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Neurodevelopmental disorder with hypotonia and gross motor and speech delay(NEDHMS)

MedGen UID:
1794241
Concept ID:
C5562031
Disease or Syndrome
Synonyms: NEDHMS; NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA AND GROSS MOTOR AND SPEECH DELAY
 
Gene (location): UBE4A (11q23.3)
 
Monarch Initiative: MONDO:0859207
OMIM®: 619639

Definition

Neurodevelopmental disorder with hypotonia and gross motor and speech delay (NEDHMS) is an autosomal recessive disorder characterized by severe global developmental delay apparent from infancy. Affected individuals have axial hypotonia and limited ability to walk, including some who are nonambulatory with lower limb spasticity, impaired intellectual development, and poor or absent speech and language. Additional more variable features may include seizures, behavioral problems, distal skeletal anomalies, and dysmorphic facial features (Melo et al., 2021). [from OMIM]

Clinical features

From HPO
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
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).
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 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.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
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.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.
Lower limb spasticity
MedGen UID:
220865
Concept ID:
C1271100
Finding
Spasticity (velocity-dependent increase in tonic stretch reflexes with increased muscle tone and hyperexcitable tendon reflexes) in the muscles of the lower limbs, hips, and pelvis
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.

Recent clinical studies

Etiology

Burdeus-Olavarrieta M, San José-Cáceres A, García-Alcón A, González-Peñas J, Hernández-Jusdado P, Parellada-Redondo M
J Neurodev Disord 2021 Jul 10;13(1):26. doi: 10.1186/s11689-021-09370-5. PMID: 34246244Free PMC Article
Mukhopadhyay K, Malhi P, Mahajan R, Narang A
Indian J Pediatr 2010 Sep;77(9):963-7. Epub 2010 Sep 3 doi: 10.1007/s12098-010-0149-3. PMID: 20814839
Ming X, Brimacombe M, Wagner GC
Brain Dev 2007 Oct;29(9):565-70. Epub 2007 Apr 30 doi: 10.1016/j.braindev.2007.03.002. PMID: 17467940
Gerdes M, Solot C, Wang PP, Moss E, LaRossa D, Randall P, Goldmuntz E, Clark BJ 3rd, Driscoll DA, Jawad A, Emanuel BS, McDonald-McGinn DM, Batshaw ML, Zackai EH
Am J Med Genet 1999 Jul 16;85(2):127-33. PMID: 10406665

Diagnosis

Kanner CH, Uher D, Zreibe K, Beard G, Patterson M, Harris M, Doerger J, Calamia S, Chung WK, Montes J
Orphanet J Rare Dis 2024 Feb 7;19(1):45. doi: 10.1186/s13023-024-03067-3. PMID: 38326877Free PMC Article
Christensen MB, Levy AM, Mohammadi NA, Niceta M, Kaiyrzhanov R, Dentici ML, Al Alam C, Alesi V, Benoit V, Bhatia KP, Bierhals T, Boßelmann CM, Buratti J, Callewaert B, Ceulemans B, Charles P, De Wachter M, Dehghani M, D'haenens E, Doco-Fenzy M, Geßner M, Gobert C, Guliyeva U, Haack TB, Hammer TB, Heinrich T, Hempel M, Herget T, Hoffmann U, Horvath J, Houlden H, Keren B, Kresge C, Kumps C, Lederer D, Lermine A, Magrinelli F, Maroofian R, Vahidi Mehrjardi MY, Moudi M, Müller AJ, Oostra AJ, Pletcher BA, Ros-Pardo D, Samarasekera S, Tartaglia M, Van Schil K, Vogt J, Wassmer E, Winkelmann J, Zaki MS, Zech M, Lerche H, Radio FC, Gomez-Puertas P, Møller RS, Tümer Z
Clin Genet 2022 Aug;102(2):98-109. Epub 2022 Jun 8 doi: 10.1111/cge.14165. PMID: 35616059Free PMC Article
Burdeus-Olavarrieta M, San José-Cáceres A, García-Alcón A, González-Peñas J, Hernández-Jusdado P, Parellada-Redondo M
J Neurodev Disord 2021 Jul 10;13(1):26. doi: 10.1186/s11689-021-09370-5. PMID: 34246244Free PMC Article
Soblet J, Dimov I, Graf von Kalckreuth C, Cano-Chervel J, Baijot S, Pelc K, Sottiaux M, Vilain C, Smits G, Deconinck N
Am J Med Genet A 2018 Jan;176(1):201-208. Epub 2017 Sep 27 doi: 10.1002/ajmg.a.38479. PMID: 28960836Free PMC Article
Wolpert CM, Menold MM, Bass MP, Qumsiyeh MB, Donnelly SL, Ravan SA, Vance JM, Gilbert JR, Abramson RK, Wright HH, Cuccaro ML, Pericak-Vance MA
Am J Med Genet 2000 Jun 12;96(3):365-72. doi: 10.1002/1096-8628(20000612)96:3<365::aid-ajmg25>3.0.co;2-x. PMID: 10898916

Therapy

Schmidt H, Kern W, Giese R, Hallschmid M, Enders A
J Med Genet 2009 Apr;46(4):217-22. Epub 2008 Oct 23 doi: 10.1136/jmg.2008.062141. PMID: 18948358

Prognosis

Burdeus-Olavarrieta M, San José-Cáceres A, García-Alcón A, González-Peñas J, Hernández-Jusdado P, Parellada-Redondo M
J Neurodev Disord 2021 Jul 10;13(1):26. doi: 10.1186/s11689-021-09370-5. PMID: 34246244Free PMC Article
Mukhopadhyay K, Malhi P, Mahajan R, Narang A
Indian J Pediatr 2010 Sep;77(9):963-7. Epub 2010 Sep 3 doi: 10.1007/s12098-010-0149-3. PMID: 20814839

Clinical prediction guides

Kanner CH, Uher D, Zreibe K, Beard G, Patterson M, Harris M, Doerger J, Calamia S, Chung WK, Montes J
Orphanet J Rare Dis 2024 Feb 7;19(1):45. doi: 10.1186/s13023-024-03067-3. PMID: 38326877Free PMC Article
Christensen MB, Levy AM, Mohammadi NA, Niceta M, Kaiyrzhanov R, Dentici ML, Al Alam C, Alesi V, Benoit V, Bhatia KP, Bierhals T, Boßelmann CM, Buratti J, Callewaert B, Ceulemans B, Charles P, De Wachter M, Dehghani M, D'haenens E, Doco-Fenzy M, Geßner M, Gobert C, Guliyeva U, Haack TB, Hammer TB, Heinrich T, Hempel M, Herget T, Hoffmann U, Horvath J, Houlden H, Keren B, Kresge C, Kumps C, Lederer D, Lermine A, Magrinelli F, Maroofian R, Vahidi Mehrjardi MY, Moudi M, Müller AJ, Oostra AJ, Pletcher BA, Ros-Pardo D, Samarasekera S, Tartaglia M, Van Schil K, Vogt J, Wassmer E, Winkelmann J, Zaki MS, Zech M, Lerche H, Radio FC, Gomez-Puertas P, Møller RS, Tümer Z
Clin Genet 2022 Aug;102(2):98-109. Epub 2022 Jun 8 doi: 10.1111/cge.14165. PMID: 35616059Free PMC Article
Burdeus-Olavarrieta M, San José-Cáceres A, García-Alcón A, González-Peñas J, Hernández-Jusdado P, Parellada-Redondo M
J Neurodev Disord 2021 Jul 10;13(1):26. doi: 10.1186/s11689-021-09370-5. PMID: 34246244Free PMC Article
Mullegama SV, Rosenfeld JA, Orellana C, van Bon BW, Halbach S, Repnikova EA, Brick L, Li C, Dupuis L, Rosello M, Aradhya S, Stavropoulos DJ, Manickam K, Mitchell E, Hodge JC, Talkowski ME, Gusella JF, Keller K, Zonana J, Schwartz S, Pyatt RE, Waggoner DJ, Shaffer LG, Lin AE, de Vries BB, Mendoza-Londono R, Elsea SH
Eur J Hum Genet 2014 Jan;22(1):57-63. Epub 2013 May 1 doi: 10.1038/ejhg.2013.67. PMID: 23632792Free PMC Article
Mukhopadhyay K, Malhi P, Mahajan R, Narang A
Indian J Pediatr 2010 Sep;77(9):963-7. Epub 2010 Sep 3 doi: 10.1007/s12098-010-0149-3. PMID: 20814839

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