Also known as SLC39A8 deficiency; carbohydrate deficient glycoprotein syndrome type IIn; congenital disorder of glycosylation Type 2n; CDG syndrome type Iin
A rare, multisystemic, inherited condition, caused by an abnormal transport protein, leading to manganese deficiency and disruption of glycosylation. Symptoms manifest in infancy, including global and psychomotor developmental delays, cognitive impairment, seizures, muscle weakness, hypotonia (low muscle tone), dwarfism, hearing and vision loss, recurrent infections, and skeletal abnormalities.
Symptoms
SLC39A8-CDG is a rare and severe inherited autosomal recessive condition which affects many organ systems simultaneously. SLC39A8-CDG primarily affects the musculoskeletal and nervous systems. Classified as a developmental disorder, SLC39A8-CDG is caused by biallelic mutations in the SLC39A8 gene. SLC39A8 encodes a manganese transporter (ZIP8) that controls and directs manganese uptake into the cell, and mutations in this gene can lead to manganese deficiency. Manganese is an important cofactor for many enzymes, including those involved in glycosylation, and serves as an essential trace element, so, SLC39A8-CDG is classified as both a congenital disorder of glycosylation (CDG) and a disorder of trace element metabolism/manganese transport.
SLC39A8-CDG is characterized by delayed psychomotor development. Most SLC39A8-CDG patients develop symptoms of the disease during infancy. Patients typically exhibit global developmental delay, intellectual disability (ranging from mild to severe), weakness of the muscles and decreased muscle tone (hypotonia), seizures, short stature and limbs (dwarfism), hearing loss, and vision impairments. Other important clinical symptoms include premature closure of skull sutures (cranial synostoses with lacunar skull), a deformed skull shape, progressive deterioration of nerve cells in the cerebellum (cerebellar atrophy), recurrent infections, decreased bone tissue density/calcification, and inability to walk.
Overall, patients with SLC39A8-CDG can show a wide spectrum of diverse phenotypes due to the many ways that manganese is involved in human metabolism.
Brain imaging results of SLC39A8-CDG patients reveal cerebral and/or cerebellar atrophy.
Laboratory investigations typically show an abnormal serum transferrin isoelectric focusing pattern. Laboratory analyses also highlight decreased blood levels of manganese and zinc (with blood manganese levels often below the detection limit). However, recent studies have documented a unique ethnic mutation in Canada where patients presented with measurable levels of manganese. In such cases where manganese is present in the blood to a certain degree, patient outcomes are much more favorable and these patients tend to live longer than patients with very low blood manganese levels.
Diagnosis
SLC39A8-CDG can be diagnosed using a screening test for CDG called “transferrin isoelectric focusing”, which detects abnormal levels of a glycoprotein called transferrin in the blood in many patients (but not all). This analysis of blood transferrin levels is the current diagnostic standard for N-glycosylation disorders. An additional diagnostic tool for SLC39A8-CDG is the measurement of blood manganese levels. Genetic testing is needed to confirm the diagnosis.
Treatment and Prognosis
Currently, high-dose manganese therapy is an effective treatment available for SLC39A8 -CDG correcting clinical and biochemical abnormalities. Studies have shown that manganese therapy has resulted in complete restoration of enzyme dysfunctions and improvement in hearing, neurological, and motor abilities.
An additional treatment option for SLC39A8-CDG is oral galactose supplementation, which corrects the hypoglycosylation aspect of SLC39A8-CDG. Oral galactose supplementation has been proven to result in the normalization of glycosylation, including improvement of the abnormal transferrin isoform pattern characteristic of SLC39A8-CDG.
Most additional treatment of SLC39A8-CDG is aimed at easing and alleviating the symptoms experienced by the patient (“symptomatic” treatment) and at the prevention of future complications. Once molecular testing has confirmed the diagnosis, affected families have the option to pursue genetic counseling. Because SLC39A8-CDG is a disorder that affects many systems in the body simultaneously, management of SLC39A8-CDG is usually guided by a multidisciplinary medical team.
The oldest known patient is 26 years old and currently, there are 14 SLC39A8-CDG patients described in medical literature.