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Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures(NEDHCAS; GPIBD22)

MedGen UID:
1710849
Concept ID:
C5394372
Disease or Syndrome
Synonym: GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 22
 
Gene (location): PIGK (1p31.1)
 
Monarch Initiative: MONDO:0030037
OMIM®: 618879

Definition

Neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures (NEDHCAS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, delayed motor skills, and poor or absent speech. Most patients develop early-onset seizures and demonstrate cerebellar ataxia or dysmetria associated with progressive cerebellar atrophy on brain imaging. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Nguyen et al., 2020). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). [from OMIM]

Clinical features

From HPO
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Prominent antitragus
MedGen UID:
369349
Concept ID:
C1968811
Finding
Increased anterosuperior prominence of the area between the bottom of the incisura and the inner margin of the antihelix.
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).
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Low alkaline phosphatase
MedGen UID:
349734
Concept ID:
C1860130
Finding
Abnormally reduced serum levels of alkaline phosphatase.
Dental crowding
MedGen UID:
11850
Concept ID:
C0040433
Finding
Changes in alignment of teeth in the dental arch
Long face
MedGen UID:
324419
Concept ID:
C1836047
Finding
Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective).
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Sparse lateral eyebrow
MedGen UID:
387768
Concept ID:
C1857206
Finding
Decreased density/number and/or decreased diameter of lateral eyebrow hairs.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
High anterior hairline
MedGen UID:
477667
Concept ID:
C3276036
Finding
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD above the mean. Alternatively, an apparently increased distance between the hairline and the glabella.
Decreased expression of GPI-anchored proteins on the cell surface
MedGen UID:
1687016
Concept ID:
C5209293
Finding
A decrease in the protein expression of GPI-anchor proteins, such as CD55 and CD59, at the cell surface, which suggests a defect in GPI-anchor biosynthesis.

Professional guidelines

PubMed

Charalambous M, Muñana K, Patterson EE, Platt SR, Volk HA
J Vet Intern Med 2024 Jan-Feb;38(1):19-40. Epub 2023 Nov 3 doi: 10.1111/jvim.16928. PMID: 37921621Free PMC Article
Zuberi SM, Wirrell E, Yozawitz E, Wilmshurst JM, Specchio N, Riney K, Pressler R, Auvin S, Samia P, Hirsch E, Galicchio S, Triki C, Snead OC, Wiebe S, Cross JH, Tinuper P, Scheffer IE, Perucca E, Moshé SL, Nabbout R
Epilepsia 2022 Jun;63(6):1349-1397. Epub 2022 May 3 doi: 10.1111/epi.17239. PMID: 35503712
Abboud H, Probasco JC, Irani S, Ances B, Benavides DR, Bradshaw M, Christo PP, Dale RC, Fernandez-Fournier M, Flanagan EP, Gadoth A, George P, Grebenciucova E, Jammoul A, Lee ST, Li Y, Matiello M, Morse AM, Rae-Grant A, Rojas G, Rossman I, Schmitt S, Venkatesan A, Vernino S, Pittock SJ, Titulaer MJ; Autoimmune Encephalitis Alliance Clinicians Network
J Neurol Neurosurg Psychiatry 2021 Jul;92(7):757-768. Epub 2021 Mar 1 doi: 10.1136/jnnp-2020-325300. PMID: 33649022Free PMC Article

Recent clinical studies

Etiology

Ziobro J, Shellhaas RA
Semin Neurol 2020 Apr;40(2):246-256. Epub 2020 Mar 6 doi: 10.1055/s-0040-1702943. PMID: 32143234
Shellhaas RA
Handb Clin Neurol 2019;162:347-361. doi: 10.1016/B978-0-444-64029-1.00017-5. PMID: 31324320
Guerreiro CA
Indian J Med Res 2016 Nov;144(5):657-660. doi: 10.4103/ijmr.IJMR_1051_16. PMID: 28361817Free PMC Article
Gavvala JR, Schuele SU
JAMA 2016 Dec 27;316(24):2657-2668. doi: 10.1001/jama.2016.18625. PMID: 28027373
Patterson JL, Carapetian SA, Hageman JR, Kelley KR
Pediatr Ann 2013 Dec;42(12):249-54. doi: 10.3928/00904481-20131122-09. PMID: 24295158

Diagnosis

Wirrell E
Continuum (Minneap Minn) 2022 Apr 1;28(2):230-260. doi: 10.1212/CON.0000000000001074. PMID: 35393959
Mauritz M, Hirsch LJ, Camfield P, Chin R, Nardone R, Lattanzi S, Trinka E
Epileptic Disord 2022 Feb 1;24(1):26-49. doi: 10.1684/epd.2021.1376. PMID: 34789447
Ziobro J, Shellhaas RA
Semin Neurol 2020 Apr;40(2):246-256. Epub 2020 Mar 6 doi: 10.1055/s-0040-1702943. PMID: 32143234
Shellhaas RA
Handb Clin Neurol 2019;162:347-361. doi: 10.1016/B978-0-444-64029-1.00017-5. PMID: 31324320
Johnson EL
Med Clin North Am 2019 Mar;103(2):309-324. Epub 2018 Dec 3 doi: 10.1016/j.mcna.2018.10.002. PMID: 30704683

Therapy

Pizzo F, Collotta AD, Di Nora A, Costanza G, Ruggieri M, Falsaperla R
Expert Rev Neurother 2022 Feb;22(2):169-177. Epub 2022 Feb 25 doi: 10.1080/14737175.2022.2030220. PMID: 35144527
Rosenthal ES
Continuum (Minneap Minn) 2021 Oct 1;27(5):1321-1343. doi: 10.1212/CON.0000000000001012. PMID: 34618762
von Wrede R, Helmstaedter C, Surges R
Clin Drug Investig 2021 Mar;41(3):211-220. Epub 2021 Feb 9 doi: 10.1007/s40261-021-01003-y. PMID: 33559102Free PMC Article
Kotulska K, Kwiatkowski DJ, Curatolo P, Weschke B, Riney K, Jansen F, Feucht M, Krsek P, Nabbout R, Jansen AC, Wojdan K, Sijko K, Głowacka-Walas J, Borkowska J, Sadowski K, Domańska-Pakieła D, Moavero R, Hertzberg C, Hulshof H, Scholl T, Benova B, Aronica E, de Ridder J, Lagae L, Jóźwiak S; EPISTOP Investigators
Ann Neurol 2021 Feb;89(2):304-314. Epub 2020 Nov 27 doi: 10.1002/ana.25956. PMID: 33180985Free PMC Article
Beniczky S, Jeppesen J
Curr Opin Neurol 2019 Apr;32(2):198-204. doi: 10.1097/WCO.0000000000000658. PMID: 30664069

Prognosis

Salanova V, Sperling MR, Gross RE, Irwin CP, Vollhaber JA, Giftakis JE, Fisher RS; SANTÉ Study Group
Epilepsia 2021 Jun;62(6):1306-1317. Epub 2021 Apr 8 doi: 10.1111/epi.16895. PMID: 33830503
Tatum WO, Langston ME, Acton EK
Epileptic Disord 2016 Jun 1;18(2):148-54. doi: 10.1684/epd.2016.0823. PMID: 27238051
Patterson JL, Carapetian SA, Hageman JR, Kelley KR
Pediatr Ann 2013 Dec;42(12):249-54. doi: 10.3928/00904481-20131122-09. PMID: 24295158
Judge BS, Rentmeester LL
Psychiatr Clin North Am 2013 Jun;36(2):245-60. Epub 2013 Apr 11 doi: 10.1016/j.psc.2013.02.004. PMID: 23688690
Rennie JM
Eur J Pediatr 1997 Feb;156(2):83-7. doi: 10.1007/s004310050559. PMID: 9039506

Clinical prediction guides

Maroofian R, Kaiyrzhanov R, Cali E, Zamani M, Zaki MS, Ferla M, Tortora D, Sadeghian S, Saadi SM, Abdullah U, Karimiani EG, Efthymiou S, Yeşil G, Alavi S, Al Shamsi AM, Tajsharghi H, Abdel-Hamid MS, Saadi NW, Al Mutairi F, Alabdi L, Beetz C, Ali Z, Toosi MB, Rudnik-Schöneborn S, Babaei M, Isohanni P, Muhammad J, Khan S, Al Shalan M, Hickey SE, Marom D, Elhanan E, Kurian MA, Marafi D, Saberi A, Hamid M, Spaull R, Meng L, Lalani S, Maqbool S, Rahman F, Seeger J, Palculict TB, Lau T, Murphy D, Mencacci NE, Steindl K, Begemann A, Rauch A, Akbas S, Aslanger AD, Salpietro V, Yousaf H, Ben-Shachar S, Ejeskär K, Al Aqeel AI, High FA, Armstrong-Javors AE, Zahraei SM, Seifi T, Zeighami J, Shariati G, Sedaghat A, Asl SN, Shahrooei M, Zifarelli G, Burglen L, Ravelli C, Zschocke J, Schatz UA, Ghavideldarestani M, Kamel WA, Van Esch H, Hackenberg A, Taylor JC, Al-Gazali L, Bauer P, Gleeson JJ, Alkuraya FS, Lupski JR, Galehdari H, Azizimalamiri R, Chung WK, Baig SM, Houlden H, Severino M
Brain 2023 Dec 1;146(12):5031-5043. doi: 10.1093/brain/awad257. PMID: 37517035Free PMC Article
Baud MO, Proix T, Rao VR, Schindler K
Curr Opin Neurol 2020 Apr;33(2):163-172. doi: 10.1097/WCO.0000000000000798. PMID: 32049738
Meisel C, Loddenkemper T
Neuropharmacology 2020 Aug 1;172:107898. Epub 2019 Dec 5 doi: 10.1016/j.neuropharm.2019.107898. PMID: 31839204
Xu MY
Stroke Vasc Neurol 2019 Mar;4(1):48-56. Epub 2018 Dec 9 doi: 10.1136/svn-2018-000175. PMID: 31105979Free PMC Article
Acharya UR, Hagiwara Y, Adeli H
Epilepsy Behav 2018 Nov;88:251-261. Epub 2018 Oct 11 doi: 10.1016/j.yebeh.2018.09.030. PMID: 30317059

Recent systematic reviews

Pressler RM, Abend NS, Auvin S, Boylan G, Brigo F, Cilio MR, De Vries LS, Elia M, Espeche A, Hahn CD, Inder T, Jette N, Kakooza-Mwesige A, Mader S, Mizrahi EM, Moshé SL, Nagarajan L, Noyman I, Nunes ML, Samia P, Shany E, Shellhaas RA, Subota A, Triki CC, Tsuchida T, Vinayan KP, Wilmshurst JM, Yozawitz EG, Hartmann H
Epilepsia 2023 Oct;64(10):2550-2570. Epub 2023 Sep 1 doi: 10.1111/epi.17745. PMID: 37655702
Jafarpour S, Hirsch LJ, Gaínza-Lein M, Kellinghaus C, Detyniecki K
Seizure 2019 May;68:9-15. Epub 2018 May 21 doi: 10.1016/j.seizure.2018.05.013. PMID: 29871784
Steinert T, Fröscher W
Pharmacopsychiatry 2018 Jul;51(4):121-135. Epub 2017 Aug 29 doi: 10.1055/s-0043-117962. PMID: 28850959
Mewasingh LD
BMJ Clin Evid 2014 Jan 31;2014 PMID: 24484859Free PMC Article
Beghi E, Carpio A, Forsgren L, Hesdorffer DC, Malmgren K, Sander JW, Tomson T, Hauser WA
Epilepsia 2010 Apr;51(4):671-5. Epub 2009 Sep 3 doi: 10.1111/j.1528-1167.2009.02285.x. PMID: 19732133

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