Hereditary spastic paraplegia
Specialty	Neurology

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.

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.^{[citation needed]}

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.^{[citation needed]}

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] 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.^[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.^{[citation needed]}

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.

Zdroj:https://en.wikipedia.org?pojem=Spastic_paraplegia
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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 recessive	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