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Microcephaly, seizures, and developmental delay(EIEE10; MCSZ; DEE10)

MedGen UID:
462017
Concept ID:
C3150667
Disease or Syndrome
Synonym: Early infantile epileptic encephalopathy 10
 
Gene (location): PNKP (19q13.33)
 
Monarch Initiative: MONDO:0013254
OMIM®: 613402

Definition

Microcephaly, seizures, and developmental delay (MCSZ) is an autosomal recessive neurodevelopmental disorder with onset in infancy. There is a range of phenotypic severity: some patients develop refractory seizures in infancy, consistent with a developmental and epileptic encephalopathy (DEE), whereas others have more well-controlled seizures and a more protracted course associated with cerebellar atrophy and peripheral neuropathy (Shen et al., 2010 and Poulton et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Additional description

From MedlinePlus Genetics
Microcephaly, seizures, and developmental delay (MCSZ) is a condition characterized by an abnormally small head size (microcephaly) and neurological problems related to impaired brain development before birth. Affected individuals typically have recurrent seizures (epilepsy) beginning in infancy and delayed development of motor skills, such as sitting and walking. Speech is also delayed, and some affected individuals are never able to speak. Intellectual disability and behavior problems, primarily hyperactivity, are also common features of MCSZ. Rarely, individuals with MCSZ also have poor balance and coordination (ataxia).  https://medlineplus.gov/genetics/condition/microcephaly-seizures-and-developmental-delay

Clinical features

From HPO
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.
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.
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.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
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.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Simplified gyral pattern
MedGen UID:
413664
Concept ID:
C2749675
Finding
An abnormality of the cerebral cortex with fewer gyri but with normal cortical thickness. This pattern is usually often associated with congenital microcephaly.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
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.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
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.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.

Professional guidelines

PubMed

Shah R, Eklund EA, Radenkovic S, Sadek M, Shammas I, Verberkmoes S, Ng BG, Freeze HH, Edmondson AC, He M, Kozicz T, Altassan R, Morava E
Mol Genet Metab 2024 Jun;142(2):108472. Epub 2024 Apr 23 doi: 10.1016/j.ymgme.2024.108472. PMID: 38703411Free PMC Article
Weissbach A, Pauly MG, Herzog R, Hahn L, Halmans S, Hamami F, Bolte C, Camargos S, Jeon B, Kurian MA, Opladen T, Brüggemann N, Huppertz HJ, König IR, Klein C, Lohmann K
Mov Disord 2022 Feb;37(2):237-252. Epub 2021 Dec 15 doi: 10.1002/mds.28874. PMID: 34908184
Guerrini R, Carrozzo R, Rinaldi R, Bonanni P
Paediatr Drugs 2003;5(10):647-61. doi: 10.2165/00148581-200305100-00001. PMID: 14510623

Recent clinical studies

Etiology

Thuresson AC, Brazina J, Akram T, Albrecht J, Dahl N, Soussi Zander C, Caldecott KW
Mol Genet Genomic Med 2024 Jan;12(1):e2295. Epub 2023 Nov 2 doi: 10.1002/mgg3.2295. PMID: 37916443Free PMC Article
Rychlowska M, Agyapong A, Weinfeld M, Schang LM
J Virol 2022 May 11;96(9):e0033322. Epub 2022 Apr 12 doi: 10.1128/jvi.00333-22. PMID: 35412344Free PMC Article
Jiang B, Murray C, Cole BL, Glover JNM, Chan GK, Deschenes J, Mani RS, Subedi S, Nerva JD, Wang AC, Lockwood CM, Mefford HC, Leary SES, Ojemann JG, Weinfeld M, Ene CI
Sci Rep 2022 Mar 30;12(1):5386. doi: 10.1038/s41598-022-09097-w. PMID: 35354845Free PMC Article
Bitarafan F, Khodaeian M, Almadani N, Kalhor A, Sardehaei EA, Garshasbi M
Fetal Pediatr Pathol 2021 Apr;40(2):174-180. Epub 2019 Nov 9 doi: 10.1080/15513815.2019.1686784. PMID: 31707899
Nair P, Hamzeh AR, Mohamed M, Saif F, Tawfiq N, El Halik M, Al-Ali MT, Bastaki F
Am J Med Genet A 2016 Aug;170(8):2127-32. Epub 2016 May 27 doi: 10.1002/ajmg.a.37766. PMID: 27232581

Diagnosis

Bitarafan F, Khodaeian M, Almadani N, Kalhor A, Sardehaei EA, Garshasbi M
Fetal Pediatr Pathol 2021 Apr;40(2):174-180. Epub 2019 Nov 9 doi: 10.1080/15513815.2019.1686784. PMID: 31707899
Garrelfs MR, Takada S, Kamsteeg EJ, Pegge S, Mancini G, Engelen M, van de Warrenburg B, Rennings A, van Gaalen J, Peters I, Weemaes C, van der Burg M, Willemsen MA
Pediatr Neurol 2020 Dec;113:26-32. Epub 2020 Jul 28 doi: 10.1016/j.pediatrneurol.2020.07.014. PMID: 32980744
Gatti M, Magri S, Nanetti L, Sarto E, Di Bella D, Salsano E, Pantaleoni C, Mariotti C, Taroni F
Am J Med Genet A 2019 Nov;179(11):2277-2283. Epub 2019 Aug 22 doi: 10.1002/ajmg.a.61339. PMID: 31436889
Nair P, Hamzeh AR, Mohamed M, Saif F, Tawfiq N, El Halik M, Al-Ali MT, Bastaki F
Am J Med Genet A 2016 Aug;170(8):2127-32. Epub 2016 May 27 doi: 10.1002/ajmg.a.37766. PMID: 27232581
Chau V, Clément JF, Robitaille Y, D'Anjou G, Vanasse M
Pediatr Neurol 2008 Apr;38(4):261-6. doi: 10.1016/j.pediatrneurol.2007.11.005. PMID: 18358405

Prognosis

Poulton C, Oegema R, Heijsman D, Hoogeboom J, Schot R, Stroink H, Willemsen MA, Verheijen FW, van de Spek P, Kremer A, Mancini GM
Neurogenetics 2013 Feb;14(1):43-51. Epub 2012 Dec 9 doi: 10.1007/s10048-012-0351-8. PMID: 23224214
Chau V, Clément JF, Robitaille Y, D'Anjou G, Vanasse M
Pediatr Neurol 2008 Apr;38(4):261-6. doi: 10.1016/j.pediatrneurol.2007.11.005. PMID: 18358405

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