IRCCS Ospedale Policlinico San Martino, UOC Medical Genetics, Genoa, Italy.
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences, University of Genoa, Genoa, Italy.
J Peripher Nerv Syst. 2024 Jun;29(2):279-285. doi: 10.1111/jns.12636. Epub 2024 Jun 14.
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.
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.
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.
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.
PTRH2 基因的双等位基因突变与婴儿多系统神经内分泌胰腺疾病（IMNEPD）有关，这是一种罕见的常染色体隐性遗传疾病，具有可变的外显率，其特征为全面发育迟缓、智力残疾或边缘智商水平、感觉神经性听力损失、共济失调和胰腺功能不全。还可能包括其他各种特征，如周围神经病、面型异常、甲状腺功能减退、肝纤维化、出生后小头畸形、小脑萎缩和癫痫。在这里，我们报告了第一个仅表现出主要神经特征的意大利家族。
自 1996 年以来，对两个受影响的兄弟及其健康的母亲进行了广泛的神经学和神经生理学评估。通过腓肠神经活检证实了可能遗传性起源的周围神经病的诊断。在外周神经病变相关主要基因分析结果为阴性后，进行了外显子组测序。
全外显子组测序分析在两个兄弟姐妹中发现 PTRH2 基因的纯合替换 c.256C>T(p.Gln86Ter)。根据美国医学遗传学与基因组学学院（ACMG）指南，该变体被归类为致病性。在 48 岁时，对先证者的重新评估证实了一种脱髓鞘感觉运动多发性神经病，双侧感觉神经性听力损失自他 13 岁起就已存在。此外，他 32 岁时出现了耐药性癫痫发作。没有出现肝脏或内分泌学迹象。年龄较小的受影响兄弟，47 岁，具有重叠的临床表现，但没有癫痫。
我们的发现扩展了临床表型，并进一步证明了与 PTRH2 变体相关的临床异质性。因此，我们希望更好地定义 IMNEPD，并促进这种新疾病实体的识别和诊断。
