Poll-The Bwee Tien, Gootjes Jeannette, Duran Marinus, De Klerk Johannis B C, Wenniger-Prick Liesbeth J Maillette de Buy, Admiraal Ronald J C, Waterham Hans R, Wanders Ronald J A, Barth Peter G
Department of Pediatrics, Emma Children's Hospital, Amsterdam, The Netherlands.
Am J Med Genet A. 2004 May 1;126A(4):333-8. doi: 10.1002/ajmg.a.20664.
The peroxisome biogenesis disorders (PBDs) with generalized peroxisomal dysfunction include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). There is clinical, biochemical, and genetic overlap among the three phenotypes, also known as Zellweger spectrum disorders. Clinical distinctions between the phenotypes are not sharply defined. Only limited sources are available to serve as a background for prognosis in PBD, especially in case of prolonged survival. We delineated the natural history of 31 PBD patients (age 1.2-24 years) through systematic clinical and biochemical investigations. We excluded classical ZS from our study, and included all patients with a biochemically confirmed generalized peroxisomal disorder over 1 year of age, irrespective of the previously diagnosed phenotype. The initial clinical suspicion, age at diagnosis, growth, development, neurological symptoms, organ involvements, and survival are summarized. Common to all patients were cognitive and motor dysfunction, retinopathy, sensorineural hearing impairment, and hepatic involvement. Many patients showed postnatal growth failure, 10 patients displayed hyperoxaluria of whom 4 had renal stones. Motor skills ranged from sitting with support to normal gait. Speech development ranged from non-verbal expression to grammatical speech and comprehensive reading. The neurodevelopmental course was variable with stable course, rapid decline with leukodystrophy, spinocerebellar syndrome, and slow decline over a wide range of faculties as outcome profiles. At the molecular level, 21 patients had mutations in the PEX1 gene. The two most common PEX1 mutations were the G843D (c.2528G-->A) missense and the c.2097insT frameshift mutation. Patients having the G843D/G843D or the G843D/c.2097insT genotypes were compared. Patients homozygous for G843D generally had a better developmental outcome. However, one patient who was homozygous for the "mild" G843D mutation had an early lethal disease, whereas two other patients had a phenotype overlapping with the G843D/c.2097insT group. This indicates that next to the PEX1 genotype other yet unknown factors determine the ultimate phenotype.
伴有全身性过氧化物酶体功能障碍的过氧化物酶体生物发生障碍（PBD）包括泽尔韦格综合征（ZS）、新生儿肾上腺脑白质营养不良（NALD）和婴儿型雷夫叙姆病（IRD）。这三种表型在临床、生化和遗传方面存在重叠，也被称为泽尔韦格谱系障碍。各表型之间的临床差异并不明确。仅有有限的资料可作为PBD预后的背景参考，尤其是在长期存活的情况下。我们通过系统的临床和生化研究描绘了31例PBD患者（年龄1.2 - 24岁）的自然病史。我们的研究排除了经典的ZS，纳入了所有年龄超过1岁、生化确诊为全身性过氧化物酶体障碍的患者，无论其先前诊断的表型如何。总结了最初的临床怀疑、诊断年龄、生长发育、神经症状、器官受累情况及存活情况。所有患者的共同特点是认知和运动功能障碍、视网膜病变、感觉神经性听力障碍以及肝脏受累。许多患者出现出生后生长发育迟缓，10例患者出现高草酸尿症，其中4例有肾结石。运动技能从在支撑下坐立到正常步态不等。语言发育从非语言表达到语法性语言和综合阅读。神经发育过程各不相同，结果表现为病程稳定、因脑白质营养不良和脊髓小脑综合征而迅速衰退以及在广泛的功能范围内缓慢衰退。在分子水平上，21例患者的PEX1基因存在突变。最常见的两种PEX1突变是G843D（c.2528G→A）错义突变和c.2097insT移码突变。对具有G843D/G843D或G843D/c.2097insT基因型的患者进行了比较。G843D纯合子患者通常发育结局较好。然而，一名“轻度”G843D突变纯合子患者患有早期致死性疾病，而另外两名患者的表型与G843D/c.2097insT组重叠。这表明除了PEX1基因型外，其他未知因素也决定了最终的表型。
