目的:PTRH2基因的双等位基因突变与婴儿多系统神经系统,内分泌,和胰腺疾病(IMNEPD),一种罕见的常染色体隐性遗传疾病,表现为整体发育迟缓,智力残疾或临界智商水平,感觉神经性听力损失,共济失调,胰腺功能不全.可以包括各种附加特征,比如周围神经病变,面部畸形,甲状腺功能减退,肝纤维化,产后小头畸形,小脑萎缩,和癫痫。这里,我们报道了第一个仅呈现主要神经系统特征的意大利家庭.
方法:自1996年以来,对两个患病的兄弟及其健康的母亲进行了广泛的神经和神经生理学评估。通过腓肠神经活检证实了可能遗传起源的周围神经病变的诊断。在主要神经病相关基因的分析产生阴性结果后进行外显子组测序。
结果:全外显子组测序分析确定了纯合置换c.256C>T(p。Gln86Ter)在两个兄弟姐妹中的PTRH2基因。根据美国医学遗传学和基因组学学院(ACMG)的指南,该变体已被归类为致病性。48岁,先证者的重新评估证实了他13岁时出现的脱髓鞘性感觉运动性多发性神经病伴双侧感觉神经性听力损失。此外,他32岁时发生了耐药癫痫发作。无肝脏或内分泌体征。受影响的弟弟,47岁,临床表现重叠,没有癫痫。
结论:我们的发现扩大了临床表型,并进一步证明了与PTRH2变异相关的临床异质性。因此,我们希望更好地定义IMNEPD,并促进这种新型疾病实体的识别和诊断。
OBJECTIVE: Biallelic mutations in the PTRH2 gene have been associated with infantile multisystem neurological, endocrine, and pancreatic disease (IMNEPD), a rare autosomal recessive disorder of variable expressivity characterized by global developmental delay, intellectual disability or borderline IQ level, sensorineural hearing loss, ataxia, and pancreatic insufficiency. Various additional features may be included, such as peripheral neuropathy, facial dysmorphism, hypothyroidism, hepatic fibrosis, postnatal microcephaly, cerebellar atrophy, and epilepsy. Here, we report the first Italian family presenting only predominant neurological features.
METHODS: Extensive neurological and neurophysiological evaluations have been conducted on the two affected brothers and their healthy mother since 1996. The diagnosis of peripheral neuropathy of probable hereditary origin was confirmed through a sural nerve biopsy. Exome sequencing was performed after the analysis of major neuropathy-associated genes yielded negative results.
RESULTS: Whole-exome sequencing analysis identified the homozygous substitution c.256C>T (p.Gln86Ter) in the PTRH2 gene in the two siblings. According to American College of Medical Genetics and Genomics (ACMG) guidelines, the variant has been classified as pathogenic. At 48 years old, the proband\'s reevaluation confirmed a demyelinating sensorimotor polyneuropathy with bilateral sensorineural hearing loss that had been noted since he was 13. Additionally, drug-resistant epileptic seizures occurred when he was 32 years old. No hepatic or endocrinological signs developed. The younger affected brother, 47 years old, has an overlapping clinical presentation without epilepsy.
CONCLUSIONS: Our findings expand the clinical phenotype and further demonstrate the clinical heterogeneity related to PTRH2 variants. We thereby hope to better define IMNEPD and facilitate the identification and diagnosis of this novel disease entity.