Supplementary Material for: PHRINL Syndrome: A Case of Infantile Cataract and Cardiomyopathy

Introduction: PHRINL Syndrome (Pontocerebellar Hypoplasia, Hypotonia, and Respiratory
Insufficiency Syndrome, Neonatal Lethal) is a rare genetic disorder caused by impaired
oxidative phosphorylation due to reduced activity of mitochondrial complexes I, IV, and V.
The condition results from homozygous or compound heterozygous pathogenic variants in the
ATAD3A gene, and is inherited in an autosomal recessive manner. Affected individuals
typically present in early infancy with hypotonia, encephalopathy, corneal clouding,
cardiomyopathy, and respiratory failure, and often die during infancy.
Case Presentation: A 40-day-old female infant was referred for evaluation of a possible
inherited metabolic disorder following the death of her brother at nine months of age. No
abnormalities were detected in the metabolic workup. Hypotonia was identified on physical
examination at three months of age, brain magnetic resonance imaging (MRI) revealed
pontocerebellar hypoplasia. Whole-exome sequencing (WES) identified two genetic
alterations in the ATAD3A gene, leading to the diagnosis of PHRINL Syndrome. ATAD3A
(NM_001170535.3: c.229C>G; p.Leu77Val) c.229C>G heterozygous missense variant was
detected, along with a 0.61 kb heterozygous deletion encompassing exons 3-4 of the ATAD3A
gene. The patient diagnosed with hypotonia at three months of age, developed cataracts at five
months, and died in the eighth month due to refractory seizures.
Conclusion: In hypotonic infants presenting with cataracts and cardiomyopathy, elevated
plasma lactate levels and increased urinary excretion of 3-methylglutaconate and 3-
methylglutarate may suggest PHRINL syndrome; however, the diagnosis should not be
excluded solely on the basis of normal metabolic test results when characteristic clinical
features are present.

引言：新生儿致死性桥小脑发育不全、肌张力低下与呼吸功能不全综合征（PHRINL Syndrome）是一种罕见的遗传性疾病，其病因是线粒体复合物I、IV、V活性降低导致的氧化磷酸化功能受损。该疾病由ATAD3A基因的纯合或复合杂合致病性变异引起，遗传方式为常染色体隐性遗传。受累患儿通常于婴儿早期起病，表现为肌张力低下、脑病、角膜混浊、心肌病及呼吸衰竭，且多在婴儿期死亡。

病例报告：1例40日龄女婴，其兄长于9月龄时死亡，后续因疑似遗传性代谢病被转诊评估。代谢筛查未发现异常。患儿3月龄时体格检查提示肌张力低下，颅脑磁共振成像（MRI）显示桥小脑发育不全。全外显子组测序（WES）检测到ATAD3A基因存在两处遗传变异，据此确诊PHRINL综合征：分别为ATAD3A（NM_001170535.3: c.229C>G; p.Leu77Val）c.229C>G杂合错义变异，以及一段覆盖ATAD3A基因第3-4外显子的0.61 kb杂合缺失。该患儿3月龄时被诊断为肌张力低下，5月龄时出现白内障，于8月龄因难治性癫痫发作死亡。

结论：对于表现为肌张力低下、白内障及心肌病的低张力婴儿，若血浆乳酸水平升高、尿3-甲基戊烯二酸与3-甲基戊二酸排泄量增加，可提示PHRINL综合征；但若存在典型临床特征，不应仅因代谢检测结果正常就排除该诊断。