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Periventricular nodular heterotopia 1(PVNH1)

MedGen UID:
376309
Concept ID:
C1848213
Congenital Abnormality; Disease or Syndrome
Synonyms: FLNA-Related Disorders; Heterotopia familial nodular; Heterotopia periventricular X-linked dominant; HETEROTOPIA, PERIVENTRICULAR, 1; Heterotopia, periventricular, Ehlers-Danlos variant; Nodular heterotopia bilateral periventricular; periventricular nodular heterotopia; PERIVENTRICULAR NODULAR HETEROTOPIA 4; PVNH1; X-linked periventricular heterotopia
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
X-linked dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: PVH - Periventricular heterotopia (448227009); X-linked periventricular heterotopia (448227009)
 
Gene (location): FLNA (Xq28)
OMIM®: 300049; 300537

Disease characteristics

FLNA-related periventricular nodular heterotopia (PVNH), a neuronal migration disorder, is characterized by the presence of uncalcified nodules of neurons ectopically situated along the surface of the lateral ventricles. Affected individuals are predominantly heterozygous females; males most often show early lethality. Affected females present with seizures at an average age of 14-15 years; intelligence ranges from normal to borderline. The risk for cardiovascular disease, stroke, and other vascular/coagulation problems appears to be increased. [from GeneReviews]
Authors:
Ming Hui Chen  |  Christopher A Walsh   view full author information

Additional descriptions

From OMIM
Periventricular nodular heterotopia is a disorder of neuronal migration in which neurons fail to migrate appropriately from the ventricular zone to the cortex during development, resulting in the formation of nodular brain tissue lining the ventricles. Most affected individuals with the X-linked form are female, while hemizygous males tend to die in utero. Affected females usually present with epilepsy, but have normal intelligence. Additional features include defects of the cardiovascular system, such as patent ductus arteriosus, bicuspid aortic valve, and dilation of the sinuses of Valsalva or the thoracic aorta (summary by Fox et al., 1998). Several patients with PVNH and mutations in the FLNA gene have been reported with a spectrum of connective tissue abnormalities characterized by combinations of vascular, cardiac, cutaneous, and joint-related symptoms (summary by Reinstein et al., 2013). Genetic Heterogeneity of Periventricular Nodular Heterotopia Periventricular nodular heterotopia is a genetically heterogeneous condition: see also PVNH2 (608097), caused by mutation in the ARFGEF2 gene (605371) on chromosome 20q13; PVNH3 (608098), associated with anomalies of 5p; PVNH5 (612881), associated with deletions of chromosome 5q; PVNH6 (615544), caused by mutation in the ERMARD gene (615532) on chromosome 6q27; and PVNH7 (617201), caused by mutation in the NEDD4L gene (606384) on chromosome 18q21. The form of PVNH that was previously designated the Ehlers-Danlos variant (PVNH4) is now considered to be the same as X-linked PVNH1.  http://www.omim.org/entry/300049
From GHR
Periventricular heterotopia is a condition in which nerve cells (neurons) do not migrate properly during the early development of the fetal brain, from about the 6th week to the 24th week of pregnancy. Heterotopia means "out of place." In normal brain development, neurons form in the periventricular region, located around fluid-filled cavities (ventricles) near the center of the brain. The neurons then migrate outward to form the exterior of the brain (cerebral cortex) in six onion-like layers. In periventricular heterotopia, some neurons fail to migrate to their proper position and form clumps around the ventricles.Periventricular heterotopia usually becomes evident when seizures first appear, often during the teenage years. The nodules around the ventricles are then typically discovered when magnetic resonance imaging (MRI) studies are done. Affected individuals usually have normal intelligence, although some have mild intellectual disability. Difficulty with reading and spelling (dyslexia) and movement problems have been reported in some people with periventricular heterotopia.Less commonly, individuals with periventricular heterotopia may have other features including more severe brain malformations, small head size (microcephaly), developmental delays, recurrent infections, blood vessel abnormalities, stomach problems, or lung disease. Periventricular heterotopia may also occur in association with other conditions such as Ehlers-Danlos syndrome, which results in extremely flexible joints, skin that stretches easily, and fragile blood vessels.  https://ghr.nlm.nih.gov/condition/periventricular-heterotopia

Clinical features

Abnormality of the coagulation cascade
MedGen UID:
604
Concept ID:
C0005779
Disease or Syndrome
Heterotopia
MedGen UID:
40280
Concept ID:
C0008519
Pathologic Function
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Stroke
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
Bicuspid aortic valve
MedGen UID:
57436
Concept ID:
C0149630
Congenital Abnormality
Abnormality of neuronal migration
MedGen UID:
324748
Concept ID:
C1837249
Congenital Abnormality

Recent clinical studies

Etiology

Mirandola L, Mai RF, Francione S, Pelliccia V, Gozzo F, Sartori I, Nobili L, Cardinale F, Cossu M, Meletti S, Tassi L
Epilepsia 2017 Nov;58(11):1962-1971. Epub 2017 Sep 7 doi: 10.1111/epi.13895. PMID: 28880999
Farquharson S, Tournier JD, Calamante F, Mandelstam S, Burgess R, Schneider ME, Berkovic SF, Scheffer IE, Jackson GD, Connelly A
Radiology 2016 Dec;281(3):896-906. Epub 2016 Jun 29 doi: 10.1148/radiol.2016150852. PMID: 27355897
Lange M, Kasper B, Bohring A, Rutsch F, Kluger G, Hoffjan S, Spranger S, Behnecke A, Ferbert A, Hahn A, Oehl-Jaschkowitz B, Graul-Neumann L, Diepold K, Schreyer I, Bernhard MK, Mueller F, Siebers-Renelt U, Beleza-Meireles A, Uyanik G, Janssens S, Boltshauser E, Winkler J, Schuierer G, Hehr U
Orphanet J Rare Dis 2015 Oct 15;10:134. doi: 10.1186/s13023-015-0331-9. PMID: 26471271Free PMC Article
Fallil Z, Pardoe H, Bachman R, Cunningham B, Parulkar I, Shain C, Poduri A, Knowlton R, Kuzniecky R; EPGP Investigators.
Epilepsy Behav 2015 Oct;51:321-7. Epub 2015 Sep 2 doi: 10.1016/j.yebeh.2015.07.041. PMID: 26340046Free PMC Article
Parrini E, Mei D, Pisanti MA, Catarzi S, Pucatti D, Bianchini C, Mascalchi M, Bertini E, Morrone A, Cavaliere ML, Guerrini R
J Med Genet 2015 Jun;52(6):405-12. Epub 2015 Mar 9 doi: 10.1136/jmedgenet-2014-102959. PMID: 25755106

Diagnosis

Mirandola L, Mai RF, Francione S, Pelliccia V, Gozzo F, Sartori I, Nobili L, Cardinale F, Cossu M, Meletti S, Tassi L
Epilepsia 2017 Nov;58(11):1962-1971. Epub 2017 Sep 7 doi: 10.1111/epi.13895. PMID: 28880999
Sahinoglu Z, Yapicier O, Ozcan N
J Clin Ultrasound 2016 Oct;44(8):510-3. Epub 2016 Mar 16 doi: 10.1002/jcu.22350. PMID: 26990213
Parrini E, Mei D, Pisanti MA, Catarzi S, Pucatti D, Bianchini C, Mascalchi M, Bertini E, Morrone A, Cavaliere ML, Guerrini R
J Med Genet 2015 Jun;52(6):405-12. Epub 2015 Mar 9 doi: 10.1136/jmedgenet-2014-102959. PMID: 25755106
Bardón-Cancho EJ, Muñoz-Jiménez L, Vázquez-López M, Ruíz-Martín Y, García-Morín M, Barredo-Valderrama E
Pediatr Neurol 2014 Sep;51(3):461-4. Epub 2014 May 15 doi: 10.1016/j.pediatrneurol.2014.05.008. PMID: 25160555
Abe Y, Kobayashi S, Wakusawa K, Tanaka S, Inui T, Yamamoto T, Kunishima S, Haginoya K
J Child Neurol 2014 Jun;29(6):818-22. Epub 2013 Feb 25 doi: 10.1177/0883073813478169. PMID: 23439715

Therapy

Venkatesan C, Angle B, Millichap JJ
Epileptic Disord 2016 Jun 1;18(2):195-200. doi: 10.1684/epd.2016.0828. PMID: 27248490
Clapham KR, Yu TW, Ganesh VS, Barry B, Chan Y, Mei D, Parrini E, Funalot B, Dupuis L, Nezarati MM, du Souich C, van Karnebeek C, Guerrini R, Walsh CA
Neurology 2012 Jan 24;78(4):269-78. Epub 2012 Jan 11 doi: 10.1212/WNL.0b013e31824365e4. PMID: 22238415Free PMC Article
de Wit MC, Schippers HM, de Coo IF, Arts WF, Lequin MH, Brooks A, Visser GH, Mancini GM
Seizure 2010 Sep;19(7):450-2. Epub 2010 Jul 15 doi: 10.1016/j.seizure.2010.06.013. PMID: 20637656
Scherer C, Schuele S, Minotti L, Chabardes S, Hoffmann D, Kahane P
Neurology 2005 Aug 9;65(3):495-6. doi: 10.1212/01.wnl.0000172350.25380.c7. PMID: 16087931
Kakita A, Hayashi S, Moro F, Guerrini R, Ozawa T, Ono K, Kameyama S, Walsh CA, Takahashi H
Acta Neuropathol 2002 Dec;104(6):649-57. Epub 2002 Jul 23 doi: 10.1007/s00401-002-0594-9. PMID: 12410386

Prognosis

Mirandola L, Mai RF, Francione S, Pelliccia V, Gozzo F, Sartori I, Nobili L, Cardinale F, Cossu M, Meletti S, Tassi L
Epilepsia 2017 Nov;58(11):1962-1971. Epub 2017 Sep 7 doi: 10.1111/epi.13895. PMID: 28880999
LaPointe MM, Spriggs EL, Mhanni AA
BMC Neurol 2014 Jun 7;14:125. doi: 10.1186/1471-2377-14-125. PMID: 24906659Free PMC Article
Recio-Rodríguez M, Fernández-Mayoralas DM, Fernández-Jaén A, Fernández-Perrone AL, Cano-Alonso R, Jiménez-de-La-Peña M
J Child Neurol 2014 Oct;29(10):NP122-6. Epub 2013 Nov 6 doi: 10.1177/0883073813508316. PMID: 24196422
Saito S, Kawamura R, Kosho T, Shimizu T, Aoyama K, Koike K, Wada T, Matsumoto N, Kato M, Wakui K, Fukushima Y
Am J Med Genet A 2008 Nov 15;146A(22):2891-7. doi: 10.1002/ajmg.a.32556. PMID: 18925681
Battaglia G, Franceschetti S, Chiapparini L, Freri E, Bassanini S, Giavazzi A, Finardi A, Taroni F, Granata T
J Child Neurol 2005 Apr;20(4):369-77. doi: 10.1177/08830738050200041701. PMID: 15921241

Clinical prediction guides

Lange M, Kasper B, Bohring A, Rutsch F, Kluger G, Hoffjan S, Spranger S, Behnecke A, Ferbert A, Hahn A, Oehl-Jaschkowitz B, Graul-Neumann L, Diepold K, Schreyer I, Bernhard MK, Mueller F, Siebers-Renelt U, Beleza-Meireles A, Uyanik G, Janssens S, Boltshauser E, Winkler J, Schuierer G, Hehr U
Orphanet J Rare Dis 2015 Oct 15;10:134. doi: 10.1186/s13023-015-0331-9. PMID: 26471271Free PMC Article
Fallil Z, Pardoe H, Bachman R, Cunningham B, Parulkar I, Shain C, Poduri A, Knowlton R, Kuzniecky R; EPGP Investigators.
Epilepsy Behav 2015 Oct;51:321-7. Epub 2015 Sep 2 doi: 10.1016/j.yebeh.2015.07.041. PMID: 26340046Free PMC Article
Capra V, Biancheri R, Morana G, Striano P, Novara F, Ferrero GB, Boeri L, Celle ME, Mancardi MM, Zuffardi O, Parrini E, Guerrini R
Am J Med Genet A 2014 Dec;164A(12):3142-7. Epub 2014 Sep 24 doi: 10.1002/ajmg.a.36742. PMID: 25257626
LaPointe MM, Spriggs EL, Mhanni AA
BMC Neurol 2014 Jun 7;14:125. doi: 10.1186/1471-2377-14-125. PMID: 24906659Free PMC Article
Blondiaux E, Sileo C, Nahama-Allouche C, Moutard ML, Gelot A, Jouannic JM, Ducou le Pointe H, Garel C
Ultrasound Obstet Gynecol 2013 Aug;42(2):149-55. doi: 10.1002/uog.12340. PMID: 23151899

Recent systematic reviews

Alcantara D, Timms AE, Gripp K, Baker L, Park K, Collins S, Cheng C, Stewart F, Mehta SG, Saggar A, Sztriha L, Zombor M, Caluseriu O, Mesterman R, Van Allen MI, Jacquinet A, Ygberg S, Bernstein JA, Wenger AM, Guturu H, Bejerano G, Gomez-Ospina N, Lehman A, Alfei E, Pantaleoni C, Conti V, Guerrini R, Moog U, Graham JM Jr, Hevner R, Dobyns WB, O'Driscoll M, Mirzaa GM
Brain 2017 Oct 1;140(10):2610-2622. doi: 10.1093/brain/awx203. PMID: 28969385

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