ABSTRACT
BACKGROUND: Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment. METHODS: This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7-17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF. RESULTS: Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6% (CI -92.0 -85.2, p < 0.001), 54.1% (CI -69.5- -38.7, p < 0,001), and 25.7% (CI -44.3- -7.1, p < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15%, p < 0.009) and 32.5, p < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p < 0.01) and in 6MWT (60.4 m (CI -8.9 -51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI -0.2-0.8, NS). CONCLUSIONS: These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.
Subject(s)
Enzyme Replacement Therapy , alpha-Mannosidase/administration & dosage , alpha-Mannosidosis/drug therapy , Adolescent , Child , Cognition/drug effects , Dose-Response Relationship, Drug , Enzyme Replacement Therapy/adverse effects , Enzyme Replacement Therapy/methods , Exercise Test , Follow-Up Studies , Humans , Psychomotor Performance/drug effects , Recombinant Proteins/administration & dosage , Recombinant Proteins/adverse effects , Recombinant Proteins/immunology , Recombinant Proteins/pharmacokinetics , Treatment Outcome , alpha-Mannosidase/adverse effects , alpha-Mannosidase/immunology , alpha-Mannosidase/pharmacokineticsABSTRACT
Adult leukoencephalopathy caused by alpha-mannosidosis deficiency (MIM248500) is a recessive inherited lysosomal storage disease associated with decreased activity of alpha-mannosidase. This enzyme degrades oligosaccharides and glycoproteins in neural and visceral tissues. There are two different disease phenotypes, type-I or severe infantile phenotype and type 2, which progresses more slowly and is compatible with survival into adulthood. We report the case of a 51-year-old man with gait disorders beginning at the age of 40 years associated with leukoencephalopathy due to alpha-mannosidosis deficiency.
Subject(s)
Cerebrovascular Disorders/etiology , alpha-Mannosidosis/diagnosis , Brain/pathology , Gait Disorders, Neurologic/etiology , Humans , Magnetic Resonance Imaging , Male , Middle AgedABSTRACT
Single nucleotide polymorphisms in protein coding regions (cSNPs) are of great interest for their effects on phenotype and potential for mapping disease genes. We have identified 5,400 novel exonic SNPs from alignments of public EST data to the draft human genome sequence, and approximately 12,000 more novel exonic SNPs from EST cluster alignments. We found 82% of the genomic-aligned SNPs and 63% of the EST-only SNPs to be detectably polymorphic in 20 Finnish DNA samples. 37% of the SNPs mapped to known protein coding regions, yielding 6,500 distinct, novel cSNPs from the two datasets. These data reveal selection against mutations that alter protein structure, and distinct classes of genes under strongly positive vs. negative pressure from natural selection for amino acid replacement (detected by K(A)/K(S)ratio). We have searched these cSNPs for compatibility with the amino acid profile at each site and structural impact on protein core stability.
