Liver function in X-linked myotubular myopathy and autosomal dominant centronuclear myopathy: Data of the unite-CNM study.

Background: Centronuclear myopathies represent a subset of debilitating genetic disorders, for which no treatment exists. The Unite-CNM trial (NCT04033159) aimed to assess the effect of an antisense oligonucleotide to reduce DNM2 mRNA expression in X-linked myotubular myopathy (XLMTM) and autosomal dominant centronuclear myopathy (ADCNM).

Objective: The trial was discontinued due to tolerability concerns (hepatic and hematological). This report aims to provide an overview of hepatic involvement in XLMTM and ADCNM adults.

Methods: The medical history and prospective liver imaging and liver function test results at screening and baseline were assessed. Furthermore, DNM2 protein expression in livers of four other pediatric patients with XLMTM and of healthy children and adults were assessed.

Results: Twenty-six patients were screened; 15 with DNM2 mutations (median age 36 years; six females), and 11 with MTM1 mutations (median age 52 years; five females). Overall, six patients had a history of liver disease (6/19;31.6%). One patient with XLMTM had elevated serum alanine transaminase and another XLMTM patient had elevated serum gamma glutamyl transpeptidase. Liver ultrasound showed no features of peliosis hepatis. Liver steatosis was observed in three ADCNM patients and two XLMTM patients. The Fibroscan CAP score was above normal range in three XLMTM patients, and borderline or normal in other patients. The histopathology study showed that DNM2 protein levels in human liver decrease with age and are lower in pediatric individuals with XLMTM compared to controls.

Conclusions: This study provides an overview of hepatic involvement in a large group of ADCNM and XLMTM patients. Findings suggest an underlying liver pathology may impact tolerability of therapeutic approaches, and will be important to consider for future trial design and clinical management. The results of DNM2 protein expression warrant further investigations on the role of DNM2 in the liver if it is to be used as a therapeutic target.