A great and short webinar was recently presented from the NASPGHAN Foundation with three lectures
Webinar: Alagille Syndrome (If this link does not work, the On Demand version of the webinar is now available on LearnOnLine, at https://learnonline.naspghan.org/products/on-demand-advances-in-diagnosis-and-treatment-of-alagille-syndrome. You can also find it by logging into LearnOnline at https://learnonline.naspghan.org/ and entering the Webinars section.)
The first lecture by Dr. Melissa Gilbert was an excellent overview of the genetics of Alagille Syndrome.
- JAG1 mutations account for ~95% of Alagille syndrome mutations and NOTCH2 about 3%
- Many mutations identified are due to missense mutations which are often variants of unknown clinical significance (VOUS). In these patients, to determine if it is pathogenic, one has to correlate the clinical picture along with specific amino acid change, location of variant, and frequency of variant in normal population. Dr. Gilbert noted that among the ~97% of cases with genetic abnormalities, about 80% have recognized pathogenic mutations and about 17% have VOUS.
- There is variability of severity of Alagille syndrome in the same family, likely related to genetic modifiers
- When using genetic panel, if panel uses only single nucleotide variants, this will miss the deletion/duplication variants which account for ~10% of cases
The second lecture by Binita Kamath was a terrific review and compared the differences between Alagille Syndrome with JAG1 mutations and NOTCH2; the latter are much less likely to have cardiac abnormalities and butterfly vertebrae. The liver phenotype/survival is similar.
- Outcomes of Alagille syndrome by 25 years of age including frequent bone fractures and development of portal hypertension.
- Severe liver disease is common. 75% in a multi-center cohort (CHILDREN) required liver transplantation by age 18 years and 10% died; in contrast, a large GALA cohort of 911 children, 41% survived with their native liver at 18 years.
- After transplantation, renal sparing strategies are needed due to frequent renal insufficiency; patients with severe cardiac disease may not be candidates for liver transplantation.
- There is work on an Alagille Syndrome growth curve.
- Screening for brain vascular malformations/Moyamoya –Dr. Kamath tends to screen after age 8 years of age at baseline (when child does not need sedation for brain imaging) and then every 4-5 years. Also, an MRI/MRA is done prior to major surgery.
- Hyperlipidemia in Alagille Syndrome is mainly due to lipoprotein X; this is not a risk factor for cardiac health.
The third (& also excellent) lecture by Saul Karpen (who disclosed his potential conflicts of interest) reviewed current treatments and emerging treatments.
- The current medical therapies have not been carefully tested; rifampin for pruritus may relieve cholestasis in about 50% of patients.
- IBAT inhibitors interrupt enterohepatic circulation. These agents improve pruritus and decrease serum bile acids.
- Dr. Karpen reminded the audience to follow fat soluble vitamin levels and if treatment is needed, to provide Vitamin D formulations with TPGS.
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