Last updated:
1/18/2023
Years published: 2023
NORD gratefully acknowledges Jiin Ying Lim, BSci, MGenCouns and Saumya Shekhar Jamuar, MBBS, MRCPCH, FAMS, FACMG, Genetics Service, Department of Pediatrics, KK Women’s and Children’s Hospital, Singapore, for the preparation of this report.
UGDH-related disorder is a rare genetic neurodevelopmental disorder characterized by global developmental delay, speech impairment, seizures and moderate to severe intellectual disability. It is caused by changes (mutations or variants) in the UGDH gene and is inherited in an autosomal recessive pattern. There is no cure for this disorder and treatment is based on the specific symptoms present in each individual.
Individuals with UGDH-related disorder present with a combination of developmental delay, epilepsy and intellectual disability. The developmental delay impacts motor skills as well as speech and language development. Low muscle tone (hypotonia) has been reported in all affected individuals and contributes to the delayed motor skills, including delayed walking. Some affected individuals may present with spasticity, dystonia, ataxia, chorea or tremor. Most affected individuals are non-verbal; however, one patient has been reported to speak in simple phrases at six years of age. All affected individuals reported so far have moderate to severe intellectual disability.
Onset of seizures can vary from the first few days of life to early childhood. Seizure types can be highly variable. Seizures tend to be severe with early onset in the neonatal period, but other seizure types have been reported and include infantile spasms, focal seizures, myoclonic jerks, febrile seizures, generalized tonic-clonic seizures and atonic seizures. Electroencephalography (EEG) is typically abnormal, and patterns include slow background activity, burst suppression patterns, multifocal spike-wave complexes and hypsarrhythmia. In many patients, seizures remain resistant to therapy, although two affected individuals have been reported to be seizure free on sodium valproate, and one showed good response to ketogenic diet.
Most affected individuals have feeding difficulties, especially in the infancy period, with 60% requiring tube feeding, either via a naso-gastric or gastrostomy tube. Drooling is commonly reported in the affected individuals. Respiratory distress secondary to hypotonia has been noted in some patients.
Facial features noted in patients with UGDH-related disorder include protruding ear lobes, drooping of eyelid (ptosis), deep set eyes, skin fold of upper eyelid covering the inner corner of the eye (epicanthal fold), short flat philtrum (vertical groove between the base of the nose and the order of the upper lip), full lower lip and pointed chin. Brain imaging usually demonstrates non-specific features, including delayed myelination, enlarged ventricles, cerebral atrophy, cerebellar atrophy and thin corpus callosum.
Researchers have been able to identify a core group of symptoms in affected individuals with UGDH-related disorder, but much of this disorder is not fully understood. While most reported affected individuals present with these features, they may not exhibit all the clinical features listed above. Parents should talk to their child’s medical team about their specific case, associated symptoms and overall prognosis.
UGDH-related disorder is caused by changes (mutations or variants) in the UGDH gene. The UGDH gene codes for UDP-glucose dehydrogenase (UDPGDH) protein, which converts UDP-glucose to UDP-glucuronate/UDP-glucuronic acid (UDP-GlcA). UDP-GlcA is a critical component involved in the extracellular matrix in the brain. When both copies of the UGDH gene have variants that affect and/or disrupt UDPGDH protein function, this leads to abnormal development of the brain and results in the clinical features seen in affected individuals.
UGDH-related disorder is inherited in an autosomal recessive manner. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
UGDH-related disorder affects males and females in equal numbers. There are less than 50 affected individuals reported worldwide with this disorder. However, the exact number of affected individuals is unknown. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Conservative estimates project a prevalence of 1:14,000,000 to 1:2,000,000. In addition, a founder mutation (p.Arg317Gln) has been reported in the Saudi Arabian population.
A diagnosis of UGDH-related disorder should be considered in a child presenting with epilepsy, developmental delay, intellectual disability, hypotonia and feeding difficulties. Molecular genetic testing of the UGDH gene is needed to confirm the diagnosis. This is usually done as part of an epilepsy panel or on whole exome/ genome sequencing.
Treatment
Management of affected individuals with UGDH-related disorder is symptomatic and anticipatory. Each patient is treated for the specific symptoms that they have. There is no gene-specific treatment available currently.
The care of affected individuals with UGDH-related disorder requires a multi-disciplinary team approach, consisting of neurologists, developmental pediatricians, geneticists, gastroenterologists, pulmonologist, neurorehabilitative therapists (including physical therapists, occupational therapists, and speech and language therapists) and dieticians.
Management can include
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.
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:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Hengel H, Bosso-Lefèvre C, Grady G, Szenker-Ravi E et al. Loss-of-function mutations in UDP-glucose 6-dehydrogenase cause recessive developmental epileptic encephalopathy. Nat Commun. 2020 Jan 30;11(1):595. doi: 10.1038/s41467-020-14360-7.
https://pubmed.ncbi.nlm.nih.gov/32001716/
Alhamoudi KM, Bhat J, Nashabat M, et al. A missense mutation in the UGDH gene is associated with developmental delay and axial hypotonia. Front Pediatr. 2020 Feb 27;8:71. doi: 10.3389/fped.2020.00071.
https://pubmed.ncbi.nlm.nih.gov/32175296/
INTERNET
UGDH Parent support group (https://www.facebook.com/groups/337904120548172)
UGDH Human Disease Genes Website Series (https://www.humandiseasegenes.nl/ugdh)
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