What is Jamuar syndrome?
Article by Sarah Upp, BS
Reviewed by Dr. Saumya Jamuar
May 2024
OVERVIEW
Jamuar syndrome, also known as UGDH-related disorder, is an ultra-rare genetic disorder.
Children with this syndrome can exhibit neurological symptoms like seizures, hypotonia, speech impairment, and intellectual disability. Currently, there is no cure. Medical management is focused on treating symptoms.
Jamuar syndrome is often referred to as developmental and epileptic encephalopathy 84 (DEE84) in scientific literature. Encephalopathies are conditions that affect the brain. Developmental and epileptic encephalopathies can be caused by mutations in many different genes. Jamuar syndrome is the developmental and epileptic encephalopathy caused by mutations in the UGDH gene.
The first major study on this disorder was published in 2020 (PMID: 32001716).
WHAT IS AN ULTRA-RARE DISEASE?
Rare diseases are conditions that affect fewer than 200,000 individuals in the United States (NIH).
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Ultra-rare diseases, on the other hand, are even more uncommon, affecting a very small number of individuals, sometimes as few as a handful worldwide. The UGDH Foundation is aware of fewer than 70 cases of Jamuar syndrome globally. This disease, however, is probably under-diagnosed since routine panel-based genetic tests for epilepsy do not yet include UGDH.
WHAT IS THE UGDH GENE?
The UGDH gene is a segment of DNA that contains instructions for a protein product called UDP-glucose dehydrogenase (also called the UDPGDH protein). Pathogenic (disease-causing) variants in the UGDH gene cause Jamuar syndrome.
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WHAT IS UDP-GLUCOSE DEHYDROGENASE?
UDP-glucose dehydrogenase, or the UDPGDH protein, converts a molecule called UDP-glucose into another molecule called UDP-glucuronate or UDP-glucuronic acid (also known as UDP-GlcA). The UDP-GlcA product plays an important role in the extracellular matrix of the brain.
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The extracellular matrix of the brain refers to the space around brain cells. The extracellular matrix is responsible for organizing brain cells and helping brain cells communicate with one another.
UDP-GlcA serves as a precursor in the synthesis of another class of molecules called glycosaminoglycans (GAGs). GAGs are long chains of carbohydrates that help regulate many biological processes, including activity within the extracellular matrix. More specifically, the GAGs help arrange cells correctly throughout development. GAGs also help to transmit messages between cells in cell-signaling pathways.
In summary, pathogenic variants in the UGDH gene cause a dysfunctional UDPGDH protein. Without the UDPGDH protein, UDP-GlcA cannot be produced. Without UDP-GlcA, it is hypothesized that the extracellular matrix of the brain will lack necessary GAGs and not develop correctly.
HOW IS JAMUAR SYNDROME INHERITED?
Jamuar syndrome is an autosomal recessive condition. This means that two pathogenic variants are needed to cause the disease; both copies of an individual’s UGDH gene will each have a pathogenic variant.
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A child with Jamuar syndrome may have inherited one UGDH pathogenic variant from an egg cell and the other pathogenic variant from a sperm cell. In other cases, pathogenic variants may be sporadic, or due to a random occurrence rather than inherited from parents.
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Someone with only one pathogenic variant will not have Jamuar syndrome but is considered to be a carrier for the condition. A carrier is someone who does not have a disease but can pass down the pathogenic variant to children. Two carriers of pathogenic UGDH variants have a 25% chance of having a child with Jamuar syndrome each pregnancy.
SIGNS & SYMPTOMS
Each child with Jamuar syndrome is unique. A child may not exhibit every feature of the disease. Additionally, a child’s signs and symptoms may go beyond what is included in the following list. Parents should talk with their child’s doctor about their child’s specific case.
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Developmental delay occurs when children are slower than expected in reaching milestones like sitting up, crawling, or speaking compared to other children their age.
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Epilepsy is a condition where a person has recurring seizures. Seizures are sudden bursts of electrical activity in the brain. In Jamuar syndrome, seizures often start in infancy. The seizures can take many different forms (infantile spasms, focal seizures, myoclonic jerks, febrile seizures, generalized tonic-clonic seizures, and atonic seizures).
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Intellectual disability refers to limitations in intellectual functioning and adaptive behavior, which affects a person's ability to learn and perform everyday tasks. In Jamuar syndrome, the intellectual disability can range from moderate to severe. Impaired speech and language development occurs when a child has difficulty with speaking or understanding language. It may involve problems with articulating words, forming sentences, or comprehending language. Most children with this disease are non-verbal, but some are able to speak simple phrases.
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Hypotonia is a condition characterized by low muscle tone. This means the patient has trouble activating their muscles, causing the muscles to feel floppy or limp. It can lead to difficulties with movement and posture, and sometimes impact breathing in severe cases. In such cases, the child is vulnerable to frequent respiratory illnesses.
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Feeding difficulties refer to challenges with feeding, such as difficulty latching, trouble swallowing, gagging, choking, or refusing to eat. Over half of children with Jamuar syndrome have required tube feeding to ensure adequate nutrients are being consumed.
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Movement disruptions like spasticity, dystonia, ataxia, chorea, or tremor can also occur. These different movements are a result of neurological issues. Spasticity involves stiffness and involuntary muscle contractions, dystonia causes twisting or repetitive movements, ataxia leads to problems with coordination and balance, chorea results in jerky, involuntary movements, and tremor causes rhythmic shaking of parts of the body.
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Facial features can include protruding ear lobes, droopy eyelids (ptosis), deep-set eyes, skin folds of the upper eyelid covering the inner eye (epicanthal folds), a short and flat philtrum (the groove between the nose and lips), a fuller lower lip, and a pointed chin.
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Structural brain differences can also be found on imaging (delayed myelination, enlarged ventricles, cerebral atrophy, cerebellar atrophy, and thin corpus callosum).
WHAT ARE GENES?
Every person has a unique genome that provides a “blueprint” for their body. A genome refers to someone’s complete set of genetic material or DNA.
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​Our genome is organized into 23 pairs of chromosomes. Each chromosome contains many genes. In fact, humans have about 20,000 genes within their entire genome.
Each gene contains a specific set of instructions for a protein product. All proteins have individualized roles within our cells. Our cells use genes to make the proteins it needs to function properly. Genes are often named by scientists using capital letters and sometimes numbers. You can spot a gene name in italicized font.
Genes are passed down from parent to child. A child receives half of their DNA from an egg cell and half from a sperm cell. Together, the DNA in the egg and the sperm form a complete genome. This is why children can inherit different traits, or even diseases, from their parents.
WHAT ARE GENETIC VARIANTS?
Genetic variants, or mutations, are changes within the genome.
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Some changes don’t affect the function of the gene, or its corresponding protein product. These genetic changes are called benign variants, meaning they don’t cause any disease. Benign variants are very common.
On the other hand, some changes can disrupt the genetic code, resulting in a non-functioning gene. These genetic changes are called pathogenic variants, meaning that they cause disease. Pathogenic variants that cannot encode the correct protein or cannot make any protein at all are called loss-of-function variants. Although not all loss-of-function variants cause disease, many pathogenic variants are also loss-of-function variants.
Sometimes, a genetic variant is not known to cause disease but cannot be classified as benign with certainty. These variants are called variants of unknown significance (abbreviated as VUS or VOUS). A VUS is a temporary classification; these variants can be reclassified as benign or pathogenic with more research. VUS reclassifications can take anywhere from months to decades.
WHAT IS GENETIC TESTING?
A molecular genetic test analyzes the DNA code, looking for variants. A genetic test will often find benign and pathogenic variants.
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The test result typically only lists pathogenic variants and sometimes variants of unknown significance (VUSs/VOUSs). Different types of molecular genetic tests vary in how much DNA is analyzed.
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A panel test analyzes a select group of genes. For example, an epilepsy panel will analyze epilepsy-related genes for pathogenic variants that could cause epilepsy.
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An exome genetic test analyzes all DNA that is expressed or coded, meaning all DNA that makes proteins. The testing software will then flag genetic changes that relate to a person’s signs and symptoms.
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A genome genetic test operates similarly to an exome test but is even more expansive. Genome genetic testing includes coding and non-coding DNA, meaning DNA that makes proteins and extra DNA that does not make proteins.
Exome and genome genetic testing is often done “in trio,” meaning both parents and child are tested simultaneously. This enables the genetic laboratory to see if genetic changes in the child were inherited from the parents. It also helps the laboratory decide which variants are pathogenic and which variants are benign in the child. Talking to a genetic counselor or geneticist before ordering genetic testing is recommended.
WHAT IS THE DIAGNOSTIC ODYSSEY?
The diagnostic odyssey refers to a patient’s journey towards a diagnosis.
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Rare diseases can often be misdiagnosed. During the diagnostic odyssey, people may undergo extensive testing and several misdiagnoses, which can lead to prolonged care for the correct diagnosis.
THE DIAGNOSTIC ODYSSEY AND JAMUAR SYNDROME
Children with Jamuar syndrome often have similar presenting symptoms including epilepsy, developmental delay, intellectual disability, hypotonia, and feeding difficulties. These signs and symptoms can be mistaken for other conditions.
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In particular, Barakat-Perenthaler syndrome shares a lot of overlap. Molecular genetic testing of the UGDH gene is needed to confirm a diagnosis of Jamuar Syndrome. Currently, UGDH genetic variants are often detected via exome or genome genetic testing.
WHAT IS THE MEDICAL MANAGEMENT OF JAMUAR SYNDROME?
Until we have a cure, medical management for children with Jamuar syndrome is focused on treating symptoms.
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For example, affected children may need anti-epileptic medication and a variety of therapies to address developmental delays and motor difficulties. Medical management is individualized for each child. Because of this, communication with your child’s care team is important.
WHO IS PART OF THE CARE TEAM?
Jamuar Syndrome requires multi-disciplinary treatment. This means a team of medical specialists will often work together to provide comprehensive treatment.
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This team can include any of the following:
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Neurologists are medical doctors who specialize in treating diseases that affect the nervous system, including the brain and spinal cord. Epilepsy is an example of a neurological condition that may require a consultation with a neurologist.
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Developmental pediatricians specialize in diagnosing and treating children with developmental delays. They use various testing tools to identify the types and severity of delays.
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Geneticists are doctors who are experts in genetics and genetic conditions. They have a deep understanding of how genetic variants cause genetic conditions and can order genetic testing.
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Genetic counselors are healthcare providers who specialize in both genetics and counseling. Genetic counselors assist patients in making informed decisions about genetic testing and provide support throughout the process.
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Gastroenterologists are doctors with specialized knowledge of the digestive tract. They can be consulted to discuss the need for feeding tubes and other gastrointestinal issues.
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Pulmonologists are doctors with respiratory system expertise. They diagnose and treat any issues with breathing.
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Physical therapists (PTs) are healthcare providers who work with patients to improve physical movement and function. They help increase strength and improve mobility.
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Occupational therapists (OTs) are healthcare providers who assist individuals with the performance of daily tasks and activities, focusing on improving independence and quality of life.
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Speech and language therapists are healthcare providers who work with patients to develop speech and language skills.
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Dieticians are healthcare providers who specialize in nutrition. They create personalized diet plans to ensure patients receive proper nourishment and manage dietary needs.
WILL JAMUAR SYNDROME HAVE A CURE IN THE FUTURE?
In rare disease communities, finding cures is both promising and challenging.
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Researchers in the rare disease space are working on different cutting-edge treatments such as gene therapies, enzyme replacement therapies, and antisense oligonucleotides (ASOs). Because each rare disease needs a unique gene-specific cure, developing individualized treatments requires time and funding. Rare disease research is a “long game."
The UGDH Foundation is working to unite patients, raise awareness, and coordinate collaboration among researchers to hasten the development of better treatments and a cure for Jamuar syndrome.
RESOURCES
The TUF Family Network connects parents of individuals with UGDH-related disorders. This enables us to combine efforts towards the development of better treatments and a cure. Families in the network will be notified of any opportunities in which scientifically useful and appropriate sharing of patient data may aid in research initiatives. Learn more and sign up here.
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The National Organization for Rare Disorders (NORD) provides patient assistance programs for a variety of challenges, like information about financial help and caregiver support. The website is also a resource for research updates and events within the rare disease space.
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Global Genes RARE Concierge is an advocacy organization that aims to connect, empower, and inspire the rare disease community. You can find resources, events, and education on their website.
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MORE ABOUT JAMUAR SYNDROME
Genetic clues lead to the identification of Jamuar Syndrome, A*Star Research
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Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy, Nature Communications, 30 January 2020
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A Missense Mutation in the UGDH Gene Is Associated With Developmental Delay and Axial Hypotonia, Frontiers in Pediatrics, 27 February 2020
SOURCES
Alhamoudi, Kheloud M et al. “A Missense Mutation in the UGDH Gene Is Associated With Developmental Delay and Axial Hypotonia.” Frontiers in pediatrics vol. 8 71. 27 Feb. 2020, doi:10.3389/fped.2020.00071
Hengel, Holger et al. “Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.” Nature communications vol. 11,1 595. 30 Jan. 2020, doi:10.1038/s41467-020-14360-7
Lim, Jiin Ying & Jamuar, Saumya Shekhar. “UGDH-Related Disorder.” NORD. Jan. 2023. https://rarediseases.org/rare-diseases/ugdh-related-disorder/#complete-report
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