Alecu Julian, Schierbaum Luca, Ebrahimi-Fakhari Darius
Movement Disorders Program, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a childhood-onset and complex form of hereditary spastic paraplegia. Spastic paraparesis is a universal feature in affected individuals. Manifestations typically begin before age one year, with infants presenting with hypotonia, mild postnatal microcephaly, and delayed developmental milestones. Seizures are common in early childhood, often starting as prolonged febrile seizures. As the disease progresses, older children have intellectual disability that is usually moderate to severe; most affected individuals communicate nonverbally. Neurobehavioral/psychiatric manifestations (e.g., impulsivity, hyperactivity, and inattention) are common. Hypotonia transitions to progressive lower-extremity weakness and spasticity, accompanied by pyramidal signs such as plantar extension, ankle clonus, and hyperreflexia. Although some children achieve independent ambulation, most eventually lose this ability and rely on mobility aids or wheelchairs. In adolescence or early adulthood, spasticity may affect the upper extremities in some individuals but is generally less severe and not significantly disabling. Complications in some individuals include contractures, foot deformities, and bladder and bowel dysfunction. Dysphagia may emerge in advanced stages of the disease.
DIAGNOSIS/TESTING: The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic pathogenic variants in , , , or identified on molecular genetic testing.
Supportive multidisciplinary care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (including neurology, orthopedics/physiatry, physical therapy, occupational therapy, developmental pediatrics, and speech-language pathology) and clinical genetics. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, affected individuals should be evaluated periodically (i.e., every 6-12 months) by their multidisciplinary care specialists.
AP-4-HSP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an , , , or 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 , , , or pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.
AP-4相关遗传性痉挛性截瘫（AP-4-HSP）是一种起病于儿童期的复杂形式的遗传性痉挛性截瘫。痉挛性轻截瘫是受累个体的普遍特征。症状通常在1岁前开始出现，婴儿表现为肌张力减退、出生后轻度小头畸形和发育里程碑延迟。癫痫在儿童早期很常见，通常始于长时间的热性惊厥。随着疾病进展，大龄儿童会出现通常为中度至重度的智力残疾；大多数受累个体通过非语言方式交流。神经行为/精神症状（如冲动、多动和注意力不集中）很常见。肌张力减退会转变为进行性下肢无力和痉挛，并伴有锥体束征，如跖伸、踝阵挛和反射亢进。虽然一些儿童能够独立行走，但大多数最终会失去这种能力，而依赖移动辅助工具或轮椅。在青少年期或成年早期，痉挛在一些个体中可能会影响上肢，但通常程度较轻且不会导致严重残疾。一些个体的并发症包括挛缩、足部畸形以及膀胱和肠道功能障碍。吞咽困难可能在疾病晚期出现。
诊断/检测：在一个先证者中，若有提示性发现且分子遗传学检测鉴定出 、 、 或 基因的双等位基因致病性变异，则可确立AP-4-HSP的诊断。
建议采取支持性多学科护理，以改善生活质量、最大化功能并减少并发症。理想情况下，这需要相关领域的专家（包括神经科、骨科/物理医学与康复科、物理治疗、职业治疗、发育儿科学和言语语言病理学）以及临床遗传学进行多学科护理。为了监测现有症状、个体对支持性护理的反应以及新症状的出现，受累个体应由其多学科护理专家定期（即每6 - 12个月）进行评估。
AP-4-HSP以常染色体隐性方式遗传。如果已知父母双方均为 、 、 或 致病性变异的杂合子，受累个体的每个同胞在受孕时有25%的概率受到影响，50%的概率为无症状携带者，25%的概率未受影响且不是携带者。一旦在受累家庭成员中鉴定出 、 、 或 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/植入前基因检测。
