Diffusion kurtosis imaging detects subclinical white matter abnormalities in Phenylketonuria

•Diffusion and diffusion kurtosis MRI metrics were examined in adults with PKU.•A candidate metric (Krad/KFA) delineated diet-compliant and non-compliant siblings.•Krad/KFA ratio was validated in a replication cohort of PKU patients and control.•DKI reveals abnormalities in PKU in the absence of clinical signs or abnormalities. Phenylketonuria (PKU) is an autosomal recessive disorder whereby deficiencies in phenylalanine metabolism cause progressive neurological dysfunction. Managing PKU is challenging, with disease monitoring focussed on short-term phenylalanine control rather than measures of neuronal damage. Conventional imaging lacks sensitivity, however diffusion kurtosis imaging (DKI), a new MRI method may reveal subclinical white matter structural changes in PKU. This cohort study involved adults with PKU recruited during routine clinical care. MRI, neurocognitive assessment and historical phenylalanine (Phe) levels were collected. A hypothesis-generating case study comparing diet-compliant and non-compliant siblings confirmed that DKI metrics are sensitive to dietary adherence and prompted a candidate metric (Krad/KFA ratio). We then tested this metric in a Replication cohort (PKU = 20; controls = 43). Both siblings scored outside the range of controls for all DKI-based metrics, with severe changes in the periventricular white matter and a gradient of severity toward the cortex. Krad/KFA provided clear separation by diagnosis in the Replication cohort (p