beta-mannosidosis

Beta-mannosidosis is a very rare lysosomal storage disorder that interferes with how cells break down certain complex sugars, leading to multi-system effects that often begin in infancy or early childhood. The condition results from pathogenic variants in the MANBA gene, which provides instructions for the lysosomal enzyme beta-mannosidase. When this enzyme is deficient, partly processed sugars accumulate inside cells and disrupt normal organ function. Males and females are affected equally, and symptom severity ranges from mild learning challenges to significant neurological and physical complications. Precise prevalence figures are not available, but only a small number of families have been reported worldwide, underscoring its rarity.

Severity and symptoms vary widely between individuals, and not all experience every feature. Neurological and developmental features are often the first to raise concern. Most affected children have developmental delay or intellectual disability, and many caregivers notice hyperactivity or other behavioral differences. Seizures are common and may begin in childhood. As the disease progresses, some individuals develop demyelinating peripheral neuropathy that can cause weakness, numbness, or balance difficulties. Hearing involvement is another hallmark. Up to four out of five individuals have sensorineural hearing loss that can range from mild to profound and may require hearing aids or other interventions. Distinctive facial characteristics, such as a prominent forehead or flattened nasal bridge, are frequently reported, and some infants are born with a thin abdominal wall that can contribute to umbilical or inguinal hernias. Recurrent respiratory infections are also common, likely related to airway muscle weakness and immune challenges. Less commonly, additional neurological or systemic issues may appear later in life, reflecting the broad phenotypic heterogeneity of beta-mannosidosis.

Beta-mannosidosis is caused by biallelic (two-copy) pathogenic variants in the MANBA gene. The MANBA protein is the lysosomal enzyme beta-mannosidase, which normally cleaves mannose-containing sugars during the breakdown of complex molecules. Without adequate enzyme activity, these sugars accumulate and interfere with cell function in the brain, nerves, and other organs, explaining the cognitive, hearing, and multisystem findings. The condition is inherited in an autosomal recessive pattern. An individual must receive one altered MANBA copy from each parent to be affected. Parents who each carry a single pathogenic variant are typically healthy but, with every pregnancy, have a 25 percent chance of having an affected child and a 50 percent chance of having a carrier child. The condition is more likely to occur when parents share a common ancestor because they have a higher chance of carrying the same rare variant. Genetic counseling can clarify individual carrier risks, guide family planning, and discuss options such as carrier testing for relatives.

Currently, management focuses on supportive care and symptom management tailored to each person’s needs. A multidisciplinary care team often includes neurologists, developmental pediatricians, audiologists, speech and occupational therapists, and genetic counselors. Seizures are treated with standard antiepileptic medications, while behavioral therapies and individualized education plans address developmental and cognitive challenges. Hearing loss is managed with hearing aids or cochlear implantation when appropriate, and physical therapy can help maintain mobility and address peripheral neuropathy. Regular surveillance is an essential part of long-term care, helping to identify potential complications before they become serious. Suggested monitoring includes periodic hearing assessments, neurodevelopmental evaluations, and screening for respiratory or orthopedic issues such as hernias. Because no FDA-approved disease-modifying therapies exist yet, families are encouraged to discuss emerging clinical trials and supportive interventions with their specialists. Genetic counseling should be offered to all families to review inheritance, carrier testing, and reproductive options.

Outcomes depend on many factors, including the severity of enzyme deficiency, age at diagnosis, access to specialized care, and the specific manifestations present in each individual. Some people with milder forms attain independent living skills and only mild cognitive challenges, while others have more significant intellectual and physical disabilities that require lifelong support. Respiratory infections and seizure control can influence overall health, but with attentive monitoring and early interventions, many individuals achieve stable day-to-day functioning. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with expert centers, genetic counselors, and patient support organizations to stay informed about care strategies and research opportunities.

Clinical trials are underway exploring new treatment approaches, including strategies aimed at replacing or augmenting beta-mannosidase activity. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.