Alpha-Mannosidosis: A Case Report on Diagnostic Challenges, Enzyme Replacement Therapy, and ongoing Hematopoietic Cell Transplantation
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Alpha-mannosidosis is an ultra-rare, autosomal recessive lysosomal storage disorder occurring in approximately 1 in 500,000 to 1,000,000 live births worldwide. It results from deficient activity of the enzyme alpha-mannosidase, leading to the accumulation of mannose-rich oligosaccharides within cells and affecting multiple organ systems. The condition is characterized by a wide range of clinical features, including progressive intellectual disability, skeletal abnormalities, immune deficiency, hearing impairment, and characteristic facial features. The rarity and broad phenotypic variability, coupled with the limited availability of discrete clinical symptoms and signs, have made identification and early diagnosis challenging.
Case Presentation
We present an 8-year-old male with a history of bilateral moderate to severe mixed hearing loss, recurrent ear infections, and three hospitalizations prior to age 3 due to upper respiratory infections. He was assessed for primary immune deficiency, revealing low platelet counts and low IgG levels. Additionally, he exhibits joint hypermobility and an umbilical hernia. He has global developmental delays, began walking at age 5, and experiences speech and cognitive delays, requiring assistance through an Individualized Education Program (IEP). Family history is significant for hearing loss in his paternal grandmother, great maternal aunt, and two second cousins. Physical examination revealed a broad forehead, mild midface hyperplasia, coarse facial appearance, pectus carinatum, and an umbilical hernia. There was reduced extension of the elbows, hyperextended knee joints, and flat feet.
Diagnostic Workup
Possible Marfan syndrome and lysosomal storage disorders (LSD) were considered, with LSD being more likely. Consequently, we ordered a lysosomal storage enzyme panel and genetic testing. MRI of the brain showed moderate thinning/volume loss of the posterior body of the corpus callosum. Abdominal ultrasound revealed mild enlargement of the liver and spleen. Echocardiography was normal. Genetic testing identified two pathogenic variants in the MAN2B1 gene: c.2248C>T (p.Arg750Trp) and c.418C>T (p.Arg140*), with parental studies confirming inheritance from both parents. Serum oligosaccharides were significantly elevated, and alpha-mannosidase activity was 1.66 nmol/hr/mg (normal range: 33.2–361.3). The diagnosis of alpha-mannosidosis was established.
Treatment and Management
In May 2024, we initiated enzyme replacement therapy (ERT) with Velmanase alfa (Lamzede), approved by the FDA on February 16, 2023. The patient received weekly infusions and tolerated them well without side effects.
Outcome and Follow-Up
After ERT, laboratory results showed no antibodies against Velmanase alfa, and serum oligosaccharide levels are pending. Notably, serum IgG levels increased from 450 mg/dL to 1,209 mg/dL (normal range: 600–1,400 mg/dL) after 5 months of ERT. The patient is currently undergoing hematopoietic cell transplantation (HCT).
Discussion
About 191 cases of alpha-mannosidosis have been reported worldwide, with clinical phenotypes varying widely and symptoms evolving slowly, leading to late diagnoses. The condition is divided into three types: Type I (mild form) recognized after 10 years of age; Type II (moderate form), the most common, recognized before 10 years of age; and Type III (severe form) with onset in early childhood. Our patient presents with Type II features, with additional Marfan-like features being unique. Long-term outcomes of Velmanase alfa treatment are still being elucidated but may include improvements in hearing, immunologic profile, and quality of life. Limited reports on bone marrow transplantation indicate some positive outcomes.
Conclusion
Early diagnosis of alpha-mannosidosis is challenging. Hearing loss with frequent infections, developmental delays, and coarse facial features should raise suspicion for rare LSDs. Early initiation of ERT may lead to better outcomes. Candidates meeting transplant criteria could be considered for bone marrow transplantation; however, more research is needed to determine long-term outcomes.
Alpha-mannosidosis is an ultra-rare, autosomal recessive lysosomal storage disorder occurring in approximately 1 in 500,000 to 1,000,000 live births worldwide. It results from deficient activity of the enzyme alpha-mannosidase, leading to the accumulation of mannose-rich oligosaccharides within cells and affecting multiple organ systems. The condition is characterized by a wide range of clinical features, including progressive intellectual disability, skeletal abnormalities, immune deficiency, hearing impairment, and characteristic facial features. The rarity and broad phenotypic variability, coupled with the limited availability of discrete clinical symptoms and signs, have made identification and early diagnosis challenging.
Case Presentation
We present an 8-year-old male with a history of bilateral moderate to severe mixed hearing loss, recurrent ear infections, and three hospitalizations prior to age 3 due to upper respiratory infections. He was assessed for primary immune deficiency, revealing low platelet counts and low IgG levels. Additionally, he exhibits joint hypermobility and an umbilical hernia. He has global developmental delays, began walking at age 5, and experiences speech and cognitive delays, requiring assistance through an Individualized Education Program (IEP). Family history is significant for hearing loss in his paternal grandmother, great maternal aunt, and two second cousins. Physical examination revealed a broad forehead, mild midface hyperplasia, coarse facial appearance, pectus carinatum, and an umbilical hernia. There was reduced extension of the elbows, hyperextended knee joints, and flat feet.
Diagnostic Workup
Possible Marfan syndrome and lysosomal storage disorders (LSD) were considered, with LSD being more likely. Consequently, we ordered a lysosomal storage enzyme panel and genetic testing. MRI of the brain showed moderate thinning/volume loss of the posterior body of the corpus callosum. Abdominal ultrasound revealed mild enlargement of the liver and spleen. Echocardiography was normal. Genetic testing identified two pathogenic variants in the MAN2B1 gene: c.2248C>T (p.Arg750Trp) and c.418C>T (p.Arg140*), with parental studies confirming inheritance from both parents. Serum oligosaccharides were significantly elevated, and alpha-mannosidase activity was 1.66 nmol/hr/mg (normal range: 33.2–361.3). The diagnosis of alpha-mannosidosis was established.
Treatment and Management
In May 2024, we initiated enzyme replacement therapy (ERT) with Velmanase alfa (Lamzede), approved by the FDA on February 16, 2023. The patient received weekly infusions and tolerated them well without side effects.
Outcome and Follow-Up
After ERT, laboratory results showed no antibodies against Velmanase alfa, and serum oligosaccharide levels are pending. Notably, serum IgG levels increased from 450 mg/dL to 1,209 mg/dL (normal range: 600–1,400 mg/dL) after 5 months of ERT. The patient is currently undergoing hematopoietic cell transplantation (HCT).
Discussion
About 191 cases of alpha-mannosidosis have been reported worldwide, with clinical phenotypes varying widely and symptoms evolving slowly, leading to late diagnoses. The condition is divided into three types: Type I (mild form) recognized after 10 years of age; Type II (moderate form), the most common, recognized before 10 years of age; and Type III (severe form) with onset in early childhood. Our patient presents with Type II features, with additional Marfan-like features being unique. Long-term outcomes of Velmanase alfa treatment are still being elucidated but may include improvements in hearing, immunologic profile, and quality of life. Limited reports on bone marrow transplantation indicate some positive outcomes.
Conclusion
Early diagnosis of alpha-mannosidosis is challenging. Hearing loss with frequent infections, developmental delays, and coarse facial features should raise suspicion for rare LSDs. Early initiation of ERT may lead to better outcomes. Candidates meeting transplant criteria could be considered for bone marrow transplantation; however, more research is needed to determine long-term outcomes.
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