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 (Krad/KFA 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. Krad/KFA 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 (Krad/KFA ratio) was sensitive to cognitive impairment and PKU control over the medium term and may provide a meaningful subclinical biomarker of end-organ damage.
['Hellewell|Sarah C|SC|', 'Welton|Thomas|T|', 'Eisenhuth|Kate|K|', 'Tchan|Michel C|MC|', 'Grieve|Stuart M|SM|']
D000328:Adult D001921:Brain D015331:Cohort Studies D038524:Diffusion Magnetic Resonance Imaging D056324:Diffusion Tensor Imaging D006801:Humans D010661:Phenylketonurias D066127:White Matter
Diffusion kurtosis imaging Phenylketonuria PKU DKI White matter pathology