Poke Gemma, Sadleir Lynette Grant, Merla Giuseppe, de Valles-Ibáñez Guillem, Skinner Jonathan Robert
University of Otago, Wellington, New Zealand
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
-related neurodevelopmental disorder (-NDD) is characterized by a spectrum of neurodevelopmental phenotypes that range from severe-to-profound intellectual disability (ID; 31/41 reported individuals), to mild-to-moderate ID (5/41), to normal intellect with severe language disorder (5/41, one extended family). A unique and specific feature of -NDD – regardless of neurodevelopmental phenotype – is nearly universal bradycardia caused by sinoatrial node dysfunction (sick sinus syndrome). Most individuals with severe and profound ID have a developmental and epileptic encephalopathy with focal seizures or epileptic spasms, as well as visual impairment (central or retinal) with nystagmus, difficulty feeding, and gastroesophageal reflux disease. The risk of early mortality is increased.
DIAGNOSIS/TESTING: The diagnosis of -NDD is established in a proband with suggestive clinical findings and biallelic pathogenic variants in identified by molecular genetic testing.
Management by multidisciplinary specialists including a general pediatrician, developmental pediatrician, pediatric neurologist, speech-language pathologist, orthopedist, physical medicine and rehabilitation specialist, physical therapist, occupational therapist, pediatric ophthalmologist, and pediatric cardiologist is recommended. Routine follow up by multidisciplinary care providers based on individual needs and circumstances. Use parasympathomimetics with extreme caution because of the potential to cause asystole. It is best to avoid other drugs that can potentiate bradycardia, particularly beta blockers. It is appropriate to clarify the genetic status of at-risk neonates (if prenatal testing was not performed) in order to identify as early as possible those who warrant developmental assessment (and monitoring) and evaluation by a pediatric cardiologist.
-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.
-相关神经发育障碍（-NDD）的特征是一系列神经发育表型，从重度至极重度智力残疾（ID；41例报告个体中有31例），到轻度至中度ID（41例中有5例），再到智力正常但有严重语言障碍（41例中有5例，其中一个大家庭）。-NDD的一个独特且特定的特征——无论神经发育表型如何——是由窦房结功能障碍（病态窦房结综合征）导致的几乎普遍存在的心动过缓。大多数重度和极重度ID个体患有伴有局灶性发作或癫痫痉挛的发育性和癫痫性脑病，以及伴有眼球震颤的视力障碍（中枢性或视网膜性）、喂养困难和胃食管反流病。早期死亡风险增加。
诊断/检测：-NDD的诊断在具有提示性临床发现且通过分子基因检测鉴定出双等位基因致病变异的先证者中确立。
建议由多学科专家进行管理，包括普通儿科医生、发育儿科医生、儿科神经科医生、言语语言病理学家、骨科医生、物理医学与康复专家、物理治疗师、职业治疗师、儿科眼科医生和儿科心脏病专家。多学科护理人员根据个体需求和情况进行常规随访。由于有导致心脏停搏的可能性，应极其谨慎地使用拟副交感神经药。最好避免使用其他可增强心动过缓的药物，尤其是β受体阻滞剂。为了尽早识别那些需要发育评估（和监测）以及由儿科心脏病专家进行评估的高危新生儿，明确其遗传状态（如果未进行产前检测）是合适的。
-NDD以常染色体隐性方式遗传。如果已知父母双方均为某一致病变异的杂合子，受影响个体的每个同胞在受孕时有25%的几率受到影响，50%的几率为无症状携带者，25%的几率未受影响且不是携带者。一旦在受影响的家庭成员中鉴定出致病变异，就可以对高危亲属进行携带者检测以及进行产前/植入前基因检测。
