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Hereditary spastic paraplegia 5A(SPG5A)

MedGen UID:: 376521
•Concept ID:: C1849115
•: Disease or Syndrome

Synonyms:	Autosomal recessive spastic paraplegia; Spastic paraplegia 5A; SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE; SPG5A
SNOMED CT:	Autosomal recessive spastic paraplegia type 5A (763373005)
Modes of inheritance:	Autosomal recessive inheritance MedGen UID: 141025 •Concept ID: C0441748 • Intellectual Product Source: Orphanet A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). Autosomal recessive inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	CYP7B1 (8q12.3)

Monarch Initiative:	MONDO:0010047
OMIM®:	270800
Orphanet:	ORPHA100986

Definition

Spastic paraplegia-5A (SPG5A) is an autosomal recessive neurologic disorder with a wide phenotypic spectrum. Some patients have pure spastic paraplegia affecting only gait, whereas others may have a complicated phenotype with additional manifestations, including optic atrophy or cerebellar ataxia (summary by Arnoldi et al., 2012). The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997). Inheritance is most often autosomal dominant (see 182600), but X-linked (see 303350) and autosomal recessive forms also occur. Genetic Heterogeneity of Autosomal Recessive Spastic Paraplegia Autosomal recessive forms of SPG include SPG7 (607259), caused by mutation in the paraplegin gene (602783) on chromosome 16q24; SPG9B (616586), caused by mutation in the ALDH18A1 gene (138250) on 10q24; SPG11 (604360), caused by mutation in the spatacsin gene (610844) on 15q21; SPG15 (270700), caused by mutation in the ZFYVE26 gene (612012) on 14q24; SPG18 (611225), caused by mutation in the ERLIN2 gene (611605) on 8p11; SPG20 (275900), caused by mutation in the spartin gene (607111) on 13q12; SPG21 (248900), caused by mutation in the maspardin gene (608181) on 15q21; SPG26 (609195), caused by mutation in the B4GALNT1 gene (601873) on 12q13; SPG28 (609340), caused by mutation in the DDHD1 gene (614603) on 14q22; SPG30 (610357), caused by mutation in the KIF1A gene (601255) on 2q37; SPG35 (612319), caused by mutation in the FA2H gene (611026) on 16q23; SPG39 (612020), caused by mutation in the PNPLA6 gene (603197) on 19p13; SPG43 (615043), caused by mutation in the C19ORF12 gene (614297) on 19q12; SPG44 (613206), caused by mutation in the GJC2 gene (608803) on 1q42; SPG45 (613162), caused by mutation in the NT5C2 gene (600417) on 10q24; SPG46 (614409), caused by mutation in the GBA2 gene (609471) on 9p13; SPG48 (613647), caused by mutation in the KIAA0415 gene (613653) on 7p22; SPG50 (612936), caused by mutation in the AP4M1 gene (602296) on 7q22; SPG51 (613744), caused by mutation in the AP4E1 gene (607244) on 15q21; SPG52 (614067), caused by mutation in the AP4S1 gene (607243) on 14q12; SPG53 (614898), caused by mutation in the VPS37A gene (609927) on 8p22; SPG54 (615033), caused by mutation in the DDHD2 gene (615003) on 8p11; SPG55 (615035), caused by mutation in the MTRFR gene on 12q24; SPG56 (615030), caused by mutation in the CYP2U1 gene (610670) on 4q25; SPG57 (615658), caused by mutation in the TFG gene (602498) on 3q12; SPG61 (615685), caused by mutation in the ARL6IP1 gene (607669) on 1p12; SPG62 (615681), caused by mutation in the ERLIN1 gene on 10q24; SPG63 (615686), caused by mutation in the AMPD2 gene (102771) on 1p13; SPG64 (615683), caused by mutation in the ENTPD1 gene (601752) on 10q24; SPG72 (615625), caused by mutation in the REEP2 gene (609347) on 5q31; SPG74 (616451), caused by mutation in the IBA57 gene (615316) on 1q42; SPG75 (616680), caused by mutation in the MAG gene (159460) on 19q13; SPG76 (616907), caused by mutation in the CAPN1 gene (114220) on 11q13; SPG77 (617046), caused by mutation in the FARS2 gene (611592) on 6p25; SPG78 (617225), caused by mutation in the ATP13A2 gene (610513) on 1p36; SPG79 (615491), caused by mutation in the UCHL1 gene (191342) on 4p13; SPG81 (618768), caused by mutation in the SELENOI gene (607915) on 2p23; SPG82 (618770), caused by mutation in the PCYT2 gene (602679) on 17q25; SPG83 (619027), caused by mutation in the HPDL gene (618994) on 1p34; SPG84 (619621), caused by mutation in the PI4KA gene (600286) on 22q11; SPG85 (619686), caused by mutation in the RNF170 gene (614649) on 8p11; SPG86 (619735), caused by mutation in the ABHD16A gene (142620) on 6p21; SPG87 (619966), caused by mutation in the TMEM63C gene (619953) on 14q24; SPG89 (620379), caused by mutation in the AMFR gene (603243) on 16q13; SPG90B (620417), caused by mutation in the SPTSSA gene (613540) on 14q13; SPG92 (620911), caused by mutation in the FICD gene (620875) on chromosome 12q23; and SPG93 (620938), caused by mutation in the NFU1 gene (608100) on chromosome 2p13. Additional autosomal recessive forms of SPG have been mapped to chromosomes 3q (SPG14; 605229), 13q14 (SPG24; 607584), 6q (SPG25; 608220), and 10q22 (SPG27; 609041). A disorder that was formerly designated SPG49 has been reclassified as hereditary sensory and autonomic neuropathy-9 with developmental delay (HSAN9; 615031). [from OMIM]

Additional description

From MedlinePlus Genetics
In addition to spasticity and weakness, people with spastic paraplegia type 5A can lose the ability to sense the position of their limbs or detect vibrations with their lower limbs. They may also have muscle wasting (amyotrophy), reduced bladder control, or high arches of the feet (pes cavus). The signs and symptoms of spastic paraplegia type 5A usually appear in adolescence but can begin at any time between infancy and mid-adulthood. The condition slowly worsens over time, often leading affected individuals to require walking support or wheelchair assistance.

Spastic paraplegia type 5A is one of a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by muscle stiffness (spasticity) and severe weakness in the lower limbs (paraplegia). Hereditary spastic paraplegias are often divided into two types: pure and complex. The pure types involve spasticity and weakness only in the lower limbs, while the complex types involve additional problems with other areas of the body; additional features can include changes in vision, changes in intellectual functioning, brain abnormalities, and disturbances in nerve function (neuropathy). Spastic paraplegia type 5A is usually a pure hereditary spastic paraplegia, although complex type features have been reported in some individuals, usually in those who have had the condition for many years. https://medlineplus.gov/genetics/condition/spastic-paraplegia-type-5a

Clinical features

From HPO

Urinary incontinence

MedGen UID:: 22579
•Concept ID:: C0042024
•: Finding

Loss of the ability to control the urinary bladder leading to involuntary urination.

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Pes cavus

MedGen UID:: 675590
•Concept ID:: C0728829
•: Congenital Abnormality

An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).

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Upper limb muscle weakness

MedGen UID:: 305607
•Concept ID:: C1698196
•: Finding

Weakness of the muscles of the arms.

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Lower limb muscle weakness

MedGen UID:: 324478
•Concept ID:: C1836296
•: Finding

Weakness of the muscles of the legs.

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Sensorineural hearing loss disorder

MedGen UID:: 9164
•Concept ID:: C0018784
•: Disease or Syndrome

A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.

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Dysarthria

MedGen UID:: 8510
•Concept ID:: C0013362
•: Mental or Behavioral Dysfunction

Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.

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Babinski sign

MedGen UID:: 19708
•Concept ID:: C0034935
•: Finding

Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.

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Spastic paraplegia

MedGen UID:: 20882
•Concept ID:: C0037772
•: Disease or Syndrome

Spasticity and weakness of the leg and hip muscles.

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Hyperreflexia

MedGen UID:: 57738
•Concept ID:: C0151889
•: Finding

Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.

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Spastic gait

MedGen UID:: 115907
•Concept ID:: C0231687
•: Finding

Spasticity is manifested by increased stretch reflex which is intensified with movement velocity. This results in excessive and inappropriate muscle activation which can contribute to muscle hypertonia. Spastic gait is characterized by manifestations such as muscle hypertonia, stiff knee, and circumduction of the leg.

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Postural tremor

MedGen UID:: 66696
•Concept ID:: C0234378
•: Sign or Symptom

A type of tremors that is triggered by holding a limb in a fixed position.

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Cognitive impairment

MedGen UID:: 90932
•Concept ID:: C0338656
•: Mental or Behavioral Dysfunction

Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.

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Lower limb spasticity

MedGen UID:: 220865
•Concept ID:: C1271100
•: Finding

Spasticity (velocity-dependent increase in tonic stretch reflexes with increased muscle tone and hyperexcitable tendon reflexes) in the muscles of the lower limbs, hips, and pelvis.

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Upper limb spasticity

MedGen UID:: 220882
•Concept ID:: C1273957
•: Finding

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Impaired vibration sensation in the lower limbs

MedGen UID:: 338617
•Concept ID:: C1849134
•: Finding

A decrease in the ability to perceive vibration in the legs.

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Limb dysmetria

MedGen UID:: 340244
•Concept ID:: C1854489
•: Finding

A type of dysmetria involving the limbs.

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Abnormal cerebellum morphology

MedGen UID:: 400925
•Concept ID:: C1866129
•: Anatomical Abnormality

Any structural abnormality of the cerebellum.

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Hyperintensity of cerebral white matter on MRI

MedGen UID:: 811125
•Concept ID:: C2938912
•: Pathologic Function

A brighter than expected signal on magnetic resonance imaging emanating from the cerebral white matter.

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Impaired distal proprioception

MedGen UID:: 867227
•Concept ID:: C4021585
•: Finding

A loss or impairment of the sensation of the relative position of parts of the body and joint position occurring at distal joints.

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Scoliosis

MedGen UID:: 11348
•Concept ID:: C0036439
•: Disease or Syndrome

The presence of an abnormal lateral curvature of the spine.

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Upper limb amyotrophy

MedGen UID:: 867165
•Concept ID:: C4021523
•: Disease or Syndrome

Muscular atrophy involving the muscles of the upper limbs.

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Lower limb amyotrophy

MedGen UID:: 870475
•Concept ID:: C4024921
•: Finding

Muscular atrophy affecting the lower limb.

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Abnormal circulating cholesterol concentration

MedGen UID:: 871179
•Concept ID:: C4025656
•: Finding

Any deviation from the normal concentration of cholesterol in the blood circulation.

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Nystagmus

MedGen UID:: 45166
•Concept ID:: C0028738
•: Disease or Syndrome

Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.

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Optic atrophy

MedGen UID:: 18180
•Concept ID:: C0029124
•: Disease or Syndrome

Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.

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Cataract

MedGen UID:: 39462
•Concept ID:: C0086543
•: Disease or Syndrome

A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.

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Show all Hide all

Abnormality of limbs
Abnormality of metabolism/homeostasis
- Abnormal circulating cholesterol concentration
Abnormality of the eye
Abnormality of the musculoskeletal system
Abnormality of the nervous system
Constitutional symptom
- Urinary incontinence
Ear malformation
- Sensorineural hearing loss disorder

Term Hierarchy

GTR
MeSH

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVHereditary spastic paraplegia 5A

Disease
- Non-Neoplastic Disorder
  - Non-Neoplastic Disorder by Special Category
    - Degenerative disorder
      - Degenerative disease of the central nervous system
        Hereditary spastic paraplegia
        Hereditary spastic paraplegia 5A

Professional guidelines

PubMed

AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model.

Deng R, Medico-Salsench E, Nikoncuk A, Ramakrishnan R, Lanko K, Kühn NA, van der Linde HC, Lor-Zade S, Albuainain F, Shi Y, Yousefi S, Capo I, van den Herik EM, van Slegtenhorst M, van Minkelen R, Geeven G, Mulder MT, Ruijter GJG, Lütjohann D, Jacobs EH, Houlden H, Pagnamenta AT, Metcalfe K, Jackson A, Banka S, De Simone L, Schwaede A, Kuntz N, Palculict TB, Abbas S, Umair M, AlMuhaizea M, Colak D, AlQudairy H, Alsagob M, Pereira C, Trunzo R, Karageorgou V, Bertoli-Avella AM, Bauer P, Bouman A, Hoefsloot LH, van Ham TJ, Issa M, Zaki MS, Gleeson JG, Willemsen R, Kaya N, Arold ST, Maroofian R, Sanderson LE, Barakat TS
Acta Neuropathol 2023 Aug;146(2):353-368. Epub 2023 Apr 29 doi: 10.1007/s00401-023-02579-9. PMID: 37119330 Free PMC Article

Genotype-phenotype correlations of KIF5A stalk domain variants.

de Boer EMJ, van Rheenen W, Goedee HS, Kamsteeg EJ, Brilstra EH, Veldink JH, van Den Berg LH, van Es MA
Amyotroph Lateral Scler Frontotemporal Degener 2021 Nov;22(7-8):561-570. Epub 2021 Apr 8 doi: 10.1080/21678421.2021.1907412. PMID: 33829936

See all (2)

Recent clinical studies

Etiology

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, Dominov JA, Kenna BJ, Nalls MA, Keagle P, Rivera AM, van Rheenen W, Murphy NA, van Vugt JJFA, Geiger JT, Van der Spek RA, Pliner HA, Shankaracharya, Smith BN, Marangi G, Topp SD, Abramzon Y, Gkazi AS, Eicher JD, Kenna A; ITALSGEN Consortium, Mora G, Calvo A, Mazzini L, Riva N, Mandrioli J, Caponnetto C, Battistini S, Volanti P, La Bella V, Conforti FL, Borghero G, Messina S, Simone IL, Trojsi F, Salvi F, Logullo FO, D'Alfonso S, Corrado L, Capasso M, Ferrucci L; Genomic Translation for ALS Care (GTAC) Consortium, Moreno CAM, Kamalakaran S, Goldstein DB; ALS Sequencing Consortium, Gitler AD, Harris T, Myers RM; NYGC ALS Consortium, Phatnani H, Musunuri RL, Evani US, Abhyankar A, Zody MC; Answer ALS Foundation, Kaye J, Finkbeiner S, Wyman SK, LeNail A, Lima L, Fraenkel E, Svendsen CN, Thompson LM, Van Eyk JE, Berry JD, Miller TM, Kolb SJ, Cudkowicz M, Baxi E; Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium, Benatar M, Taylor JP, Rampersaud E, Wu G, Wuu J; SLAGEN Consortium, Lauria G, Verde F, Fogh I, Tiloca C, Comi GP, Sorarù G, Cereda C; French ALS Consortium, Corcia P, Laaksovirta H, Myllykangas L, Jansson L, Valori M, Ealing J, Hamdalla H, Rollinson S, Pickering-Brown S, Orrell RW, Sidle KC, Malaspina A, Hardy J, Singleton AB, Johnson JO, Arepalli S, Sapp PC, McKenna-Yasek D, Polak M, Asress S, Al-Sarraj S, King A, Troakes C, Vance C, de Belleroche J, Baas F, Ten Asbroek ALMA, Muñoz-Blanco JL, Hernandez DG, Ding J, Gibbs JR, Scholz SW, Floeter MK, Campbell RH, Landi F, Bowser R, Pulst SM, Ravits JM, MacGowan DJL, Kirby J, Pioro EP, Pamphlett R, Broach J, Gerhard G, Dunckley TL, Brady CB, Kowall NW, Troncoso JC, Le Ber I, Mouzat K, Lumbroso S, Heiman-Patterson TD, Kamel F, Van Den Bosch L, Baloh RH, Strom TM, Meitinger T, Shatunov A, Van Eijk KR, de Carvalho M, Kooyman M, Middelkoop B, Moisse M, McLaughlin RL, Van Es MA, Weber M, Boylan KB, Van Blitterswijk M, Rademakers R, Morrison KE, Basak AN, Mora JS, Drory VE, Shaw PJ, Turner MR, Talbot K, Hardiman O, Williams KL, Fifita JA, Nicholson GA, Blair IP, Rouleau GA, Esteban-Pérez J, García-Redondo A, Al-Chalabi A; Project MinE ALS Sequencing Consortium, Rogaeva E, Zinman L, Ostrow LW, Maragakis NJ, Rothstein JD, Simmons Z, Cooper-Knock J, Brice A, Goutman SA, Feldman EL, Gibson SB, Taroni F, Ratti A, Gellera C, Van Damme P, Robberecht W, Fratta P, Sabatelli M, Lunetta C, Ludolph AC, Andersen PM, Weishaupt JH, Camu W, Trojanowski JQ, Van Deerlin VM, Brown RH Jr, van den Berg LH, Veldink JH, Harms MB, Glass JD, Stone DJ, Tienari P, Silani V, Chiò A, Shaw CE, Traynor BJ, Landers JE
Neuron 2018 Mar 21;97(6):1267-1288. doi: 10.1016/j.neuron.2018.02.027. PMID: 29566793 Free PMC Article

A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia.

Yang Y, Liu W, Fang Z, Shi J, Che F, He C, Yao L, Wang E, Wu Y
Hum Mutat 2016 Feb;37(2):165-9. Epub 2015 Dec 10 doi: 10.1002/humu.22930. PMID: 26553276

CYP7B1: novel mutations and magnetic resonance spectroscopy abnormalities in hereditary spastic paraplegia type 5A.

Roos P, Svenstrup K, Danielsen ER, Thomsen C, Nielsen JE
Acta Neurol Scand 2014 May;129(5):330-4. Epub 2013 Oct 1 doi: 10.1111/ane.12188. PMID: 24117163

See all (3)

Diagnosis

Expanding the spectrum of KIF5A mutations-case report of a large kindred with familial ALS and overlapping syndrome.

Dulski J, Strongosky AJ, Al-Shaikh RH, Wszolek ZK
Amyotroph Lateral Scler Frontotemporal Degener 2023 May;24(3-4):347-350. Epub 2023 Jan 5 doi: 10.1080/21678421.2022.2164204. PMID: 36604770

Previously Undescribed Gross HACE1 Deletions as a Cause of Autosomal Recessive Spastic Paraplegia.

Kovalskaia VA, Zabnenkova VV, Petukhova MS, Markova ZG, Tabakov VY, Ryzhkova OP
Genes (Basel) 2022 Nov 23;13(12) doi: 10.3390/genes13122186. PMID: 36553453 Free PMC Article

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

A novel frameshift mutation of DDHD1 in a Japanese patient with autosomal recessive spastic paraplegia.

Miura S, Morikawa T, Fujioka R, Kosaka K, Yamada K, Hattori G, Motomura M, Taniwaki T, Shibata H
Eur J Med Genet 2016 Aug;59(8):413-6. Epub 2016 May 20 doi: 10.1016/j.ejmg.2016.05.010. PMID: 27216551

SPG5 and multiple sclerosis: clinical and genetic overlap?

Criscuolo C, Carbone R, Lieto M, Peluso S, Guacci A, Filla A, Quarantelli M, Lanzillo R, Morra VB, De Michele G
Acta Neurol Scand 2016 Jun;133(6):410-4. Epub 2015 Sep 15 doi: 10.1111/ane.12476. PMID: 26370385

See all (5)

Therapy

AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model.

See all (1)

Prognosis

A novel loss of function mutation in adaptor protein complex 4, subunit mu-1 causing autosomal recessive spastic paraplegia 50.

Bellad A, Girimaji SC, Muthusamy B
Neurol Sci 2021 Dec;42(12):5311-5319. Epub 2021 Apr 21 doi: 10.1007/s10072-021-05262-7. PMID: 33884525

Clinical and neuroimaging features of autosomal recessive spastic paraplegia 35 (SPG35): case reports, new mutations, and brief literature review.

Mari F, Berti B, Romano A, Baldacci J, Rizzi R, Grazia Alessandrì M, Tessa A, Procopio E, Rubegni A, Lourenḉo CM, Simonati A, Guerrini R, Santorelli FM
Neurogenetics 2018 May;19(2):123-130. Epub 2018 Feb 8 doi: 10.1007/s10048-018-0538-8. PMID: 29423566

SPG5 and multiple sclerosis: clinical and genetic overlap?

Comparative modeling of 25-hydroxycholesterol-7α-hydroxylase (CYP7B1): ligand binding and analysis of hereditary spastic paraplegia type 5 CYP7B1 mutations.

Siam A, Brancale A, Simons C
J Mol Model 2012 Feb;18(2):441-53. Epub 2011 May 4 doi: 10.1007/s00894-011-1084-6. PMID: 21541746

Three novel spastin (SPG4) mutations in families with autosomal dominant hereditary spastic paraplegia.

Proukakis C, Hart PE, Cornish A, Warner TT, Crosby AH
J Neurol Sci 2002 Sep 15;201(1-2):65-9. doi: 10.1016/s0022-510x(02)00192-2. PMID: 12163196

See all (7)