Hereditary spastic paraplegia

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Hereditary spastic paraplegia
Classification and external resources
Specialty neurology
ICD-10 G11.4
ICD-9-CM 334.1
OMIM 312920 PS303350
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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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[edit]

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 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
SPG3A 182600 ATL1 14q22.1 Autosomal dominant Early Strumpell disease
SPG4 182601 SPAST 2p22.3 Autosomal dominant Variable
SPG5A 270800 CYP7B1 8q12.3 Autosomal recessive Variable
SPG6 600363 NIPA1 15q11.2 Autosomal dominant Teenage
SPG7 602783 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 SPG21 15q22.31 Autosomal recessive Early onset MAST syndrome
SPG22 300523 SLC16A2 Xq13.2 X-linked recessive Early onset Allan–Herndon–Dudley syndrome
SPG23 270750 ? 1q24–q32 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 Childhhod
SPG56 615030 CYP2U1 4q25 Autosomal recessive Childhhod
SPG57 615658 TFG 3q12.2 Autosomal recessive Early
SPG58 611302 KIF1C 17p13.2 Autosomal recessive Within first two decades Spastic ataxia 2
SPG59 USP8 15q21.2 ? Childhood
SPG60 WDR48 3p22.2 ? 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 ARSI 5q32 ? Infancy
SPG67 615802 PGAP1 2q33.1 Autosomal recessive Infancy
SPG68 609541 KLC2 11q13.1 Autosomal recessive Childhood SPOAN syndrome
SPG69 RAB3GAP2 1q41
SPG70 MARS 12q13 ? Infancy
SPG71 ZFR 5p13.3 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
HSNSP 256840 CCT5 5p15.2 Autosomal recessive Childhood Hereditary sensory neuropathy with spastic paraplegia

Symptoms[edit]

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 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[edit]

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[edit]

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[edit]

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
  • Tizanidine – to treat nocturnal or intermittent spasms
  • 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 tartate – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems
  • Botulinum toxin – to reduce muscle overactivity
  • 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.

Epidemiology[edit]

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]

References[edit]

  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. ^ a b c 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 494557free to read. 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 CN (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. ^ a b 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. ^ a b 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. ^ a b 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. 132 (Pt 6): 1577–88. doi:10.1093/brain/awp056. PMID 19339254. 

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