New NR1H4 mutation identified in baby girl with PFIC5

Mutation found in only one gene copy

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A new mutation in the NR1H4 gene was identified as the cause of progressive familial intrahepatic cholestasis type 5 (PFIC5) in a baby girl who rapidly progressed to liver failure, scientists in Taiwan reported.

It seemed to mark the second documented case of PFIC5 caused by a single mutated copy of the NR1H4 gene. Most of the few reports linking NR1H4 mutations and this condition to date have found that patients carried mutations in both NR1H4 gene copies.

“To determine whether a [single] mutation is sufficient to induce a rapid progression to liver failure or the mutation of [the other gene copy] may be beyond current detection methods, more studies are needed to clarify this issue,” the researchers wrote.

The case study, “NR1H4 mutation and rapid progressive intrahepatic cholestasis in infancy: A case report and literature review,” was published in Clinical Case Reports.

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Algorithm for genetic tests helps spot cause of newborn cholestasis

Mutations in the NR1H4 gene, which codes for a key regulator of bile acid metabolism, have been associated with several types of cholestasis, or slowing of the flow of bile, a digestive fluid made in the liver that flows out to the intestines. These include drug-induced cholestasis, intrahepatic cholestasis of pregnancy, and PFIC5.

Cholestasis can lead to the toxic accumulation of bile in the liver, which can ultimately result in liver failure.

PFIC5 belongs to a group of genetic disorders called progressive familial intrahepatic cholestasis (PFIC) that are characterized by impaired production and/or secretion of bile by liver cells that typically causes cholestasis in early childhood.

This type is marked by low to normal levels of gamma-glutamyl transferase (GGT), a marker of liver or bile duct disease; blood clotting problems that are resistant to vitamin K treatment; and rapid progression to liver failure.

Just 10 cases of PFIC5 have been published to date, and the majority of reported patients carried mutations in both NR1H4 gene copies. Only one case was reported to carry a single NR1H4 mutation.

“The correlation between [genetic makeup] and [clinical profile] in PFIC-5 is unclear, and variable disease presentations and different age of disease onset are described in the literature,” the researchers wrote.

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Itching and scratching our way to a PFIC diagnosis

The researchers described the case of a baby girl with PFIC5 caused by a previously unknown NR1H4 mutation that was detected in only one of the gene copies.

The girl was born just shy of 40 weeks after an uneventful pregnancy.  At a vaccination visit when she was 2 months old, doctors noted jaundice — yellowing of the skin and whites of the eyes — which is a common sign of liver damage. She was also found to have an enlarged liver.

Blood tests revealed signs of liver damage, including low GGT levels, and signs of reduced blood-clotting ability.

The patient was initially tested for a battery of infections that can cause cholestasis, but these tests came back negative. Imaging assessments looking for blockages that could obstruct bile flow also revealed nothing remarkable. Liver biopsy showed signs of damage and scarring, but didn’t pinpoint a clear cause.

Treatment with ursodeoxycholic acid (UDCA), a mainstay therapy for many forms of cholestasis sold under the brand names Urso and Actigall, didn’t have any benefit, with the girl still showing low GGT levels. Treatment with vitamin K injections, designed to improve blood clotting, also didn’t have much effect.

Genetic sequencing revealed a new mutation, dubbed c.788C>A, p.Ser263*, in a single copy of the NR1H4 gene, which was found to result in a smaller, non-working protein, and was predicted to be disease-causing. No mutation in the other NR1H4 gene copy was detected, as was the case in genes associated with other forms of PFIC.

The genetic results, along with clinical features, confirmed a PFIC5 diagnosis.

“Genetic testing can help us to diagnose this rare and serious disease and provide the appropriate treatment,” the team wrote. The scientists noted a need for further investigation into exactly how specific mutations in this gene can contribute to cholestasis, and whether some mutations may be missed by current methods.

The baby’s PFIC progressed rapidly to liver failure. She developed hepatic encephalopathy, a condition marked by neuropsychiatric problems resulting from advanced liver dysfunction, while waiting for a liver transplant. She died at 9 months, before a transplant could be performed.