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.

中文翻译：

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扩散峰度成像可检测苯丙酮尿症的亚临床白质异常

目的

苯丙酮尿症（PKU）是一种常染色体隐性遗传疾病，苯丙氨酸代谢不足会引起进行性神经功能障碍。控制PKU具有挑战性，疾病监测的重点是短期苯丙氨酸的控制，而不是神经元损伤的测量。常规成像缺乏敏感性，但是弥散峰度成像（DKI）是一种新的MRI方法，可能会揭示PKU的亚临床白质结构变化。

方法

这项队列研究涉及在常规临床护理期间招募的患有PKU的成年人。收集MRI，神经认知评估和苯丙氨酸（Phe）历史水平。进行假设假设的案例研究，比较了符合饮食习惯的兄弟姐妹和不符合饮食习惯的兄弟姐妹，证实DKI指标对饮食依从性敏感，并提出了候选指标（K _rad / K _FA比）。然后，我们在复制队列中测试了该指标（PKU = 20；控件= 43）。

结果

对于基于DKI的所有指标，两个兄弟姐妹的得分都超出了控制范围，并且脑室周围白质发生了严重变化，并且皮质的严重程度呈梯度变化。通过在复制队列中的诊断，K _rad / K _FA提供了明确的分离（在脑室，深层和皮层周围区室中p <0.001）。该比率也与注意力呈负相关（r = -0.51＆-0.50，p <0.05），与3年平均Phe正相关（r = 0.45＆0.58，p <0.01）。

结论

即使没有常规MRI上明显的临床体征或异常，DKI仍可揭示PKU的区域特异性，脑扩散特征的进行性异常。从这些分数（K _rad / K _FA比）得出的基于DKI的标记在中期对认知障碍和PKU控制敏感，并且可能提供有意义的终末器官损害的亚临床生物标记。