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Severe neonatal-onset encephalopathy with microcephaly

MedGen UID:
409616
Concept ID:
C1968556
Disease or Syndrome
Synonyms: Encephalopathy, neonatal severe; Encephalopathy, neonatal severe, due to MECP2 mutations
SNOMED CT: MECP2-related severe neonatal encephalopathy (711487002); Methyl-cytosine phosphate guanine binding protein 2 related severe neonatal encephalopathy (711487002)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
 
Gene (location): MECP2 (Xq28)
 
Monarch Initiative: MONDO:0010397
OMIM®: 300673
Orphanet: ORPHA209370

Disease characteristics

Excerpted from the GeneReview: MECP2 Disorders
The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years. [from GeneReviews]
Authors:
Simranpreet Kaur  |  John Christodoulou   view full author information

Additional descriptions

From OMIM
The MECP2 gene is mutated in Rett syndrome (RTT; 312750), a severe neurodevelopmental disorder that almost always occurs in females. Although it was first thought that MECP2 mutations causing Rett syndrome were lethal in males, later reports identified a severe neonatal encephalopathy in surviving male sibs of patients with Rett syndrome. Since then, additional reports have confirmed a severe phenotype in males with RTT-associated MECP2 mutations (Moog et al., 2003; Villard, 2007). Males with non-RTT mutations in the MECP2 gene can demonstrate a wide variety of phenotypes: see also X-linked syndromic intellectual developmental disorder-13 (300055), Lubs-type X-linked syndromic intellectual developmental disorder (300260), and neonatal severe encephalopathy (300673).  http://www.omim.org/entry/300673
From MedlinePlus Genetics
MECP2-related severe neonatal encephalopathy is a neurological disorder that primarily affects males and causes brain dysfunction (encephalopathy). Affected males have a small head size (microcephaly), poor muscle tone (hypotonia) in infancy, movement disorders, rigidity, and seizures. Infants with this condition appear normal at birth but then develop severe encephalopathy within the first week of life. These babies experience poor feeding, leading to a failure to gain weight and grow at the expected rate (failure to thrive). Individuals with MECP2-related severe neonatal encephalopathy have severe to profound intellectual disability. Affected males have breathing problems, with some having episodes in which breathing slows or stops for short periods (apnea). As the child ages, the apnea episodes tend to last longer, especially during sleep, and affected babies often require use of a machine to help regulate their breathing (mechanical ventilation). Most males with MECP2-related severe neonatal encephalopathy do not live past the age of 2 because of respiratory failure.

MECP2-related severe neonatal encephalopathy is the most severe condition in a spectrum of disorders with the same genetic cause. The mildest is PPM-X syndrome, followed by MECP2 duplication syndrome, then Rett syndrome (which exclusively affects females), and finally MECP2-related severe neonatal encephalopathy.  https://medlineplus.gov/genetics/condition/mecp2-related-severe-neonatal-encephalopathy

Clinical features

From HPO
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 in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised 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.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Polymicrogyria
MedGen UID:
78605
Concept ID:
C0266464
Congenital Abnormality
Polymicrogyria is a congenital malformation of the cerebral cortex characterized by abnormal cortical layering (lamination) and an excessive number of small gyri (folds).
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.
Intellectual disability, progressive
MedGen UID:
337397
Concept ID:
C1846149
Mental or Behavioral Dysfunction
The term progressive intellectual disability should be used if intelligence decreases/deteriorates over time.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Anatomical Abnormality
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Central hypoventilation
MedGen UID:
812169
Concept ID:
C3805839
Finding

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Severe neonatal-onset encephalopathy with microcephaly in Orphanet.

Professional guidelines

PubMed

Wang PJ, Lee WT, Hwu WL, Young C, Yau KI, Shen YZ
Brain Dev 1998 Oct;20(7):530-5. doi: 10.1016/s0387-7604(98)00042-4. PMID: 9840674

Recent clinical studies

Etiology

Ergene M, Yarar N, Öncel EP, Sezer T, Çavdarlı B, Ecevit İZ, Aydın Hİ
Turk J Pediatr 2021;63(4):716-720. doi: 10.24953/turkjped.2021.04.021. PMID: 34449156
Ho CC, Tsung LL, Liu KT, Poon WT
BMC Med Genet 2018 Sep 12;19(1):162. doi: 10.1186/s12881-018-0679-5. PMID: 30208878Free PMC Article

Diagnosis

Kaya Özçora GD, Söbü E, Gümüş U
Neurol Res 2023 Mar;45(3):226-233. Epub 2023 Feb 2 doi: 10.1080/01616412.2023.2170917. PMID: 36731496
Carapancea E, Cornet MC, Milh M, De Cosmo L, Huang EJ, Granata T, Striano P, Ceulemans B, Stein A, Morris-Rosendahl D, Conti G, Mitra N, Raymond FL, Rowitch DH, Solazzi R, Vercellino F, De Liso P, D'Onofrio G, Boniver C, Danhaive O, Carkeek K, Salpietro V, Weckhuysen S, Fedrigo M, Angelini A, Castellotti B, Lederer D, Benoit V, Raviglione F, Guerrini R, Dilena R, Cilio MR
Neurology 2023 Mar 21;100(12):e1234-e1247. Epub 2023 Jan 4 doi: 10.1212/WNL.0000000000206755. PMID: 36599696Free PMC Article
Ergene M, Yarar N, Öncel EP, Sezer T, Çavdarlı B, Ecevit İZ, Aydın Hİ
Turk J Pediatr 2021;63(4):716-720. doi: 10.24953/turkjped.2021.04.021. PMID: 34449156
Ho CC, Tsung LL, Liu KT, Poon WT
BMC Med Genet 2018 Sep 12;19(1):162. doi: 10.1186/s12881-018-0679-5. PMID: 30208878Free PMC Article
Wang PJ, Lee WT, Hwu WL, Young C, Yau KI, Shen YZ
Brain Dev 1998 Oct;20(7):530-5. doi: 10.1016/s0387-7604(98)00042-4. PMID: 9840674

Therapy

Gupta S, Schwab M, Valdez-Gonzalez K, Segal E
Eur J Med Genet 2020 Sep;63(9):103970. Epub 2020 Jun 10 doi: 10.1016/j.ejmg.2020.103970. PMID: 32531460
Wang PJ, Lee WT, Hwu WL, Young C, Yau KI, Shen YZ
Brain Dev 1998 Oct;20(7):530-5. doi: 10.1016/s0387-7604(98)00042-4. PMID: 9840674

Prognosis

Kaya Özçora GD, Söbü E, Gümüş U
Neurol Res 2023 Mar;45(3):226-233. Epub 2023 Feb 2 doi: 10.1080/01616412.2023.2170917. PMID: 36731496
Vetro A, Nielsen HN, Holm R, Hevner RF, Parrini E, Powis Z, Møller RS, Bellan C, Simonati A, Lesca G, Helbig KL, Palmer EE, Mei D, Ballardini E, Van Haeringen A, Syrbe S, Leuzzi V, Cioni G, Curry CJ, Costain G, Santucci M, Chong K, Mancini GMS, Clayton-Smith J, Bigoni S, Scheffer IE, Dobyns WB, Vilsen B, Guerrini R; ATP1A2/A3-collaborators
Brain 2021 Jun 22;144(5):1435-1450. doi: 10.1093/brain/awab052. PMID: 33880529

Clinical prediction guides

Carapancea E, Cornet MC, Milh M, De Cosmo L, Huang EJ, Granata T, Striano P, Ceulemans B, Stein A, Morris-Rosendahl D, Conti G, Mitra N, Raymond FL, Rowitch DH, Solazzi R, Vercellino F, De Liso P, D'Onofrio G, Boniver C, Danhaive O, Carkeek K, Salpietro V, Weckhuysen S, Fedrigo M, Angelini A, Castellotti B, Lederer D, Benoit V, Raviglione F, Guerrini R, Dilena R, Cilio MR
Neurology 2023 Mar 21;100(12):e1234-e1247. Epub 2023 Jan 4 doi: 10.1212/WNL.0000000000206755. PMID: 36599696Free PMC Article
Vetro A, Nielsen HN, Holm R, Hevner RF, Parrini E, Powis Z, Møller RS, Bellan C, Simonati A, Lesca G, Helbig KL, Palmer EE, Mei D, Ballardini E, Van Haeringen A, Syrbe S, Leuzzi V, Cioni G, Curry CJ, Costain G, Santucci M, Chong K, Mancini GMS, Clayton-Smith J, Bigoni S, Scheffer IE, Dobyns WB, Vilsen B, Guerrini R; ATP1A2/A3-collaborators
Brain 2021 Jun 22;144(5):1435-1450. doi: 10.1093/brain/awab052. PMID: 33880529
Marcé-Grau A, Dalton J, López-Pisón J, García-Jiménez MC, Monge-Galindo L, Cuenca-León E, Giraldo J, Macaya A
Orphanet J Rare Dis 2016 Apr 12;11:38. doi: 10.1186/s13023-016-0416-0. PMID: 27072799Free PMC Article

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