Also known as SSR4-deficiency; Deficiency of Signal Sequence Receptor Protein 4; Congenital Disorder of Glycosylation Iy
A rare, X-linked recessive, multisystemic, inherited condition, caused by an abnormal transport protein disrupting N-linked glycosylation. Symptoms manifest in infancy, including global developmental delay, intellectual disability, seizures, hypotonia (low muscle tone), failure to thrive, facial dysmorphism (abnormal difference in structure), connective tissue symptoms, and skeletal, gastrointestinal, and eye abnormalities.
SSR4-CDG is an extremely rare inherited condition that affects multiple parts of the body. The affected individuals often develop signs of the condition during infancy, and many show delayed growth even before birth (IUGR, intrauterine growth retardation). SSR4-CDG is a primarily neurologic disorder. Frequent and characteristic symptoms are developmental delay, intellectual disability, a decreased muscle tone (hypotonia), which is often already present at birth, and an abnormally small head (microcephaly). Seizures are possible, but appeared to be well treatable in the reported patients. Most patients had gastrointestinal abnormalities (reflux, vomiting), and feeding difficulties (often due to chewing problems and an aversion to foods with a certain texture) can lead to a failure to gain weight and growth delay (failure to thrive). The patients show distinct facial features and strabismus (eyes that do not look in the same direction) is a common feature. Some individuals have fat pads in unusual locations, skeletal abnormalities or connective tissue symptoms, like excessive skin, joint laxity, blue sclerae (the white outer layer of the eye is thinner than usual, so it appears blue) or arterial tortuosity (a “twisted” appearance of the blood vessels). Abnormalities of the heart (ductus arteriosus), the respiratory system (stridor) or the kidneys (“horseshoe kidney”) are possible. Brain imaging may show abnormalities, but is often normal.
Laboratory investigations may reveal abnormal coagulation factor activities, but notably, none of the laboratory abnormalities that are associated with many other CDGs have been seen in SSR4-CDG so far.
There are 13 individuals with SSR4-CDG that have been published in the medical literature so far.
Diagnostic testing relies on testing the appropriate glycosylation of common proteins (one commonly used glycoprotein is transferrin), which can be done by different methods in blood. Notably, the abnormalities seen in transferrin testing in SSR4-CDG are relatively mild compared to many other CDGs. Genetic testing is needed to confirm the diagnosis. Individuals with SSR4-CDG have one faulty copy of the SSR4-gene, which is on the X chromosome. It is often caused by a new genetic mutation in the affected individual, but can also be inherited.
Treatment and Prognosis
To date, there are no curative treatment options available for SSR4-CDG. Treatment is aimed at the management of symptoms and the prevention of complications, which is particularly relevant for the connective tissue symptoms to prevent unnecessary surgical interventions.
Long-term prognosis seems to be good, but is still difficult to predict due to the young age of the known individuals. The oldest patient with SSR4-CDG that has been published in the medical literature was 16 years old when his case was reported in 2014. We also know of an adult patient with SSR4-CDG who was 25 years old as of 2021.