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Neurodevelopmental disorder with or without autism or seizures(NEDAUS)

MedGen UID:
1784023
Concept ID:
C5543225
Disease or Syndrome
Synonym: NEDAUS
 
Gene (location): CUL3 (2q36.2)
 
Monarch Initiative: MONDO:0030994
OMIM®: 619239

Definition

CUL3-related neurodevelopmental disorder is a condition that affects neurological and physical development. Children with CUL3-related neurodevelopmental disorder may have intellectual disability or specific learning disorders. They may also experience delayed development of speech and motor skills, such as sitting and walking. Some individuals with this condition may have autism spectrum disorder, a developmental condition that affects communication and social skills. 

Movement abnormalities can also occur in people with CUL3-related neurodevelopmental disorder. Affected individuals may have weak muscle tone (hypotonia) in childhood. In adulthood, they may develop involuntary muscle tensing (dystonia), rhythmic shaking (tremor), or other uncontrolled movements (spasms). 

People with CUL3-related neurodevelopmental disorder can have distinctive facial features, including a long, triangular-shaped face; a large forehead; a large, rounded nose; small ears; deep-set eyes; or a pointed chin. Some affected individuals have a larger than normal head (macrocephaly). 

Many people with CUL3-related neurodevelopmental disorder have hand and foot abnormalities. Hand abnormalities can include small pinky (fifth) fingers that curve inward (clinodactyly), narrow thumbs, underdevelopment of the muscle at the base of the thumb (thenar hypoplasia), or a single crease across the palm of the hand. Foot abnormalities can include high arches of the feet (pes cavus); bunions; fusion of the skin between some toes (cutaneous syndactyly); or joint deformities (contractures) in the ankles, feet, or toes. A few individuals with CUL3-related neurodevelopmental disorder have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis). 

Some affected infants have a backflow of stomach acids into the esophagus (gastroesophageal reflux disease or GERD), which tends to go away after childhood. Rarely, recurrent seizures (epilepsy), congenital heart abnormalities, or genitourinary abnormalities occur in people with CUL3-related neurodevelopmental disorder.  [from MedlinePlus Genetics]

Clinical features

From HPO
Absent thumb
MedGen UID:
480441
Concept ID:
C3278811
Finding
Absent thumb, i.e., the absence of both phalanges of a thumb and the associated soft tissues.
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Pulmonic stenosis
MedGen UID:
408291
Concept ID:
C1956257
Disease or Syndrome
A narrowing of the right ventricular outflow tract that can occur at the pulmonary valve (valvular stenosis), below the pulmonary valve (infundibular stenosis), or above the pulmonary valve (supravalvar stenosis).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
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.
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.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Tonic seizure
MedGen UID:
82855
Concept ID:
C0270844
Disease or Syndrome
A tonic seizure is a type of motor seizure characterized by unilateral or bilateral limb stiffening or elevation, often with neck stiffening.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a condition characterized by constant and unusually high levels of activity, even in situations where it is deemed inappropriate.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
EEG with burst suppression
MedGen UID:
369943
Concept ID:
C1969156
Finding
The burst suppression pattern in electroencephalography refers to a characteristic periodic pattern of low voltage (<10 microvolts) suppressed background and a relatively shorter pattern of higher amplitude slow, sharp, and spiking complexes.
Infantile spasms
MedGen UID:
854616
Concept ID:
C3887898
Disease or Syndrome
Infantile spasms represent a subset of "epileptic spasms". Infantile Spasms are epileptic spasms starting in the first year of life (infancy).
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
Delayed ability to sit
MedGen UID:
1368737
Concept ID:
C4476710
Finding
A failure to achieve the ability to sit at an appropriate developmental stage. Most children sit with support at 6 months of age and sit steadily without support at 9 months of age.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Submucous cleft hard palate
MedGen UID:
98472
Concept ID:
C0432103
Congenital Abnormality
Hard-palate submucous clefts are characterized by bony defects in the midline of the bony palate that are covered by the mucous membrane of the roof of the mouth. It may be possible to detect a submucous cleft hard palate upon palpation as a notch in the bony palate.
Bifid uvula
MedGen UID:
1646931
Concept ID:
C4551488
Congenital Abnormality
Uvula separated into two parts most easily seen at the tip.

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
Faraone SV, Banaschewski T, Coghill D, Zheng Y, Biederman J, Bellgrove MA, Newcorn JH, Gignac M, Al Saud NM, Manor I, Rohde LA, Yang L, Cortese S, Almagor D, Stein MA, Albatti TH, Aljoudi HF, Alqahtani MMJ, Asherson P, Atwoli L, Bölte S, Buitelaar JK, Crunelle CL, Daley D, Dalsgaard S, Döpfner M, Espinet S, Fitzgerald M, Franke B, Gerlach M, Haavik J, Hartman CA, Hartung CM, Hinshaw SP, Hoekstra PJ, Hollis C, Kollins SH, Sandra Kooij JJ, Kuntsi J, Larsson H, Li T, Liu J, Merzon E, Mattingly G, Mattos P, McCarthy S, Mikami AY, Molina BSG, Nigg JT, Purper-Ouakil D, Omigbodun OO, Polanczyk GV, Pollak Y, Poulton AS, Rajkumar RP, Reding A, Reif A, Rubia K, Rucklidge J, Romanos M, Ramos-Quiroga JA, Schellekens A, Scheres A, Schoeman R, Schweitzer JB, Shah H, Solanto MV, Sonuga-Barke E, Soutullo C, Steinhausen HC, Swanson JM, Thapar A, Tripp G, van de Glind G, van den Brink W, Van der Oord S, Venter A, Vitiello B, Walitza S, Wang Y
Neurosci Biobehav Rev 2021 Sep;128:789-818. Epub 2021 Feb 4 doi: 10.1016/j.neubiorev.2021.01.022. PMID: 33549739Free PMC Article
Wolraich ML, Hagan JF Jr, Allan C, Chan E, Davison D, Earls M, Evans SW, Flinn SK, Froehlich T, Frost J, Holbrook JR, Lehmann CU, Lessin HR, Okechukwu K, Pierce KL, Winner JD, Zurhellen W; SUBCOMMITTEE ON CHILDREN AND ADOLESCENTS WITH ATTENTION-DEFICIT/HYPERACTIVE DISORDER
Pediatrics 2019 Oct;144(4) doi: 10.1542/peds.2019-2528. PMID: 31570648Free PMC Article

Recent clinical studies

Etiology

Li C, Fleck JS, Martins-Costa C, Burkard TR, Themann J, Stuempflen M, Peer AM, Vertesy Á, Littleboy JB, Esk C, Elling U, Kasprian G, Corsini NS, Treutlein B, Knoblich JA
Nature 2023 Sep;621(7978):373-380. Epub 2023 Sep 13 doi: 10.1038/s41586-023-06473-y. PMID: 37704762Free PMC Article
Máčová L, Bičíková M, Ostatníková D, Hill M, Stárka L
Physiol Res 2017 Sep 26;66(Suppl 3):S333-S340. doi: 10.33549/physiolres.933721. PMID: 28948817
Stessman HA, Xiong B, Coe BP, Wang T, Hoekzema K, Fenckova M, Kvarnung M, Gerdts J, Trinh S, Cosemans N, Vives L, Lin J, Turner TN, Santen G, Ruivenkamp C, Kriek M, van Haeringen A, Aten E, Friend K, Liebelt J, Barnett C, Haan E, Shaw M, Gecz J, Anderlid BM, Nordgren A, Lindstrand A, Schwartz C, Kooy RF, Vandeweyer G, Helsmoortel C, Romano C, Alberti A, Vinci M, Avola E, Giusto S, Courchesne E, Pramparo T, Pierce K, Nalabolu S, Amaral DG, Scheffer IE, Delatycki MB, Lockhart PJ, Hormozdiari F, Harich B, Castells-Nobau A, Xia K, Peeters H, Nordenskjöld M, Schenck A, Bernier RA, Eichler EE
Nat Genet 2017 Apr;49(4):515-526. Epub 2017 Feb 13 doi: 10.1038/ng.3792. PMID: 28191889Free PMC Article
Lai MC, Lombardo MV, Baron-Cohen S
Lancet 2014 Mar 8;383(9920):896-910. Epub 2013 Sep 26 doi: 10.1016/S0140-6736(13)61539-1. PMID: 24074734
McPartland J, Volkmar FR
Handb Clin Neurol 2012;106:407-18. doi: 10.1016/B978-0-444-52002-9.00023-1. PMID: 22608634Free PMC Article

Diagnosis

Singhi P, Malhi P
Indian J Pediatr 2023 Apr;90(4):364-368. Epub 2022 Oct 18 doi: 10.1007/s12098-022-04363-1. PMID: 36255651
Robertson CE, Baron-Cohen S
Nat Rev Neurosci 2017 Nov;18(11):671-684. Epub 2017 Sep 29 doi: 10.1038/nrn.2017.112. PMID: 28951611
Wang SS, Kloth AD, Badura A
Neuron 2014 Aug 6;83(3):518-32. doi: 10.1016/j.neuron.2014.07.016. PMID: 25102558Free PMC Article
Lai MC, Lombardo MV, Baron-Cohen S
Lancet 2014 Mar 8;383(9920):896-910. Epub 2013 Sep 26 doi: 10.1016/S0140-6736(13)61539-1. PMID: 24074734
McPartland J, Volkmar FR
Handb Clin Neurol 2012;106:407-18. doi: 10.1016/B978-0-444-52002-9.00023-1. PMID: 22608634Free PMC Article

Therapy

Holopainen A, de Veld DMJ, Hoddenbach E, Begeer S
J Autism Dev Disord 2019 Oct;49(10):3965-3972. doi: 10.1007/s10803-018-3671-1. PMID: 30074122Free PMC Article
Kashefimehr B, Kayihan H, Huri M
OTJR (Thorofare N J) 2018 Apr;38(2):75-83. Epub 2017 Dec 27 doi: 10.1177/1539449217743456. PMID: 29281930
Máčová L, Bičíková M, Ostatníková D, Hill M, Stárka L
Physiol Res 2017 Sep 26;66(Suppl 3):S333-S340. doi: 10.33549/physiolres.933721. PMID: 28948817
Sanchack KE, Thomas CA
Am Fam Physician 2016 Dec 15;94(12):972-979. PMID: 28075089
Mesibov GB, Shea V
Autism 2011 Jan;15(1):114-33. Epub 2010 Sep 27 doi: 10.1177/1362361309348070. PMID: 20876165

Prognosis

Dawson G, Rieder AD, Johnson MH
Lancet Neurol 2023 Mar;22(3):244-254. Epub 2022 Nov 22 doi: 10.1016/S1474-4422(22)00407-0. PMID: 36427512Free PMC Article
Lai MC, Lombardo MV, Baron-Cohen S
Lancet 2014 Mar 8;383(9920):896-910. Epub 2013 Sep 26 doi: 10.1016/S0140-6736(13)61539-1. PMID: 24074734
Baird G, Cass H, Slonims V
BMJ 2003 Aug 30;327(7413):488-93. doi: 10.1136/bmj.327.7413.488. PMID: 12946972Free PMC Article
Rapin I
N Engl J Med 1997 Jul 10;337(2):97-104. doi: 10.1056/NEJM199707103370206. PMID: 9211680
Lee-Dukes G
Am Fam Physician 1986 Jun;33(6):149-55. PMID: 3716967

Clinical prediction guides

Li C, Fleck JS, Martins-Costa C, Burkard TR, Themann J, Stuempflen M, Peer AM, Vertesy Á, Littleboy JB, Esk C, Elling U, Kasprian G, Corsini NS, Treutlein B, Knoblich JA
Nature 2023 Sep;621(7978):373-380. Epub 2023 Sep 13 doi: 10.1038/s41586-023-06473-y. PMID: 37704762Free PMC Article
Dawson G, Rieder AD, Johnson MH
Lancet Neurol 2023 Mar;22(3):244-254. Epub 2022 Nov 22 doi: 10.1016/S1474-4422(22)00407-0. PMID: 36427512Free PMC Article
Takumi T, Tamada K, Hatanaka F, Nakai N, Bolton PF
Neurosci Biobehav Rev 2020 Mar;110:60-76. Epub 2019 May 3 doi: 10.1016/j.neubiorev.2019.04.012. PMID: 31059731
Máčová L, Bičíková M, Ostatníková D, Hill M, Stárka L
Physiol Res 2017 Sep 26;66(Suppl 3):S333-S340. doi: 10.33549/physiolres.933721. PMID: 28948817
Amaral DG, Schumann CM, Nordahl CW
Trends Neurosci 2008 Mar;31(3):137-45. Epub 2008 Feb 6 doi: 10.1016/j.tins.2007.12.005. PMID: 18258309

Recent systematic reviews

Zeidan J, Fombonne E, Scorah J, Ibrahim A, Durkin MS, Saxena S, Yusuf A, Shih A, Elsabbagh M
Autism Res 2022 May;15(5):778-790. Epub 2022 Mar 3 doi: 10.1002/aur.2696. PMID: 35238171Free PMC Article
Jutla A, Foss-Feig J, Veenstra-VanderWeele J
Autism Res 2022 Mar;15(3):384-412. Epub 2021 Dec 29 doi: 10.1002/aur.2659. PMID: 34967130Free PMC Article
Hume K, Steinbrenner JR, Odom SL, Morin KL, Nowell SW, Tomaszewski B, Szendrey S, McIntyre NS, Yücesoy-Özkan S, Savage MN
J Autism Dev Disord 2021 Nov;51(11):4013-4032. Epub 2021 Jan 15 doi: 10.1007/s10803-020-04844-2. PMID: 33449225Free PMC Article
Schoen SA, Lane SJ, Mailloux Z, May-Benson T, Parham LD, Smith Roley S, Schaaf RC
Autism Res 2019 Jan;12(1):6-19. Epub 2018 Dec 12 doi: 10.1002/aur.2046. PMID: 30548827Free PMC Article
Geretsegger M, Elefant C, Mössler KA, Gold C
Cochrane Database Syst Rev 2014 Jun 17;2014(6):CD004381. doi: 10.1002/14651858.CD004381.pub3. PMID: 24936966Free PMC Article

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