Retrospective Study of Clinical and Genetic Profiles of Alpha-Mannosidosis Patients From the UAE
Ali K Saad1, Tasneem Al-Hammadi1, Shaikha Al-Ameri1
1Department of Genetics and Genomics College of Medicine and Health Sciences Al Ain UAE.
Abstract:
Alpha-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.
Insights
Alpha-mannosidosis (AM) is a rare genetic disorder affecting children and adults. This study highlights a high birth prevalence in the UAE, emphasizing the need for genetic counseling and early diagnosis.
Area of Science:
- Genetics
- Biochemistry
- Pediatrics
Background:
- Alpha-mannosidosis (AM) is a rare autosomal recessive lysosomal storage disorder.
- It is caused by mutations in the MAN2B1 gene, leading to deficient lysosomal alpha-mannosidase (LAMAN) activity.
- Clinical features include developmental delay, hearing impairment, and recurrent infections.
Purpose of the Study:
- To analyze the clinical characteristics and genetic mutations of Alpha-mannosidosis in consanguineous families in the UAE.
- To investigate the prevalence and diagnostic delay of AM in the region.
- To evaluate treatment outcomes for AM patients.
Main Methods:
- Retrospective analysis of nine case series of patients with AM.
- Genetic analysis to identify mutations in the MAN2B1 gene.
- Review of clinical data, including onset, symptoms, diagnosis, and treatment.
Main Results:
- Identified homozygous nonsense and splicing mutations in MAN2B1 in Emirati and Syrian families.
- Common clinical features observed were coarse facies, developmental delays, hearing loss, and recurrent infections.
- Significant diagnostic delay was noted, with a mean age of 14 years for adults and 2 years for pediatric patients.
Conclusions:
- High birth prevalence of AM in the UAE necessitates increased awareness and genetic counseling.
- Truncating mutations in MAN2B1 are associated with early-onset AM with variable clinical presentations.
- Enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) showed potential benefits in managing AM symptoms.
