Novel gene mutation is likely cause of newborn’s rare liver disease
Baby's diagnosis of PFIC5, a cholestasis type, is first reported in Tunisia
A novel mutation in the NR1H4 gene was the likely cause of progressive familial intrahepatic cholestasis (PFIC) type 5 in a baby girl in Tunisia, according to a case report that noted that fewer than 20 individuals have been diagnosed with this form of the disease to date.
At the age of 2 months, the infant showed signs of severe cholestasis, or slowed flow of the digestive fluid bile from the liver to the intestines. She also had high blood levels of alpha-fetoprotein, or AFP, a liver protein that can be a marker of liver damage and cancer.
Her blood levels of gamma-glutamyl transferase, known as GGT, were normal, however. GGT is a liver enzyme commonly used as a liver damage marker, but whose levels may be low or normal in PFIC.
“This is the first case of PFIC5 reported in Tunisia,” the researchers wrote, noting that “the diagnosis was made based on a molecular study.”
The team added that, while the disease is rare, “we emphasize that in [cases] of severe early onset of cholestasis with normal GGT and persistently elevated AFP, the diagnosis of PFIC type 5 should be considered.”
The case study, “Progressive familial intrahepatic cholestasis type 5 due to a novel mutation in the NR1H4 gene,” was published in the journal BMC Pediatrics.
PFIC, which typically manifests in infancy or early childhood, refers to a group of rare liver conditions caused by genetic mutations. It leads to defects in the production or transport of bile in the liver.
This results in the toxic accumulation of bile in the liver and its leakage into the bloodstream, leading to symptoms such as itching, dark urine, and jaundice, which is characterized by the yellowing of the skin and the whites of the eyes. Without treatment, PFIC can cause liver failure, where a liver transplant is the only therapeutic option.
Mutations in NR1H4 gene are the cause of PFIC type 5
PFIC type 5 (PFIC5) is caused by mutations in the NR1H4 gene, which encodes the farnesoid X receptor (FXR) protein. FXR is involved in maintaining balanced levels of bile acids, which are its main components.
A limited number of PFIC5 cases, 14 in all, had been previously reported in the literature, according to the researchers. Disease features are cholestasis shortly after birth, low to normal GGT levels in the blood, and elevated blood levels of bile acids and AFP.
In addition, some children with PFIC5 have shown early-onset blood clotting problems that are independent of vitamin K. Vitamin K is a fat-soluble vitamin essential for blood clotting whose absorption in the intestines is dependent on bile. As such, it is usually found at deficient levels in people with cholestasis.
In this report, a team led by researchers from Hedi Chaker University Hospital described the case of an infant girl who carried a new NR1H4 mutation that was likely the cause of her PFIC5.
The girl, who was born to blood-related parents, was admitted to the clinic due to persistent jaundice since the age of 2 days, and failure to thrive. On physical examination, she also had an enlarged spleen, dark urine, and pale stools.
Blood work showed high levels of several liver damage markers, including bile acids, AFP, bilirubin, and certain liver enzymes, but not GGT, whose levels were within the normal range.
Imaging scans showed some signs of severe liver damage, such as mild fluid accumulation in the abdomen, but there was no evidence of portal hypertension — high blood pressure in the blood vessel that carries blood from abdominal organs to the liver. The bile ducts, which transport bile, and the gallbladder, an organ where bile accumulates, were normal.
Genetic analysis revealed that the girl had inherited an extremely rare NR1H4 mutation, called c.762+1G>A, from both parents, resulting in two mutated copies of the NR1H4 gene. The gene variant was a splicing mutation, meaning it disrupts splicing, a natural process that can change the length and sequence of the resulting protein.
The mutation, which had not been previously described, was considered disease-causing, as “it is most likely responsible for an adverse effect on FXR function,” the researchers wrote.
UDCA, other treatments failed to improve baby’s condition
The girl was given UDCA, a first-line cholestasis treatment sold under the brand names Urso and Actigall, which helps restore the normal flow of bile. She also received fat-soluble vitamin K supplementation and a water pill to lessen fluid accumulation.
The child was also found to have an active cytomegalovirus infection that was transmitted from her mother during pregnancy, for which she received appropriate antiviral treatment.
However, at the age of 4 months, the girl continued to show signs of cholestasis and blood clotting problems that were independent of vitamin K.
A liver transplant was indicated, but her low weight and rapid worsening of her condition made it unfeasible. At the age of 6 months, the girl died due to liver failure and abnormal blood clotting through the body’s blood vessels.
The active cytomegalovirus infection, which can cause liver problems, “may be responsible for accelerating the liver cell failure in our case,” the researchers wrote.
Reported cases so far have shown that “patients with PFIC 5 had a significantly worse prognosis due to a more rapid progression,” the researchers wrote. “All patients without [liver transplant] died, and survival with a native liver has not been observed.”
About the Author
