Parikh Sumit, Bernard Geneviève, Leventer Richard J, van der Knaap Marjo S, van Hove Johan, Pizzino Amy, McNeill Nathan H, Helman Guy, Simons Cas, Schmidt Johanna L, Rizzo William B, Patterson Marc C, Taft Ryan J, Vanderver Adeline
Department of Neurogenetics/Neurometabolism, Neuroscience Institute, Cleveland Clinic Children's Hospital, Cleveland, OH, USA.
Departments of Pediatrics, Neurology and Neurosurgery, Montreal Children's Hospital, McGill University Health Center, Montreal, Canada.
Mol Genet Metab. 2015 Apr;114(4):501-515. doi: 10.1016/j.ymgme.2014.12.434. Epub 2014 Dec 29.
Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.
脑白质营养不良（LD）和遗传性脑白质病（gLE）是导致中枢神经系统（CNS）白质异常的疾病。磁共振（MR）成像（MRI）极大地改善并系统化了LD和gLE的诊断，并且结合特定的临床特征，如肾上腺脑白质营养不良中的Addison病或与聚合酶III相关的或4H脑白质营养不良中的牙发育不全，通常只需最少的检查就能确诊。然而，大多数LD和gLE患者的诊断过程仍然漫长——许多患者要等将近十年才能得到明确诊断，至少一半患者的病情仍无法确诊。MRI、仔细的临床评估和下一代基因测序相结合，有望加快诊断过程并大幅减少未确诊病例的数量。在此，我们介绍一个工作流程，详细说明全球脑白质营养不良倡议（GLIA）关于临床诊断方法的共识建议，包括提示特定诊断的显著临床特征、神经影像学特征和分子遗传学检测。我们还讨论了在MRI或临床发现不明确的情况下使用广谱下一代测序的建议。鉴于与这些疾病相关的基因数量不断增加，我们最后提议对全基因组无偏倚检测进行系统试验，作为LD和gLE的一线诊断方法。
