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The common trait found in Trisomy 18, Emanuel Syndrome, Pontocerebellar hypoplasia type 6, and Lenz microphthalmia syndrome. 

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The common trait found in Trisomy 18, Emanuel Syndrome, Pontocerebellar hypoplasia type 6, and Lenz microphthalmia syndrome. 

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Microcephaly is a consequence of at least seventeen different types of genes [1]. It has an autosomal recessive pattern of inheritance [2] presents itself right from birth and affects between 1 in 30,000 to 1 in 250,000 newborns worldwide [3]. When compared to other infants that are the same age and sex, the ones with microcephaly usually have a small head circumference which affects their brain volume because it will make it also smaller than normal [4]. Some of these individuals also have a narrow forehead that slopes and can cause mild seizures [4]. People with microcephaly also show signs of behavioral and attention problems along with a bit of short stature when compared to the rest of their family [4]. However, there are no signs of microcephaly causing any other health or major organ system problems [4]. Even though individuals with microcephaly have a decreased head size it does not necessarily cause any major abnormalities to how the brain itself is structured, but it does cause some mild to moderate intellectual disability [3]. It results in a delay in both motor skills which include sitting, standing, or walking, and language and speech skills [3]. Also, in some cases, as the individual grows, their head and brain will continue to grow throughout their childhood and adolescents, but the size will always be much smaller than the average person [3].

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Karyotype that shows Emanuel Syndrome [29]

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Mapping of the MAA2 locus and mutations in the BCOR gene [25].

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The chromosome disorder that causes this disease state is an extra chromosome 18 [5].

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A lot of the fetuses diagnosed with trisomy 18 don't survive to birth, but even in the womb, they exhibit some symptoms such as intrauterine growth retardation which means that even before birth they have slow growth and once they are born they will have a low birth weight [6]. If the fetus lives to be an infant, some of the physical signs that are seen are a cleft palate, ears that are lower than others, rocker-bottom feet, chest deformity, a clenched fist with fingers that overlap and microcephaly [7]. Some internal symptoms include defects of important organs such as the lungs, kidneys, stomach/intestines and some have a hole in their heart between the upper and lower chambers of the heart [8] .

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Maternally inherited Leigh syndrome (MILS) can be caused by many gene mutations, but the most common one is a mutation on the mitochondrial DNA which affects the MT-ATP6 gene [18].

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The majority of trisomy 18 cases are due to random events such as nondisjunction which means chromosomes don’t separate properly during meiosis so the gamete ends up with an extra chromosome 18 [9].
Even with the random occurrences, the prevalence of live-born babies with trisomy 18 is between 1 in 6000 and 1 in 8000, but only five to ten percent of these babies will live to be one year old [10]. However, there is also a large number of babies who don’t live past the second or third trimester and if they were included the prevalence would be closer to 1 in 2500 to 1 in 2600 [10].

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How does this aneuploidy cause microcephaly? 

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How does this aneuploidy cause microcephaly? 

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The extra chromosome 18 in individuals with trisomy 18 causes a disruption in the normal development route which results in a growth deficiency [11]. So, in the prenatal phase, it causes specific craniofacial dysmorphism which includes microcephaly [11].

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Trisomy 18 is unfortunately untreatable because currently there are no treatments or cures [12].

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The chromosomal aberration that causes this disease state is a translocation of chromosome 22q11.2 [13]. More specifically, it is due to an error of segregation resulting in a t(11;22)(q23;q11.2) non-Robertsonian translocation [13].

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Some of the symptoms that individuals with Emanuel Syndrome experience start as early as prenatal with a growth deficiency that will continue on into their postnatal phase [14]. Once the baby is born they are going to have symptoms such as severe developmental delays, hypotonia, microcephaly, congenital heart defects, and organ abnormalities such as kidney [14]. Other physical signs include an ear anomaly, preauricular pits or tags, and a high-arched or cleft palate [14].

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Emanuel Syndrome is a rare disorder and the prevalence of the disease state is unknown, but based on a study done at St. Christopher’s children hospital estimates that the frequency of this disease is 1 in every 30,000 to 50,000 births [15]. However, the data was based on cases between 1964 and 1972 so it is now assumed that due to the advancement in technology and increased use of prenatal diagnosis there is going to be a decrease in the frequency [15].

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How does this chromosomal aberration cause microcephaly? 

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How does this chromosomal aberration cause microcephaly? 

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The translocation of chromosome 11 onto a part of chromosome 22 causes the individual to have three copies of chromosome 11 instead of two [16]. This extra chromosome causes a disruption in the development of the child during both prenatal and postnatal phases which leads to different parts of the body developing slower than normal including the head resulting in microcephaly [16].

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There is no cure for Emanuel syndrome and there are not many treatments available either [17]. This is because since there will be an extra chromosome 11 in every cell, gene therapy can only help to some extent, but not enough to successfully treat or cure symptoms [17].

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The symptoms that individuals with maternally inherited Leigh syndrome experience start during infancy and it includes the inability to gain weight and grow due to the disruption of eating caused by dysphagia, vomiting and diarrhea [19]. Because of the lack of nutrients, it is common for these infants to develop weakness in their limbs and over severe muscle problems such as hypotonia and dystonia [19]. Throughout the rest of their life, individuals with MILS will also experience a continuous loss of both motor and mental abilities [19].

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Individuals with MILS typically live no more than two to three years, but there are also a few rare instances where they will either have slower worsening symptoms or the symptoms won’t develop until they are adults [20]. It is a rare disease because it affects about 1 in 40,000 newborns [21]. However in certain populations it is more common such as in Saguenay Lac-Saint-Jean in Quebec, Canada MILS affects 1 in 2,000 newborns and in the Faroe Islands it affects 1 in 1,700 newborns [20].

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How does this mitochondrial disorder cause microcephaly? 

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How does this mitochondrial disorder cause microcephaly? 

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There are many ways that maternally inherited Leigh syndrome can occur, but the most common mutation caused by mitochondrial DNA affects the MT-ATP6 gene [19]. This gene is responsible for giving instructions for making ATP synthase protein complex which is a piece of complex V that generates ATP [19]. This mutation of the gene MT-ATP6 causes the generation of ATP to be blocked [19]. The exact mechanism is still being researched, but scientists have found that along with the mutation of gene MT-ATP6 there are other mtDNA mutations that can cause the impairment of oxidative phosphorylation [19]. Due to these mutations it can cause a decrease in available energy in the cell which may lead to the death of the cell [19]. This can cause microcephaly because with the decrease in available cell energy it affects the functioning of certain tissues especially the ones that require a lot of energy which includes the brain [19]. With the brain cell tissues not getting enough energy it can result in the brain not developing properly which can then cause microcephaly.

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Is Maternally inherited Leigh syndrome treatable?

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Is Maternally inherited Leigh syndrome treatable?

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Since there are other many different genetic mutations that are not mtDNA related that can cause MILS there is no one set treatment [22]. Most treatments are developed based on the specific symptoms that the patient is exhibiting [22]. A primary treatment given to individuals with maternally inherited Leigh syndrome is the administration of vitamin B1 or thiamine derivatives [22]. This can cause an improvement in their symptoms and a small decrease in the speed of the progression, but it will only be temporary [22]. Any further treatments will be based on the individual and their specific symptoms [22].

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Lenz microphthalmia syndrome is usually a part of another anomaly called the  Oculofaciocardiodental microphthalmia syndrome and they both have similar traits and are caused by a mutation in the BCOR gene on chromosome Xq11.4 [23].

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One of the more characteristic symptoms of Lenz microphthalmia syndrome is the abnormal development of one or both of the eyes which can either be size or absence [24]. They can also have problems with vision loss, blindness, cataracts (clouded lens), and coloboma (split/gap in eye structure) [24]. Along with the eyes, they will also have abnormal growth of teeth, hands, skeleton, and urinary system [24]. With the abnormality in the growth of eyes and ears, it also includes an abnormal development of the size of their head which leads to microcephaly [25]. All of the characteristics and traits that are seen in patients with Lenz microphthalmia syndrome are very noticeable at birth [25].

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Lenz microphthalmia syndrome is a very rare disorder that has only been seen in a few families all around the world, so there is no data regarding the incidence or prevalence of Lenz microphthalmia syndrome [24].

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How does this nuclear gene disorder cause microcephaly? 

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How does this nuclear gene disorder cause microcephaly? 

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The BCOR gene on the Xp11.4 chromosome is the only identified gene that is known to cause Lenz microphthalmia syndrome [25]. The BCOR gene is responsible for making the BCL6 corepressor protein which helps in the regulation of the other genes' activities [25]. It has a very important role in early embryonic development and a mutation in this gene results in the many abnormalities that are seen in Lenz microphthalmia including microcephaly [25].

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Is Lenz microphthalmia syndrome treatable?

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Is Lenz microphthalmia syndrome treatable?

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Because it is such a rare disorder, there is no treatment or cure for this disease [26].

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1. Hashmi JA, Al-Harbi KM, Ramzan K, Albalawi AM, Mehmood A, Samman MI, Basit S. 2016.  A novel splice-site mutation in the ASPM gene underlies autosomal recessive primary microcephaly. Annals of Saudi Medicine. 36(6):391–396. doi:10.5144/0256-4947.2016.391.

2. National Library of Medicine (NlH). Mosaic variegated aneuploidy syndrome 1 (Concept Id: C1850343) - MedGen - NCBI. wwwncbinlmnihgov. [accessed 2022 Sep 30]. https://www.ncbi.nlm.nih.gov/medgen/338026.

3. MedlinePlus 2011. Autosomal recessive primary microcephaly: MedlinePlus Genetics. medlineplusgov. [accessed 2022 Sep 30]. https://medlineplus.gov/genetics/condition/autosomal-recessive-primary-microcephaly/#references.

4. Roberts E. 2002. Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. Journal of Medical Genetics. 39(10):718–721. doi:10.1136/jmg.39.10.718.

5. Online Mendelian Inheritance in Man (OMIM). 2010. Entry - 601161 - TRISOMY 18-LIKE SYNDROME - OMIM. wwwomimorg. [accessed 2022 Sep 30]. https://www.omim.org/entry/601161?search=trisomy%2018%20gene&highlight=18%20gene%20trisomy.

6. Outtaleb FZ, Errahli R, Imelloul N, Jabrane G, Serbati N, Dehbi H. 2020. La trisomie 18 ou syndrome d’Edwards en post-natal: étude descriptive au Centre Hospitalier Universitaire de Casablanca et revue de littérature. The Pan African Medical Journal. 37. doi:10.11604/pamj.2020.37.309.26205. [accessed 2021 Apr 28]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896527/.

7. Watson S. 2012 Jan 29. What Is Trisomy 18? WebMD. https://www.webmd.com/baby/what-is-trisomy-18.

8. MedlinePlus. 2021 February 16. Trisomy 18: MedlinePlus Genetics. medlineplusgov. [accessed 2020 Oct 21]. https://medlineplus.gov/genetics/condition/trisomy-18/#inheritance.

9. Watson S. 2012 Jan 29. What Is Trisomy 18? WebMD. https://www.webmd.com/baby/what-is-trisomy-18.

10. Cereda A, Carey JC. 2012. The trisomy 18 syndrome. Orphanet Journal of Rare Diseases. 7(1):81. doi:10.1186/1750-1172-7-81.

11. Outtaleb FZ, Errahli R, Imelloul N, Jabrane G, Serbati N, Dehbi H. 2020. La trisomie 18 ou syndrome d’Edwards en post-natal: étude descriptive au Centre Hospitalier Universitaire de Casablanca et revue de littérature. The Pan African Medical Journal. 37. doi:10.11604/pamj.2020.37.309.26205. [accessed 2021 Apr 28]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896527/.

12. Trisomy 18. wwwcincinnatichildrensorg. https://www.cincinnatichildrens.org/health/t/trisomy-18#:~:text=There%20are%20no%20treatments%20or.

13. OMIM Entry - # 609029 - EMANUEL SYNDROME. omimorg. [accessed 2021 Nov 27]. https://omim.org/entry/609029.

14. Emanuel BS, Zackai EH, Medne L. 1993. Emanuel Syndrome. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, Amemiya A, editors. PubMed. [accessed 2021 Nov 20]. https://www.ncbi.nlm.nih.gov/books/NBK1263/.

15. Ohye T, Inagaki H, Kato T, Tsutsumi M, Kurahashi H. 2014. Prevalence of Emanuel syndrome: Theoretical frequency and surveillance result. Pediatrics International. 56(4):462–466. doi:10.1111/ped.12437.

16. Emanuel syndrome: MedlinePlus Genetics. medlineplusgov. [accessed 2022 Feb 3]. https://medlineplus.gov/genetics/condition/emanuel-syndrome/.

17. Emanuel BS, Zackai EH, Medne L. 1993. Emanuel Syndrome. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G, Amemiya A, editors. PubMed. [accessed 2021 Nov 20]. https://www.ncbi.nlm.nih.gov/books/NBK1263/.

18. Entry - #256000 - LEIGH SYNDROME; LS - OMIM. omimorg. [accessed 2022 Nov 15]. https://omim.org/entry/256000?search=Leigh%27s%20Disease&highlight=disease%20leigh.

19. Leigh syndrome: MedlinePlus Genetics. medlineplusgov. [accessed 2020 Oct 5]. https://medlineplus.gov/genetics/condition/leigh-syndrome/#causes.

20. Leigh Syndrome (Leigh’s Disease): Causes & Symptoms. Cleveland Clinic. [accessed 2022 Sep 11]. https://my.clevelandclinic.org/health/diseases/6037-leigh-syndrome-leighs-disease.

21. Weerasinghe C, Bui B, Vu T, Nguyen H, Phung B, Nguyen V, Pham V, Cao V, Phan T. 2018 Mar 1. Leigh syndrome T8993C mitochondrial DNA mutation: Heteroplasmy and the first clinical presentation in a Vietnamese family. Molecular Medicine Reports. doi:10.3892/mmr.2018.8670.

22. Maternally Inherited Leigh Syndrome and NARP Syndrome - NORD (National Organization for Rare Disorders). 2015. NORD (National Organization for Rare Disorders). [accessed 2019 Nov 4]. https://rarediseases.org/rare-diseases/maternally-inherited-leigh-syndrome-and-narp-syndrome/.

23. Entry - #300166 - MICROPHTHALMIA, SYNDROMIC 2; MCOPS2 - OMIM. omimorg. [accessed 2022 Sep 30]. https://omim.org/entry/300166?search=LENZ%20MICROPHTHALMIA%20SYNDROME&highlight=lenz%20microphthalmia%20syndrome%20syndromic

24. Lenz microphthalmia syndrome: MedlinePlus Genetics. medlineplusgov. [accessed 2022 Sep 30]. https://medlineplus.gov/genetics/condition/lenz-microphthalmia-syndrome/.

25. Lenz Microphthalmia Syndrome. NORD (National Organization for Rare Disorders). [accessed 2022 Sep 30]. https://rarediseases.org/rare-diseases/lenz-microphthalmia-syndrome/#:~:text=Most%20infants%20with%20Lenz%20microphthalmia.

26. Lenz microphthalmia syndrome | Hereditary Ocular Diseases. disorderseyesarizonaedu. [accessed 2022 Sep 30]. https://disorders.eyes.arizona.edu/category/alternate-names/lenz-microphthalmia-syndrome#:~:text=In%20addition%20there%20is%20a.

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27. CDC. 2021 Mar 11. Congenital Anomalies of the Nervous System: Microcephaly. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/quick-reference-handbook/microcephaly.html.

28. What Is the Karyotype of Trisomy 18? MedicineNet. https://www.medicinenet.com/what_is_the_karyotype_of_trisomy_18/article.htm

29. Atli EI, Gürkan H, Vatansever Ü, Ulusal S, Tozkır H. 2015. A case with Emanuel syndrome: extra derivative 22 chromosome inherited from the mother. Balkan journal of medical genetics : BJMG. doi:10.1515/bjmg-2015-0089. [accessed 2022 Sep 30]. https://www.semanticscholar.org/paper/A-case-with-Emanuel-syndrome%3A-extra-derivative-22-Atli-G%C3%BCrkan/446aacc965a836debeb28e95eec7afca6410852b.