Newly ID’d LSR gene mutations are likely cause of PFIC in 3 children
Study: Gene-linked cholestatis is 'new and likely underdiagnosed disease'
Newly identified mutations in the LSR gene were the likely cause of progressive familial intrahepatic cholestasis (PFIC) in three unrelated children — two of whom showed a more complex clinical profile that included growth issues and neurological impairment.
That’s according to a new case series that detailed the diagnosis of PFIC in the three youngsters, all treated at a hospital in Germany. These three cases add to the small number of similar ones reported thus far involving LSR gene variants, the researchers noted.
The team noted that all three of these children experienced mild to severe itching and signs of liver disease.
Treatment with IBAT inhibitors, a class of medications that includes Bylvay (odevixibat) and Livmarli (maralixibat) — both approved for PFIC-related itch — helped ease symptoms in the two children with more severe itching, the scientists noted.
“LSR-associated early onset intrahepatic cholestasis is a new and likely underdiagnosed disease,” the researchers wrote. “Patients with an unclear progressive familial intrahepatic cholestasis (PFIC)-like clinical picture should therefore undergo genetic testing of the LSR gene,” and “treatment with an IBAT inhibitor should be considered.”
The study, “The role of LSR gene variants in early onset intrahepatic cholestasis: a case series with treatment options,” was published in the journal Frontiers in Pediatrics.
Researchers say LSR gene-related disease could be new PFIC type
PFIC refers to a group of rare liver conditions caused by mutations that disrupt the normal production or secretion of the digestive fluid bile in the liver. This leads to intrahepatic cholestasis, when the flow of bile slows or stops within the liver instead of being transported into the intestines, as normally occurs.
The toxic buildup of bile in the liver can cause liver damage and symptoms such as severe itching. Over time, the disease may progress to scarring, known medically as fibrosis, or cirrhosis, when liver scarring becomes irreversible.
There are several PFIC types, each linked to mutations in a specific gene. More recently, mutations in the LSR gene have been reported as the likely cause of PFIC-like disease in a small number of children, raising the possibility that LSR-related disease could represent a new PFIC type.
The LSR protein is present in several organs and glands, such as the liver, intestines, reproductive glands, and the brain. It is involved in fat uptake and metabolic control and in the formation of cell-binding structures.
Here, a research team described the cases of three unrelated children with PFIC-like disease that was found to be likely caused by mutations in the LSR gene. All of the children were seen at the Essen University Children’s Hospital. The three were a 2-year-old girl of Indian origin, a 9-year-old boy of German origin, and a 2-year-old girl of Albanian origin.
Itching in 2 children successfully treated with Bylvay
All three children experienced mild to severe itching in infancy or early childhood. Each also showed elevated levels of bile acids — bile’s main components — in the blood, as well as signs of liver damage on biopsy that ranged from early and moderate fibrosis to cirrhosis.
The girl of Indian origin showed liver-limited disease. Genetic testing revealed a new, distinct mutation in each of the child’s two LSR gene copies. The mutations, called c.257A>T and c.1274dup, were both classified as likely disease-causing.
The boy had a more complex clinical picture that included seizures from infancy, delayed development, learning and behavior difficulties, and progressive muscle weakness. He also had short stature and a smaller-than-normal head size (microcephaly).
This child was found to carry two novel, different LSR mutations (c.745C>T and c.496G>A), most likely one in each copy of the gene. These also were classified as likely disease-causing.
The girl of Albanian origin, born to blood-related parents, also showed progressive muscle weakness, short stature, and microcephaly. Genetic analysis identified a new mutation, called c.571C>T, in both LSR gene copies that was classified as of uncertain significance.
Further analyses of liver biopsy samples showed that LSR protein levels were much lower than normal in all three children, and that the protein was misplaced inside liver cells. This further emphasized that disrupted or deficient LSR interferes with normal bile secretion.
Although the long-term results of [IBAT inhibitor] use remain to be seen, and the number of cases is small, the use of [such treatment] appears to be promising.
The researchers noted that all of the children also carried variants in other PFIC-related genes; however, these were considered of uncertain significance and unlikely to explain their condition. While these findings point to LSR mutations as the cause of the children’s PFIC, the researchers noted that these additional variants may have influenced the disease course.
Itching was safely and successfully managed with Bylvay in the first two children, who had more severe and persistent itching. Ursodeoxycholic acid was successfully used for the third child.
The girl of Indian origin had previously failed to respond to ursodeoxycholic acid and other standard cholestasis treatments before starting Bylvay. The boy was later switched from Bylvay to Livmarli, and his symptoms remained under control.
“Although the long-term results of its use remain to be seen, and the number of cases is small, the use of an IBAT inhibitor appears to be promising,” the researchers wrote, calling them “a conservative treatment” for itch.
The team said more research into LSR gene mutations is needed.
“Further biochemical investigations into the function of the LSR protein in the liver — but also in other tissues such as the brain — should be performed for a better understanding of [underlying mechanisms] of this disease,” the scientists wrote, adding that such studies could also clarify whether LSR mutations “are the exclusive … cause of the neurological symptoms.”
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