Hereditary spastic paraplegia

Hereditary spastic paraplegia
Classification and external resources
Specialty
ICD-10	G11.4
ICD-9-CM	334.1
OMIM	312920 PS303350
DiseasesDB	33207
eMedicine	pmr/45
Patient UK	Hereditary spastic paraplegia
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, as a result of damage to or dysfunction of the nerves.

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. 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.

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. 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.

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.

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. 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. 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.

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. 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.

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.

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.

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:

• 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

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, 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.

See also

• Genetics

External links

• GeneReviews/NCBI/NIH/UW entry on Spastic Paraplegia 3A
• Hereditary spastic paraplegia at DMOZ
• GeneReviews/NCBI/NIH/UW entry on Hereditary Spastic Paraplegia Overview
• Hereditary Spastic Paraplegia Support Group
• Hereditary Spastic Paraplegia multi-language communication platform