Also known as VMA21 deficiency with liver disease
VMA21-CDG is an extremely rare inherited condition that has only very recently been reported to cause CDG. There are only three individuals with VMA21-CDG that have been published in the medical literature so far.
The main symptoms that have been described are fatty liver disease (steatohepatitis) with chronic elevation of liver transaminases (called ALT and AST) and mild hyperlipidemia (an increase in total blood cholesterol, specifically LDL cholesterol). Mild signs of cholestasis (impaired bile flow from the liver) are possible, including elevated GGT (gamma‐glutamyltransferase) and ALP (alkaline phosphatase). Other laboratory abnormalities that have been found are low serum ceruloplasmin and copper, mildly elevated creatine kinase, neutropenia and coagulation abnormalities. Hypoglycemia (low blood sugar) can also be a presenting symptom for this disease and patients are advised to monitor their blood glucose levels and consult a metabolic dietitian to adjust their diet to prevent episodes of low blood sugar. Abnormal facial features have been reported in two of the three known patients, other features were macrocephaly, feeding difficulties, mild hypotonia and multiple congenital anomalies, including hearing loss, ocular keratitis (inflammation of the outer layer of the eyes), as well as kidney and ureteral abnormalities. Unlike many patients with other forms of CDG, the reported patients with VMA21-CDG have normal neurological and cognitive functions.
Notably, until 2020, mutations in VMA21 have only been linked to XMEA (X‐linked myopathy with excessive autophagy), which is not associated with a glycosylation defect and predominantly results in muscle weakness and fatigue. However, a subgroup of patients with XMEA also presented with liver symptoms, ranging from increased liver aminotransferases to fatal liver failure.
Disorders with mutations in VMA21 are X-linked inherited disorders. This means that affected individuals have one faulty copy of the VMA21-gene, which is located on the X chromosome. The disease can be passed on from the mother to the children or can also be caused by a new genetic mutation in an affected individual.
Diagnostic testing relies on genetic testing of the V‐ATPase assembly factors and screening for CDG. Transferrin isoelectric focusing, a common screening test for CDG done in the patient’s blood, shows abnormal transferrin glycosylation (but notably, is normal in patients with XMEA). Additionally, biopsies of the liver can provide more information about the grade of liver involvement and consolidate the diagnosis. Typically, a liver sample will show the presence of fatty liver disease with enlarged structures in the liver cells that store excessive amounts of fat (lipid droplet‐containing autolysosomes). Studies on cultured skin fibroblasts, which can be attained via a skin biopsy of affected patients, have been reported to show signs of altered lipid turnover with accumulation of fat (particularly triglycerides and cholesterol) within the cells.
Treatment and Prognosis
To date, there are no known specific treatment options for VMA21-CDG. Treatment is aimed at the management of symptoms and the prevention of complications (for example, the prevention and treatment of hypoglycemic episodes). Long-term prognosis is difficult to predict due to the low number of known affected individuals. The three patients with VMA21-CDG that have been published in the medical literature in 2020 were 35, 26 and 9 years old.