LSR gene mutations may cause new type of rare liver disease PFIC
Study details cases of two young children in Turkey
Mutations in the LSR gene, including one previously unreported, were the likely cause of progressive familial intrahepatic cholestasis (PFIC) in two young children in Turkey, a study showed.
The two children had severe itching and normal blood levels of gamma-glutamyl transferase (GGT), a liver enzyme commonly used as a liver damage marker, but whose levels may be low or normal in PFIC and other genetic conditions affecting the digestive fluid bile.
Off-label treatment with ursodeoxycholic acid (UDCA), sold under the brand names Urso and Actigall, and/or the antibiotic rifampicin, sold as Rimactane and Rifadin, helped ease symptoms and laboratory abnormalities in both children.
“The identification of novel … LSR variants in patients with GGT-normal cholestasis contributes to the growing body of evidence that LSR deficiency may represent a novel subtype of PFIC,” researchers wrote.
The study, “GGT-Normal Cholestasis Associated with LSR Deficiency: A Potential New Subtype of PFIC,” was published in Clinics and Research in Hepatology and Gastroenterology.
‘Newly identified candidate genes continue to expand the PFIC spectrum’
PFIC is a group of rare liver conditions caused by genetic mutations that lead to defects in the production or transport of bile in the liver. This results in intrahepatic cholestasis, when bile flow is slowed or stopped entirely inside the liver, which typically manifests in infancy or early childhood. Bile accumulates to toxic levels, causing symptoms such as itching and jaundice, or the yellowing of the skin and white parts of the eyes.
Currently, several PFIC types have been identified based on the gene that is mutated.
“Newly identified candidate genes continue to expand the PFIC spectrum. LSR gene mutations have been reported before as a novel cause of infantile intrahepatic cholestasis in two patients,” the researchers wrote.
The LSR protein is mainly found in the liver and intestinal cells. It is involved in the uptake of fatty molecules, metabolic regulation, and the formation of cell-binding structures.
The two previous cases of PFIC associated with LSR mutations displayed severe itching several months after birth and normal blood GGT levels.
In this study, a team of researchers in Turkey described the cases of two unrelated children who carried LSR mutations that were likely the cause of their PFIC with normal GGT levels.
Mutations not previously linked to cholestasis
Both patients, a 4-year-old girl and an 8-month-old boy, were admitted to the clinic due to severe itching and jaundice. The girl also had episodes of dark urine and pale stools, other known PFIC symptoms. The boy was born to blood-related parents.
Laboratory analysis indicated elevated blood levels of the liver enzymes aspartate aminotransferase and alanine aminotransferase, with normal GGT and alkaline phosphatase levels. The girl also had elevated bile acids, which are bile’s main component, while the boy had elevated bilirubin, a marker of liver damage. A liver biopsy of the girl and an imaging scan of the boy showed signs of liver scarring.
Genetic analysis revealed missense mutations in both copies of the LSR gene that were not previously linked to cholestasis. Missense mutations result in a swap of one of the protein’s building blocks, which can potentially change its structure and function.
The girl’s mutation was called c.376A>G and was classified as potentially disease-causing by certain tools and of unknown significance by others. The boy’s mutation, called c.745T>C, was previously reported in the population, but not in both LSR gene copies, and was classified by all tools as likely disease-causing.
“One of our cases uniquely responded to rifampicin, significantly reducing severe itching, unlike previously reported cases with limited treatment success.
The girl was given UDCA, a first-line cholestasis treatment, but her itching did not change. Rifampicin was added, and the combination treatment resolved all symptoms. The boy did not respond to UDCA and was started on rifampicin, which lessened itching and jaundice. The rifampicin dose was gradually decreased throughout the follow-up.
“One of our cases uniquely responded to rifampicin, significantly reducing severe itching, unlike previously reported cases with limited treatment success,” the researchers wrote.
At their last evaluation, when the girl was 12 and the boy was 1, they had no symptoms. The girl achieved typical neuromotor developmental milestones despite low academic performance and speech delay, while the boy presented a delay in gross motor skills.
“While our clinical and genetic findings support this association [between LSR mutations and PFIC], the [damaging nature] of the identified missense variants, particularly in Case 1, requires confirmation through functional studies,” the researchers wrote. “Further reports … are needed to establish LSR-related cholestasis as a distinct disease entity.”
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