Clinical characteristics.

Beta-mannosidosis is characterized by developmental delay (speech is more significantly affected than motor skills), mild-to-severe intellectual disability, behavioral abnormalities, sensorineural hearing loss, recurrent infections, angiokeratomas, seizures, and ataxia. Most individuals have no dysmorphic features; some have mild coarseness.

Diagnosis/testing.

The diagnosis of beta-mannosidosis is established in a proband with suggestive findings and markedly reduced or absent beta-mannosidase activity in leukocytes, serum, or plasma. Enzyme testing is the gold standard for diagnosis. Identification of biallelic pathogenic variants in MANBA by molecular genetic testing can aid in assessment of recurrence risk for sibs of the proband.

Management.

Treatment of manifestations: Developmental and educational support; rehabilitation, physical therapy, and occupational therapy as needed for musculoskeletal manifestations; orthotic devices for progressive scoliosis or ataxia; hearing aids may be helpful; specific antimicrobial treatment for recurrent infections; feeding tube as needed; nutrition support; treatment of chronic diarrhea or constipation; standard treatments for seizures; ventriculoperitoneal shunt for hydrocephalus; transitional care plan for adult life; family and social work support.

Surveillance: At each visit assess developmental and educational needs, neurobehavioral and psychiatric issues, frequency of infections, growth, gastrointestinal manifestations, abnormal movements, head circumference, neurologic regression, and family and social work needs; annual audiology evaluation.

Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Genetic counseling.

Beta-mannosidosis is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a MANBA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the MANBA pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

Beta-mannosidosis should be suspected in probands with the following clinical, supportive laboratory, and imaging findings and family history.

Clinical findings

• Mild-to-severe developmental delay / intellectual disability
• Hypotonia, predominantly axial
• Behavioral manifestations, including self-injurious behavior, hyperactivity, and autistic features
• Hearing loss
• Recurrent infections
• Angiokeratomas
• Subtle dysmorphic facial features, including mild coarseness (e.g., thick lips, wide and/or depressed nasal bridge, prominent cheeks)

Supportive laboratory findings. Oligosacchariduria with the characteristic disaccharides mannosyl-β(1→4)-N-acetylglucosamine and sialyl-α(2→6)-mannosyl-β(1→4)-N-acetylglucosamine, and a third compound, sialyl-dimannosyl-di-N-acetylchitobiose, in the most severely affected individuals.

Imaging findings

• Brain MRI shows delayed myelination or hypomyelination.
• Skeletal survey is often normal.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of beta-mannosidosis is established in a proband with suggestive findings and markedly reduced or absent beta-mannosidase activity in leukocytes, serum, or plasma. Enzyme testing is the gold standard for diagnosis. Identification of biallelic pathogenic (or likely pathogenic) variants in MANBA by molecular genetic testing (see Table 1) can aid in assessment of recurrence risk for sibs of the proband.

Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic MANBA variants of uncertain significance (or of one known MANBA pathogenic variant and one MANBA variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Beta-mannosidosis is characterized by developmental delay and/or intellectual disability, behavioral abnormalities, hearing loss, angiokeratomas, seizures, and ataxia. To date, 46 individuals have been identified with biallelic pathogenic variants in MANBA [Martin Rios et al 2025]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay. The area of development most frequently affected is speech, even in individuals without hearing loss. Some individuals have normal developmental milestones in the first year, after which acquisition of new developmental skills begins to slow down. Other individuals have normal gross motor development with compromise of other areas. Three reported individuals had regression of milestones at different ages [Martin Rios et al 2025]. Delayed motor development is frequently associated with hypotonia, predominantly axial.

Intellectual disability can range from mild to severe.

Neurobehavioral/psychiatric manifestations. Behavioral and psychiatric disturbances include attention-deficit/hyperactivity disorder (ADHD), anxiety and/or depression [Levade et al 1994], Tourette syndrome [Sedel et al 2006], autistic features, hyperphagia, psychotic episodes, obsessive-compulsive-like behavior, and aggressiveness [Martin Rios et al 2025]. Pseudobulbar syndrome and abnormal sleep pattern have each been reported in one individual [Labauge et al 2009].

Hearing impairment. Sensorineural hearing loss is a very frequent finding, ranging from mild to profound. Even in the same family, affected members have different degrees of hearing loss [Safka Brozkova et al 2020].

Recurrent infections. Affected individuals can develop recurrent infections, mainly of respiratory and gastrointestinal origin. Two individuals died at age nine years and 20 years, both due to severe sepsis of respiratory origin [Kleijer et al 1990, He et al 2023]. Immunodeficiency was not confirmed in these individuals.

Skin. Approximately half of the reported individuals have angiokeratomas [Martin Rios et al 2025]. These lesions can appear at any age; however, they are not typically the first manifestation of beta-mannosidosis. Other rare skin findings, including pseudoxanthoma elasticum [Suzuki et al 2004], skin flushing [Blomqvist et al 2019], and erythromelalgia (episodic burning pain, redness, and warmth) [Martin Rios et al 2025], have each been reported in one individual.

Gastrointestinal. Up to 9.4% of affected individuals have feeding difficulties as a first manifestation [Martin Rios et al 2025]. Feeding difficulties can lead to poor weight gain and growth deficiency. Upper and lower gastrointestinal manifestations have been reported, including dysphagia, megaesophagus, gastroesophageal reflux, chronic abdominal pain, chronic diarrhea, and constipation.

Facial characteristics. Most individuals with beta-mannosidosis have no dysmorphic features. In those with dysmorphic features, mild coarseness is described (e.g., thick lips, wide and/or depressed nasal bridge, prominent cheeks). Two individuals [Kleijer et al 1990, Alshoraim & Al Agili 2021] have been reported with dysmorphic facial features including coarse face, hypertelorism, macroglossia, gingival hyperplasia, widely spaced teeth, short and depressed nasal bridge, prominent forehead, large ears, and rounded eyebrows. Additional findings in the eyes (epicanthal folds, long palpebral fissures, blepharophimosis, upslanted palpebral fissures), mouth and jaw (smooth philtrum, thin lips, microretrognathia), and increased posterior angulation of the ears have also been described (see Figure 1). Microcephaly or macrocephaly are rarely described.

Figure 1.

Phenotypic features of individuals with beta-mannosidosis A. Affected child does not have dysmorphic features.

Seizures can manifest at any age, and the semiology can vary between individuals, including absence, generalized tonic-clonic, and focal seizures. Severely affected individuals can present with epileptic encephalopathy or intractable epilepsy [Broomfield et al 2013].

Other neurologic manifestations include ataxia. One individual developed progressive ataxia at age 12 years [Labauge et al 2009]. Another individual developed ataxia and nystagmus six months after receiving an umbilical cord transplantation at age four years [Lund et al 2019]. This individual showed worsening of ataxia at age ten years, requiring orthoses and devices for mobilization [Martin Rios et al 2025]. A third individual with a mild phenotype was diagnosed at age 31 years, and at that time she had modest signs of ataxic gait and tremors of the upper limbs [Martin Rios et al 2025]. Peripheral neuropathy, spastic tetraparesis, and intention tremor are all rare features.

Brain imaging. Brain MRI can be normal in 60% of individuals [Martin Rios et al 2025]. In those with brain imaging abnormalities, the most common finding is delayed myelination before age two years, and hypomyelination in those age ≥2 years (see Figure 2) [Renaud 2023, Martin Rios et al 2025]. Hydrocephalus was described in one individual [Broomfield et al 2013].

Figure 2.

Brain MRI images from two individuals with beta-mannosidosis. A. Male age 4 years with abnormal mild T₂ hyperintensity in the periventricular and subcortical white matter (white arrow) corresponding to isointense T₁ signal, changes suggestive of hypomyelination. (more...)

Skeletal manifestations were reported in only two individuals [Kleijer et al 1990, Alshoraim & Al Agili 2021], including short stature, short neck, midface retrusion, thorax deformities, and lumbar hyperlordosis. On bone radiographs, broad ribs, pelvic asymmetry, spina bifida occulta, and severe scoliosis were found in one of these individuals [Kleijer et al 1990].

Ocular manifestations. Tortuosity of conjunctival vessels and strabismus have been described in individuals with beta-mannosidosis. Each of the following have been described in one individual: dry eyes, nystagmus, and optic nerve damage.

Other

• Precocious puberty
• Primary hypogonadism
• Ethanolaminuria
• Pulmonary cysts
• Urinary incontinence
• Kidney failure
• Cleft palate
• Intrauterine growth restriction

Prognosis. It is unknown whether life span is reduced in individuals with beta-mannosidosis. One reported individual was alive at age 51 years [Suzuki et al 2004], demonstrating that survival into adulthood is possible.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations have been identified.

Prevalence

Incidence of beta-mannosidosis is unknown. Reported prevalences are 0.13, 0.12, and 0.16 in 100,000 live births in the Netherlands, Portugal, and the Czech Republic, respectively.

A recurrent splice-site variant (c.2158-2A>G) has been described as a founder pathogenic variant in Roma populations from the Czech Republic, Slovakia, and Hungary [Schrauwen et al 2019, Safka Brozkova et al 2020].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with beta-mannosidosis, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. (Note: Some individuals with beta-mannosidosis may have normal intelligence and only mild hearing loss and/or angiokeratomas as manifestations, which may forestall diagnosis of beta-mannosidosis.) Evaluations include:

• Molecular genetic testing if the causative MANBA pathogenic variants have been identified in the proband;
• Beta-mannosidase enzyme activity assay in leukocytes. (Enzyme activity testing is the gold standard diagnostic test for beta-mannosidosis and is recommended for confirmation of the diagnosis if the causative MANBA pathogenic variants have not been confirmed in the proband.)

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Beta-mannosidosis is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are presumed to be heterozygous for a MANBA pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a MANBA pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a MANBA pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with beta-mannosidosis are obligate heterozygotes (carriers) for a pathogenic variant in MANBA. (Note: To date, individuals with beta-mannosidosis are not known to reproduce.)

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a MANBA pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the MANBA pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk sibs for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. A founder variant has been identified in Roma populations from the Czech Republic, Slovakia, and Hungary (see Prevalence).

Prenatal Testing and Preimplantation Genetic Testing

If the MANBA pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Beta-mannosidosis is a disorder of complex molecule degradation, caused by a deficiency of beta-mannosidase activity, which catalyzes the last step of N-glycoprotein degradation, cleaving mannosyl-β(1→4)-N-acetylglucosamine into mannose and N-acetylglucosamine [Thomas 2019]. Disease-causing variants result in severely reduced or absent enzyme activity, leading to the accumulation of mannosyl-β(1→4)-N-acetylglucosamine and intermediate species, including sialyl-α(2→6)-mannosyl-β(1→4)-N-acetylglucosamine and sialyl-dimannosyl-di-N-acetylchitobiose, identified in the urine in two severely affected individuals [Martin Rios et al 2025].

Mechanism of disease causation. Loss of function

Author Notes

Kimonis Lab

Acknowledgments

The authors thank The Lost Enzyme Project group for research support, and affected individuals and their families for their participation.

Revision History

• 19 May 2026 (sw) Review posted live
• 2 February 2026 (vk) Original submission

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