New mutation props up woman’s Alagille syndrome diagnosis
Disease rarely ID'd in adults, who don't often have same symptoms as children
An unreported mutation in the JAG1 gene was identified as the likely cause of Alagille syndrome in a 28-year-old woman, a case report from China suggests.
Alagille syndrome is rarely diagnosed in adulthood and, because adults and children may not have the same symptoms, diagnosing the disease in older people can be difficult.
“We think that traditional diagnostic criteria are not applicable to adult [Alagille syndrome] and the diagnosis should rely more on genetic testing than clinical features,” the researchers wrote. The case report, “A patient with Alagille syndrome had a novel JAG1 gene mutation,” was published in Genes & Diseases.
Alagille syndrome is mainly caused by mutations in the JAG1 gene and, less frequently, in the NOTCH2 gene that result in abnormalities in several organs and systems during early development. A hallmark of the disease is a shortage of the tubes, called bile ducts, that carry bile from the liver to the small intestine to aid digestion. Symptoms can vary from person to person, but may include abnormalities in the heart, bones, eyes, and kidneys, along with characteristic facial features.
Alagille “is primarily observed in children, and confirmed cases in adults are rarely reported,” the researchers wrote. Its diagnosis can be a complicated process that relies on a combination of several signs and symptoms, with genetic testing confirming it in most patients. This can be even more challenging in adults, in whom less information is available about typical disease features.
Genetic testing supports Alagille diagnosis
In this case, the woman was found to carry a previously unknown JAG1 gene mutation, which was thought to be the cause of her Alagille syndrome. She had elevated levels of liver enzymes in her blood tests, suggesting liver damage. Imaging studies showed an enlarged liver, with lesions throughout the organ, but blood tests didn’t reveal a clear cause for the deficits.
She was admitted to the researchers’ hospital, where she was started on a liver-protecting treatment regimen that partially reduced her liver damage markers.
A comprehensive evaluation to identify the cause of her condition showed “distinctive physical characteristics, including a small stature, blindness in the right eye, a prominent forehead, and widely spaced eyes, resulting in a unique facial appearance,” the researchers wrote. “Considering the patient’s medical history and distinctive physical features, we suspect that the patient may be suffering from an inherited metabolic liver disease, most likely [Alagille syndrome].”
The woman’s medical history did include blindness in the right eye since birth and several episodes of abnormal liver function during infancy.
Further tests showed no eye, heart, or bone abnormalities. However, a liver biopsy showed some small bile ducts that hadn’t developed properly and genetic testing identified a new JAG1 mutation, called c.933-934dup, supporting an Alagille diagnosis.
The mutation was predicted to affect splicing, a natural process that can change the length and sequence of the resulting protein. The researchers hypothesized that c.933-934dup could change the protein sequence and “produce abnormal protein products,” classifying it as disease-causing. The mutation wasn’t present in the woman’s unaffected parents, suggesting it had occurred spontaneously rather than being inherited.
“We suspect the potential influence of environmental factors in conjunction with the JAG1 mutation to manifest the [disease],” wrote the researchers, who said the case both highlighted a new JAG1 mutation and demonstrated some challenges of diagnosing Alagille in adults, which they proposed in some instances ought to be based more on genetic testing than on clinical features.
