Hereditary spastic paraplegia
Encyclopedia
Hereditary Spastic Paraplegia (HSP), also called Familial Spastic Paraplegias or Strumpell-Lorrain disease, is a group of inherited diseases whose main feature is progressive stiffness and contraction (spasticity
) in the lower limbs. as a result of damage to dysfunction of the nerves. It 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. 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.
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.
Technically HSP is not spastic diplegia
but it usually presents with similar effects and may be helped by similar solutions such as baclofen
and orthopedic surgery
.
. 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. Loss of anterior spinal horn is observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are normal.
. This means that Hereditary Spastic Paraplegia affects less than 200,000 people in the US population. Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people. 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. Average age at onset was 24 years old.
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
.
.
Autosomal dominant represents the most common mode of inheritance. Autosomal means that the HSP gene is located on one of the autosomal chromosomes. The gene
can be present in either sex, and it can be passed down from either the mother or the father to a son or a daughter. Dominant means that only one HSP gene
is needed to cause the disorder.
Autosomal recessive forms of HSP are also located on one of the autosomes. Therefore, they can be present in males or females and passed to males or females. Since it is recessive
, two copies of the gene
are needed to result in the disorder, one from each parent. In these forms, neither parent has HSP. Instead, they are carriers
. They each have one mutant HSP gene
and one normal HSP gene. A mutant HSP gene that is recessive can be passed down silently for generations until someone finally inherits the recessive gene from both parents and inherits the disorder. If both parents are carriers for a recessive HSP gene mutation, each of their children has a 25% chance of developing HSP. There is a 50% risk the child will be a carrier like the parents. Finally, there is a 25% chance that the child will receive only the non-mutated forms of the gene. This child would not be affected by HSP, nor would be a carrier.
Finally, some genes
responsible for HSP are found on the X chromosome
, hence are called X-linked. The inheritance risks and severity of this type of HSP differ depending on the individual’s sex. Women with an X-linked mutant HSP gene are generally not affected by the disorder, or, if they are, usually have less severe symptoms than males.
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.
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
.
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.
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
, mental retardation
, ichthyosis
, epilepsy
, optic neuropathy, dementia
, deafness, or problems with speech, swallowing or breathing.
, but also to detect associated abnormalities such as cerebellar or corpus callosum
atrophy as well as white matter
abnormalities.
.
, designated SPG (SPastic parapleGia) 1 through 21 in order of their discovery. Different genetic types of HSP usually cannot be distinguished by clinical and neuroimaging parameters alone. This reflects both the clinical similarity between different types of HSP and the phenotypic variability within a given genetic type of HSP. Furthermore, there may be significant clinical variability within a given family in which all subjects have the same HSP gene mutation; between families with the same genetic type of HSP; and between families with different genetic types of HSP.
} || -
|-
| X-linked || SPG2 (Proteolipid protein) || Xq22 || || Mutations in the proteolipid protein cause progressive leukodystrophy
and dysmyelination, resulting in axonal degeneration.
|-
| X-linked || SPG1, Neuronal Cell Adhesion Molecule L1 (L1CAM) || || || Mutations in this protein interfere with its role in neurite
outgrowth guidance, neuronal cell migration and neuronal cell survival, causing reduced corticospinal tracts.
|-
| Autosomal dominant || SPG17 || 11q13 || || Silver syndrome.
|-
| Autosomal recessive || SPG23 || 1q24-q32 || || Lison syndrome.
|-
| Autosomal recessive || SPG15
|| 14q24.1 || || Kjellin syndrome.
|-
| Autosomal recessive || SPG25 || 6q23-q24.1 || ||
|-
| ? || ? || ? || || Kallmann syndrome
with Spastic paraplegia.
|-
| ? || ? || ? || || Precocious puberty
with Spastic paraplegia.
|-
| Autosomal dominant || SPG9 || 10q23.3-q24.1 || ||
|-
| X-linked || SPG1 || Xq28 || || Masa syndrome. Also known as Gareis-Mason syndrome and Crash syndrome.
|-
| Autosomal recessive || SPG5A || 8q21.3 || ||
|-
| X-linked || SPG34 || Xq24-q25 || ||
|-
| Autosomal recessive || ? || 11q13 || || SPOAN (Spastic paraplegia, optic atrophy and neuropathy).
|-
| X-linked || SPG16 || Xq11.2 || ||
|-
| Autosomal dominant || SPG29 || 1p31.1-p21.1 || ||
|-
| Autosomal dominant || SPG8 || 8q24.13 || ||
|-
| Autosomal dominant || SPG31 || 2p11.2 || ||
|-
| Autosomal dominant || SPG12 || 19q13 || ||
|-
| Autosomal dominant || SPG33 || 10q24.2 || ||
|-
| Autosomal dominant || SPG42 || 3q25.31 || ||
|-
| Autosomal dominant || SPG37 || 8p21.1-q13.3 || ||
|-
| Autosomal recessive || SPG26 || 12p11.1-q14 || ||
|-
| Autosomal dominant || SPG19 || 9q || ||
|-
| Autosomal recessive || SPG14 || 3q27-q28 || ||
|-
| ? || ? || ? || || Fryns macrocephaly with spastic paraplagia
|-
| Autosomal recessive || SPG27 || 10q22.1-q24.1 || ||
|-
| ? || ? || ? || || SPAR (Spastic paraplagia, ataxia and mental retardation).
|-
| Autosomal recessive || SPG35 || 16q21-q23.1 || ||
|-
| Autosomal recessive || SPG5B || ? || ||
|-
| Autosomal recessive || SPG28 || 14q21.3-q22.3 || ||
|-
|}
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
) in the lower limbs. as a result of damage to dysfunction of the nerves. It 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. 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.
Hereditary Spastic Paraplegia was first described in 1883 by Adolph Strümpell
Adolph Strümpell
Ernst Adolf Gustav Gottfried von Strümpell was a German neurologist who was born at Neu-Autz Estate, Courland Governorate...
, a German neurologist, and was later described more extensively in 1888 by Maurice Lorrain, a French physician.
Technically HSP is not spastic diplegia
Spastic diplegia
Spastic diplegia, historically known as Little's Disease, is a form of cerebral palsy that is a neuromuscular condition of hypertonia and spasticity in the muscles of the lower extremities of the human body, usually those of the legs, hips and pelvis...
but it usually presents with similar effects and may be helped by similar solutions such as baclofen
Baclofen
Baclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
and orthopedic surgery
Orthopedic surgery
Orthopedic surgery or orthopedics is the branch of surgery concerned with conditions involving the musculoskeletal system...
.
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 gracilisFasciculus gracilis
The fasciculus gracilis is a bundle of axon fibres in the posterior column of the spinal cord and carries information from the middle thoracic and lower limbs of the body...
. The spinocerebellar tract
Spinocerebellar tract
The spinocerebellar tract is a set of axonal fibers originating in the spinal cord and terminating in the ipsilateral cerebellum. This tract conveys information to the cerebellum about limb and joint position ....
is involved to a lesser extent. Neuronal cell bodies of degenerating fibers are preserved and there is no evidence of primary demyelination. Loss of anterior spinal horn is observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are normal.
Incidence and Prevalence
Hereditary Spastic Paraplegia is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of HealthNational Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
. This means that Hereditary Spastic Paraplegia affects less than 200,000 people in the US population. Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people. 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. Average age at onset was 24 years old.
Classification
Hereditary Spastic Paraplegias are classified based on the symptoms (pure form versus complicated form); based on their mode of inheritance (autosomal dominant, autosomal recessive or x-linked); and based on the patient’s age at onset.Based on symptoms
SpasticitySpasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
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
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, 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
Leukodystrophy
Leukodystrophy refers to a group of disorders characterized by dysfunction of the white matter of the brain. The leukodystrophies are caused by imperfect growth or development of the myelin sheath, the fatty covering that acts as an insulator around nerve fibers...
.
Based on mode of inheritance
As mentioned above, HSP is group of genetic disorders, each caused by different genes that cause very similar symptoms. The mode of inheritance of the HSP, hence the particular features of the gene involved, affect the risk of inheriting the disorder. There are four different modes of inheritance: autosomal dominant, autosomal recessive, Mitochondrial inheritance and x-linked recessiveX-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
.
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
can be present in either sex, and it can be passed down from either the mother or the father to a son or a daughter. Dominant means that only one HSP gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is needed to cause the disorder.
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
, two copies of the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
are needed to result in the disorder, one from each parent. In these forms, neither parent has HSP. Instead, they are carriers
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
. They each have one mutant HSP gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
and one normal HSP gene. A mutant HSP gene that is recessive can be passed down silently for generations until someone finally inherits the recessive gene from both parents and inherits the disorder. If both parents are carriers for a recessive HSP gene mutation, each of their children has a 25% chance of developing HSP. There is a 50% risk the child will be a carrier like the parents. Finally, there is a 25% chance that the child will receive only the non-mutated forms of the gene. This child would not be affected by HSP, nor would be a carrier.
Finally, some genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
responsible for HSP are found on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
, hence are called X-linked. The inheritance risks and severity of this type of HSP differ depending on the individual’s sex. Women with an X-linked mutant HSP gene are generally not affected by the disorder, or, if they are, usually have less severe symptoms than males.
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 spasticitySpasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
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
Spasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
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.
Symptoms
Symptoms depend on the type of HSP inherited. The main feature of the disease is progressive spasticitySpasticity
Spasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
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
Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
.
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.
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
Iliopsoas
-External links:*...
, tibialis anterior, and to a lesser extent, hamstring
Hamstring
In human anatomy, the hamstring refers to any one of the three posterior thigh muscles, or to the tendons that make up the borders of the space behind the knee. In modern anatomical contexts, however, they usually refer to the posterior thigh muscles, or the tendons of the semitendinosus, the...
muscles.
In the complex form of the disorder, additional symptoms are present. These include: peripheral neuropathy, amyotrophy
Amyotrophy
Amyotrophy is progressive wasting of muscle tissues. Muscle pain is also a symptom. It can occur in middle age males with type 2 diabetes. It also occurs with Motor Neuron Disease.-See also:* Diabetic amyotrophy* Monomelic amyotrophy...
, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, ichthyosis
Ichthyosis
Ichthyosis is a heterogeneous family of at least 28, generalized, mostly genetic skin disorders. All types of ichthyosis have dry, thickened, scaly or flaky skin...
, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, optic neuropathy, dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, deafness, or problems with speech, swallowing or breathing.
Diagnosis
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. Specialized genetic testing targeted towards known genetic mutations are available at certain specialized centers. Cerebral and spinal MRI is an important procedure to rule out other frequent neurological conditions, such as multiple sclerosisMultiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, but also to detect associated abnormalities such as cerebellar or corpus callosum
Corpus callosum
The corpus callosum , also known as the colossal commissure, is a wide, flat bundle of neural fibers beneath the cortex in the eutherian brain at the longitudinal fissure. It connects the left and right cerebral hemispheres and facilitates interhemispheric communication...
atrophy as well as white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
abnormalities.
Prognosis
Although HSP is a progressive condition and usually starts in the legs and spreads to other muscles, ultimately leading to confinement to bed, the prognosis for individuals with HSP varies greatly. 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 expectancyLife expectancy
Life expectancy is the expected number of years of life remaining at a given age. It is denoted by ex, which means the average number of subsequent years of life for someone now aged x, according to a particular mortality experience...
.
Genetic Causes
The symptoms previously described are the results of a degeneration of the corticospinal tracts. The longest fibers, innervating the lower extremities, are the most affected. This explains why the spasticity and pyramidal signs are often limited to the lower limbs in patients. This neuronal degeneration is thought to be caused by mutations at specific genes. Genetic mapping has identified 20 different HSP lociLocus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
, designated SPG (SPastic parapleGia) 1 through 21 in order of their discovery. Different genetic types of HSP usually cannot be distinguished by clinical and neuroimaging parameters alone. This reflects both the clinical similarity between different types of HSP and the phenotypic variability within a given genetic type of HSP. Furthermore, there may be significant clinical variability within a given family in which all subjects have the same HSP gene mutation; between families with the same genetic type of HSP; and between families with different genetic types of HSP.
| Type | Gene | Locus Locus (genetics) In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map... |
OMIM | Description | >- | SPG4 (spastin Spastin The human gene SPAST codes for the microtubule-severing protein of the same name, commonly known as spastin.-External Links:* -Further reading:... protein) |
2p22-p21 | haploinsufficiency Haploinsufficiency Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene and the single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state... (that is, decreased abundance of functionally normal spastin Spastin The human gene SPAST codes for the microtubule-severing protein of the same name, commonly known as spastin.-External Links:* -Further reading:... ) rather that a dominant negative mechanism. Emerging evidence suggests that spastin Spastin The human gene SPAST codes for the microtubule-severing protein of the same name, commonly known as spastin.-External Links:* -Further reading:... may interact with microtubules. A recent research showed that antitubulin antibodies could precipitate spastin in vitro, hence indicating that spastin can bind to tubulin. More recently, another study showed that a spastin fusion protein colocalized with microtubules in Cos-7 and HeLa cells transfected with wild type and mutant SPG4 expression vectors. Findings that spastin may interact with microtubules support the hypothesis that disturbances in axonal cytoskeleton Cytoskeleton The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton... or transport underlie some forms of HSP. >- | Autosomal dominant |
SPG3A SPG3A Atlastin, or Atlastin-1, is a protein that in humans is encoded by the ATL1 gene.-External Links:* -Further reading:... (atlastin protein) |
14q11-q21 | GTPase GTPase GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:... binding site and hydrolysis Hydrolysis Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization... and is structurally homologous to guanylate binding protein 1 (GBP1 GBP1 Interferon-induced guanylate-binding protein 1 is a protein that in humans is encoded by the GBP1 gene. It belongs to the dynamin superfamily of large GTPases.- Function :Guanylate binding protein expression is induced by interferon... ). The functional importance of atlastin’s GTPase motif is indicated by a recently identified HSP mutation that showed a disrupted GTPase GTPase GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:... motif which is usually conserved. GBP1 GBP1 Interferon-induced guanylate-binding protein 1 is a protein that in humans is encoded by the GBP1 gene. It belongs to the dynamin superfamily of large GTPases.- Function :Guanylate binding protein expression is induced by interferon... , to which atlastin shows homology Homology (chemistry) In chemistry, homology refers to the appearance of homologues. A homologue is a compound belonging to a series of compounds differing from each other by a repeating unit, such as a methylene group, a peptide residue, etcetera.... , is a member of the dynamin Dynamin Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamins are principally involved in the scission of newly formed vesicles from the membrane of one cellular compartment and their targeting to, and fusion with, another compartment, both at the cell surface as well as at the... family of large GTPases. Dynamins play essential roles in a wide variety of vesicle trafficking events: regulation of neurotrophic factors Neurotrophic factors Neurotrophic factors are a family of proteins that are responsible for the growth and survival of developing neurons and the maintenance of mature neurons... ; recycling of synaptic vesicles; maintenance and distribution of mitochondria; maintenance of the cytoskeleton Cytoskeleton The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton... via association to actin Actin Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans... and microtubules. The important and diverse functions of dynamins raise many interesting possibilities by which atlastin mutations could cause axonal degeneration. These possibilities include defective synaptic vesicle recycling leading to abnormal synaptic structure and impaired neurotransmission Neurotransmission Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron... , impaired activation of selected neurotrophic factors, and impaired mitochondria distribution. Also known as Strumpell disease. >- | Autosomal dominant |
SPG10 (KIF5A KIF5A Kinesin heavy chain isoform 5A is a protein that in humans is encoded by the KIF5A gene.-Further reading:... protein) |
12q13 | muscle atrophy Muscle atrophy Muscle atrophy, or disuse atrophy, is defined as a decrease in the mass of the muscle; it can be a partial or complete wasting away of muscle. When a muscle atrophies, this leads to muscle weakness, since the ability to exert force is related to mass... . The HSP-specific KIF5A mutation disrupted an asparagine residue, present on the kinesin heavy chain motor protein, that prevented stimulation of the motor ATPase ATPase ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur... by microtubule binding. >- | Autosomal dominant |
SPG13 (chaperonin 60, or heat shock protein 60 - HSP60 HSP60 Heat shock proteins are generally responsible for preventing damage to proteins in response to high levels of heat. Heat shock proteins are classified into six major families based on their molecular mass: small HSPs, HSP40, HSP60, HSP70, HSP90, and HSP110... ) |
2q33.1 | >- | SPG6 (NIPA1 NIPA1 Non-imprinted in Prader-Willi/Angelman syndrome region protein 1 is a protein that in humans is encoded by the NIPA1 gene.-Further reading:... ) |
15q11.1 | central nervous system Central nervous system The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish... . The presence of nine alternating hydrophobic-hydrophilic domains suggests that NIPA1 might encode a transmembrane protein Transmembrane protein A transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as... . This feature makes NIPA1 unique among HSP related proteins. The mutation on the NIPA1 gene appears to act through a dominant negative gain of function. This prediction is based on the fact that subjects who are missing one NIPA1 gene entirely do not develop HSP. >- | Autosomal recessive HSP |
SPG7 SPG7 Paraplegin is a protein that in humans is encoded by the SPG7 gene.-External Links:* -Further reading:... (paraplegin protein) |
16q24.3 | >- | SPG20 SPG20 Spartin is a protein that in humans is encoded by the SPG20 gene.-External Links:* -Further reading:... (spartin protein) |
13q12.3 | >- | SPG11 SPG11 Spatacsin is a protein that in humans is encoded by the SPG11 gene.-External Links:* -Further reading:... |
15q21.1 | >- | SPG21 SPG21 Maspardin is a protein that in humans is encoded by the SPG21 gene.-Further reading:... |
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| X-linked || SPG2 (Proteolipid protein) || Xq22 || || Mutations in the proteolipid protein cause progressive leukodystrophy
Leukodystrophy
Leukodystrophy refers to a group of disorders characterized by dysfunction of the white matter of the brain. The leukodystrophies are caused by imperfect growth or development of the myelin sheath, the fatty covering that acts as an insulator around nerve fibers...
and dysmyelination, resulting in axonal degeneration.
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| X-linked || SPG1, Neuronal Cell Adhesion Molecule L1 (L1CAM) || || || Mutations in this protein interfere with its role in neurite
Neurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
outgrowth guidance, neuronal cell migration and neuronal cell survival, causing reduced corticospinal tracts.
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| Autosomal dominant || SPG17 || 11q13 || || Silver syndrome.
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| Autosomal recessive || SPG23 || 1q24-q32 || || Lison syndrome.
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| Autosomal recessive || SPG15
SPG15
Spastic paraplegia 15 , autosomal recessive, is a rare syndrome characterized mainly by progressive stiffness and increased reflexes in the leg muscles as well as vision problems....
|| 14q24.1 || || Kjellin syndrome.
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| Autosomal recessive || SPG25 || 6q23-q24.1 || ||
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| ? || ? || ? || || Kallmann syndrome
Kallmann syndrome
Kallmann syndrome is a genetic disorder marked by anosmia and hypogonadism - the decreased functioning of the glands that produce sex hormones. Abnormalities in various genes may cause a defect in the hypothalamus, causing a deficiency of gonadotropin-releasing hormone ; this in turn causes...
with Spastic paraplegia.
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| ? || ? || ? || || Precocious puberty
Precocious puberty
As a medical term, precocious puberty describes puberty occurring at an unusually early age. In most of these children, the process is normal in every respect except the unusually early age, and simply represents a variation of normal development. In a minority of children, the early development is...
with Spastic paraplegia.
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| Autosomal dominant || SPG9 || 10q23.3-q24.1 || ||
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| X-linked || SPG1 || Xq28 || || Masa syndrome. Also known as Gareis-Mason syndrome and Crash syndrome.
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| Autosomal recessive || SPG5A || 8q21.3 || ||
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| X-linked || SPG34 || Xq24-q25 || ||
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| Autosomal recessive || ? || 11q13 || || SPOAN (Spastic paraplegia, optic atrophy and neuropathy).
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| X-linked || SPG16 || Xq11.2 || ||
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| Autosomal dominant || SPG29 || 1p31.1-p21.1 || ||
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| Autosomal dominant || SPG8 || 8q24.13 || ||
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| Autosomal dominant || SPG31 || 2p11.2 || ||
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| Autosomal dominant || SPG12 || 19q13 || ||
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| Autosomal dominant || SPG33 || 10q24.2 || ||
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| Autosomal dominant || SPG42 || 3q25.31 || ||
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| Autosomal dominant || SPG37 || 8p21.1-q13.3 || ||
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| Autosomal recessive || SPG26 || 12p11.1-q14 || ||
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| Autosomal dominant || SPG19 || 9q || ||
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| Autosomal recessive || SPG14 || 3q27-q28 || ||
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| ? || ? || ? || || Fryns macrocephaly with spastic paraplagia
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| Autosomal recessive || SPG27 || 10q22.1-q24.1 || ||
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| ? || ? || ? || || SPAR (Spastic paraplagia, ataxia and mental retardation).
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| Autosomal recessive || SPG35 || 16q21-q23.1 || ||
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| Autosomal recessive || SPG5B || ? || ||
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| Autosomal recessive || SPG28 || 14q21.3-q22.3 || ||
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Treatment
There are no specific treatments to prevent, slow, or reverse HSP. Treatment of HSP mainly consists of symptomatic medical management, to promote physical and emotional well-being. Some of the treatments include:- BaclofenBaclofenBaclofen is a derivative of gamma-aminobutyric acid . It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism....
- a voluntary muscle relaxant to relax muscles and reduce tone - TizanidineTizanidineTizanidine is a drug that is used as a muscle relaxant. It is a centrally acting α2 adrenergic agonist. It is used to treat the spasms, cramping, and tightness of muscles caused by medical problems such as multiple sclerosis, spastic diplegia, back pain, or certain other injuries to the spine or...
- to treat nocturnal or intermittent spasmSpasmIn medicine a spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It is sometimes accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes...
s - DiazepamDiazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
and ClonazepamClonazepamClonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
- 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
- TolterodineTolterodineTolterodine is an antimuscarinic drug that is used to treat urinary incontinence.It is marketed by Pfizer in Canada and the United States by its brand name Detrol. In Egypt it is also found under the trade names Tolterodine by Sabaa and Incont L.A...
tartate - an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems - Botulinum toxinBotulinum toxinBotulinum toxin is a protein produced by the bacterium Clostridium botulinum, and is considered the most powerful neurotoxin ever discovered. Botulinum toxin causes Botulism poisoning, a serious and life-threatening illness in humans and animals...
- to reduce muscle overactivity - Antidepressants (such as Selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors) - for patients experiencing clinical depression
- Physical TherapyPhysical therapyPhysical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...
- 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.