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Microcephaly 5, primary, autosomal recessive(MCPH5)

MedGen UID:
373344
Concept ID:
C1837501
Disease or Syndrome
Synonym: MCPH5
 
Gene (location): ASPM (1q31.3)
 
Monarch Initiative: MONDO:0012106
OMIM®: 608716

Disease characteristics

Excerpted from the GeneReview: ASPM Primary Microcephaly
ASPM primary microcephaly (ASPM-MCPH) is characterized by: (1) significant microcephaly (below -3 SD for age) usually present at birth and always present before age one year and (2) the absence of other congenital anomalies. While developmental milestones are usually normal in young children, older children have variable levels of intellectual disability. Neurologic examination is usually normal except for mild spasticity. Seizures are not common. [from GeneReviews]
Authors:
Alain Verloes  |  Séverine Drunat  |  Sandrine Passemard   view full author information

Additional descriptions

From OMIM
Autosomal recessive primary microcephaly-5 (MCPH5) is characterized by decreased occipitofrontal circumference (OFC), usually less than 3 standard deviations (SD) of the mean, present at birth and associated with mental retardation and speech delay. Other features may include short stature or mild seizures. MCPH5 is associated with a simplification of the cerebral cortical gyral pattern in some cases, which is considered within the phenotypic spectrum of primary microcephaly (review by Woods et al., 2005; Saadi et al., 2009; Passemard et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of primary microcephaly (MCPH), see MCPH1 (251200).  http://www.omim.org/entry/608716
From MedlinePlus Genetics
Autosomal recessive primary microcephaly (often shortened to MCPH, which stands for "microcephaly primary hereditary") is a condition in which infants are born with a very small head and a small brain. The term "microcephaly" comes from the Greek words for "small head."

Infants with MCPH have an unusually small head circumference compared to other infants of the same sex and age. Head circumference is the distance around the widest part of the head, measured by placing a measuring tape above the eyebrows and ears and around the back of the head. Affected infants' brain volume is also smaller than usual, although they usually do not have any major abnormalities in the structure of the brain. The head and brain grow throughout childhood and adolescence, but they continue to be much smaller than normal.

People with MCPH usually have few or no other features associated with the condition. Some have a narrow, sloping forehead; mild seizures; problems with attention or behavior; or short stature compared to others in their family. The condition typically does not affect any other major organ systems or cause other health problems.

MCPH causes intellectual disability, which is typically mild to moderate and does not become more severe with age. Most affected individuals have delayed speech and language skills. Motor skills, such as sitting, standing, and walking, may also be mildly delayed.  https://medlineplus.gov/genetics/condition/autosomal-recessive-primary-microcephaly

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).
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
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.
Corpus callosum, agenesis of
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Cortical dysplasia
MedGen UID:
98129
Concept ID:
C0431380
Congenital Abnormality
The presence of developmental dysplasia of the cerebral cortex.
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.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention deficit-hyperactivity disorder (ADHD) is the most common childhood-onset behavioral disorder, affecting approximately 5 to 10% of children and adolescents (Wolraich et al., 1996). In this condition, persistent inattention and/or hyperactive-impulsive behavior results in impaired social and/or academic functioning. Boys are affected about 8 times more frequently than girls (Zametkin et al., 1990). Genetic Heterogeneity of Attention Deficit-Hyperactivity Disorder Susceptibility to ADHD7 (607478) may be conferred by variation in the TPH2 gene (607478) on chromosome 12q21. ADHD8 (619957) is caused by mutation in the CDH2 gene (114020) on chromosome 18q12. Several loci for susceptibility to ADHD have been mapped, including ADHD1 (608903) on chromosome 16p13, ADHD2 (608904) on chromosome 17p11, ADHD3 (608905) on chromosome 6q12, ADHD4 (608906) on chromosome 5p13, ADHD5 (612311) on 2q21.1, and ADHD6 (612312) on 13q12.11. Also see MOLECULAR GENETICS.
Small cerebral cortex
MedGen UID:
325187
Concept ID:
C1837503
Finding
Reduced size of the cerebral cortex.
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Flat occiput
MedGen UID:
332439
Concept ID:
C1837402
Finding
Reduced convexity of the occiput (posterior part of skull).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
Sloping forehead
MedGen UID:
346640
Concept ID:
C1857679
Finding
Inclination of the anterior surface of the forehead from the vertical more than two standard deviations above the mean (objective); or apparently excessive posterior sloping of the forehead in a lateral view.
Highly arched eyebrow
MedGen UID:
358357
Concept ID:
C1868571
Finding
Increased height of the central portion of the eyebrow, forming a crescent, semicircular, or inverted U shape.
Proptosis
MedGen UID:
41917
Concept ID:
C0015300
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.

Professional guidelines

PubMed

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Recent clinical studies

Etiology

Zaqout S, Mannaa A, Klein O, Krajewski A, Klose J, Luise-Becker L, Elsabagh A, Ferih K, Kraemer N, Ravindran E, Makridis K, Kaindl AM
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J Med Genet 2020 Jun;57(6):389-399. Epub 2020 Feb 3 doi: 10.1136/jmedgenet-2019-106474. PMID: 32015000
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Diagnosis

Gönenc II, Elcioglu NH, Martinez Grijalva C, Aras S, Großmann N, Praulich I, Altmüller J, Kaulfuß S, Li Y, Nürnberg P, Burfeind P, Yigit G, Wollnik B
Clin Genet 2022 May;101(5-6):559-564. Epub 2022 Mar 11 doi: 10.1111/cge.14125. PMID: 35218564
Tran TH, Diep QM, Cao MH, Luong LH, Pham VA, Lan Dinh OT, Bui TH, Van Ta T, Tran VK
Taiwan J Obstet Gynecol 2021 Sep;60(5):907-910. doi: 10.1016/j.tjog.2021.07.022. PMID: 34507672
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Eur J Med Genet 2021 Jul;64(7):104233. Epub 2021 Apr 30 doi: 10.1016/j.ejmg.2021.104233. PMID: 33933664
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Therapy

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Prognosis

Waseem SS, Moawia A, Budde B, Tariq M, Khan A, Ali Z, Khan S, Iqbal M, Malik NA, Haque SU, Altmüller J, Thiele H, Hussain MS, Cirak S, Baig SM, Nürnberg P
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Clinical prediction guides

Zaqout S, Mannaa A, Klein O, Krajewski A, Klose J, Luise-Becker L, Elsabagh A, Ferih K, Kraemer N, Ravindran E, Makridis K, Kaindl AM
Ann Hum Genet 2023 Mar;87(1-2):50-62. Epub 2022 Nov 29 doi: 10.1111/ahg.12489. PMID: 36448252
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Clin Genet 2022 May;101(5-6):559-564. Epub 2022 Mar 11 doi: 10.1111/cge.14125. PMID: 35218564
Batool T, Irshad S, Mahmood K
Braz J Biol 2021;83:e246040. Epub 2021 Aug 6 doi: 10.1590/1519-6984.246040. PMID: 34378666
Moawia A, Shaheen R, Rasool S, Waseem SS, Ewida N, Budde B, Kawalia A, Motameny S, Khan K, Fatima A, Jameel M, Ullah F, Akram T, Ali Z, Abdullah U, Irshad S, Höhne W, Noegel AA, Al-Owain M, Hörtnagel K, Stöbe P, Baig SM, Nürnberg P, Alkuraya FS, Hahn A, Hussain MS
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Neurology 2009 Sep 22;73(12):962-9. doi: 10.1212/WNL.0b013e3181b8799a. PMID: 19770472

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