Together, our genetic and experimental findings provide evidence that mutations affecting functionally conserved domains in NBAS resulting in severely decreased NBAS levels cause RALF in infancy. Although no changes in glycosylation patterns were observed in the conditions investigated, expression profiles in NBAS mutant fibroblasts are suggestive for ER stress. RALF due to mutated NBAS is a presumably relatively frequent inherited cause of RALF, because NBAS screening of 15 individuals with RALF or acute infantile liver failure resulted in the discovery of six affected individuals from five additional families. The pivotal feature of this disease is RALF precipitated by intercurrent febrile illnesses during infancy and childhood. Intriguingly, with conservative management, liver function recovered completely and was normal in the interval. Crises are heralded by vomiting and lethargy and start rather uniformly with massively elevated ASAT and ALAT (range of maximum ALAT 4,001–17,700 U/l; normal < 50 U/l), followed by coagulopathy requiring FFP substitution (maximum INR 10; normal < 1.2) and mild to moderate jaundice (range of maximum total bilirubin 46.8–207.4 μmol/l; normal < 20.4 μmol/l). In some cases, significant hypoglycemia, hyperammonemia (maximum 209 μmol/l; normal < 53 μmol/l), and hepatic encephalopathy developed, which we consider to be secondary to ALF. Several affected individuals suffered from a range of comorbidities including cardiomyopathy, autoimmune gastrointestinal diseases, and neurological phenotypes such as epilepsy. However, none of those conditions is present in two individuals (Table 1).