Baple Emma L, Salter Claire, Uhlig Holm, Wolf Nicole I, Crosby Andrew H
University of Exeter Medical School, Exeter, United Kingdom
NIHR Oxford Biomedical Research Centre, Oxford, United Kingdom
-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects). Age of onset is typically antenatal or in early childhood; individuals can present with any combination of these features. Rare individuals present with later-onset hereditary spastic paraplegia. Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria.
DIAGNOSIS/TESTING: The diagnosis of -related disorder is established in a proband with characteristic features and biallelic pathogenic variants identified by molecular genetic testing.
Individualized care by a multidisciplinary team; physical therapy, occupational therapy, mobility aids, and medical management as needed for limb spasticity and motor issues; speech-language therapy for speech impairment and/or dysphagia; communication aids as needed; educational support for intellectual disability; anti-seizure medication as needed for seizures; gastrostomy as needed for feeding issues; treatments for multiple intestinal atresia and inflammatory bowel disease per surgeon and gastroenterologist; treatment of immunodeficiency per immunologist; standard treatment for hearing and vision issues. Neurologic, developmental, and gastrointestinal assessments annually or as needed; consider complete blood count and inflammatory markers annually or as indicated by symptomatology; endoscopy as needed; monitor for increased susceptibility to infection; annual audiology and ophthalmology evaluations throughout childhood.
-related disorder 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 inheriting neither of the familial pathogenic variants. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
[疾病名称]相关疾病是一种临床症状多变的疾病，主要特征为神经功能障碍（肢体痉挛、发育迟缓、智力残疾、癫痫发作、共济失调、眼球震颤）、胃肠道表现（多处肠道闭锁、炎症性肠病）以及联合免疫缺陷（白细胞减少、可变免疫球蛋白缺陷）。发病年龄通常在产前或幼儿期；个体可能出现这些特征的任意组合。极少数个体表现为迟发性遗传性痉挛性截瘫。脑部磁共振成像（MRI）结果可能包括髓鞘形成不良性脑白质营养不良、小脑发育不全/萎缩、胼胝体变薄或发育异常以及/或外侧裂周围多小脑回。
诊断/检测：[疾病名称]相关疾病的诊断通过先证者具有特征性表现且经分子基因检测鉴定出双等位基因致病性变异来确立。
由多学科团队提供个体化护理；针对肢体痉挛和运动问题，必要时进行物理治疗、职业治疗、使用辅助移动设备以及药物治疗；针对言语障碍和/或吞咽困难进行言语治疗；必要时使用沟通辅助设备；为智力残疾提供教育支持；针对癫痫发作必要时使用抗癫痫药物；针对喂养问题必要时进行胃造口术；外科医生和胃肠病学家针对多处肠道闭锁和炎症性肠病进行治疗；免疫学家针对免疫缺陷进行治疗；针对听力和视力问题进行标准治疗。每年或根据需要进行神经、发育和胃肠道评估；根据症状考虑每年进行全血细胞计数和炎症指标检测；必要时进行内镜检查；监测感染易感性增加情况；儿童期每年进行听力和眼科评估。
[疾病名称]相关疾病以常染色体隐性方式遗传。如果已知父母双方均为致病性变异的杂合子，受影响个体的每个同胞在受孕时有25%的几率受影响，50%的几率为无症状携带者，25%的几率既不继承家族性致病性变异中的任何一个。一旦在受影响的家庭成员中鉴定出致病性变异，就可以对有风险的亲属进行携带者检测以及进行产前和植入前基因检测。
