Effective treatment of α-mannosidosis by allogeneic hematopoietic stem cell transplantation

doi:10.1016/j.jpeds.2004.01.025

The Journal of Pediatrics

Volume 144, Issue 5, May 2004, Pages 569-573

https://doi.org/10.1016/j.jpeds.2004.01.025 Get rights and content

Abstract

Objectives

To study the efficacy of hematopoietic stem cell transplantation (HCT) for ameliorating the clinical manifestations of α-mannosidosis.

Study design

Four patients with α-mannosidosis underwent allogeneic HCT at the University of Minnesota. Diagnosis was established by assay of leukocyte α-mannosidase activity level. Physical features, donor engraftment, leukocyte α-mannosidase activity, neuropsychologic function, and hearing were monitored before and after transplantation, with follow-up ranging from 1 to 6 years.

Results

All 4 patients showed slowing of their neurocognitive development and sensorineural hearing loss before HCT. All patients are alive, with normalization of leukocyte enzyme activity after HCT. Intellectual function has stabilized, with improvement in adaptive skills and verbal memory function in 3 of 4 patients. Hearing has improved to normal or near normal for speech frequencies in 3 patients. No new skeletal abnormalities have developed.

Conclusions

HCT can halt the progressive cognitive loss in patients with α-mannosidosis. Early diagnosis and treatment with HCT is critical for optimal results.

Section snippets

Patients

This study includes all 4 patients with α-mannosidosis transplanted at the University of Minnesota. These transplants were performed between January 1997 and October 2002, with follow-up through October 2003. Diagnosis was confirmed by measurement of leukocyte acid α-mannosidase. Clinical features before HCT are summarized in Table I.

Conditioning regimen and donor grafts

The conditioning regimen consisted of one of the following (1) Bu/Cy/ATG/TBI: 320 mg/m² busulfan PO, 120 mg/kg cyclophosphamide IV, 60 mg/kg antithymocyte globulin

Results

After HCT, all 4 patients are alive with follow-up after HCT at 6 years, 6 years, 4 years, and 1 year, respectively. All four patients show complete donor-derived engraftment and normalization of leukocyte α-mannosidase activity (>170 nmol/h per milligram of protein) for the duration of follow-up. All patients had acute GVHD, and patient 3 also had chronic GVHD.

Discussion

HCT has been effective therapy to prevent neurocognitive decline and ensure long-term survival in selected inherited metabolic storage disorders.7., 10. Benefits stem from enzyme-replete donor cells repopulating various host tissues and adoptively transferring enzyme to nearby enzyme-deficient host cells.¹⁴ The neuronal benefits are consequent to the migration of donor-derived cells to the central nervous system of the recipient.¹⁰ Patients with α-mannosidosis, including those with the type II

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Hearing loss in inherited metabolic disorders: A systematic review
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Therapy strategies include ERT and bone marrow transplantation. ERT appears to be more appropriate for improving biochemical and functional parameters [78], while bone marrow transplant may permit improved hearing, possibly due the reduction of serous otitis [79]. β-Mannosidosis (OMIM #248510) is an AR lysosomal storage disorder linked to β-mannosidase activity deficiency.
Inherited metabolic disorders (IMDs) have been observed in individuals with hearing loss (HL), but IMDs are rarely the cause of syndromic HL. With early diagnosis, management of HL is more effective and cortical reorganization is possible with hearing aids or cochlear implants. This review describes relationships between IMDs and HL in terms of incidence, etiology of HL, pathophysiology, and treatment. Forty types of IMDs are described in the literature, mainly in case reports. Management and prognosis are noted where existing. We also describe IMDs with HL given age of occurrence of HL. Reviewing the main IMDs that are associated with HL may provide an additional clinical tool with which to better diagnose syndromic HL.
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Treatment options for alpha-mannosidosis are limited. Allogeneic hematopoietic stem cell transplantation (HSCT) has been used to preserve neurocognitive function, improve general status, and prevent early death [10–12], although a better understanding of HSCT timing and regimens as well as impact on outcomes is needed [10,13]. Enzyme replacement therapy (ERT) with a recombinant human alpha-mannosidase (velmanase alfa) is scheduled for clinical development in the US beginning in 2020 and has been approved in the EU for treatment of non-neurological manifestations in individuals with mild to moderate disease.
Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder resulting from deficient lysosomal alpha-mannosidase activity. Clinical manifestations include progressive balance disorders, immune deficiency, skeletal abnormalities and cognitive deficits beginning in early childhood. Enzyme replacement therapy with recombinant human alpha-mannosidase (velmanase alfa) is scheduled for clinical development in the US beginning in 2020 and has been approved in the EU for treatment of non-neurological manifestations in cases of mild to moderate disease. This study assessed effects of velmanase alfa on fine and gross motor proficiency in children and adults.
Integrated Bruininks-Oseretsky (BOT-2) test of Motor Proficiency data from velmanase alfa clinical trials was stratified by age for 14 adults and 19 children treated for up to 4 years.
Patients showed global developmental delays at baseline. For the combined adult and pediatric group there was a statistically significant increase (improvement) in BOT-2 total point score of 13% (p = .035, 95% CI 1.0, 25.0) from baseline to last observation. When stratified by pediatric versus adult patients, there was improvement in BOT-2 total point score in patients <18 years (mean percent increase from baseline to last observation 23%) compared to adults (mean decrease of −0.7%). Subtest analysis of individual BOT-2 items captured some improvement following velmanase alfa treatment in pediatric patients.
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Thus, produced enzyme will be taken up by mannose-6-phosphate receptors on the cells, endocytosed, and delivered to the lysosome showing the normalized function. LSDs like MPS I, MPS II, MPS III, MPS VI, MPS VII, GLD/Krabbe disease, MLD, Wolman's disease, Mucolipidosis type II (I-cell disease), α-Mannosidosis, Fucosidosis, Niemann–Pick type A and B, Gaucher's disease, ceroid-lipofuscinosis neuronal 3 (CLN3)/Batten disease, Fabry disease, Sandhoff disease, and aspartylglucosaminuria (Grewal et al., 2004; Krivit, 2004; Ringdén et al., 2006) were treated with HSCT and showed some progressive reports. The major drawback in HSCT is its high morbidity, mortality, and graft failure.
Lysosomal storage disorders (LSDs) are a collection of inborn errors of metabolic disorders affected by mutations in lysosome functional genes, commonly acid hydrolases. From the past decades, many approaches like enzyme replacement therapy, substrate reduction therapy are followed to treat these conditions. However, all these approaches have their own limitations. Proof-of-concept studies on pharmacological chaperone therapy (PCT) is now transformed into clinical practice to treat LSDs. Furthermore, it is narrowed with individuals to chaperone sensitive, specific mutations. Hence, personalizing the PCT will be a new direction to combat LSDs. In this review, we have discussed the available clinical strategies and pointed the light on how pharmacological chaperones can be personalized and hopeful to be a next-generation approach to address LSDs.
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^☆: Supplementary data associated with this article can be found at doi:10.1016/j.jpeds.2004.01.025

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Original ArticlesEffective treatment of α-mannosidosis by allogeneic hematopoietic stem cell transplantation☆

Abstract

Objectives

Study design

Results

Conclusions

Section snippets

Patients

Conditioning regimen and donor grafts

Results

Discussion

Am J Med

Lancet

Blood

J Pediatr

Disorders of glycoprotein degradation: alpha-mannosidosis, beta-mannosidosis, fucosidosis, and sialidosis

The clinical course of mannosidosis

Ann Clin Res

Mannosidosis

Screening for lysosomal disorders

Bone marrow transplantation for globoid cell leukodystrophy, adrenoleukodystrophy, metachromatic leukodystrophy, and Hurler syndrome

Curr Opin Hematol

Original Articles
Effective treatment of α-mannosidosis by allogeneic hematopoietic stem cell transplantation☆