Hereditary spastic paraplegia

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. 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.

Anita Harding 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.

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. 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.

{| class="wikitable" style="font-size: 90%;"

! 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 (this Wiki)

| SPG4

| SPAST

| 2p22.3

| Autosomal dominant

| Variable

| SPG5A

| CYP7B1

| 8q12.3

| Autosomal recessive

| Variable

| SPG6

| NIPA1

| 15q11.2

| Autosomal dominant

|Variable

| 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

| 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

| 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;<br />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

Pathophysiology

The major feature of HSP is a length-dependent axonal degeneration. These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis. The spinocerebellar tract is involved to a lesser extent. Neuronal cell bodies of degenerating axons are preserved and there is no evidence of primary demyelination. Several genes were linked to myelin malformation, namely PLP1, GFC2 and FA2H.)

Tizanidine – to treat nocturnal or intermittent spasms (studies available )
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 tartrate – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems
Cro System – to reduce muscle overactivity (existing studies for spasticity )
Botulinum toxin – to reduce muscle overactivity (existing studies for HSP patients)
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.

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 whilst others leave people able to do most ordinary activities to an ordinary extent without needing adjustments. The majority of individuals with HSP have a normal life expectancy. 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. 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.