NORD gratefully acknowledges Jacqueline Kirsh and Eve Takazawa, Editorial Interns from the University of Notre Dame, Angela M. Mabb, PhD, Assistant Professor, Center for Behavioral Neuroscience, Neuroscience Institute, Georgia State University and Arlene J. George, Graduate Fellow, Neuroscience Institute, Georgia State University, for assistance in the preparation of this report.
Juberg-Marsidi syndrome (JMS) is an extremely rare genetic disorder that is apparent at birth (congenital) or during the first few weeks of life (neonatal period). This syndrome was first noted by Richard Juberg and Irene Marsidi in 1980 when three male relatives with similar physical abnormalities and intellectual disability were observed. JMS is caused by a changed (mutated) gene on the X chromosome and follows X-linked inheritance.
Physical findings and symptoms associated with JMS are fully present in males only and the range and severity of symptoms vary from person to person. The primary findings include abnormalities in the urinary tract and reproductive organs (urogenital abnormalities), short stature/delayed growth, and craniofacial abnormalities. Affected children also exhibit severe intellectual disability; delays in reaching developmental milestones (e.g., crawling, walking, etc.); muscle weakness; and diminished muscle tone (hypotonia). They may also have hearing loss; underdevelopment of the genitals (microgenitalism); malformations of hands and feet; and/or abnormalities of the head and facial (craniofacial) area. Craniofacial features include an abnormally small head (microcephaly), a flat or depressed nasal bridge, an upward slant in the opening between the eyelids (upslanting palpebral fissures), eye abnormalities such as increased distance between the eyes (orbital hypertelorism) and a prominent forehead.
Some females who carry a single copy of the disease gene (heterozygous carriers) may exhibit milder symptoms such as low cognitive ability/IQ and/or microcephaly.
A full list of notable symptoms include:
Head and Neck
Signs of hypogonadism (hypogenetalism) including:
Growth and Development
The gene that causes Juberg-Marsidi syndrome is located on the X chromosome and is called the HUWE1 gene.
When the disease is present, the HUWE1 gene has undergone a missense mutation. The missense mutation leads to one of the building blocks of protein (amino acid) to be incorrectly exchanged for another, which creates an abnormal protein. There are numerous different HUWE1 missense mutations recorded and they affect a process called protein ubiquitination. This process involves modifying numerous proteins in order to mediate a variety of cell functions. There are three main enzymes that work in protein ubiquitination; E1, E2, and E3. E3 is called ubiquitin ligase and is the final step in the process. The HUWE1 gene makes a specific E3 ubiquitin ligase. Mutations in HUWE1 may result in decreased expression of the protein and abnormal enzyme function, which could affect protein ubiquitination. Little is known about the direct relationship between specific HUWE1 mutations and the physical manifestations of the disease, but this is being studied in a mouse model.
JMS is inherited in an X-linked recessive pattern. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes, one normal X chromosome and one X chromosome that carries the non-working gene. Males have one X chromosome that is inherited from their mother. If a male inherits an X chromosome that contains a non-working gene, he will develop the disease.
With each pregnancy, female carriers of an X-linked disorder have a 25% chance to have a carrier daughter like themselves, 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.
If a male with an X-linked disorder is able to reproduce, he will pass the non-working gene to all of 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 offspring.
Approximately six families (kindreds) affected with JMS have been reported in the medical literature and the prevalence is estimated to be less than one in one million births.
JMS may be recognized at birth or during early infancy, but there is often delayed diagnosis due to the large variety of symptoms possible and similarities to other diseases. A thorough clinical evaluation and characteristic physical findings, as well as an evaluation of family history, are used to create an initial diagnosis. Craniofacial abnormalities, low birth weight, genital malformations, and/or hearing impairment may be apparent at birth and are considered particularly suggestive of JMS. Abnormalities in motor coordination, speech, and intellect may also be monitored during infancy and childhood. Additionally, genetic testing may be possible to rule out other X-linked diseases with similar symptoms and to confirm a diagnosis for JMS.
The treatment of this syndrome is directed toward the specific symptoms that are apparent in each individual and focused on supporting patients. Treatment requires the coordinated efforts of a team of specialists. Pediatricians, speech pathologists, nutritionists, specialists who assess and treat hearing problems (audiologists), eye specialists, urologists and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
Urogenital symptoms indicate an increased need for kidney and renal function monitoring because of a possible increased risk for kidney swelling (hydronephrosis) caused by urine accumulation or recurrent urinary tract infections.
A variety of methods may be used to treat and correct eye abnormalities. Surgery, corrective glasses, or contact lenses may be used to help improve vision. In some cases, hearing aids may be used for those with hearing impairment.
Early intervention is important in ensuring that affected children with JMS reach their potential. Special services that may be beneficial to affected children may include special remedial education and other medical, social, and/or vocational services.
Genetic counseling is recommended for affected individuals and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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George AJ, Hoffiz YC, Charles AJ, Zhu Y, Mabb AM. A comprehensive atlas of E3 ubiquitin ligase mutations in neurological disorders. Front Genet. 2018;9:29. Published 2018 Feb 14. doi:10.3389/fgene.2018.00029
Moortgat S, Berland S, Aukrust I, et al. HUWE1 variants cause dominant x-linked intellectual disability: a clinical study of 21 patients. Eur J Hum Genet. 2018 Jan;26(1):64-74. doi: 10.1038/s41431-017-0038-6. Epub 2017 Nov 27.
Friez MJ, Brooks SS, Stevenson RE, et al. HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study. BMJ Open. 2016;6(4):e009537. Published 2016 Apr 29. doi:10.1136/bmjopen-2015-009537
Villard L, Geez J, Mattei JF, et al. XNP mutation in a large family with Juberg-Marsidi syndrome. Nat Genet. 1996;12:359-60.
Juberg RC, Marsidi I. A new form of X-linked mental retardation with growth retardation, deafness, and microgenitalism. Am J Hum Genet. 1980;32(5):714–722.
McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Entry Number 309590. Last Edit Date: 01/27/2020. Available at: https://www.omim.org/entry/309590 Accessed April 27, 2020.
Orphanet. Last update: May 2008. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=93972 Accessed April 27, 2020.
DoveMed. Last updated Oct. 17, 2018. https://www.dovemed.com/diseases-conditions/juberg-marsidi-syndrome/ Accessed April 27, 2020.
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