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Neurodevelopmental disorder with hypotonia and characteristic brain abnormalities(NEDHBA)

MedGen UID:
1053175
Concept ID:
CN377037
Disease or Syndrome
Synonym: NEDHBA
 
Gene (location): SLC4A10 (2q24.2)
 
Monarch Initiative: MONDO:0958278
OMIM®: 620746

Definition

Neurodevelopmental disorder with hypotonia and characteristic brain abnormalities (NEDHBA) is an autosomal recessive disorder characterized by impaired intellectual development with striking radiologic abnormalities of the lateral ventricles (Fasham et al., 2023). [from OMIM]

Clinical features

From HPO
Ankle contracture
MedGen UID:
575402
Concept ID:
C0343148
Acquired Abnormality
Tapered finger
MedGen UID:
98098
Concept ID:
C0426886
Finding
The gradual reduction in girth of the finger from proximal to distal.
Coxa vara
MedGen UID:
1790477
Concept ID:
C5551440
Anatomical Abnormality
Coxa vara includes all forms of decrease of the femoral neck shaft angle (the angle between the neck and the shaft of the femur) to less than 120 degrees.
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
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.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
Protruding ear
MedGen UID:
343309
Concept ID:
C1855285
Finding
Angle formed by the plane of the ear and the mastoid bone greater than the 97th centile for age (objective); or, outer edge of the helix more than 2 cm from the mastoid at the point of maximum distance (objective).
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.
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).
Chorea
MedGen UID:
3420
Concept ID:
C0008489
Disease or Syndrome
Chorea (Greek for 'dance') refers to widespread arrhythmic involuntary movements of a forcible, jerky and restless fashion. It is a random-appearing sequence of one or more discrete involuntary movements or movement fragments. Movements appear random because of variability in timing, duration or location. Each movement may have a distinct start and end. However, movements may be strung together and thus may appear to flow randomly from one muscle group to another. Chorea can involve the trunk, neck, face, tongue, and extremities.
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.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Gray matter heterotopia
MedGen UID:
452349
Concept ID:
C0266491
Finding
Heterotopia or neuronal heterotopia are macroscopic clusters of misplaced neurons (gray matter), most often situated along the ventricular walls or within the subcortical white matter.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
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.
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.
Thick corpus callosum
MedGen UID:
371993
Concept ID:
C1835194
Finding
Increased vertical dimension of the corpus callosum. This feature can be visualized by sagittal sections on magnetic resonance tomography imaging of the brain.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Short corpus callosum
MedGen UID:
867519
Concept ID:
C4021902
Anatomical Abnormality
Recurrent hand flapping
MedGen UID:
867996
Concept ID:
C4022387
Mental or Behavioral Dysfunction
A type of repetitive behavior in which the affected individual repeatedly waves the hands and/or arms rhythmically.
Appendicular spasticity
MedGen UID:
937224
Concept ID:
C4313257
Finding
A type of spasticity that affects one or more limbs (arms or legs).
Bilateral tonic-clonic seizure with generalized onset
MedGen UID:
1368929
Concept ID:
C4476643
Sign or Symptom
A bilateral tonic-clonic seizure with generalized onset is a type of bilateral tonic-clonic seizure characterized by generalized onset; these seizures rapidly engage networks in both hemispheres at the start of the seizure.
Thin corpus callosum
MedGen UID:
1785336
Concept ID:
C5441562
Anatomical Abnormality
An abnormally thin corpus callous, due to atrophy, hypoplasia or agenesis. This term is intended to be used in situations where it is not known if thinning of the corpus callosum (for instance, as visualized by magnetic resonance tomography) is due to abnormal development (e.g. a leukodystrophy) or atrophy following normal development (e.g. neurodegeneration).
Slit-like lateral ventricle
MedGen UID:
1052552
Concept ID:
CN378341
Finding
Abnormally small lateral ventricle with a slit-like appearance.
Scarring
MedGen UID:
3093
Concept ID:
C0008767
Pathologic Function
A scar refers to a lesion in which wound, burn, or sore has not healed completely and fibrous connective tissue has developed.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Retrognathia
MedGen UID:
19766
Concept ID:
C0035353
Congenital Abnormality
An abnormality in which the mandible is mislocalised posteriorly.
Craniosynostosis 4
MedGen UID:
322167
Concept ID:
C1833340
Disease or Syndrome
Craniosynostosis (CRS) is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by Fitzpatrick, 2013). Craniosynostosis-4 (CRS4) includes lambdoid, sagittal, metopic, coronal, and multisuture forms. For a discussion of genetic heterogeneity of craniosynostosis, see CRS1 (123100).
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Prominent metopic ridge
MedGen UID:
387953
Concept ID:
C1857949
Finding
Vertical bony ridge positioned in the midline of the forehead.
Appendicular hypotonia
MedGen UID:
868520
Concept ID:
C4022919
Finding
Muscular hypotonia of one or more limbs.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Recurrent upper respiratory tract infections
MedGen UID:
154380
Concept ID:
C0581381
Disease or Syndrome
An increased susceptibility to upper respiratory tract infections as manifested by a history of recurrent upper respiratory tract infections (running ears - otitis, sinusitis, pharyngitis, tonsillitis).
Recurrent lower respiratory tract infections
MedGen UID:
756211
Concept ID:
C3163798
Disease or Syndrome
An increased susceptibility to lower respiratory tract infections as manifested by a history of recurrent lower respiratory tract infections.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
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).
Tented upper lip vermilion
MedGen UID:
326574
Concept ID:
C1839767
Finding
Triangular appearance of the oral aperture with the apex in the midpoint of the upper vermilion and the lower vermilion forming the base.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Long philtrum
MedGen UID:
351278
Concept ID:
C1865014
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
Synophrys
MedGen UID:
98132
Concept ID:
C0431447
Congenital Abnormality
Meeting of the medial eyebrows in the midline.
Long eyelashes
MedGen UID:
342955
Concept ID:
C1853738
Finding
Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective).
Preauricular skin tag
MedGen UID:
395989
Concept ID:
C1860816
Finding
A rudimentary tag of skin often containing ear tissue including a core of cartilage and located just anterior to the auricle (outer part of the ear).
Inversion of nipple
MedGen UID:
82844
Concept ID:
C0269269
Anatomical Abnormality
The presence of nipples that instead of pointing outward are retracted inwards.
Hypotelorism
MedGen UID:
96107
Concept ID:
C0424711
Finding
Interpupillary distance less than 2 SD below the mean (alternatively, the appearance of an decreased interpupillary distance or closely spaced eyes).
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.

Professional guidelines

PubMed

Sudnawa KK, Li W, Calamia S, Kanner CH, Bain JM, Abdelhakim AH, Geltzeiler A, Mebane CM, Provenzano FA, Sands TT, Fee RJ, Montes J, Shen Y, Chung WK
Genet Med 2024 Aug;26(8):101169. Epub 2024 May 21 doi: 10.1016/j.gim.2024.101169. PMID: 38785164Free PMC Article
Oyama N, Vaneynde P, Reynhout S, Pao EM, Timms A, Fan X, Foss K, Derua R, Janssens V, Chung W, Mirzaa GM
J Med Genet 2023 May;60(5):511-522. Epub 2022 Oct 10 doi: 10.1136/jmg-2022-108713. PMID: 36216457
Spahiu L, Behluli E, Grajçevci-Uka V, Liehr T, Temaj G
J Mother Child 2022 Mar 1;26(1):118-123. Epub 2023 Feb 22 doi: 10.34763/jmotherandchild.20222601.d-22-00034. PMID: 36803942Free PMC Article

Recent clinical studies

Etiology

Khan TR, Leprince I, Messahel S, Minassian BA, Kayani S
Pediatr Neurol 2023 Mar;140:40-46. Epub 2022 Dec 7 doi: 10.1016/j.pediatrneurol.2022.12.002. PMID: 36599233
Correa-da-Silva F, Fliers E, Swaab DF, Yi CX
J Neuroendocrinol 2021 Jul;33(7):e12994. Epub 2021 Jun 22 doi: 10.1111/jne.12994. PMID: 34156126Free PMC Article
Rots D, Chater-Diehl E, Dingemans AJM, Goodman SJ, Siu MT, Cytrynbaum C, Choufani S, Hoang N, Walker S, Awamleh Z, Charkow J, Meyn S, Pfundt R, Rinne T, Gardeitchik T, de Vries BBA, Deden AC, Leenders E, Kwint M, Stumpel CTRM, Stevens SJC, Vermeulen JR, van Harssel JVT, Bosch DGM, van Gassen KLI, van Binsbergen E, de Geus CM, Brackel H, Hempel M, Lessel D, Denecke J, Slavotinek A, Strober J, Crunk A, Folk L, Wentzensen IM, Yang H, Zou F, Millan F, Person R, Xie Y, Liu S, Ousager LB, Larsen M, Schultz-Rogers L, Morava E, Klee EW, Berry IR, Campbell J, Lindstrom K, Pruniski B, Neumeyer AM, Radley JA, Phornphutkul C, Schmidt B, Wilson WG, Õunap K, Reinson K, Pajusalu S, van Haeringen A, Ruivenkamp C, Cuperus R, Santos-Simarro F, Palomares-Bralo M, Pacio-Míguez M, Ritter A, Bhoj E, Tønne E, Tveten K, Cappuccio G, Brunetti-Pierri N, Rowe L, Bunn J, Saenz M, Platzer K, Mertens M, Caluseriu O, Nowaczyk MJM, Cohn RD, Kannu P, Alkhunaizi E, Chitayat D, Scherer SW, Brunner HG, Vissers LELM, Kleefstra T, Koolen DA, Weksberg R
Am J Hum Genet 2021 Jun 3;108(6):1053-1068. Epub 2021 Apr 27 doi: 10.1016/j.ajhg.2021.04.008. PMID: 33909990Free PMC Article
Van Dijck A, Vulto-van Silfhout AT, Cappuyns E, van der Werf IM, Mancini GM, Tzschach A, Bernier R, Gozes I, Eichler EE, Romano C, Lindstrand A, Nordgren A; ADNP Consortium, Kvarnung M, Kleefstra T, de Vries BBA, Küry S, Rosenfeld JA, Meuwissen ME, Vandeweyer G, Kooy RF
Biol Psychiatry 2019 Feb 15;85(4):287-297. Epub 2018 Mar 15 doi: 10.1016/j.biopsych.2018.02.1173. PMID: 29724491Free PMC Article
Magoulas PL, El-Hattab AW
Orphanet J Rare Dis 2012 Jan 4;7:2. doi: 10.1186/1750-1172-7-2. PMID: 22216833Free PMC Article

Diagnosis

Oyama N, Vaneynde P, Reynhout S, Pao EM, Timms A, Fan X, Foss K, Derua R, Janssens V, Chung W, Mirzaa GM
J Med Genet 2023 May;60(5):511-522. Epub 2022 Oct 10 doi: 10.1136/jmg-2022-108713. PMID: 36216457
Spahiu L, Behluli E, Grajçevci-Uka V, Liehr T, Temaj G
J Mother Child 2022 Mar 1;26(1):118-123. Epub 2023 Feb 22 doi: 10.34763/jmotherandchild.20222601.d-22-00034. PMID: 36803942Free PMC Article
Karaer K, Karaer D, Yüksel Z, Işikay S
Clin Dysmorphol 2022 Oct 1;31(4):167-173. Epub 2022 Jul 14 doi: 10.1097/MCD.0000000000000426. PMID: 36004946
Vetrini F, McKee S, Rosenfeld JA, Suri M, Lewis AM, Nugent KM, Roeder E, Littlejohn RO, Holder S, Zhu W, Alaimo JT, Graham B, Harris JM, Gibson JB, Pastore M, McBride KL, Komara M, Al-Gazali L, Al Shamsi A, Fanning EA, Wierenga KJ, Scott DA, Ben-Neriah Z, Meiner V, Cassuto H, Elpeleg O, Holder JL Jr, Burrage LC, Seaver LH, Van Maldergem L, Mahida S, Soul JS, Marlatt M, Matyakhina L, Vogt J, Gold JA, Park SM, Varghese V, Lampe AK, Kumar A, Lees M, Holder-Espinasse M, McConnell V, Bernhard B, Blair E, Harrison V; DDD study, Muzny DM, Gibbs RA, Elsea SH, Posey JE, Bi W, Lalani S, Xia F, Yang Y, Eng CM, Lupski JR, Liu P
Genome Med 2019 Feb 28;11(1):12. doi: 10.1186/s13073-019-0623-0. PMID: 30819258Free PMC Article
Magoulas PL, El-Hattab AW
Orphanet J Rare Dis 2012 Jan 4;7:2. doi: 10.1186/1750-1172-7-2. PMID: 22216833Free PMC Article

Therapy

Curie A, Lion-François L, Valayannopoulos V, Perreton N, Gavanon M, Touil N, Brun-Laurisse A, Gheurbi F, Buchy M, Halep H, Cheillan D, Mercier C, Brassier A, Desnous B, Kassai B, De Lonlay P, Des Portes V
Neurology 2024 Apr 23;102(8):e209243. Epub 2024 Mar 26 doi: 10.1212/WNL.0000000000209243. PMID: 38531017
Majnemer A, Limperopoulos C
Semin Pediatr Neurol 1999 Mar;6(1):12-9. doi: 10.1016/s1071-9091(99)80042-4. PMID: 10098225

Prognosis

Sudnawa KK, Li W, Calamia S, Kanner CH, Bain JM, Abdelhakim AH, Geltzeiler A, Mebane CM, Provenzano FA, Sands TT, Fee RJ, Montes J, Shen Y, Chung WK
Genet Med 2024 Aug;26(8):101169. Epub 2024 May 21 doi: 10.1016/j.gim.2024.101169. PMID: 38785164Free PMC Article
Ho NT, Kroner B, Grinspan Z, Fureman B, Farrell K, Zhang J, Buelow J, Hesdorffer DC; Rare Epilepsy Network Steering Committee
J Pediatr 2018 Dec;203:249-258.e5. Epub 2018 Sep 5 doi: 10.1016/j.jpeds.2018.07.055. PMID: 30195559
Magoulas PL, El-Hattab AW
Orphanet J Rare Dis 2012 Jan 4;7:2. doi: 10.1186/1750-1172-7-2. PMID: 22216833Free PMC Article
Patel KP, O'Brien TW, Subramony SH, Shuster J, Stacpoole PW
Mol Genet Metab 2012 Jan;105(1):34-43. Epub 2011 Oct 7 doi: 10.1016/j.ymgme.2011.09.032. PMID: 22079328Free PMC Article
Parisi MA
Am J Med Genet C Semin Med Genet 2009 Nov 15;151C(4):326-40. doi: 10.1002/ajmg.c.30229. PMID: 19876931Free PMC Article

Clinical prediction guides

Oyama N, Vaneynde P, Reynhout S, Pao EM, Timms A, Fan X, Foss K, Derua R, Janssens V, Chung W, Mirzaa GM
J Med Genet 2023 May;60(5):511-522. Epub 2022 Oct 10 doi: 10.1136/jmg-2022-108713. PMID: 36216457
Musante L, Faletra F, Meier K, Tomoum H, Najarzadeh Torbati P, Blair E, North S, Gärtner J, Diegmann S, Beiraghi Toosi M, Ashrafzadeh F, Ghayoor Karimiani E, Murphy D, Murru FM, Zanus C, Magnolato A, La Bianca M, Feresin A, Girotto G, Gasparini P, Costa P, Carrozzi M
Am J Med Genet A 2022 Sep;188(9):2652-2665. Epub 2022 Jun 7 doi: 10.1002/ajmg.a.62852. PMID: 35670379Free PMC Article
Nøstvik M, Kateta SM, Schönewolf-Greulich B, Afenjar A, Barth M, Boschann F, Doummar D, Haack TB, Keren B, Livshits LA, Mei D, Park J, Pisano T, Prouteau C, Umair M, Waqas A, Ziegler A, Guerrini R, Møller RS, Tümer Z
Clin Genet 2021 Nov;100(5):628-633. Epub 2021 Aug 31 doi: 10.1111/cge.14051. PMID: 34415064
Vetrini F, McKee S, Rosenfeld JA, Suri M, Lewis AM, Nugent KM, Roeder E, Littlejohn RO, Holder S, Zhu W, Alaimo JT, Graham B, Harris JM, Gibson JB, Pastore M, McBride KL, Komara M, Al-Gazali L, Al Shamsi A, Fanning EA, Wierenga KJ, Scott DA, Ben-Neriah Z, Meiner V, Cassuto H, Elpeleg O, Holder JL Jr, Burrage LC, Seaver LH, Van Maldergem L, Mahida S, Soul JS, Marlatt M, Matyakhina L, Vogt J, Gold JA, Park SM, Varghese V, Lampe AK, Kumar A, Lees M, Holder-Espinasse M, McConnell V, Bernhard B, Blair E, Harrison V; DDD study, Muzny DM, Gibbs RA, Elsea SH, Posey JE, Bi W, Lalani S, Xia F, Yang Y, Eng CM, Lupski JR, Liu P
Genome Med 2019 Feb 28;11(1):12. doi: 10.1186/s13073-019-0623-0. PMID: 30819258Free PMC Article
Magoulas PL, El-Hattab AW
Orphanet J Rare Dis 2012 Jan 4;7:2. doi: 10.1186/1750-1172-7-2. PMID: 22216833Free PMC Article

Recent systematic reviews

Zhao A, Shu D, Zhang D, Yang B, Hong L, Wang A, Yao R, Wang J, Lv H, Wang J, Shen Y, Wang H, Gu Q
Int J Dev Neurosci 2022 Feb;82(1):96-103. Epub 2021 Nov 4 doi: 10.1002/jdn.10154. PMID: 34708882

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