Ogden Syndrome

Ogden Syndrome, also known as n-terminal acetyltransferase deficiency (NATD),^[1] is an x-linked disorder of infancy comprising a distinct combination of distinctive craniofacial features producing an aged appearance, growth failure, hypotonia, global developmental delays, cryptorchidism, and acquired cardiac arrhythmias. The first family was identified in Ogden, Utah, with five affected boys in two generations of family members. A mutation was identified as a c.109T>C (p.Ser37Pro) variant in NAA10, a gene encoding the protein Naa10 catalytic subunit of the major human N-terminal acetyltransferase (NatA). This same mutation was identified in a second unrelated family, with three affected boys in two generations. This X-linked Malformation and Infantile Lethality Syndrome has provisionally been named Ogden Syndrome, in honor of the hometown where the first family resides.

Presentation

This is an X-linked condition affecting males and characterized by postnatal growth failure with developmental delays and dysmorphic features characterized by wrinkled forehead, anterior and posterior fontanels, prominent eyes, large down-slanting palpebral fissures, thickened or hooded eyelids, large ears, flared nares, hypoplastic alae nasi, short columella, protruding upper lip, and microretrognathia. There is also delayed closing of fontanelle, and the boys also have broad great toes. Skin is characterized by redundancy or laxity with minimal subcutaneous fat, cutaneous capillary malformations, and very fine hair and eyebrows. Death resulted from cardiogenic shock following arrhythmia, which was noted in all affected individuals. The boys had heart rhythm abnormalities and craniofacial abnormalities, which accounted for their similar appearance. The boys were never able to sit up on their own, and none learned how to talk.^[2] They all have a characteristically aged appearance, earning them the family nickname of “little old men.”^[2] Several of the boys had structural anomalies of their hearts including ventricular septal defect, atrial septal defect, and pulmonary artery stenosis. Arrhythmias at the time of death included torsades de pointes, premature ventricular contraction (PVC), premature atrial contraction (PAC), supraventricular tachycardia (SVtach), and ventricular tachycardia (Vtach). Most of the children had inguinal hernias, and the majority had, at least, unilateral cryptorchidism. All had neonatal hypotonia progressing to hypertonia, and cerebral atrophy on MRI; several, but not all, had neurogenic scoliosis. Death occurred prior to 2 years in all cases and prior to 1 year in the majority. There are extensive clinical details for each child reported in the original publication

Molecular genetics

Ogden Syndrome is a lethal X-linked recessive condition. Because the affected gene is on the X-chromosome, it affects only males. It was the first reported human genetic disorder linked with a mutation in an N-terminal acetyltransferase (NAT) gene.^[3] Males have the Ser37Pro (S37P) mutation in the gene encoding NAA10, the catalytic subunit of NatA, the major human NAT involved in the co-translational acetylation of proteins. The S37P mutation swaps one amino acid for another, a Serine amino acid for a Proline, in just one part at the end of the resulting protein.^[3] This mutation changes the structure of the protein, which makes it less effective than a normal protein, causing a multitude of effects for the babies.^[2] A mutation in an enzyme involved in N-terminal acetylation of proteins has thus far been associated with this distinct X-linked phenotype in two families, with 8 males who carried the hypomorphic hNaa10 p.Ser37Pro allele dying in infancy with cardiomegaly and cardiac arrhythmias. N-terminal acetylation is one of the most common protein modifications in humans, occurring on approximately 80% of all human proteins.^[4]

History

Halena Black had her first son, Kenny Rae, in 1979. Being that he was her first born child, Black did not notice that something was wrong. Kenny Rae Black passed in 1980, right before his first birthday and was the first know infant to die from Ogden Syndrome.^[5] However, it did not end there. Halena Black continued to have children and in 1987 she had her next boy, Hyrum. From the start, Black noticed that Hyrum had the same characteristics as Kenny Rae but thought it was due to the fact that they were brothers. It did not cross her mind that they could share the same underlying disease. Like Kenny Rae, Hyrum passed before his first birthday. It was only until Black's daughters began having children of their own that she realized something was not right. The sons born to Black's daughters looked identical to her own sons and that was when Halena sought medical help.^[5] Answers came thirty years after Kenny Rae's death. Ogden Syndrome was discovered in 2011 by a team of researchers led by Gholson J. Lyon, consisting of: Alan F. Rope, Kai Wang, Rune Evjenth, Jinchuan Xing, Jennifer J. Johnston, Jeffrey J. Swensen, W. Evan Johnson, Barry Moore, Chad D. Huff, Lynne M. Bird, John C. Carey, John M. Opitz, Cathy A. Stevens, Tao Jiang, Christa Schank, Heidi Deborah Fain, Reid J. Robison, and 10 others.Just before Lyon was about to publish his findings, another team researching a family living mainly in California contacted him. The newly found family had also lost three infant boys all with shockingly similar characteristics. Lyon tested the new family and found they shared the same rare mutation as the Black family.The existence of another family made this mutation a syndrome, and not something isolated to the Blacks.^[2]

References

1. ↑ Rope, A.F. (2011). "Using VAAST to Identify an X-linked disorder resulting in lethality in male infants due to N-terminal acetyltransferase deficiency". American Journal of Human Genetics. 89 (1): 28–43. doi:10.1016/j.ajhg.2011.05.017. PMC 3135802. PMID 21700266. 
2. 1 2 3 4 "More news on Ogden Syndrome from AAAS | Utah Foundation For Biomedical Research". Retrieved 2015-09-25. 
3. 1 2 Myklebust, Line; et al. (2015-01-08). "Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects" (PDF). Human Molecular Genetics. 24: 1956–76. doi:10.1093/hmg/ddu611. PMID 25489052. Retrieved 2015-10-02. 
4. ↑ Arnesen, T. (2009). "Proteomics analyses reveal the evolutionary conservation and divergence of N-terminal acetyltransferases from yeast and humans.". Proc Natl Acad Sci U S A. 106 (20): 8157–62. doi:10.1073/pnas.0901931106. PMID 19420222. 
5. 1 2 "Rare genetic mutation causes infant deaths in small town | AAAS MemberCentral". membercentral.aaas.org. Retrieved 2015-09-25.