2026-01-22 | Unveiling alpha-mannosidosis in Iraqi children: A series of clinically and genetically characterized cases with novel MAN2B1 variant.
Alpha-mannosidosis is a rare lysosomal storage disorder caused by MAN2B1 mutations, leading to cognitive decline, hearing loss, infections, and skeletal abnormalities. Limited data exist from the Middle East; this study describes the clinical and genetic features of affected Iraqi children. This study was conducted at Children Welfare Teaching Hospital, and Al Emamayn Al Khadimiyan Medical City Baghdad, Iraq. We retrospectively reviewed children diagnosed with alpha-mannosidosis (2017-2025). Diagnosis was confirmed by enzyme assay and MAN2B1 testing. Clinical and imaging data were collected from medical records. A total of nine children from five unrelated families were identified. The cohort included seven males and two females. The mean age at symptoms onset was 1.1 ± 0.5 years, while the mean age at diagnosis was 10.7 ± 7.6 years, indicating a diagnostic delay of approximately 9.6 ± 7.4 years. All the patients were born to consanguineous parents. The most common clinical features included psychomotor delay, sensorineural hearing loss and coarse facial features (100 % for each). Neuroimaging of the brain revealed variable findings, and skeletal radiographs showed dysostosis multiplex in 4/9 patients. Genetic testing revealed three pathogenic/likely pathogenic MAN2B1 variants, including one novel variant [c.830C > T (p.Pro277Leu)]. Our findings represent the first clinical and molecular characterization of alpha-mannosidosis in Iraqi children and reveal previously unreported genetic features in this population. It highlights that clinical and laboratory findings in our patients were largely consistent with previously published regional and international data. It demonstrates notable diagnostic delay and identified novel variants, expanding the mutational spectrum associated with the disease.
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2025-09-02 | Effect of disease progression on CSF-directed AAV gene therapy in a large brain animal model of lysosomal storage disease.
The lysosomal storage disease alpha-mannosidosis (AMD) is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions in the brain and other tissues. Animal models of lysosomal diseases have demonstrated the benefit of early treatment; however, many human diagnoses occur after patients are symptomatic. We demonstrate here partial correction of the globally distributed storage lesions by infusion of a high dose of adeno-associated virus 1-feline alpha-mannosidase into the cerebrospinal fluid via the cisterna magna in the gyrencephalic AMD cat brain at different ages, corresponding with different stages of disease progression. Significant improvements in clinical parameters were observed, and partial correction was documented pre mortem by non-invasive magnetic resonance spectroscopy and diffusion tensor imaging. Post mortem analysis demonstrated that higher levels of lysosomal alpha-mannosidase activity in animals treated at 12 weeks of age did not translate into increased correction of lysosomal storage lesions throughout the brain when compared with animals treated at earlier time points. These results further demonstrate the importance of early detection and treatment of a lysosomal storage disease to successful outcomes.
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2025-08-08 | A Review on the Structure-function Relationship of Class II α-Mannsoidases
Of fundamental importance to every function an enzyme or a protein performs is its three-dimensional structure. The structure plays a crucial, though often subtle, role in catalysis. The conformational changes in enzymes are often small, and even these small changes could be significant. Glycosylation modifications of proteins and glycan hydrolysis are critical for protein function in biological processes. Aberrations in glycosylation enzymes are linked to lysosomal storage disorders (LSD), immune interactions, congenital disorders, and tumour progression. Alpha-Mannosidases Class 2B is a lysosomal hydrolase. Dysfunction of this has been implicated as a causative factor in mannosidosis, a lysosomal storage disorder characterized by cognitive impairment, hearing loss, and immune system and skeletal anomalies. Despite decades of research, its role in pathogenic infections, autoimmune conditions, cancers, and neurodegenerative pathologies is highly ambiguous. Although many Class II α-mannosidases have been reported from various sources but not many of them have been characterized structurally. Through the combined efforts of various types of spectroscopies and protein crystallography, structure-function relationship studies in some Class II α-mannosidases from various sources have been carried out, and the same has been reported. The structure of Class II α-mannosidases from different sources has revealed the involvement of various types of folding of the protein, the presence of metal ions such as Zn+ in the active site, and their role in substrate specificity and catalytic mechanism is reviewed here.
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