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Hereditary spastic paraplegia 14(SPG14)

MedGen UID:
343157
•Concept ID:
C1854568
•
Disease or Syndrome
Synonyms: Spastic paraplegia 14; SPASTIC PARAPLEGIA 14, AUTOSOMAL RECESSIVE
SNOMED CT: Autosomal recessive spastic paraplegia type 14 (783094006)
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)
 
Monarch Initiative: MONDO:0011522
OMIM®: 605229
Orphanet: ORPHA100995

Definition

A rare complex hereditary spastic paraplegia with characteristics of adulthood onset of slowly progressive spastic paraplegia of lower limbs presenting with spastic gait, hyperreflexia and mild lower limb hypertonicity associated with mild intellectual disability, visual agnosia, short and long-term memory deficiency and mild distal motor neuropathy. Bilateral pes cavus and extensor plantar responses are also associated. [from SNOMEDCT_US]

Clinical features

From HPO
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).
See: Feature record | Search on this feature
Lower limb muscle weakness
MedGen UID:
324478
•Concept ID:
C1836296
•
Finding
Weakness of the muscles of the legs.
See: Feature record | Search on this feature
Intellectual disability, mild
MedGen UID:
10044
•Concept ID:
C0026106
•
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
Spastic paraplegia
MedGen UID:
20882
•Concept ID:
C0037772
•
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
See: Feature record | Search on this feature
Hyperreflexia
MedGen UID:
57738
•Concept ID:
C0151889
•
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
Motor axonal neuropathy
MedGen UID:
413108
•Concept ID:
C2749625
•
Disease or Syndrome
Progressive impairment of function of motor axons with muscle weakness, atrophy, and cramps. The deficits are length-dependent, meaning that muscles innervated by the longest nerves are affected first, so that for instance the arms are affected at a later age than the onset of deficits involving the lower leg.
See: Feature record | Search on this feature
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHereditary spastic paraplegia 14
Follow this link to review classifications for Hereditary spastic paraplegia 14 in Orphanet.

Professional guidelines

PubMed

Genotype-phenotype characterisation of long survivors with motor neuron disease in Scotland.
Leighton DJ, Ansari M, Newton J, Parry D, Cleary E, Colville S, Stephenson L, Larraz J, Johnson M, Beswick E, Wong M, Gregory J, Carod Artal J, Davenport R, Duncan C, Morrison I, Smith C, Swingler R, Deary IJ, Porteous M, Aitman TJ, Chandran S, Gorrie GH, Pal S; Lothian Birth Cohorts Group; and the CARE-MND Consortium
J Neurol 2023 Mar;270(3):1702-1712. Epub 2022 Dec 14 doi: 10.1007/s00415-022-11505-0. PMID: 36515702Free PMC Article
The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment.
Meyyazhagan A, Kuchi Bhotla H, Pappuswamy M, Orlacchio A
Int J Mol Sci 2022 Jul 11;23(14) doi: 10.3390/ijms23147665. PMID: 35887006Free PMC Article
Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations.
Méreaux JL, Firanescu C, Coarelli G, Kvarnung M, Rodrigues R, Pegoraro E, Tazir M, Taithe F, Valter R, Huin V, Lidström K, Banneau G, Morais S, Parodi L, Coutelier M, Papin M, Svenningsson P, Azulay JP, Alonso I, Nilsson D, Brice A, Le Guern E, Press R, Vazza G, Loureiro JL, Goizet C, Durr A, Paucar M, Stevanin G
Neurogenetics 2021 Mar;22(1):71-79. Epub 2021 Jan 23 doi: 10.1007/s10048-020-00633-2. PMID: 33486633Free PMC Article

Recent clinical studies

Etiology

Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.
Méreaux JL, Davoine CS, Pellerin D, Coarelli G, Coutelier M, Ewenczyk C, Monin ML, Anheim M, Le Ber I, Thobois S, Gobert F, Guillot-Noël L, Forlani S, Jornea L, Heinzmann A, Sangare A, Gaymard B, Guyant-Maréchal L, Charles P, Marelli C, Honnorat J, Degos B, Tison F, Sangla S, Simonetta-Moreau M, Salachas F, Tchikviladzé M, Castelnovo G, Mochel F, Klebe S, Castrioto A, Fenu S, Méneret A, Bourdain F, Wandzel M, Roth V, Bonnet C, Riant F, Stevanin G, Noël S, Fauret-Amsellem AL, Bahlo M, Lockhart PJ, Brais B, Renaud M, Brice A, Durr A
EBioMedicine 2024 Jan;99:104931. Epub 2023 Dec 27 doi: 10.1016/j.ebiom.2023.104931. PMID: 38150853Free PMC Article
Hereditary spastic paraplegia in Mali: epidemiological and clinical features.
Diarra S, Coulibaly T, Dembélé K, Ngouth N, Cissé L, Diallo SH, Ouologuem M, Diallo S, Coulibaly O, Bagayoko K, Coulibaly D, Simaga A, Sango HA, Traoré M, Jacobson S, Fischbeck KH, Landouré G, Guinto CO; H3Africa consortium
Acta Neurol Belg 2023 Dec;123(6):2155-2165. Epub 2022 Nov 17 doi: 10.1007/s13760-022-02113-w. PMID: 36396882
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
Mov Disord 2022 Jun;37(6):1175-1186. Epub 2022 Feb 12 doi: 10.1002/mds.28959. PMID: 35150594Free PMC Article
Clinical and genetic heterogeneity in hereditary spastic paraplegias: from SPG1 to SPG72 and still counting.
Klebe S, Stevanin G, Depienne C
Rev Neurol (Paris) 2015 Jun-Jul;171(6-7):505-30. Epub 2015 May 23 doi: 10.1016/j.neurol.2015.02.017. PMID: 26008818
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

Diagnosis

Outcome Measures and Biomarkers for Clinical Trials in Hereditary Spastic Paraplegia: A Scoping Review.
Siow SF, Yeow D, Rudaks LI, Jia F, Wali G, Sue CM, Kumar KR
Genes (Basel) 2023 Sep 3;14(9) doi: 10.3390/genes14091756. PMID: 37761896Free PMC Article
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: 36516086Free PMC Article
Hereditary spastic paraplegia in Mali: epidemiological and clinical features.
Diarra S, Coulibaly T, Dembélé K, Ngouth N, Cissé L, Diallo SH, Ouologuem M, Diallo S, Coulibaly O, Bagayoko K, Coulibaly D, Simaga A, Sango HA, Traoré M, Jacobson S, Fischbeck KH, Landouré G, Guinto CO; H3Africa consortium
Acta Neurol Belg 2023 Dec;123(6):2155-2165. Epub 2022 Nov 17 doi: 10.1007/s13760-022-02113-w. PMID: 36396882
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
An update on the leukodsytrophies.
Schiffmann R, Boespflüg-Tanguy O
Curr Opin Neurol 2001 Dec;14(6):789-94. doi: 10.1097/00019052-200112000-00018. PMID: 11723390

Therapy

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
The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment.
Meyyazhagan A, Kuchi Bhotla H, Pappuswamy M, Orlacchio A
Int J Mol Sci 2022 Jul 11;23(14) doi: 10.3390/ijms23147665. PMID: 35887006Free 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: 34538260Free PMC Article
Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial.
Schöls L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, Jägle C, Fraidakis MJ, Martinuzzi A, Saute JA, Scarlato M, Antenora A, Stendel C, Höflinger P, Lourenco CM, Abreu L, Smets K, Paucar M, Deconinck T, Bis DM, Wiethoff S, Bauer P, Arnoldi A, Marques W, Jardim LB, Hauser S, Criscuolo C, Filla A, Züchner S, Bassi MT, Klopstock T, De Jonghe P, Björkhem I, Schüle R
Brain 2017 Dec 1;140(12):3112-3127. doi: 10.1093/brain/awx273. PMID: 29126212Free PMC Article
Hereditary spastic paraplegia: clinical genomics and pharmacogenetic perspectives.
Contino G, Novelli G
Expert Opin Pharmacother 2006 Oct;7(14):1849-56. doi: 10.1517/14656566.7.14.1849. PMID: 17020412

Prognosis

RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.
Maroofian R, Sarraf P, O'Brien TJ, Kamel M, Cakar A, Elkhateeb N, Lau T, Patil SJ, Record CJ, Horga A, Essid M, Selim L, Benrhouma H, Ben Younes T, Zifarelli G, Pagnamenta AT, Bauer P, Khundadze M, Mirecki A, Kamel SM, Elmonem MA, Ghayoor Karimiani E, Jamshidi Y, Offiah AC, Rossor AM, Youssef-Turki IB, Hübner CA, Munot P, Reilly MM, Brown AEX, Nagy S, Houlden H
Brain 2024 Jul 5;147(7):2334-2343. doi: 10.1093/brain/awae091. PMID: 38527963Free PMC Article
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: 37356024Free PMC Article
Hereditary spastic paraplegia in Mali: epidemiological and clinical features.
Diarra S, Coulibaly T, Dembélé K, Ngouth N, Cissé L, Diallo SH, Ouologuem M, Diallo S, Coulibaly O, Bagayoko K, Coulibaly D, Simaga A, Sango HA, Traoré M, Jacobson S, Fischbeck KH, Landouré G, Guinto CO; H3Africa consortium
Acta Neurol Belg 2023 Dec;123(6):2155-2165. Epub 2022 Nov 17 doi: 10.1007/s13760-022-02113-w. PMID: 36396882
Neuro-Ophthalmic Phenotype of OPA3.
Huna-Baron R, Yahalom G, Anikster Y, Ben Zeev B, Hoffmann C, Hassin-Baer S
J Neuroophthalmol 2022 Mar 1;42(1):e147-e152. Epub 2021 Apr 14 doi: 10.1097/WNO.0000000000001249. PMID: 33870938
Hereditary spastic paraplegia: clinical genomics and pharmacogenetic perspectives.
Contino G, Novelli G
Expert Opin Pharmacother 2006 Oct;7(14):1849-56. doi: 10.1517/14656566.7.14.1849. PMID: 17020412

Clinical prediction guides

Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.
Méreaux JL, Davoine CS, Pellerin D, Coarelli G, Coutelier M, Ewenczyk C, Monin ML, Anheim M, Le Ber I, Thobois S, Gobert F, Guillot-Noël L, Forlani S, Jornea L, Heinzmann A, Sangare A, Gaymard B, Guyant-Maréchal L, Charles P, Marelli C, Honnorat J, Degos B, Tison F, Sangla S, Simonetta-Moreau M, Salachas F, Tchikviladzé M, Castelnovo G, Mochel F, Klebe S, Castrioto A, Fenu S, Méneret A, Bourdain F, Wandzel M, Roth V, Bonnet C, Riant F, Stevanin G, Noël S, Fauret-Amsellem AL, Bahlo M, Lockhart PJ, Brais B, Renaud M, Brice A, Durr A
EBioMedicine 2024 Jan;99:104931. Epub 2023 Dec 27 doi: 10.1016/j.ebiom.2023.104931. PMID: 38150853Free PMC Article
Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4-Related Hereditary Spastic Paraplegia.
Alecu JE, Saffari A, Ziegler M, Jordan C, Tam A, Kim S, Leung E, Szczaluba K, Mierzewska H, King SD, Santorelli FM, Yoon G, Trombetta B, Kivisäkk P, Zhang B, Sahin M, Ebrahimi-Fakhari D
Mov Disord 2023 Sep;38(9):1742-1750. Epub 2023 Jul 22 doi: 10.1002/mds.29524. PMID: 37482941Free PMC Article
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: 37356024Free PMC Article
Hereditary spastic paraplegia in Mali: epidemiological and clinical features.
Diarra S, Coulibaly T, Dembélé K, Ngouth N, Cissé L, Diallo SH, Ouologuem M, Diallo S, Coulibaly O, Bagayoko K, Coulibaly D, Simaga A, Sango HA, Traoré M, Jacobson S, Fischbeck KH, Landouré G, Guinto CO; H3Africa consortium
Acta Neurol Belg 2023 Dec;123(6):2155-2165. Epub 2022 Nov 17 doi: 10.1007/s13760-022-02113-w. PMID: 36396882
The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment.
Meyyazhagan A, Kuchi Bhotla H, Pappuswamy M, Orlacchio A
Int J Mol Sci 2022 Jul 11;23(14) doi: 10.3390/ijms23147665. PMID: 35887006Free PMC Article

Recent systematic reviews

Movement disorders in hereditary spastic paraplegia (HSP): a systematic review and individual participant data meta-analysis.
Fereshtehnejad SM, Saleh PA, Oliveira LM, Patel N, Bhowmick S, Saranza G, Kalia LV
Neurol Sci 2023 Mar;44(3):947-959. Epub 2022 Nov 28 doi: 10.1007/s10072-022-06516-8. PMID: 36441344Free PMC Article
Selective dorsal rhizotomy for spasticity of genetic etiology.
Lohkamp LN, Coulter I, Ibrahim GM
Childs Nerv Syst 2020 Jul;36(7):1357-1365. Epub 2020 Apr 16 doi: 10.1007/s00381-020-04601-x. PMID: 32300873
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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