Zellweger syndrome

Zellweger syndrome is the most severe peroxisome biogenesis disorder, characterised by absent or non-functional peroxisomes, profound hypotonia, seizures, craniofacial dysmorphism, liver disease and renal cysts.Zellweger 综合征是最严重的过氧化物酶体生成障碍，以过氧化物酶体缺失或功能丧失、严重肌张力低下、癫痫、颅面畸形、肝病与肾囊肿为特征。

It is an autosomal recessive disorder caused by biallelic pathogenic variants in PEX genes, and most affected infants die before their first birthday despite intensive supportive care.本病为常染色体隐性遗传病，由 PEX 基因双等位基因致病变异引起，尽管给予积极支持治疗，多数受累婴儿仍在满一岁前死亡。

The syndrome was first described in 1964 and remains the reference disorder for the Zellweger spectrum, which also includes neonatal adrenoleukodystrophy and infantile Refsum disease.该综合征于 1964 年首次描述，至今仍是 Zellweger 谱系的参照疾病，该谱系还包括新生儿肾上腺脑白质营养不良与婴儿型 Refsum 病。

Terminology and classification

• Zellweger syndrome, abbreviated ZS, is also called cerebrohepatorenal syndrome, a descriptive name that reflects the combination of brain, liver and kidney involvement.Zellweger 综合征（缩写 ZS）又称脑-肝-肾综合征，这一描述性名称反映脑、肝与肾同时受累的组合。
• The eponym honours Hans Zellweger (1909–1990), a Swiss-American paediatrician and professor of paediatrics and genetics at the University of Iowa who researched the disorder.该人名名称纪念 Hans Zellweger（1909–1990），他是瑞士裔美国儿科医生，曾任爱荷华大学儿科与遗传学教授并研究该病。
• Zellweger syndrome is the severe end of the Zellweger spectrum disorders, a group of peroxisome biogenesis disorders that also includes neonatal adrenoleukodystrophy and infantile Refsum disease.Zellweger 综合征是 Zellweger 谱系障碍的重症端，该谱系为一组过氧化物酶体生成障碍，还包括新生儿肾上腺脑白质营养不良与婴儿型 Refsum 病。
• ICD-10 has no specific code and Orphanet attributes Q87.8, while ICD-11 MMS assigns 5C57.0, a broader code to which ORPHA:912 is mapped as narrower than the target.ICD-10 无专属编码，Orphanet 将其归入 Q87.8，ICD-11 MMS 编码为 5C57.0，ORPHA:912 以「窄于目标码」的关系映射至该码。
• MONDO assigns MONDO:0019609, Orphanet uses ORPHA:912, OMIM lists 214100 together with several locus-specific entries, MeSH uses D015211, UMLS uses C0043459 and GARD uses 7917.MONDO 编为 MONDO:0019609，Orphanet 使用 ORPHA:912，OMIM 列出 214100 及若干基因座特异性条目，MeSH 使用 D015211，UMLS 使用 C0043459，GARD 使用 7917。
• Inheritance is autosomal recessive, and pathogenic variants in at least 13 PEX genes can produce the phenotype, with PEX1, PEX6, PEX10, PEX12 and PEX26 among the most frequently implicated.遗传方式为常染色体隐性，至少 13 个 PEX 基因的致病变异均可产生该表型，其中 PEX1、PEX6、PEX10、PEX12 与 PEX26 最常受累。
• The older label cerebrohepatorenal syndrome has largely been replaced by Zellweger syndrome and by the spectrum term severe PBD-ZSD, reflecting the shift from a descriptive triad to a molecular classification.旧称脑-肝-肾综合征已基本被 Zellweger 综合征及谱系术语「重度 PBD-ZSD」取代，反映分类依据从描述性三联征转向分子机制。

History

• In 1964 Bowen, Lee, Zellweger and Lindenberg described a familial syndrome of multiple congenital defects with hypotonia, seizures, hepatomegaly and renal cysts, which became known as Zellweger syndrome.1964 年 Bowen、Lee、Zellweger 与 Lindenberg 描述了一个伴肌张力低下、癫痫、肝大与肾囊肿的家族性多发先天缺陷综合征，即后来的 Zellweger 综合征。^[1]
• In 1973 Goldfischer and colleagues demonstrated that peroxisomes were absent in hepatocytes and renal tubular cells and also noted mitochondrial abnormalities, which redirected attention from mitochondria to peroxisomes.1973 年 Goldfischer 及其同事证明肝细胞与肾小管细胞中过氧化物酶体缺失，并同时观察到线粒体异常，使研究焦点从线粒体转向过氧化物酶体。
• Early reports framed the disorder as a primary mitochondrial disease, but the demonstration of a generalised peroxisomal defect overturned that hypothesis and established the peroxisome biogenesis disorder concept.早期报告将该病视为原发性线粒体病，但全身性过氧化物酶体缺陷的发现推翻了这一假说，并确立了过氧化物酶体生成障碍的概念。
• Complementation analysis in the 1980s showed that the Zellweger spectrum was genetically heterogeneous, and the identification of distinct complementation groups anticipated the discovery of multiple PEX genes.1980 年代的互补分析显示 Zellweger 谱系具有遗传异质性，不同互补群的识别为后来发现多个 PEX 基因奠定了基础。
• From the 1990s onward, cloning of PEX1, PEX2, PEX5, PEX6 and other PEX genes linked the phenotype to defects in peroxisomal matrix protein import and provided a molecular basis for genetic testing.自 1990 年代起，PEX1、PEX2、PEX5、PEX6 等基因的克隆将表型与过氧化物酶体基质蛋白输入缺陷联系起来，并为基因检测提供了分子基础。
• Modern management has been shaped by GeneReviews and by negative trials of docosahexaenoic acid and other candidate therapies, which shifted emphasis from disease modification to early diagnosis and supportive care.现代管理受 GeneReviews 与二十二碳六烯酸等候选治疗阴性试验的影响，重点已从疾病修饰转向早期诊断与支持治疗。

Epidemiology

• The birth prevalence of peroxisome biogenesis disorders is traditionally estimated at 1 in 50,000 to 1 in 100,000, and Zellweger syndrome accounts for the most severe portion of that spectrum.过氧化物酶体生成障碍的出生患病率传统估计为 5 万分之一至 10 万分之一，Zellweger 综合征构成该谱系中最严重的部分。
• A Swedish national cohort covering 2005 to 2024 reported a birth prevalence of about 1 in 73,800 for peroxisome biogenesis disorders, a figure consistent with earlier international estimates.一项覆盖 2005 至 2024 年的瑞典全国队列报告过氧化物酶体生成障碍出生患病率约为 73,800 分之一，与早期国际估计一致。
• The disorder occurs worldwide and in all ethnic groups, and no consistent sex predilection has been reported.该病呈全球分布，见于所有种族，未见一致的性别易感倾向。
• Consanguinity and founder effects increase the risk in affected families, and PEX1 variants, particularly the missense allele p.Gly843Asp, are especially frequent in European-ancestry populations.近亲婚配与奠基者效应会增加受累家系的风险，PEX1 变异尤其是错义等位基因 p.Gly843Asp 在欧洲血统人群中尤为常见。
• PEX1 is involved in about 60 percent of PBD-ZSD cases, which makes it the first gene tested in most diagnostic algorithms.PEX1 约涉及 60% 的 PBD-ZSD 病例，因此在多数诊断流程中作为首选检测基因。
• Zellweger syndrome is the least common and most severe phenotype within the spectrum, whereas milder neonatal adrenoleukodystrophy and infantile Refsum disease are more often recognised in survivors.Zellweger 综合征是谱系中最少见且最严重的表型，而较轻的新生儿肾上腺脑白质营养不良与婴儿型 Refsum 病更多见于存活者。
• Because the disorder is rare and not universally screened, ascertainment depends on clinical recognition and biochemical testing, and no GBD estimates are available.由于疾病罕见且未普遍筛查，病例发现依赖临床识别与生化检测，目前没有全球疾病负担估计。
• Most affected infants die before one year of age from respiratory failure, infection, seizures or liver failure, and survival into childhood is exceptional and usually associated with profound disability.多数受累婴儿在一岁前死于呼吸衰竭、感染、癫痫或肝衰竭，存活至儿童期者极少，且通常遗留严重残疾。

Pathophysiology

• Peroxisomes are single-membrane organelles that import matrix proteins through PEX-encoded machinery, and failure of this import leaves the organelle empty or structurally abnormal.过氧化物酶体是单膜细胞器，通过 PEX 编码的机制输入基质蛋白，该输入失败会使细胞器空虚或结构异常。
• Biallelic loss-of-function variants in PEX genes abolish or severely reduce peroxisomal matrix protein import, and genotype severity correlates broadly with the clinical phenotype.PEX 基因双等位基因功能丧失变异使过氧化物酶体基质蛋白输入消失或严重减少，基因型严重度与临床表型大致相关。
• Very-long-chain fatty acids such as C26:0 accumulate because their peroxisomal beta-oxidation is impaired, and phytanic acid and pristanic acid also rise because their alpha-oxidation depends on peroxisomes.由于过氧化物酶体 β 氧化受损，C26:0 等极长链脂肪酸蓄积，而植烷酸与降植烷酸也因 α 氧化依赖过氧化物酶体而升高。
• Plasmalogen synthesis falls because the first enzymes of ether lipid biosynthesis are peroxisomal, and bile acid synthesis is disrupted at the side-chain oxidation steps, producing atypical bile acid intermediates.由于醚脂生物合成的起始酶位于过氧化物酶体，缩醛磷脂合成下降，胆汁酸合成在侧链氧化步骤受阻并产生异常胆汁酸中间体。
• During fetal brain development, the absence of peroxisomal metabolism disrupts neuronal migration and cortical layering, and hypomyelination further impairs white-matter function.在胎儿脑发育过程中，过氧化物酶体代谢缺失破坏神经元迁移与皮层分层，髓鞘形成不足进一步损害白质功能。
• In the liver, defective bile acid synthesis and peroxisomal dysfunction cause cholestasis, steatosis and fibrosis, while renal tubular cysts and chondrodysplasia punctata reflect the systemic lipid abnormalities.在肝脏，胆汁酸合成缺陷与过氧化物酶体功能障碍引起胆汁淤积、脂肪变与纤维化，而肾小管囊肿与点状软骨发育不良则反映全身性脂质异常。
• Complete absence of functional peroxisomes produces the severe Zellweger phenotype, whereas residual import activity permits the milder neonatal adrenoleukodystrophy or infantile Refsum phenotypes.功能性过氧化物酶体完全缺失产生严重的 Zellweger 表型，而残存的输入活性可形成较轻的新生儿肾上腺脑白质营养不良或婴儿型 Refsum 表型。

Clinical features

• Affected newborns are profoundly hypotonic and floppy, feed poorly, and may require respiratory support because of weak suck, aspiration and central apnoea.受累新生儿肌张力严重低下、全身松软、喂养困难，并因吸吮无力、误吸与中枢性呼吸暂停可能需要呼吸支持。
• Seizures usually begin in the neonatal period and are often refractory to standard anticonvulsants, contributing to early morbidity.癫痫通常在新生儿期起病，常对标准抗癫痫药物耐药，是早期致病与致死的重要原因。
• Craniofacial features include a high forehead, large anterior fontanelle, hypoplastic supraorbital ridges, epicanthal folds, broad nasal bridge and midface hypoplasia.颅面特征包括高额、前囟大、眶上嵴发育不良、内眦赘皮、鼻梁宽与面中部发育不良。
• Ocular abnormalities include cataracts, glaucoma, corneal clouding, optic atrophy and retinal dystrophy, and sensorineural hearing loss is common.眼部异常包括白内障、青光眼、角膜混浊、视神经萎缩与视网膜营养不良，感音神经性听力损失常见。
• Hepatomegaly, prolonged jaundice, cholestasis, coagulopathy and elevated transaminases reflect peroxisomal liver disease, and liver failure may dominate the terminal course.肝大、黄疸迁延、胆汁淤积、凝血障碍与转氨酶升高反映过氧化物酶体性肝病，肝衰竭可主导终末期病程。
• Renal cortical cysts and chondrodysplasia punctata are characteristic, and the latter produces stippled epiphyses on neonatal radiographs.肾皮质囊肿与点状软骨发育不良具有特征性，后者在新生儿 X 线上表现为骨骺点状钙化。
• Profound developmental delay is universal, and most infants never achieve independent sitting, speech or feeding, which distinguishes ZS from later-onset spectrum phenotypes.严重发育迟缓普遍存在，多数婴儿始终不能独立坐、说话或进食，这使 ZS 区别于晚发型谱系表型。
• Major complications include aspiration pneumonia, respiratory distress, refractory seizures, liver failure and coagulopathic bleeding, and these account for most deaths in infancy.主要并发症包括吸入性肺炎、呼吸窘迫、难治性癫痫、肝衰竭与凝血障碍性出血，这些也是婴儿期多数死亡的原因。

Diagnosis

• Diagnosis is suspected from the clinical picture and confirmed biochemically, following the GeneReviews approach of combining plasma analytes, fibroblast studies and molecular testing.诊断先由临床表现提出怀疑，再经生化确认，遵循 GeneReviews 将血浆分析物、成纤维细胞研究与分子检测结合的策略。
• Plasma very-long-chain fatty acids are elevated, with increased C26:0 and C26:1 and an increased C24:0 to C22:0 ratio, and C26:0 often exceeds 1 micromole per litre in severe ZS.血浆极长链脂肪酸升高，表现为 C26:0 与 C26:1 增高及 C24:0 与 C22:0 比值升高，重症 ZS 中 C26:0 常超过 1 微摩尔/升。
• Phytanic acid, pristanic acid, plasmalogens and bile acid intermediates are measured to define the extent of peroxisomal dysfunction and to distinguish ZS from other peroxisomal disorders.测定植烷酸、降植烷酸、缩醛磷脂与胆汁酸中间体可界定过氧化物酶体功能障碍的范围，并将 ZS 与其他过氧化物酶体病区分。
• Cultured skin fibroblasts show impaired very-long-chain fatty acid beta-oxidation, phytanic acid alpha-oxidation and plasmalogen synthesis, which confirms the defect when plasma results are ambiguous.培养的皮肤成纤维细胞显示极长链脂肪酸 β 氧化、植烷酸 α 氧化与缩醛磷脂合成受损，可在血浆结果不明确时确认缺陷。
• Molecular testing with a PEX gene panel or exome sequencing identifies biallelic pathogenic variants, and PEX1 should be prioritised because of its high contribution.使用 PEX 基因组或外显子组测序可发现双等位基因致病变异，鉴于 PEX1 贡献率高应优先检测。
• Newborn screening for Zellweger spectrum disorders using C26:0-lysophosphatidylcholine in dried blood spots is feasible and has been introduced in some programmes, but it is not universal.利用干血斑 C26:0-溶血磷脂酰胆碱进行 Zellweger 谱系新生儿筛查可行，并已在部分项目中开展，但尚未普及。
• Prenatal diagnosis is available through measurement of VLCFA and plasmalogens in amniocytes or chorionic villi, or through targeted testing when familial variants are known.产前诊断可通过测定羊水细胞或绒毛膜绒毛的极长链脂肪酸与缩醛磷脂，或在已知家系变异时进行靶向检测。
• The differential diagnosis includes Down syndrome, congenital hypothyroidism, neonatal sepsis, mitochondrial disorders, Smith-Lemli-Opitz syndrome, chondrodysplasia punctata and the milder PBD-ZSD phenotypes.鉴别诊断包括唐氏综合征、先天性甲状腺功能减退、新生儿脓毒症、线粒体病、Smith-Lemli-Opitz 综合征、点状软骨发育不良及较轻的 PBD-ZSD 表型。

Management

• There is no cure for Zellweger syndrome, and management is multidisciplinary and supportive, focusing on nutrition, seizures, respiration, vision, hearing and liver complications.Zellweger 综合征无法治愈，治疗为多学科支持性，重点在营养、癫痫、呼吸、视力、听力与肝脏并发症。
• Feeding usually requires an elemental formula low in long-chain triglycerides, delivered by nasogastric or gastrostomy tube, because of poor suck and fat malabsorption.由于吸吮无力与脂肪吸收不良，喂养通常需要低长链甘油三酯的要素配方，并经鼻胃管或胃造瘘给予。
• Fat-soluble vitamins A, D, E and K are supplemented because bile acid deficiency impairs their absorption, and vitamin K is particularly important for coagulopathy.由于胆汁酸缺乏影响吸收，需补充脂溶性维生素 A、D、E 与 K，其中维生素 K 对凝血障碍尤为重要。
• Ursodeoxycholic acid is used for cholestasis, anticonvulsants such as levetiracetam for seizures, and hearing aids or vision support for sensory deficits.胆汁淤积可使用熊去氧胆酸，癫痫可使用左乙拉西坦等抗癫痫药，感觉缺陷可配助听器或视力辅助。
• Liver transplantation has been performed in selected children with dominant liver disease, but it does not correct the neurological disorder and remains controversial.对以肝病为主的少数患儿曾实施肝移植，但移植不能纠正神经系统病变，且仍存争议。
• Genetic counselling should explain the 25 percent recurrence risk, offer carrier testing for relatives and discuss prenatal or preimplantation diagnosis.遗传咨询应说明 25% 的再发风险，为亲属提供携带者检测，并讨论产前或植入前诊断。
• Illness and fasting should be avoided because they accelerate catabolism and worsen the biochemical derangement, and routine vaccinations and early treatment of infection are recommended.应避免疾病与禁食，因为它们加速分解代谢并加重生化紊乱，同时建议按计划接种疫苗并早期治疗感染。
• Prognosis is poor, with most infants dying before one year and survivors showing profound developmental disability, and care should include advance planning and family support.预后不良，多数婴儿在一岁前死亡，存活者存在严重发育残疾，照护应包括预先照护计划与家庭支持。

Research and controversies

• AAV8-PEX1 subretinal gene therapy is being developed for the retinal degeneration of Zellweger spectrum disorders, with the aim of restoring local peroxisomal function rather than correcting the systemic disease.AAV8-PEX1 视网膜下基因治疗正在针对 Zellweger 谱系障碍的视网膜变性进行开发，目标是恢复局部过氧化物酶体功能而非纠正全身疾病。
• AAV9-based base editing and other systemic gene-replacement strategies are at preclinical stages, and their ability to cross the blood-brain barrier and correct neuronal migration defects remains unproven.基于 AAV9 的碱基编辑及其他全身基因替代策略仍处于临床前阶段，其穿越血脑屏障并纠正神经元迁移缺陷的能力尚未证实。
• Docosahexaenoic acid supplementation showed no clinical benefit in a double-blind randomised trial, and 4-phenylbutyrate, which was proposed as a chemical chaperone, also failed to improve outcomes.二十二碳六烯酸补充在一项双盲随机试验中未见临床获益，曾作为化学伴侣提出的 4-苯丁酸盐同样未能改善结局。
• Newborn screening using C26:0-lysophosphatidylcholine and other dried-blood-spot biomarkers is a major research priority, because early diagnosis may allow earlier supportive care and family planning.利用 C26:0-溶血磷脂酰胆碱及其他干血斑标志物进行新生儿筛查是重要研究优先事项，因为早期诊断可能带来更早的支持治疗与生育计划。
• International natural-history registries are needed to define survival, genotype-phenotype correlations and outcome measures for future trials, which are currently limited by small samples and phenotypic heterogeneity.需要国际自然史登记来界定生存、基因型-表型相关性与未来试验的结局指标，目前这些工作受样本量小与表型异质性限制。
• The most visible controversy concerns liver transplantation and aggressive life support in infants with severe neurological disease, with some centres offering transplantation for liver-dominant disease and others arguing that it prolongs suffering without altering the neurological prognosis.最显著的争议在于对严重神经系统疾病婴儿是否实施肝移植与积极生命支持，部分中心为肝病为主者提供移植，另一些则认为这只会延长痛苦而不改变神经预后。