Congenital Disorder of Glycosylation Type 1a (PMM2-CDG) is a rare genetic condition stemming from mutations in the PMM2 gene. This genetic alteration results in insufficient phosphomannomutase 2 (PMM2) activity, crucial in the complex glycosylation process. Glycosylation involves attaching sugar molecules to proteins and lipids, a process vital for properly functioning various proteins within the body. It is estimated that this disorder has a frequency in the general population of between 1 case per 50.000-100.000 individuals.
Congenital disorder of glycosylation type 1a genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Individuals with PMM2-CDG often exhibit a spectrum of clinical symptoms, showcasing the variability and complexity of the disorder. These symptoms may manifest in infancy, but the onset, severity, and specific features can vary widely.
Neurological abnormalities are common, leading to developmental delay, intellectual disability, hypotonia (low muscle tone), and ataxia (lack of coordination). Seizures may also be a part of the clinical presentation. Beyond the neurological domain, PMM2-CDG can affect other organ systems, potentially leading to issues such as liver dysfunction, coagulation abnormalities, and eye involvement.
Gastrointestinal symptoms are frequently observed, including feeding difficulties and failure to thrive. Some affected individuals may display subtle dysmorphic facial features.
Three groups are distinguished according to the clinical severity of the symptoms: the infantile form, the late infantile form, and the adult form. The infantile form is the most severe and develops after birth, in which axial hypotonicity, hyporeflexia, strabismus, and developmental delay are observed. Symptoms can be very intense, and there are cases with severe neurological damage in which patients do not survive more than one year. Cerebellar hypoplasia, hepatomegaly, and retinitis pigmentosa may occur.
In the late infantile form (onset between 3-10 years of age), hypotonia, ataxia, delayed motor and language development, seizures, retinitis pigmentosa, and skeletal abnormalities occur.
Symptoms that develop in adult form are usually less severe; peripheral neuropathy and retinitis pigmentosa occur. Skeletal alterations and premature aging, defects in the development of the gonads such as hypogonadism, and increased risk of deep vein thrombosis have also been observed.
PMM2-CDG is inherited in an autosomal recessive manner, requiring both parents to carry a mutated PMM2 gene for a child to be affected. Genetic testing is instrumental in diagnosing PMM2-CDG, involving the identification of mutations in the PMM2 gene. Additionally, laboratory analysis of glycosylation patterns in blood samples may contribute to the diagnostic process.
Currently, there is no cure for PMM2-CDG. Management is primarily supportive, focusing on addressing specific symptoms and complications. Multidisciplinary care, including physical and occupational therapy, is often recommended to enhance the quality of life for affected individuals.
Genetic counseling is a crucial component for families impacted by PMM2-CDG. It provides valuable insights into the inheritance pattern, facilitates understanding of the condition's implications, and assists in assessing the risk for future generations. Research continues to deepen our understanding of PMM2-CDG, offering hope for improved therapeutic approaches in the future. Early diagnosis and comprehensive medical care remain essential for optimizing outcomes in individuals with this rare genetic disorder.
The ancestry population's three most common pathogenic variants are c.422G>A, c.338C>T, and c.357C>A. The c.422G>A variant (p.Arg141His) is found in approximately 40% of individuals in the compound heterozygous state. It has not been observed in homozygosis because it is estimated to be lethal. This mutation is associated with a severe phenotype. Functional studies indicate that the enzyme's activity is null, which supports the idea that in homozygosis, it is lethal early in development.
The c.338C>T (p.Pro113Leu) mutation is common throughout Europe and has been found in both homozygosis and compound heterozygosis. It consists of a highly conserved amino acid substitution for which functional studies show a residual activity of 19-43% relative to regular enzyme activity.
The c.357C>A (p.Phe119Leu) mutation is frequently found in Northern Europe, where the c.422G>A + c.357C>A genotype constitutes the majority of pathogenic variants.
The genetic test of Congenital Disorder of Glycosylation Type 1a (PMM2-CDG) analyzes the 15 most frequent pathogenic mutations of the PMM2 gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).
