Raininko Raili, Gosky Michael, Padiath Quasar S
Department of Radiology Uppsala University Uppsala, Sweden
University of Pittsburgh Pittsburgh, Pennsylvania
-related autosomal dominant leukodystrophy (ADLD) is a slowly progressive disorder of central nervous system white matter characterized by onset of autonomic dysfunction in the fourth to fifth decade, followed by pyramidal and cerebellar abnormalities resulting in spasticity, ataxia, and tremor. Autonomic dysfunction can include bladder dysfunction, constipation, postural hypotension, erectile dysfunction, and (less often) impaired sweating. Pyramidal signs are often more prominent in the lower extremities (e.g., spastic weakness, hypertonia, clonus, brisk deep tendon reflexes, and bilateral Babinski signs). Cerebellar signs typically appear at the same time as the pyramidal signs and include gait ataxia, dysdiadochokinesia, intention tremor, dysmetria, and nystagmus. Many individuals have sensory deficits starting in the lower limbs. Pseudobulbar palsy with dysarthria, dysphagia, and forced crying and laughing may appear in the seventh or eighth decade. Although cognitive function is usually preserved or only mildly impaired early in the disease course, dementia and psychiatric manifestations can occur as late manifestations. Affected individuals may survive for decades after onset.
DIAGNOSIS/TESTING: The diagnosis of -related ADLD is established in a proband with suggestive clinical and MRI findings and either an duplication or (more rarely) a heterozygous deletion upstream of the promoter identified by molecular genetic testing.
Treatment is symptomatic. For autonomic dysfunction: Neurogenic bladder may require management of urinary retention and/or urgency and recurrent urinary tract infection. Constipation may require good hydration, increased dietary fiber, stool softeners, and/or laxatives. Orthostatic hypotension can be minimized by pharmacologic intervention, compression stockings, physical therapy, and increased dietary salt. Erectile dysfunction is treated medically. Impaired sweating is managed with cool environment and attention to fever during infection. Spasticity may be treated with medications and physical therapy. Ataxia can be managed with strategies to minimize falls and increase strength, and adaptive equipment such as walkers or wheelchairs. Feeding difficulties can be managed with speech therapy and appropriate feeding interventions to assure adequate nutrition while preventing aspiration pneumonia. Routine assessment of: weight, nutrition, and feeding; pulmonary status (re possible recurrent pneumonia); bladder and erectile function; psychosocial well-being; and medications/doses to avoid iatrogenic polypharmacy. At least yearly assessment: by a neurologist for disease manifestations and progression; and by a physiatrist, orthopedist, physical therapist, and occupational therapist to address orthopedic, equipment, and functional needs.
-related ADLD is inherited in an autosomal dominant manner. To date, all individuals diagnosed with -related ADLD whose parents have undergone molecular genetic testing have the disorder as the result of a large duplication (or a deletion upstream of inherited from an affected parent. Each child of an individual with -related ADLD has a 50% chance of inheriting the duplication (or deletion upstream of ). Once the causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for -related ADLD are possible.
相关常染色体显性遗传性脑白质营养不良（ADLD）是一种中枢神经系统白质的缓慢进展性疾病，其特征为在40至50岁时出现自主神经功能障碍，随后出现锥体束和小脑异常，导致痉挛、共济失调和震颤。自主神经功能障碍可包括膀胱功能障碍、便秘、体位性低血压、勃起功能障碍，以及（较少见）出汗障碍。锥体束征通常在下肢更为明显（如痉挛性无力、张力亢进、阵挛、深腱反射亢进和双侧巴宾斯基征）。小脑征通常与锥体束征同时出现，包括步态共济失调、轮替运动障碍、意向性震颤、辨距不良和眼球震颤。许多患者从下肢开始出现感觉缺陷。在70或80岁时可能出现伴有构音障碍、吞咽困难以及强哭强笑的假性球麻痹。虽然在疾病早期认知功能通常得以保留或仅轻度受损，但痴呆和精神症状可作为晚期表现出现。患病个体在发病后可能存活数十年。
诊断/检测：在具有提示性临床和MRI表现的先证者中，通过分子遗传学检测确定存在相关基因的重复或（更少见）启动子上游的杂合缺失，即可诊断相关ADLD。
治疗以对症治疗为主。对于自主神经功能障碍：神经源性膀胱可能需要处理尿潴留和/或尿急以及反复的尿路感染。便秘可能需要充足的水分摄入、增加膳食纤维、使用大便软化剂和/或泻药。体位性低血压可通过药物干预、弹力袜、物理治疗以及增加饮食中的盐分来尽量减轻。勃起功能障碍采用药物治疗。出汗障碍通过保持凉爽环境并在感染时注意发热情况来处理。痉挛可采用药物和物理治疗。共济失调可通过采取尽量减少跌倒和增强力量的策略以及使用助行器或轮椅等适应性设备来处理。喂养困难可通过言语治疗和适当的喂养干预来处理，以确保充足营养同时预防吸入性肺炎。定期评估：体重、营养和喂养情况；肺部状况（可能出现反复肺炎）；膀胱和勃起功能；心理社会健康状况；以及药物/剂量以避免医源性多药联用。至少每年进行评估：由神经科医生评估疾病表现和进展情况；由物理医学与康复医生、骨科医生、物理治疗师和职业治疗师评估骨科、设备和功能需求。
相关ADLD以常染色体显性方式遗传。迄今为止，所有被诊断为相关ADLD且其父母已接受分子遗传学检测的个体，该疾病均是由于一个大的基因重复（或从患病父母遗传的基因上游缺失）所致。相关ADLD患者的每个孩子有50%的机会继承该基因重复（或基因上游缺失）。一旦在患病家庭成员中确定了致病的致病变异，就可以进行相关ADLD的产前和植入前基因检测。
