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Spastic paraplegia 39(SPG39)

MedGen UID:
383142
Concept ID:
C2677586
Disease or Syndrome
Synonyms: NTE related motor neuron disorder; SPASTIC PARAPLEGIA 39, AUTOSOMAL RECESSIVE; SPG39
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 (HPO, OMIM, Orphanet)
 
Gene (location): PNPLA6 (19p13.2)
OMIM®: 612020

Disease characteristics

Excerpted from the GeneReview: PNPLA6-Related Disorders
PNPLA6-related disorders span a phenotypic continuum characterized by variable combinations of cerebellar ataxia, upper motor neuron involvement manifesting as spasticity and/or brisk reflexes, chorioretinal dystrophy associated with variable degrees of reduced visual function, and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics), either in isolation or as part of anterior hypopituitarism (growth hormone, thyroid hormone, or gonadotropin deficiencies). Common but less frequent features are peripheral neuropathy (usually of axonal type manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting), hair anomalies (long eyelashes, bushy eyebrows, or scalp alopecia), short stature, and impaired cognitive functioning (learning disabilities in children and deficits in attention, visuospatial abilities, and recall in adults). Some of these features can occur in distinct clusters on the phenotypic continuum: Boucher-Neuhäuser syndrome (cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism); Gordon Holmes syndrome (cerebellar ataxia, hypogonadotropic hypogonadism, and – to a variable degree – brisk reflexes); Oliver-McFarlane syndrome (trichomegaly, chorioretinal dystrophy, short stature, intellectual disability, and hypopituitarism); Laurence-Moon syndrome; and spastic paraplegia type 39 (SPG39) (upper motor neuron involvement, peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia). [from GeneReviews]
Authors:
Matthis Synofzik  |  Robert B Hufnagel  |  Stephan Züchner   view full author information

Additional description

From OMIM
The form of motor neuron disease designated spastic paraplegia-39 (SPG39) by Rainier et al. (2008) is an autosomal recessive progressive spastic paraplegia associated with distal upper and lower extremity wasting. For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.  http://www.omim.org/entry/612020

Clinical features

From HPO
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- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
A reflex characterized by upward movement of the great toe and an outward movement of the rest of the toes, when the sole of the foot is stroked. It is a normal reflex up to the age of two. Its presence beyond that age indicates neurological damage.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Autonomic nervous system overreaction to stimuli, most commonly after spinal cord injury at a T-5 level and above.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
A finding referring to walking difficulties.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Atrophy (wasting) of the cerebellum.
Atrophy of the spinal cord
MedGen UID:
235592
Concept ID:
C1389102
Disease or Syndrome
Progressive spastic paraplegia
MedGen UID:
344505
Concept ID:
C1855483
Finding
Distal lower limb muscle weakness
MedGen UID:
324514
Concept ID:
C1836450
Finding
Reduced strength of the distal musculature of the legs.
Distal lower limb muscle weakness
MedGen UID:
324514
Concept ID:
C1836450
Finding
Reduced strength of the distal musculature of the legs.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Progressive spastic paraplegia
MedGen UID:
344505
Concept ID:
C1855483
Finding

Recent clinical studies

Etiology

Sadeghi N, Arrigoni F, D'Angelo MG, Thomas C, Irfanoglu MO, Hutchinson EB, Nayak A, Modi P, Bassi MT, Pierpaoli C
Hum Brain Mapp 2018 Dec;39(12):4643-4651. Epub 2018 Sep 25 doi: 10.1002/hbm.24278. PMID: 30253021
Lu C, Li LX, Dong HL, Wei Q, Liu ZJ, Ni W, Gitler AD, Wu ZY
J Mol Med (Berl) 2018 Jul;96(7):701-712. Epub 2018 Jun 11 doi: 10.1007/s00109-018-1655-4. PMID: 29934652
Sitthinamsuwan B, Khampalikit I, Phonwijit L, Nitising A, Nunta-Aree S, Suksompong S
World Neurosurg 2018 Aug;116:e476-e484. Epub 2018 May 16 doi: 10.1016/j.wneu.2018.05.008. PMID: 29753900
Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, Federoff M, Preza E, Hughes D, Pittman A, Jaunmuktane Z, Brandner S, Xiromerisiou G, Wiethoff S, Schottlaender L, Proukakis C, Morris H, Warner T, Bhatia KP, Korlipara LV, Singleton AB, Hardy J, Wood NW, Lewis PA, Houlden H
Brain 2016 Jul;139(Pt 7):1904-18. Epub 2016 May 23 doi: 10.1093/brain/aww111. PMID: 27217339Free PMC Article
Agosta F, Scarlato M, Spinelli EG, Canu E, Benedetti S, Bassi MT, Casali C, Sessa M, Copetti M, Pagani E, Comi G, Ferrari M, Falini A, Filippi M
Radiology 2015 Jul;276(1):207-18. Epub 2015 Jan 22 doi: 10.1148/radiol.14141715. PMID: 25611737

Diagnosis

Sadeghi N, Arrigoni F, D'Angelo MG, Thomas C, Irfanoglu MO, Hutchinson EB, Nayak A, Modi P, Bassi MT, Pierpaoli C
Hum Brain Mapp 2018 Dec;39(12):4643-4651. Epub 2018 Sep 25 doi: 10.1002/hbm.24278. PMID: 30253021
Lu C, Li LX, Dong HL, Wei Q, Liu ZJ, Ni W, Gitler AD, Wu ZY
J Mol Med (Berl) 2018 Jul;96(7):701-712. Epub 2018 Jun 11 doi: 10.1007/s00109-018-1655-4. PMID: 29934652
Sitthinamsuwan B, Khampalikit I, Phonwijit L, Nitising A, Nunta-Aree S, Suksompong S
World Neurosurg 2018 Aug;116:e476-e484. Epub 2018 May 16 doi: 10.1016/j.wneu.2018.05.008. PMID: 29753900
Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, Federoff M, Preza E, Hughes D, Pittman A, Jaunmuktane Z, Brandner S, Xiromerisiou G, Wiethoff S, Schottlaender L, Proukakis C, Morris H, Warner T, Bhatia KP, Korlipara LV, Singleton AB, Hardy J, Wood NW, Lewis PA, Houlden H
Brain 2016 Jul;139(Pt 7):1904-18. Epub 2016 May 23 doi: 10.1093/brain/aww111. PMID: 27217339Free PMC Article
Klebe S, Depienne C, Gerber S, Challe G, Anheim M, Charles P, Fedirko E, Lejeune E, Cottineau J, Brusco A, Dollfus H, Chinnery PF, Mancini C, Ferrer X, Sole G, Destée A, Mayer JM, Fontaine B, de Seze J, Clanet M, Ollagnon E, Busson P, Cazeneuve C, Stevanin G, Kaplan J, Rozet JM, Brice A, Durr A
Brain 2012 Oct;135(Pt 10):2980-93. doi: 10.1093/brain/aws240. PMID: 23065789Free PMC Article

Therapy

Beuriat PA, Melloul S, Galmiche L, Cristofori I, Zerah M, Beccaria K
J Pediatr Hematol Oncol 2017 Nov;39(8):e479-e482. doi: 10.1097/MPH.0000000000000878. PMID: 28582275
Chung T, Thien C, Wang YY
Spine (Phila Pa 1976) 2014 Feb 1;39(3):E228-30. doi: 10.1097/BRS.0000000000000092. PMID: 24153167
Etz CD, Zoli S, Mueller CS, Bodian CA, Di Luozzo G, Lazala R, Plestis KA, Griepp RB
J Thorac Cardiovasc Surg 2010 Jun;139(6):1464-72. doi: 10.1016/j.jtcvs.2010.02.037. PMID: 20494193
Wahman K, Nash MS, Westgren N, Lewis JE, Seiger A, Levi R
J Rehabil Med 2010 Mar;42(3):272-8. doi: 10.2340/16501977-0510. PMID: 20419873
Nash MS, van de Ven I, van Elk N, Johnson BM
Arch Phys Med Rehabil 2007 Jan;88(1):70-5. doi: 10.1016/j.apmr.2006.10.003. PMID: 17207678

Prognosis

Helal M, Mazaheri N, Shalbafan B, Malamiri RA, Dilaver N, Buchert R, Mohammadiasl J, Golchin N, Sedaghat A, Mehrjardi MYV, Haack TB, Riess O, Chung WK, Galehdari H, Shariati G, Maroofian R
Neurol Sci 2018 Nov;39(11):1917-1925. Epub 2018 Aug 21 doi: 10.1007/s10072-018-3526-8. PMID: 30128655
Ruaud L, Rice GI, Cabrol C, Piard J, Rodero M, van Eyk L, Boucher-Brischoux E, de Noordhout AM, Maré R, Scalais E, Pauly F, Debray FG, Dobyns W, Uggenti C, Park JW, Hur S, Livingston JH, Crow YJ, Van Maldergem L
Hum Mutat 2018 Aug;39(8):1076-1080. Epub 2018 Jun 4 doi: 10.1002/humu.23554. PMID: 29782060Free PMC Article
Durand CM, Dhers L, Tesson C, Tessa A, Fouillen L, Jacqueré S, Raymond L, Coupry I, Benard G, Darios F, El-Hachimi KH, Astrea G, Rivier F, Banneau G, Pujol C, Lacombe D, Durr A, Babin PJ, Santorelli FM, Pietrancosta N, Boucher JL, Mansuy D, Stevanin G, Goizet C
Hum Mutat 2018 Jan;39(1):140-151. Epub 2017 Nov 11 doi: 10.1002/humu.23359. PMID: 29034544
Zhang Y, Roxburgh R, Huang L, Parsons J, Davies TC
Gait Posture 2014 Apr;39(4):1074-9. Epub 2014 Jan 29 doi: 10.1016/j.gaitpost.2014.01.010. PMID: 24556467
de Bot ST, Burggraaff RC, Herkert JC, Schelhaas HJ, Post B, Diekstra A, van Vliet RO, van der Knaap MS, Kamsteeg EJ, Scheffer H, van de Warrenburg BP, Verschuuren-Bemelmans CC, Kremer HP
Eur J Hum Genet 2013 Nov;21(11):1312-5. Epub 2013 Feb 27 doi: 10.1038/ejhg.2013.27. PMID: 23443022Free PMC Article

Clinical prediction guides

Sitthinamsuwan B, Khampalikit I, Phonwijit L, Nitising A, Nunta-Aree S, Suksompong S
World Neurosurg 2018 Aug;116:e476-e484. Epub 2018 May 16 doi: 10.1016/j.wneu.2018.05.008. PMID: 29753900
Durand CM, Dhers L, Tesson C, Tessa A, Fouillen L, Jacqueré S, Raymond L, Coupry I, Benard G, Darios F, El-Hachimi KH, Astrea G, Rivier F, Banneau G, Pujol C, Lacombe D, Durr A, Babin PJ, Santorelli FM, Pietrancosta N, Boucher JL, Mansuy D, Stevanin G, Goizet C
Hum Mutat 2018 Jan;39(1):140-151. Epub 2017 Nov 11 doi: 10.1002/humu.23359. PMID: 29034544
Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, Federoff M, Preza E, Hughes D, Pittman A, Jaunmuktane Z, Brandner S, Xiromerisiou G, Wiethoff S, Schottlaender L, Proukakis C, Morris H, Warner T, Bhatia KP, Korlipara LV, Singleton AB, Hardy J, Wood NW, Lewis PA, Houlden H
Brain 2016 Jul;139(Pt 7):1904-18. Epub 2016 May 23 doi: 10.1093/brain/aww111. PMID: 27217339Free PMC Article
Agosta F, Scarlato M, Spinelli EG, Canu E, Benedetti S, Bassi MT, Casali C, Sessa M, Copetti M, Pagani E, Comi G, Ferrari M, Falini A, Filippi M
Radiology 2015 Jul;276(1):207-18. Epub 2015 Jan 22 doi: 10.1148/radiol.14141715. PMID: 25611737
Racis L, Storti E, Pugliatti M, Agnetti V, Tessa A, Santorelli FM
BMC Med Genet 2014 Apr 1;15:39. doi: 10.1186/1471-2350-15-39. PMID: 24690193Free PMC Article

Recent systematic reviews

Huang Q, Chen XM, Yang H, Lin QN, Qin X
Eur J Vasc Endovasc Surg 2018 Nov;56(5):644-651. Epub 2018 Aug 16 doi: 10.1016/j.ejvs.2018.07.018. PMID: 30122331
Moulakakis KG, Karaolanis G, Antonopoulos CN, Kakisis J, Klonaris C, Preventza O, Coselli JS, Geroulakos G
J Vasc Surg 2018 Aug;68(2):634-645.e12. doi: 10.1016/j.jvs.2018.03.410. PMID: 30037680
Williams N, Cundy PJ, Eastwod DM
Spine (Phila Pa 1976) 2017 Dec 1;42(23):1817-1825. doi: 10.1097/BRS.0000000000002242. PMID: 28538597
Tranchant C, Koob M, Anheim M
Parkinsonism Relat Disord 2017 Jun;39:4-16. Epub 2017 Feb 22 doi: 10.1016/j.parkreldis.2017.02.025. PMID: 28256436
Chiodo AE, Sitrin RG, Bauman KA
J Spinal Cord Med 2016 Jul;39(4):374-82. Epub 2016 Mar 15 doi: 10.1080/10790268.2015.1126449. PMID: 27077573Free PMC Article

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