Hereditary spastic paraplegia

Hereditary spastic paraplegia
Classification and external resources
Specialty neurology
ICD-10 G11.4
ICD-9-CM 334.1
OMIM 312920 PS303350
DiseasesDB 33207
eMedicine pmr/45
MeSH D015419

Hereditary spastic paraplegia (HSP), also known as hereditary spastic paraparesis, familial spastic paraplegias, French settlement disease, or Strumpell-Lorrain disease, is a group of inherited diseases whose main feature is progressive stiffness and contraction (spasticity) in the lower limbs,[1] as a result of damage to or dysfunction of the nerves.[2][3]

HSP is not a form of cerebral palsy even though it physically may appear and behave much the same as, for example, spastic diplegia. The origins of HSP are entirely separate phenomena from cerebral palsy. Despite this, some of the same anti-spasticity medications used in spastic cerebral palsy are sometimes used to try to treat HSP symptomatology.

The condition sometimes also affects the optic nerve and retina of the eye, causes cataracts, ataxia (lack of muscle coordination), epilepsy, cognitive impairment, peripheral neuropathy, and deafness.[4] HSP is caused by defects in the mechanisms that transport proteins and other substances through the cell. Long nerves are affected because they have to transport cellular material through long distances, and are particularly sensitive to defects of cellular transport.[5]

Hereditary spastic paraplegia was first described in 1883 by Adolph Strümpell, a German neurologist, and was later described more extensively in 1888 by Maurice Lorrain, a French physician.

Neuropathology

The major neuropathologic feature of HSP is axonal degeneration that is maximal in the terminal portions of the longest descending and ascending tracts. These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis.[6] The spinocerebellar tract is involved to a lesser extent. Neuronal cell bodies of degenerating fibers are preserved and there is no evidence of primary demyelination.[7] Loss of anterior spinal horn is observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are normal.[8]

Classification

Hereditary spastic paraplegias are classified based on the symptoms; on their mode of inheritance; on the patient’s age at onset; and, ultimately, on the gene associated with the condition.

Based on symptoms


Spasticity in the lower limbs alone is described as pure HSP. On the other hand, HSP is classified as complex or complicated when associated with other neurological signs, including ataxia, mental retardation, dementia, extrapyramidal signs, visual dysfunction or epilepsy, or with extraneurological signs. Complicated forms are diagnosed as HSPs when pyramidal signs are the predominant neurological characteristic. This classification, however, is subjective and patients with complex HSPs are sometimes diagnosed as having cerebellar ataxia, mental retardation or leukodystrophy.[9]

Based on mode of inheritance


HSP being a group of genetic disorders, they follow 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 have been described.

Over 50 genetic loci have been linked to this condition.[10] Ten genes have been identified with autosomal dominant inheritance. One of these SPG4 accounts for ~50% of all cases. Twelve genes are known to be inherited in an autosomal recessive fashion. Collectively this latter group account for ~1/3 cases.

The functions of a number of these genes are known: spastin (SPG4) and paraplegin (SPG7) are both AAA ATPases.[11] Spastizin (ZFYVE26) is zinc finger transcription factor: mutations in this gene cause SPG15. The inheritance of SPG15 is autosomal recessive.

Based on patient's age at onset


In the past, HSP also has been classified as type I or type II on the basis of the patient's age at the onset of symptoms, which influences the amount of spasticity versus weakness. Type I is characterized by age onset below 35 years, whereas Type II is characterized by onset over 35 years. In the type I cases, delay in walking is not infrequent and spasticity of the lower limbs is more marked than weakness. In the type II muscle weakness, urinary symptoms and sensory loss are more marked. Furthermore, type II form of HSP usually evolves more rapidly.[12]

Summary of 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.

Genotype Gene name Gene function Inheritance Age of onset Gene location
SPG1 L1 cell adhesion molecule (CD171) Glycoprotein X linked recessive Early Xq28
SPG2 Proteolipid protein 1 Transmembrane protein X linked recessive Variable Xq22.2
SPG3A Atlastin Membrane anchored GTPase Autosomal dominant Early 14q22.1
SPG4 Spastin AAA ATPase Autosomal dominant Variable 2p22.3
SPG5 25-hydroxycholesterol 7-alpha-hydroxylase Cytochrome P45 Autosomal recessive Variable 8q12.3
SPG6 Non-imprinted in Prader-Willi/Angelman syndrome region protein 1 Transmembrane protein Autosomal dominant Teenage 15q11.2
SPG7 Paraplegin AAA ATPase Autosomal dominant Variable 16q24.3
SPG8 Strumpellin Valosin containing endoplasmic reticulum protein Autosomal dominant Adult 8q24.13
SPG9 Not currently known Autosomal dominant Teenage 10q23.3–24.2
SPG10 Kinesin heavy chain isoform 5A Kinesin chain Autosomal dominant Early 12q13.3
SPG11 Spatacsin Lysosomal protein Autosomal recessive Variable 15q21.1
SPG12 Reticulon 2 Endoplasmic reticulum protein Autosomal dominant Early 19q13.32
SPG13 Chaperonin 60/Heat shock protein 60 Heat shock protein Autosomal dominant Variable 2q33.1
SPG14 Not currently known Autosomal recessive Adult 3q27–q28
SPG15 Spastizin Zinc finger containing protein Autosomal recessive Early 14q24.1
SPG16 Not currently known X linked recessive Early Xq11.2
SPG17 Seipin Integral membrane protein of the endoplasmic reticulum Autosomal dominant Teenage 11q12.3
SPG18 ERLIN2 Endoplasmic reticulum protein Autosomal recessive Early 8p11.23
SPG19 Not currently known Autosomal dominant Adult onset 9q
SPG20 Spartin FK506-binding protein Autosomal recessive Early onset 13q13.3
SPG21 Acidic cluster protein 33/Maspardin Membrane protein Autosomal recessive Early onset 15q22.31
SPG22 Monocarboxylate transporter 8 Transmembrane transport protein X linked recessive Early onset Xq13.2
SPG23 Not currently known Autosomal recessive Early onset 1q24–q32
SPG24 Not currently known Autosomal recessive Early onset 13q14
SPG25 Not currently known Autosomal recessive Adult 6q23–q24.1
SPG26 Beta-1,4 N-acetylgalactosaminyltransferase 1 Autosomal recessive Early onset 12p11.1–q14
SPG27 Not currently known Autosomal recessive Variable 10q22.1–q24.1
SPG28 DDHD1/Phosphatidic acid phospholipase A1 Autosomal recessive Early onset 14q22.1
SPG29 Not currently known Autosomal dominant Teenage 1p31.1–p21.1
SPG30 Kinesin 3 Kinesin protein Autosomal recessive Teenage 2q37.3
SPG31 Receptor expression-enhancing protein 1 Endoplasmic reticulum protein Autosomal dominant Early onset 2p11.2
SPG32 Unknown Autosomal recessive 14q12-q21
SPG33 Protrudin Membrane protein Autosomal dominant Adult 10q24.2
SPG34 Unknown X linked recessive Teenage/Adult Xq24-q25
SPG35 Fatty acid 2-hydroxylase Autosomal recessive Childhood 16q23.1
SPG36 Unknown Autosomal dominant Teenage/Adult 12q23-q24
SPG37 Unknown Autosomal dominant 8p21.1-q13.3
SPG38 Unknown Autosomal dominant Teenage/Adult 4p16-p15
SPG39 Neuropathy target esterase Endoplasmic reticulum protein Autosomal recessive Childhood 19p13.2
SPG40 Unknown Autosomal dominant Unknown
SPG41 Unknown Autosomal dominant Adolescence 11p14.1-p11.2
SPG42 Acetylcoenzyme A transporter 1 Autosomal dominant Variable 3q25.31
SPG43 C19orf12 Autosomal recessive Childhood 19q12
SPG44 Gap junction protein GJA12/GJC2, Connexin 47 Autosomal recessive Childhood/teenage 1q42.13
SPG45 5'-nucleotidase, cytosolic II Autosomal recessive Infancy 10q24.32-q24.33
SPG46 Non lysosomal glucosylceramidase Autosomal recessive Variable 9p13.3
SPG47 Adaptor protein 4 complex subunit beta 1 Involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system Autosomal recessive Childhood 1p13.2
SPG48 Adaptor protein 5 complex subunit zeta 1 Puative helicase Autosomal recessive 6th decade 7p22.1
SPG49 Tectonin beta propeller repeat containing protein 2 Involved in autophagy Autosomal recessive Infancy 14q32.31
SPG50 Adaptor protein 4 complex subunit mu 1 Involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system Autosomal recessive Infancy 7q22.1
SPG51 Adaptor protein 4 complex subunit epsilon 1 Involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system Autosomal recessive Infancy 15q21.2
SPG52 Adaptor protein 4 complex subunit sigma 1 Involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system Autosomal recessive Infancy 14q12
SPG53 Vacuolar protein sorting-associated protein 37A Component of the ESCRT-I complex, a regulator of vesicular trafficking process Autosomal recessive Childhood 8p22
SPG54 Phospholipase DDHD2 Autosomal recessive Childhood 8p11.23
SPG55 C12orf65 Mitochondrial protein Autosomal recessive Childhhod 12q24.31
SPG56 CYP2U1 (Cytochrome P450 2U1) Long chain fatty acid ω-hydroxylase; metabolizes arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE) and 19-HETE Autosomal recessive Childhhod 4q25
SPG57 TFG Endoplasmic reticulum protein Autosomal recessive Early-onset 3q12.2
SPG58 Kinesin family member 1C Kinesin protein Autosomal recessive Onset within first two decades 17p13.2
SPG59 Ubiquitin specific protease 8 Unknown Childhood 15q21.2
SPG60 WD repeat domain 48 Lysosomal protein Unknown Infancy 3p22.2
SPG61 ADP-Ribosylation factor like 6 interacting protein 1 Membrane protein Autosomal recessive Infancy 16p12.3
SPG62 ER lipid raft associated protein 1 Lipid raft protein Unknown 10q24.31
SPG63 Adenosine monophosphate deaminase 2 Unknown Infancy 1p13.3
SPG64 Ectonucleoside triphosphate diphosphohydrolase 1 (CD39) Autosomal recessive 10q24.1
SPG65 5′-nucleosidase, cytosolic II 10q24.32–q24.33
SPG66 Arylsulfatase family, member I Unknown Infancy 5q32
SPG67 Post-GPI attachment to proteins 1 Protein transport Autosomal recessive Infancy 2q33.1
SPG68 Fibronectin leucine rich transmembrane protein 1 11q13.1
SPG69 Rab3 GTPase activating protein subunit 2 (non-catalytic) 1q41
SPG70 Methionyl-tRNA synthetase Unknown Infancy 12q13
SPG71 Zinc finger RNA binding protein 5p13.3
SPG72 Receptor expression enhancing protein 2 Dominant negative Infancy 5q31
SPG not assigned Glutamate decarboxylase 1 Autosomal recessive Infancy 2q31.1
SPG not assigned (SPOAN syndrome) Unknown Autosomal recessive Early onset 11q13
SPG not assigned Cytosolic chaperonin containing T complex peptide 1 episilon subunit Autosomal recessive 5p15.2
SPG not assigned Mitochondrial ATPase 6 Mitochondrial protein Mitochondrial inheritance Adult Mitochondrial DNA
SPG not assigned Optic atrophy 3 protein 19q13.32
SPG not assigned Bicaudal D homolog 2 Autosomal dominant Childhood 9q22.31
SPG not assigned Myelin associated glycoprotein Autosomal recessive Childhood 19q13.1
SPG not assigned Lysomal trafficing regulator Adult 1q42.3

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.[13] 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 insidiously over many years. Canes, walkers, and wheelchairs may eventually be required, although some people never require assistance devices.[14] 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.[12] In the complex form of the disorder, additional symptoms are present. These include: peripheral neuropathy, amyotrophy, ataxia, mental retardation, ichthyosis, epilepsy, optic neuropathy, dementia, deafness, or problems with speech, swallowing or breathing.[2]

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.[9]

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.

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.[2]

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:

Epidemiology

Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people.[15] 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.[16] 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.[15]

See also

References

  1. ↑ Fink JK (August 2003). "The hereditary spastic paraplegias: nine genes and counting". Arch. Neurol. 60 (8): 1045–9. doi:10.1001/archneur.60.8.1045. PMID 12925358.
  2. 1 2 3 Depienne C, Stevanin G, Brice A, Durr A (2007). "Hereditary Spastic Paraplegia: An Update". Current Opinion in Neurology 20 (6): 674–680. doi:10.1097/WCO.0b013e3282f190ba. PMID 17992088.
  3. ↑ "Classification".
  4. ↑ NINDS Hereditary Spastic Paraplegia Information Page
  5. ↑ De Matteis, M. A.; Luini, A. (2011). "Mendelian Disorders of Membrane Trafficking". New England Journal of Medicine 365 (10): 927–938. doi:10.1056/NEJMra0910494. PMID 21899453.
  6. ↑ Behan W, Maia M (1974). "Strümpell's familial spastic paraplegia: genetics and neuropathology". J Neurol Neurosurg Psychiatry 37 (1): 8–20. doi:10.1136/jnnp.37.1.8. PMC 494557. PMID 4813430.
  7. ↑ Harding AE (1993). "Hereditary Spastic Paraplegias". Semin Neurol 13 (4): 333–336. doi:10.1055/s-2008-1041143. PMID 8146482.
  8. ↑ Schwarz GA, Liu C-N (1956). "Hereditary (familial) spastic paraplegia. Further clinical and pathologic observations". AMA Arch Neurol Psychiatry 75 (2): 144–162. doi:10.1001/archneurpsyc.1956.02330200038005. PMID 13282534.
  9. 1 2 Harding, AE (1983). Classification of the hereditary ataxias and paraplegias. New York: Lancet.
  10. ↑ Schüle R, Schöls L (2011) Genetics of hereditary spastic paraplegias. Semin Neurol 31(5):484-493
  11. ↑ Wang YG, Shen L (2009) AAA ATPases and hereditary spastic paraplegia. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 26(3):298-301
  12. 1 2 Harding AE (1981). "Hereditary "pure" spastic paraplegia: a clinical and genetic study of 22 families". Journal of Neurology, Neurosurgery and Psychiatry. 44 (10): 871–883. doi:10.1136/jnnp.44.10.871.
  13. ↑ McAndrew CR, Harms P. (2003). "Paraesthesias during needle-through-needle combined spinal epidural versus single-shot spinal for elective caesarean section". Anaesthesia and Intensive Care. 31 (5): 514–517. PMID 14601273.
  14. ↑ Fink JK (2003). "The Hereditary Spastic Paraplegias". Archives of Neurology 60 (8): 1045–1049. doi:10.1001/archneur.60.8.1045. PMID 12925358.
  15. 1 2 National Institute of Health (2008). "Hereditary Spastic Paraplegia Information Page". Retrieved 2008-04-30.
  16. ↑ Erichsen, AK; Koht, J; Stray-Pedersen, A; Abdelnoor, M; Tallaksen, CM (June 2009). "Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study." (PDF). Brain : a journal of neurology 132 (Pt 6): 1577–88. doi:10.1093/brain/awp056. PMID 19339254.

External links

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