Retrospective Study of Clinical and Genetic Profiles of Alpha‐Mannosidosis Patients From the UAE

ABSTRACTAlpha‐mannosidosis (AM; OMIM 248500) is a rare autosomal recessive lysosomal storage disorder caused by mutations in MAN2B1, which codes for the lysosomal alpha‐mannosidase enzyme (LAMAN; EC:3.2.1.24). Clinical characteristics include developmental delay, hearing impairment, and recurrent infections. A retrospective analysis of nine case series of patients with AM (23 months–42 years) from six consanguineous families in the United Arab Emirates (UAE) was conducted. In two Emirati families, homozygous nonsense mutations were present: c.2368C> T, p.(Gln790*) and c.2119C> T, p.(Gln707*). Further, in the Emirati and Syrian families two splicing variants c.2356‐2A>G and c.1929‐2A>G were present, respectively. All patients had infantile‐onset and common clinical features, including coarse facies, developmental delays, hearing loss, and recurrent infections. Macrocephaly was observed in all patients with documented head circumference, except one microcephalic patient who had a dual genetic diagnosis. Hepatosplenomegaly and autoimmune diseases were reported in one and three patients, respectively. Additionally, psychiatric manifestations were noted in two adult patients. The mean age of diagnosis was 14 years for adults (> 16 years) and 2 years for pediatric patients (< 16 years). Significant diagnostic delay comparing older and younger generations is likely due to the increasing awareness of genetic disorders and the availability of genetic testing. In terms of treatment, enzyme replacement therapy (ERT) was administered to two patients, alleviating recurrent infections. Two patients underwent hematopoietic stem cell transplantation (HSCT), whereas one patient underwent combined ERT and HSCT. This retrospective analysis identified different truncating mutations associated with early‐onset AM. The clinical presentations of these mutations range from attenuated to moderate. Our analysis clearly highlights the high birth prevalence of AM in the UAE, indicating the need for awareness and genetic counseling for prevention.