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Hereditary spastic paraplegia 10(SPG10)

MedGen UID:: 349003
•Concept ID:: C1858712
•: Disease or Syndrome

Synonyms:	Spastic paraplegia 10; SPASTIC PARAPLEGIA 10 WITH OR WITHOUT PERIPHERAL NEUROPATHY; SPASTIC PARAPLEGIA 10 WITH PERIPHERAL NEUROPATHY; SPASTIC PARAPLEGIA 10, AUTOSOMAL DOMINANT; SPG10
SNOMED CT:	Autosomal dominant spastic paraplegia type 10 (732948003)
Modes of inheritance:	Autosomal dominant inheritance MedGen UID: 141047 •Concept ID: C0443147 • 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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele. Autosomal dominant inheritance (Orphanet)

Gene (location): Gene(s) directly associated with this condition or phenotype.	KIF5A (12q13.3)

Monarch Initiative:	MONDO:0011408
OMIM®:	604187
Orphanet:	ORPHA100991

Definition

Spastic paraplegia-10 (SPG10) is an autosomal dominant neurologic disorder with variable manifestations. Some patients have onset of a 'pure' spastic paraplegia, with lower limb spasticity, hyperreflexia, extensor plantar responses, and variable involvement of the upper limbs beginning in childhood or young adulthood. Some patients show distal sensory impairment, which can be part of the 'pure' phenotype. However, some patients also show an axonal sensorimotor peripheral neuropathy with distal sensory impairment and distal muscle atrophy reminiscent of Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A, 118210). Rarely, patients with KIF5A mutations may have additional neurologic features, including parkinsonism or cognitive decline, consistent with a 'complicated' phenotype. Spastic paraplegia and peripheral neuropathy in isolation may represent extreme ends of the phenotypic spectrum of KIF5A mutations (summary by Goizet et al., 2009 and Crimella et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600). [from OMIM]

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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Urinary urgency

MedGen UID:: 39315
•Concept ID:: C0085606
•: Finding

Urge incontinence is the strong, sudden need to urinate.

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Urinary bladder sphincter dysfunction

MedGen UID:: 334804
•Concept ID:: C1843663
•: Finding

Abnormal function of a sphincter of the urinary bladder.

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Ankle clonus

MedGen UID:: 68672
•Concept ID:: C0238651
•: Finding

Clonus is an involuntary tendon reflex that causes repeated flexion and extension of the foot. Ankle clonus is tested by rapidly flexing the foot upward.

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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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Lower limb hypertonia

MedGen UID:: 375612
•Concept ID:: C1845245
•: Finding

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Cerebellar ataxia

MedGen UID:: 849
•Concept ID:: C0007758
•: Disease or Syndrome

Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).

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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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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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Parkinsonian disorder

MedGen UID:: 66079
•Concept ID:: C0242422
•: Disease or Syndrome

Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.

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Knee clonus

MedGen UID:: 488908
•Concept ID:: C0520823
•: Finding

Clonus is an involuntary tendon reflex that causes repeated flexion and extension of the foot. Knee clonus can be tested by rapidly pushing the patella towards the toes.

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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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Distal sensory impairment

MedGen UID:: 335722
•Concept ID:: C1847584
•: Finding

An abnormal reduction in sensation in the distal portions of the extremities.

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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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Scoliosis

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

The presence of an abnormal lateral curvature of the spine.

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Abnormality of limbs
Abnormality of the genitourinary system
- Urinary bladder sphincter dysfunction
- Urinary urgency
Abnormality of the musculoskeletal system
- Scoliosis
Abnormality of the nervous system
Constitutional symptom
- Urinary incontinence

Term Hierarchy

GTR
MeSH
Orphanet

CClinical test, RResearch test, OOMIM, GGeneReviews, VClinVar

CROGVHereditary spastic paraplegia 10

Pure or complex autosomal dominant spastic paraplegia
- Hereditary spastic paraplegia 10

Follow this link to review classifications for Hereditary spastic paraplegia 10 in Orphanet.

Professional guidelines

PubMed

Liver X receptor-agonist treatment rescues degeneration in a Drosophila model of hereditary spastic paraplegia.

Byrne DJ, Garcia-Pardo ME, Cole NB, Batnasan B, Heneghan S, Sohail A, Blackstone C, O'Sullivan NC
Acta Neuropathol Commun 2022 Mar 28;10(1):40. doi: 10.1186/s40478-022-01343-6. PMID: 35346366 Free PMC Article

Functional and Clinical Outcomes of Combined Simultaneous Bilateral Anterior Distal Femoral Plate Hemiepiphysiodesis and Hamstrings Release in Management of Knee Flexion Contractures in Children With Neuromuscular Disorders.

Zaghloul A, Manoukian D, Barrett MC, Geronta I, Maizen C
J Pediatr Orthop 2021 Oct 1;41(9):559-565. doi: 10.1097/BPO.0000000000001942. PMID: 34387232

Genotype-phenotype correlations in spastic paraplegia type 7: a study in a large Dutch cohort.

van Gassen KL, van der Heijden CD, de Bot ST, den Dunnen WF, van den Berg LH, Verschuuren-Bemelmans CC, Kremer HP, Veldink JH, Kamsteeg EJ, Scheffer H, van de Warrenburg BP
Brain 2012 Oct;135(Pt 10):2994-3004. Epub 2012 Sep 10 doi: 10.1093/brain/aws224. PMID: 22964162

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Recent clinical studies

Etiology

Genetic characterization of primary lateral sclerosis.

de Boer EMJ, de Vries BS, Pennings M, Kamsteeg EJ, Veldink JH, van den Berg LH, van Es MA
J Neurol 2023 Aug;270(8):3970-3980. Epub 2023 May 3 doi: 10.1007/s00415-023-11746-7. PMID: 37133535 Free PMC Article

Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia.

Morsy H, Benkirane M, Cali E, Rocca C, Zhelcheska K, Cipriani V, Galanaki E, Maroofian R, Efthymiou S, Murphy D, O'Driscoll M, Suri M, Banka S, Clayton-Smith J, Wright T, Redman M, Bassetti JA, Nizon M, Cogne B, Jamra RA, Bartolomaeus T, Heruth M, Krey I, Gburek-Augustat J, Wieczorek D, Gattermann F, Mcentagart M, Goldenberg A, Guyant-Marechal L, Garcia-Moreno H, Giunti P, Chabrol B, Bacrot S, Buissonnière R, Magry V, Gowda VK, Srinivasan VM, Melegh B, Szabó A, Sümegi K, Cossée M, Ziff M, Butterfield R, Hunt D, Bird-Lieberman G, Hanna M, Koenig M, Stankewich M, Vandrovcova J, Houlden H; Genomics England Research Consortium
Genet Med 2023 Jan;25(1):76-89. Epub 2022 Nov 4 doi: 10.1016/j.gim.2022.09.013. PMID: 36331550 Free PMC Article

De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia.

Van de Vondel L, De Winter J, Beijer D, Coarelli G, Wayand M, Palvadeau R, Pauly MG, Klein K, Rautenberg M, Guillot-Noël L, Deconinck T, Vural A, Ertan S, Dogu O, Uysal H, Brankovic V, Herzog R, Brice A, Durr A, Klebe S, Stock F, Bischoff AT, Rattay TW, Sobrido MJ, De Michele G, De Jonghe P, Klopstock T, Lohmann K, Zanni G, Santorelli FM, Timmerman V, Haack TB, Züchner S; PREPARE Consortium, Schüle R, Stevanin G, Synofzik M, Basak AN, Baets J
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Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K, Brechmann B, Ziegler M, Jensen DM, Nagabhyrava P, Geisel G, Carmody E, Shamshad U, Dies KA, Yuskaitis CJ, Salussolia CL, Ebrahimi-Fakhari D, Pearson TS, Saffari A, Ziegler A, Kölker S, Volkmann J, Wiesener A, Bearden DR, Lakhani S, Segal D, Udwadia-Hegde A, Martinuzzi A, Hirst J, Perlman S, Takiyama Y, Xiromerisiou G, Vill K, Walker WO, Shukla A, Dubey Gupta R, Dahl N, Aksoy A, Verhelst H, Delgado MR, Kremlikova Pourova R, Sadek AA, Elkhateeb NM, Blumkin L, Brea-Fernández AJ, Dacruz-Álvarez D, Smol T, Ghoumid J, Miguel D, Heine C, Schlump JU, Langen H, Baets J, Bulk S, Darvish H, Bakhtiari S, Kruer MC, Lim-Melia E, Aydinli N, Alanay Y, El-Rashidy O, Nampoothiri S, Patel C, Beetz C, Bauer P, Yoon G, Guillot M, Miller SP, Bourinaris T, Houlden H, Robelin L, Anheim M, Alamri AS, Mahmoud AAH, Inaloo S, Habibzadeh P, Faghihi MA, Jansen AC, Brock S, Roubertie A, Darras BT, Agrawal PB, Santorelli FM, Gleeson J, Zaki MS, Sheikh SI, Bennett JT, Sahin M
Brain 2020 Oct 1;143(10):2929-2944. doi: 10.1093/brain/awz307. PMID: 32979048 Free PMC Article

The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies.

Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

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Diagnosis

ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization.

Schlüter A, Vélez-Santamaría V, Verdura E, Rodríguez-Palmero A, Ruiz M, Fourcade S, Planas-Serra L, Launay N, Guilera C, Martínez JJ, Homedes-Pedret C, Albertí-Aguiló MA, Zulaika M, Martí I, Troncoso M, Tomás-Vila M, Bullich G, García-Pérez MA, Sobrido-Gómez MJ, López-Laso E, Fons C, Del Toro M, Macaya A; HSP/ataxia workgroup, Beltran S, Gutiérrez-Solana LG, Pérez-Jurado LA, Aguilera-Albesa S, de Munain AL, Casasnovas C, Pujol A
Genome Med 2023 Sep 7;15(1):68. doi: 10.1186/s13073-023-01214-2. PMID: 37679823 Free PMC Article

Genetic characterization of primary lateral sclerosis.

Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.

Pellerin D, Danzi MC, Wilke C, Renaud M, Fazal S, Dicaire MJ, Scriba CK, Ashton C, Yanick C, Beijer D, Rebelo A, Rocca C, Jaunmuktane Z, Sonnen JA, Larivière R, Genís D, Molina Porcel L, Choquet K, Sakalla R, Provost S, Robertson R, Allard-Chamard X, Tétreault M, Reiling SJ, Nagy S, Nishadham V, Purushottam M, Vengalil S, Bardhan M, Nalini A, Chen Z, Mathieu J, Massie R, Chalk CH, Lafontaine AL, Evoy F, Rioux MF, Ragoussis J, Boycott KM, Dubé MP, Duquette A, Houlden H, Ravenscroft G, Laing NG, Lamont PJ, Saporta MA, Schüle R, Schöls L, La Piana R, Synofzik M, Zuchner S, Brais B
N Engl J Med 2023 Jan 12;388(2):128-141. Epub 2022 Dec 14 doi: 10.1056/NEJMoa2207406. PMID: 36516086 Free PMC Article

Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia.

The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies.

Ruano L, Melo C, Silva MC, Coutinho P
Neuroepidemiology 2014;42(3):174-83. Epub 2014 Mar 5 doi: 10.1159/000358801. PMID: 24603320

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Therapy

AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.

Dowling JJ, Pirovolakis T, Devakandan K, Stosic A, Pidsadny M, Nigro E, Sahin M, Ebrahimi-Fakhari D, Messahel S, Varadarajan G, Greenberg BM, Chen X, Minassian BA, Cohn R, Bonnemann CG, Gray SJ
Nat Med 2024 Jul;30(7):1882-1887. Epub 2024 Jun 28 doi: 10.1038/s41591-024-03078-4. PMID: 38942994 Free PMC Article

Dalfampridine as a promising agent in the management of hereditary spastic paraplegia: A triple-blinded, randomized, placebo-controlled pilot trial.

Selcuk Muhtaroglu F, Belgen Kaygisiz B, Usar Incirli S, Kahraman T
J Clin Neurosci 2023 Nov;117:136-142. Epub 2023 Oct 5 doi: 10.1016/j.jocn.2023.09.026. PMID: 37804674

Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies.

Chen X, Dong T, Hu Y, De Pace R, Mattera R, Eberhardt K, Ziegler M, Pirovolakis T, Sahin M, Bonifacino JS, Ebrahimi-Fakhari D, Gray SJ
J Clin Invest 2023 May 15;133(10) doi: 10.1172/JCI164575. PMID: 36951961 Free PMC Article

Gait-Adaptability Training in People With Hereditary Spastic Paraplegia: A Randomized Clinical Trial.

van de Venis L, van de Warrenburg B, Weerdesteyn V, Geurts ACH, Nonnekes J
Neurorehabil Neural Repair 2023 Jan;37(1):27-36. Epub 2023 Jan 25 doi: 10.1177/15459683221147839. PMID: 36695288 Free PMC Article

Potential markers for sample size estimations in hereditary spastic paraplegia type 5.

Lin Q, Liu Y, Ye Z, Hu J, Cai W, Weng Q, Chen WJ, Wang N, Cao D, Lin Y, Fu Y
Orphanet J Rare Dis 2021 Sep 19;16(1):391. doi: 10.1186/s13023-021-02014-w. PMID: 34538260 Free PMC Article

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Prognosis

AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.

ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization.

Economic evaluation of Motor Neuron Diseases: a nationwide cross-sectional analysis in Germany.

Heinrich F, Cordts I, Günther R, Stolte B, Zeller D, Schröter C, Weyen U, Regensburger M, Wolf J, Schneider I, Hermann A, Metelmann M, Kohl Z, Linker RA, Koch JC, Radelfahr F, Schönfelder E, Gardt P, Mohajer-Peseschkian T, Osmanovic A, Klopstock T, Dorst J, Ludolph AC, Schöffski O, Boentert M, Hagenacker T, Deschauer M, Lingor P, Petri S, Schreiber-Katz O
J Neurol 2023 Oct;270(10):4922-4938. Epub 2023 Jun 25 doi: 10.1007/s00415-023-11811-1. PMID: 37356024 Free PMC Article

Expansion of the mutation and phenotypic spectrum of hereditary spastic paraplegia.

Xing F, Du J
Neurol Sci 2022 Aug;43(8):4989-4996. Epub 2022 Mar 28 doi: 10.1007/s10072-022-05921-3. PMID: 35348942

The emerging genetic diversity of hereditary spastic paraplegia in Korean patients.

Yang JO, Yoon JY, Sung DH, Yun S, Lee JJ, Jun SY, Halder D, Jeon SJ, Woo EJ, Seok JM, Cho JW, Jang JH, Choi JK, Kim BJ, Kim NS
Genomics 2021 Nov;113(6):4136-4148. Epub 2021 Oct 27 doi: 10.1016/j.ygeno.2021.10.014. PMID: 34715294

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Clinical prediction guides

Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.

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