22.3 | Autosomal dominant | Variable | ||
| SPG5A | CYP7B1 | 8q12.3 | Autosomal recessive | Variable | ||
| SPG6 | NIPA1 | 15q11.2 | Autosomal dominant | Variable | ||
| 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 | Adult | Kufor–Rakeb syndrome | |
| SPG79 | UCHL1 | 4p13 | Autosomal recessive | Childhood | ||
| HSNSP | CCT5 | 5p15.2 | Autosomal recessive | Childhood | Hereditary sensory neuropathy with spastic paraplegia | |
| SPG? | SERAC1 | 6q25.3 | Juvenile | MEGDEL syndrome | ||
| SPG? | 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 | KCNA2-related disorders | |
| SPG? | Granulin | 17q21.31 | ||||
| SPG? | POLR3A | 10q22.3 | Autosomal recessive |