Cortese Andrea, Reilly Mary M, Houlden Henry
Department of Neuromuscular Diseases, University College London, London, United Kingdom
Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
The phenotypic spectrum associated with biallelic AAGGG repeat expansion encompasses a range including (1) typical erebellar taxia, europathy, estibular reflexia yndrome (CANVAS); (2) cerebellar, sensory, and vestibular impairment; (3) more limited phenotypes involving predominantly or exclusively one of the systems involved in balance control; (4) autonomic dysfunction; and (5) cough. Onset begins after age 35 years. In a retrospective study of 100 affected individuals after ten years of disease duration, two thirds had clinical features of CANVAS; 16 had a complex sensory ataxia with cerebellar or vestibular involvement; and 15 had a sensory neuropathy as the only clinically detectable manifestation.
DIAGNOSIS/TESTING: The diagnosis of CANVAS / spectrum disorder is established in a proband with suggestive findings and biallelic intronic AAGGG pentanucleotide expansions in identified by molecular genetic testing that is targeted to detect these expansions. Note that pathogenic AAGGG repeat expansions cannot be detected by sequence-based multigene panels or exome sequencing. However, they can be suspected by genome sequencing.
The goals of treatment are to maximize function and reduce complications. Depending on the clinical manifestations, each affected individual should be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, and (depending on individual needs) speech therapists, respiratory therapists, nutritionists, and gastroenterologists. Routine follow up by multidisciplinary specialists to assess: progression of neurologic findings; mobility, self-help skills; need for alternative communication methods; and aspiration risk and feeding methods. Medications of known toxicity for peripheral nerves (e.g., neurotoxic chemotherapy agents, pyridoxine), the cerebellum (e.g., phenytoin), or the vestibular system (e.g., aminoglycosides); chronic alcohol consumption.
CANVAS / spectrum disorder is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AAGGG repeat expansion, 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 biallelic AAGGG repeat expansions have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
与双等位基因AAGGG重复序列扩增相关的表型谱范围包括：（1）典型的小脑共济失调、周围神经病、前庭反射综合征（CANVAS）；（2）小脑、感觉和前庭功能障碍；（3）更局限的表型，主要或仅涉及平衡控制相关系统之一；（4）自主神经功能障碍；（5）咳嗽。发病始于35岁以后。一项对100例患病个体进行的为期10年的回顾性研究发现，三分之二的患者具有CANVAS的临床特征；16例有复杂的感觉性共济失调，伴有小脑或前庭受累；15例仅有感觉神经病作为唯一可临床检测到的表现。
诊断/检测：对于具有提示性发现且经分子遗传学检测鉴定出双等位基因内含子AAGGG五核苷酸扩增的先证者，可确立CANVAS/谱系障碍的诊断。请注意，基于序列的多基因检测板或外显子组测序无法检测到致病性AAGGG重复序列扩增。然而，可通过全基因组测序怀疑其存在。
治疗目标是使功能最大化并减少并发症。根据临床表现，每个受影响个体应由多学科团队管理，团队成员包括神经科医生、职业治疗师、物理治疗师、物理医学与康复医生，以及（根据个体需求）言语治疗师、呼吸治疗师、营养师和胃肠病学家。多学科专家进行定期随访，以评估：神经学检查结果的进展；活动能力、自助技能；是否需要替代沟通方法；以及误吸风险和喂养方式。避免使用已知对周围神经（如神经毒性化疗药物、吡哆醇）、小脑（如苯妥英）或前庭系统（如氨基糖苷类）有毒性的药物；避免长期饮酒。
CANVAS/谱系障碍以常染色体隐性方式遗传。如果已知父母双方均为AAGGG重复序列扩增的杂合子，则患病个体的每个同胞在受孕时有25%的几率患病，50%的几率为无症状携带者，25%的几率未患病且不是携带者。一旦在患病家庭成员中鉴定出双等位基因AAGGG重复序列扩增，就可以对有风险的亲属进行携带者检测、对高风险妊娠进行产前检测以及进行植入前基因检测。
