Diffusion kurtosis imaging detects subclinical white matter abnormalities in Phenylketonuria

Objective: 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. Methods: 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 (K-rad/K-FA ratio). We then tested this metric in a Replication cohort (PKU = 20; controls = 43). Results: 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. K-rad/K-FA provided clear separation by diagnosis in the Replication cohort (p < 0.001 in periventricular, deep and pericortical compartments). The ratio also correlated negatively with attention (r = 0.51 & 0.50, p < 0.05) and positively with 3-year mean Phe (r = 0.45 & 0.58, p < 0.01). Conclusion: DKI reveals regionally-specific, progressive abnormalities of brain diffusion characteristics in PKU, even in the absence of conspicuous clinical signs or abnormalities on conventional MRI. A DKI-based marker derived from these scores (K-rad/K-FA ratio) was sensitive to cognitive impairment and PKU control over the medium term and may provide a meaningful subclinical biomarker of end-organ damage.

Automated summary

Phenylketonuria (PKU) is a genetic disorder causing progressive neurological dysfunction due to phenylalanine metabolism deficiency. This study utilized diffusion kurtosis imaging (DKI) to reveal subclinical changes in white matter structure in PKU patients, providing potential for a sensitive biomarker of cognitive impairment and disease control. The DKI-based metric (K-rad/K-FA ratio) showed clear separation between PKU and control groups in detecting brain abnormalities, highlighting its potential for monitoring disease progression and treatment effectiveness.