Years published: 2023
NORD gratefully acknowledges Amanda J. Grieco, PhD, Troy C. Lund, MD, PhD, Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, University of Minnesota, Virginia Kimonis, MD, MRCP, Professor, Department of Pediatrics, Division of Genetic and Genomic Medicine, University of California-Irvine Medical Center and the International Society for Mannosidosis & Related Diseases, for the preparation of this report.
Beta-mannosidosis (β-mannosidosis) is an extremely rare genetic disease that belongs to a larger group of lysosomal storage disorders. Lysosomal storage disorders are characterized by metabolic abnormalities that cause a build-up of various toxic materials in the lysosomal compartment of cells throughout the body. The signs and symptoms of beta-mannosidosis vary in both the severity and age of onset. Almost all affected individuals experience some degree of intellectual disability, and some have delayed motor development. Other signs and symptoms can include muscle abnormalities, seizures, speech and hearing difficulties, reduced sensations in extremities, repeat ear and respiratory infections, unique facial features, and behavioral and psychiatric challenges. Beta-mannosidosis is caused by changes (variants or mutations) in the MANBA gene and is typically inherited in an autosomal recessive pattern.
The signs and symptoms, progression and severity of beta-mannosidosis vary widely among affected individuals. Individuals may develop signs and symptoms between infancy and adulthood. It is important to note that every individual is unique and how the disorder affects one person can be different from how it affects another.
Degrees of developmental features are present in most individuals affected by beta-mannosidosis. A child’s progression through predictable developmental phases may be slowed, stopped or reversed (developmental delays). Global developmental delays, where more than one developmental area is affected, may be present. Most affected individuals experience intellectual delays ranging from mild to severe that can lead to intellectual disabilities. Some individuals may experience muscle function (motor) delays that can cause difficulty coordinating muscle movements needed to complete tasks. Speech development may be affected, leading to speech impairments.
Many individuals affected by beta-mannosidosis have altered muscle tone which can affect motor developmental milestones. Low muscle tone (hypotonia) is common and can contribute to difficulties with speech and swallowing, which can lead to feeding difficulties. Underdeveloped or incompletely developed muscles (hypoplasia) of the abdominal wall can cause the belly to appear bloated.
Nervous system features can include recurring seizures, hearing impairments or pain and reduced sensation in the extremities (peripheral neuropathy).
Immune dysfunction can occur in individuals affected by beta-mannosidosis leading to frequent and recurrent bacterial respiratory and ear infections.
Facial differences and skin anomalies can often be present. Affected individuals may have a different facial shape and coarse facial features are common. Occasionally, small, dark red spots may appear on the skin (angiokeratomas) formed from enlarged blood vessels.
Some individuals affected by beta-mannosidosis experience behavioral or psychiatric issues, including being extremely shy or being prone to depression, hyperactivity or impulsive or aggressive behavior.
Brain imaging findings
Limited information is available on brain MRI findings in people with beta-mannosidosis. A one-year-old male was reported to have mild-to-moderate cerebral hypomyelination on a brain MRI. A repeat MRI at age 4 years, 3 months of age redemonstrated poor myelination with hyperintensities in the white matter of the brain (Lund, et al 2019).
Beta-mannosidosis is caused by changes (variants or mutations) in the MANBA gene. The MANBA gene contains instructions for creating a type of protein (enzyme) called beta-mannosidase. Inside cells throughout the body are specialized compartments called lysosomes that contain enzymes to break down (metabolize) and recycle materials to support normal body functions. One type of material is glycoproteins that are composed of chains of sugar molecules (oligosaccharides). During metabolism, the chain is taken apart by separating the sugar molecules. Beta-mannosidase helps this process in certain oligosaccharides that contain a particular sugar molecule called mannose. The enzyme’s function is to specifically separate mannose from its neighboring sugar molecule and help break down the chain.
Individuals affected by beta-mannosidosis have a variant of the MANBA gene that causes insufficient beta-mannosidase enzyme activity. Mannose-containing oligosaccharides cannot be completely metabolized and instead abnormally accumulate in the cell. This progressive accumulation can cause toxicity in the cell and leads to the dysfunction of various tissues and organs of the body.
Beta-mannosidosis is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Beta-mannosidosis affects females and males in equal numbers. The exact number of people who have this disorder is unknown. Beta-mannosidosis may often go misdiagnosed or undiagnosed, especially in individuals with mild or non-specific symptoms, making it difficult to determine its true frequency in the general population. As of May 2023, the International Society for Mannosidosis and Related Diseases estimates approximately 20 individuals in the world are reported to be affected.
A diagnosis of beta-mannosidosis is based on characteristic clinical features, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A blood test to measure beta-mannosidase enzyme activity in blood plasma or white blood cells (leukocytes) can reveal less activity than expected. A urine test (urinalysis) can show a higher amount of mannose-containing oligosaccharides in the urine. A diagnosis of beta-mannosidosis can be confirmed with molecular genetic testing.
Molecular genetic testing can detect variants in the MANBA gene but is available only as a diagnostic service at specialized laboratories. More recently, the MANBA gene has been added to some molecular genetic test panels for lysosomal storage disorders. These panels examine genes found throughout the genome that have known associations with lysosomal storage disorders. A blood or saliva sample can be used for this testing. This more targeted approach means the test can be less expensive. However, if no variant is found using this targeted approach, a molecular genetic test called whole exome sequencing (WES) might be recommended, either in the patient only or as a trio test including the parents. WES examines the parts of genes that provide instructions to create proteins called exons and evaluates all the exons (exome) at the same time. WES can detect variants in the MANBA gene that may have gone undetected by the panel test but also identifies variants in other genes that cause similar clinical features.
The treatment of beta-mannosidosis is directed toward the specific clinical features that are present. Coordinated efforts of a team of specialists can help tailor treatments to prevent and alleviate the unique signs and symptoms of an affected individual.
Healthcare professionals that may be part of the care team can include pediatricians and physicians who specialize in diagnosing and treating neurological disorders (neurologists) and hearing disorders (otolaryngology, ENT). Feeding and swallowing issues can be addressed by physical medicine and rehabilitation therapists. Muscle strengthening and motor function improvements can be managed by physical and occupational therapy. Speech therapy may be required. Special services for children with hearing loss and prescription hearing aids can be helpful.
Proactive monitoring for respiratory or ear infections can lead to prompt administration of antibiotic medications for bacterial infection. Seizures may also be alleviated by medications.
Behavioral issues can be addressed by a developmental pediatrician and psychiatric concerns can be treated by a psychiatrist or psychologist.
Early intervention is important to ensure that individuals with beta-mannosidosis reach their highest potential. Individualized learning plans (IEP) and 504 plans that are updated regularly can help develop specialized learning programs.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is also often recommended.
Umbilical cord blood transplantation has been studied in beta-mannosidosis. Blood stem cells from a donor with a functional MANBA gene were given to an individual with early-onset beta-mannosidosis. At 2-years post-transplant, enzyme activity levels increased and mannose-containing oligosaccharides in the urine decreased; however, improvements in clinical features were more modest.
Bone marrow transplantation is under investigation for the treatment of other lysosomal storage disorders to deliver a functional MANBA gene. Researchers acknowledge that early diagnosis and prompt treatment with a bone marrow transplant increases the chances of improving symptoms and preventing cognitive decline. Advancements in bone marrow transplants for other lysosomal storage disorders may inform future therapeutic interventions in beta-mannosidosis. However, transplants are not without drawbacks. The procedure carries the risk of serious complications including graft-versus-host disease and other long-term and late effects. More research is necessary to determine the long-term safety and effectiveness of this potential therapy.
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
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Alshoraim MA and Al Agili DE. Oral manifestation and dental treatment of pediatric patient with beta-mannosidosis: A case report. SAGE Open Med Case Rep. 2021;9:2050313X211065796. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8679027/
Lund TC, Miller WP, Eisengart JB, et al. Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood‐onset beta‐mannosidosis. Mol Genet Genomic Med. 2019;7(7):e00712. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625138/
Bedilu R, Nummy KA, Cooper A, et al. Variable clinical presentation of lysosomal β-mannosidosis in patients with null mutations. Molec Genet Metab. 2002;77(4):282-290. https://www.sciencedirect.com/science/article/abs/pii/S1096719202001725?via%3Dihub
Michalski JC, Klein A, et al. Glycoprotein lysosomal storage disorders: α- and β-mannosidosis, fucosidosis and α-N-acetylgalactosaminidase deficiency. Biocchim Biophys Acta. 1999;1455(2-3):69-84. https://www.sciencedirect.com/science/article/pii/S0925443999000770
Alkhayat AH, Kraemer SA, Leipprandt JR, et al. Human β-Mannosidase cDNA Characterization and First Identification of a Mutation Associated with Human β-Mannosidosis. Hum Molec Genet. 1998;7:75-83. https://academic.oup.com/hmg/article/7/1/75/640017
Cooper A, Hatton C, Thornley M et al. Human β-mannosidase deficiency: Biochemical findings in plasma, fibroblasts, white cells and urine. Inherit Metab Dis. 1988;11:17-29. https://onlinelibrary.wiley.com/doi/abs/10.1007/BF01800054?sid=nlm%3Apubmed
Beta-Mannosidosis. International Society for Mannosidosis & Related Diseases. https://www.ismrd.org/glycoprotein-diseases/beta-mannosidosis/ Accessed Sept 25, 2023.
Beta-mannosidosis. Medline Plus. Last Update: Feb 1, 2023. Available at: https://medlineplus.gov/genetics/condition/beta-mannosidosis/ Accessed Sept 25,2023.
MANBA gene. Medline Plus. Last Update: Feb 1, 2023. Available at: https://medlineplus.gov/genetics/condition/beta-mannosidosis/ Accessed Sept 25, 2023.
Mannosidosis, beta A. Online Mendelian Inheritance in Man (OMIM) Entry No: 248510; Last Update:7/18/2012. Available at: https://omim.org/entry/248510 Accessed Sept 25, 2023.
Mannosidosis, beta A, lysosomal. Genetic and Rare Diseases Information Center. Last Update: 02/2023. Available at: https://rarediseases.info.nih.gov/diseases/869/mannosidosis-beta-a-lysosomal Accessed Sept 25, 2023.
Beta-mannosidosis. Boston Children’s Hospital. Available at: https://www.childrenshospital.org/conditions/beta-mannosidosis Accessed Sept 25, 2023.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/
Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/
This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/