• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
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Ogden Syndrome

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Last updated: 3/29/2024
Years published: 2024


Acknowledgment

NORD gratefully acknowledges Ruhi Shah, MS, CGC, NYS Institute for Basic Research, George A. Jervis Clinic and Gholson J. Lyon, MD, PhD, George A. Jervis Clinic and Institute for Basic Research in Developmental Disabilities, for the preparation of this report.


Disease Overview

Summary

Ogden syndrome is a rare genetic condition characterized by a spectrum of clinical features, including facial differences, aged appearance, developmental disabilities, skeletal anomalies, genitourinary anomalies, irregular heartbeat (cardiac arrhythmia) and other conditions. Ogden syndrome is an X-linked genetic condition caused by disease-causing (pathogenic) variants in the NAA10 gene. Treatment for this condition is based on the individual’s symptoms.

Introduction

The name Ogden syndrome was suggested by the first family identified with the condition, in honor of their hometown. The syndrome was first described in 2011 by Dr. Gholson Lyon, who cared for the family and obtained DNA samples to identify the genetic cause. Originally, Ogden syndrome was thought to affect males only, with severe, often fatal health problems. Ogden syndrome is now known to have a range of mild to severe symptoms and can also affect females. This condition is also known as NAA10-related neurodevelopmental syndrome. In this report, Ogden syndrome refers to the wide spectrum of features associated with a disease-causing variant in the NAA10 gene.

 

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Synonyms

  • NAA10-related neurodevelopmental syndrome
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Signs & Symptoms

Individuals with Ogden syndrome present at different ages and with a wide spectrum of symptoms and severity. Males with Ogden syndrome tend to be affected more severely and may have life-threatening symptoms in infancy. Females with one disease-causing variant in the NAA10 gene can vary from having no symptoms to having the same features as an affected male.

Ogden syndrome can affect several organ systems and include a variety of symptoms such as:

Facial: Common features include large spaces between the bones of the skull, wrinkled forehead, prominent eyes, hypertelorism or widely spaced eyes, thick eyebrows, long eyelashes, relatively large ears, flared or prominent nostrils, upturned nose, protruding upper lip, small jaw or micrognathia, narrow palate and small hands and feet.

Heart: Some individuals have heart abnormalities including prolonged QT intervals that cause irregular heart rhythm or heart defects such as atrial septal defects and ventricular septal defects. Heart issues may be present at different ages. However features such as issues with the heart rate or rhythm also known as cardiac arrhythmias or congenital heart defects, can be identified prenatally.

Respiratory: There have been a few reports in the medical literature of respiratory issues. These include respiratory distress in infancy, pneumonia or frequent respiratory infections, apnea, pulmonary hypertension and bronchiolitis.

Gastrointestinal: Most individuals with Ogden syndrome have feeding difficulties during infancy. Other gastrointestinal problems may include difficulty swallowing (dysphagia), aspiration issues, gastroesophageal reflux disease (GERD), vomiting, constipation and diarrhea. Some individuals have been reported to need a feeding tube.

Genitourinary: Over half of the affected males have genitourinary malformations including inguinal hernia, small testes and undescended testes (cryptorchidism). Less frequently, there have been reports of cystic renal dysplasia that can block urine flow and scar tissue in the kidneys (glomerulosclerosis).

Growth: Affected individuals may be short for their height, have low weight and have smaller head circumference in the first year of life. There have also been some reports of low muscle tone (hypotonia) or muscle weakness.

Neurological and Brian: Some Individuals may have brain abnormalities at birth such as a thin or smaller corpus callosum in the brain and a small head size (microcephaly). Other findings include enlarged spaces or ventricles of the brain, abnormal brain development and an injury to the brain’s white matter known as periventricular leukomalacia. Tonic-clonic seizures are also a common feature.

Cognitive and Psychiatric: Some individuals have global developmental delays, speech delays, learning difficulties, autism spectrum disorder (ASD), intellectual disability that varies from mild to severe and behavioral disorders including short attention span, hyperactivity, attention deficit hyperactivity disorder (ADHD), unmotivated laughter, harming behaviors (self and others), self-hugging, and compulsive and obsessive behaviors.

Skeletal and Skin: Skeletal features such as late closure of the space between the bones of the skull, a short neck, scoliosis, chest wall deformities, curved fingers, hip dysplasia, rotated foot and large or broad big toes may be present. Many children also have impaired motor skills and as a result, may have difficulty walking or may be wheelchair-bound. Individuals may have skin laxity, recurrent eczema, vascular anomalies and fine scalp or eyebrow hair.

Eyes and Vision: Most individuals with Ogden syndrome have vision abnormalities. Common features include astigmatism, myopia, strabismus and visual impairment.

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Causes

Ogden syndrome is caused by disease-causing variants in the NAA10 gene. This gene encodes for the enzyme N-terminal acetyltransferase 10. This enzyme along with another protein known as NAA15, makes up the N-terminal acetyltransferase A (NatA) complex. The NatA complex aids in the attachment of a chemical group called acetyl-CoA to the first section of proteins. This attachment process is known as acetylation. Acetylation regulates protein stability, interaction, formation and activity. Certain variants in the NAA10 gene change the structure and function of the protein. This change can reduce stability and cause the symptoms of Ogden syndrome. Therefore, the severity of the disease is dependent on the remaining activity of the enzyme.

Ogden syndrome is usually inherited in an X-linked manner. X-linked genetic disorders are conditions caused by a disease-causing gene variant on the X chromosome and mostly affect males. Females who have a disease-causing gene variant on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the gene variant. However, there have been reports in the medical literature of carrier females with a range of clinical symptoms associated with Ogden syndrome. Symptoms and severity in females depend on which X chromosome is active and in what proportion in their cells.

Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease-causing gene variant, he will develop the disease.

Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter who may have a range of clinical symptoms, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

Currently, there are no reports of affected males that have reproduced. If a male with an X-linked disorder can reproduce, he will pass the gene variant to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children

A NAA10 gene variant may be inherited from a parent or may have occurred for the first time in the child, also known as de novo. If the gene variant occurred de novo, there is a <1% chance for the parents to have another affected child.

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Affected populations

Ogden Syndrome is a rare genetic disorder that is usually fully expressed in males. Carrier females may have a wide range of symptoms, from asymptomatic to having the same symptoms as affected males. As of 2024, the disorder has been reported in just over 100 individuals. The overall worldwide prevalence is currently unknown. Data is not available to estimate ethnic-based prevalence.

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Diagnosis

A diagnosis of Ogden syndrome may be considered based on clinical findings and a thorough patient and family history. Suggestive findings include developmental delays and intellectual disability, cardiac abnormalities, postnatal growth restriction and characteristic facial features. Heart anomalies may include cardiac arrhythmias and/or ECG abnormalities as well as heart defects such as patent ductus arteriosus, atrial septal defect, ventricular septal defect, patent foramen ovale, aortic valve abnormality and peripheral pulmonary stenosis. Distinctive facial features may include large fontanels, widely spaced eyes, prominent eyes, thick eyelids, relatively large ears, flared or prominent nostrils, protruding upper lip, small jaw, narrow palate and small hands and feet. Some infants also have an aged appearance.

Molecular genetic testing that shows a disease-causing variant in the NAA10 gene can confirm a diagnosis of Ogden syndrome. Two types of molecular testing can be considered based on the child’s symptoms. Children with characteristic symptoms may have a genetic test that looks for variants in the NAA10 gene only. Children with symptoms that fit many different conditions may have genomic testing which looks at NAA10 along with multiple other genes.

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Standard Therapies

Treatment

Treatment for Ogden syndrome is symptomatic and supportive. Management may include the following evaluations: annual heart evaluation, which includes both an echocardiogram and electrocardiogram, a neurologic assessment, an evaluation for apnea, feeding and nutrition assessment, a brain MRI, an orthopedic consultation, evaluation of cryptorchidism, renal ultrasound and eye examination by an ophthalmologist. After a diagnosis is established, other therapies may be included as part of the individual’s care plan. These may include physical, occupational, speech and applied behavior analysis (ABA) therapy.

Genetic counseling is recommended for affected individuals and their families. The counseling can include a discussion of the causes of Ogden syndrome and the chances of having additional children with this syndrome. Psychosocial support for the entire family may be beneficial.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

Contact for more information about Ogden syndrome: Dr. Gholson Lyon Email: gholsonjlyon@gmail.com

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References

JOURNAL ARTICLES

Makwana R, Christ C, Marchi E, Harpell R, Lyon G. Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention. medRxiv (Cold Spring Harbor Laboratory). Published online 2024. doi:10.1101/2024.02.23.24303144

Lyon GJ, Longo J, Garcia A, et al. Evaluating possible maternal effect lethality of Naa10 knockout mice, and modulation of phenotypes for embryonic and neonatal lethality by genetic background and environment. bioRxiv (Cold Spring Harbor Laboratory). Published online April 27, 2023. doi:10.1101/2023.04.27.538618

Lyon GJ, Vedalia M, Beis Heim T, et al. Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome. European Journal of Human Genetics. 2023;31(7):824-833. doi:10.1038/s41431-023-01368-y

McTiernan N, Tranebjærg L, Bjørheim AS, et al. Biochemical analysis of novel NAA10 variants suggests distinct pathogenic mechanisms involving impaired protein N-terminal acetylation. Human Genetics. 2022;141(8):1355-1369. doi:10.1007/s00439-021-02427-4.

Maini I, Carafes SG, Peluso F, et al. Clinical manifestations in a girl with NAA10-related syndrome and genotype–phenotype correlation in females. Genes. 2021;12(6):900. doi:10.3390/genes12060900

McTiernan N, Darpak C, Ree R, Arnesen T. NAA10 P.(D10G) and NAA10 P.(L11R) variants hamper formation of the NATA N-Terminal acetyltransferase complex. International Journal of Molecular Sciences. 2020;21(23):8973. doi:10.3390/ijms21238973

Cheng H, Gottlieb L, Marchi E, et al. Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15. Human Molecular Genetics. 2019;28(17):2900-2919. doi:10.1093/hmg/ddz111

Gupta A, Saif HA, Lent JM, Couser NL. Ocular manifestations of the NAA10-related syndrome. Case Reports in Genetics. 2019; 2019:1-6. doi:10.1155/2019/8492965

Wu Y, Lyon GJ. NAA10-related syndrome. Experimental & Molecular Medicine. 2018;50(7):110. doi:10.1038/s12276-018-0098-x

Sidhu MS, Brady L, Tarnopolsky MA, Ronen GM. Clinical manifestations associated with the N-Terminal-Acetyltransferase NAA10 gene mutation in a girl: Ogden syndrome. Pediatric Neurology. 2017; 76:82-85. Doi: 10.1016/j.pediatrneurol.2017.07.010

Saunier C, Steve SI, Popp B, et al. Expanding the phenotype associated with NAA10‐related N‐terminal acetylation deficiency. Human Mutation. 2016;37(8):755-764. doi:10.1002/humu.23001

Casey JP, stave SI, McGurrin C, et al. NAA10 mutation causing a novel intellectual disability syndrome with long QT due to N-terminal acetyltransferase impairment. Scientific Reports. 2015;5(1). doi:10.1038/srep16022

Derrel M, Lyon GJ. The biological functions of Naa10—from amino-terminal acetylation to human disease. bioRxiv (Cold Spring Harbor Laboratory). Published online January 29, 2015. doi:10.1101/014324

Popp B, Stave SI, Endel S, et al. De novo missense mutations in the NAA10 gene cause severe non-syndromic developmental delay in males and females. European Journal of Human Genetics. 2014;23(5):602-609. doi:10.1038/ejhg.2014.150

Myklebust LM, Van Damme P, Støve SI, et al. Biochemical and cellular analysis of Ogden syndrome reveals downstream Nt-acetylation defects. Human Molecular Genetics. 2014;24(7):1956-1976. doi:10.1093/hmg/ddu611

Rope AF, Wang K, Events R, et al. Using VAAST to identify an X-Linked disorder resulting in lethality in male infants due to N-Terminal acetyltransferase deficiency. The American Journal of Human Genetics. 2011;89(1):28-43. Doi: 10.1016/j.ajhg.2011.05.017

INTERNET

ACETYLTRANSFERASE 10, NATA CATALYTIC SUBUNIT; NAA10. Online Mendelian Inheritance in Man (OMIM). Entry No: 300013.Updated 09/09/2022.https://www.omim.org/entry/300013?search=NAA10&highlight=naa10. Accessed Jan 16, 2024.

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