Clinical Characteristics

Most patients with biallelic variants in ALPK3 present with severe cardiomyopathy prenatally or within the first years of life. In at least half of all patients, the cardiomyopathy progresses from dilated to hypertrophic cardiomyopathy. ECG recordings often show prolonged QTc intervals, repolarization abnormalities (inferolateral ST depression) and QRS voltages consistent with biventricular or left ventricular hypertrophy. ALPK3-cardiomyopathy may result in intrauterine or early neonatal death. Some patients may need an implantable cardioverter defibrillator or heart transplant.

Prenatal findings include increased nuchal fold and/or fetal hydrops. The majority of patients display postnatal growth retardation. About half of patients have musculoskeletal abnormalities, including severe scoliosis, webbed neck and joint contractures. Less common features include developmental delay and hypotonia. Many patients have cleft palate or velopharyngeal insufficiency. Facial dysmorphisms are frequently observed and may include hypertelorism, ptosis, ankyloglossia, intra-oral pterygia, micrognathia and low-set ears.

The occurrence and severity of additional clinical features is variable among individuals with ALPK3-cardiomyopathy.