CASE: 

Zac is a 13-year-old boy who presented with his parents to developmental-behavioral pediatrics seeking diagnostic clarity. He was born by vaginal delivery at full term after an uncomplicated pregnancy. Developmental milestones were met at typical ages until he was noted to have language delay and to be hyperactive and impulsive on entering preschool at age 4 years. Although he used some phrases in speech, he often used physical force to take toys from other children, rather than using words.

On entering preschool at age 4 years, he was noted to have language delay (i.e., continued use of phrase speech only) and to be hyperactive and impulsive. An evaluation to determine eligibility for an Individualized Education Program (IEP) was completed and found him to have delays in cognition, receptive language, expressive language, social-emotional, and adaptive skills. His fine motor skills were in the low average range, and his gross motor skills were in the average range. He was admitted into an early childhood special education program, and aggressive behavior and hyperactivity decreased in the structured classroom.

At age 7 years, Zac was re-evaluated by the school district and found to have moderate intellectual disability (ID). Chromosomal microarray analysis and testing for Fragile X syndrome were normal. He was noted to enjoy interacting with other children and adults, but his play was very immature (e.g., preference for cause/effect toys). He was able to respond appropriately when asked his name and age, but he also frequently demonstrated echolalia. He was also evaluated by his primary care physician and found to meet the criteria for attention-deficit/hyperactivity disorder, combined presentation (ADHD). Treatment with methylphenidate was initiated but discontinued after a brief time because of increased aggressive behaviors.

Owing to continued significant tantrums, aggressive tendencies, and inability to communicate his basic needs, Zac was evaluated at a local Regional Center (statewide system for resources and access to services for individuals with developmental disabilities) at age 10 years and found to meet the criteria for autism spectrum disorder (ASD), and previous diagnosis of ID was confirmed. Zac received applied behavior analysis (ABA), but this was discontinued after 1 year because of a combination of a change in the insurance provider and parental perception that the therapy had not been beneficial.

Zac became less hyperactive and energetic as he grew older. By the time Zac presented to the developmental-behavioral clinic at age 13 years, he was consistently using approximately 30 single words and was no longer combining words into phrases. He had a long latency in responding to verbal and nonverbal cues and seemed to be quite withdrawn. Physical examination revealed scoliosis and hand tremors while executing fine motor tasks. Seizures were not reported, but neuromotor regression was apparent from the examination and history. Laboratory studies including thyroid-stimulating hormone, free T4, creatine kinase, very-long-chain fatty acids, lactate, pyruvate, urine organic acids, and plasma amino acids were normal. Cranial magnetic resonance imaging demonstrated abnormal T2 hyperintensities in the periventricular and deep cerebral white matter and peridentate cerebellar white matter, consistent with a “tigroid” pattern seen in metachromatic leukodystrophy (MLD) and other white matter neurodegenerative diseases. Arylsulfatase A mutation was detected with an expanded ID/ASD panel, and leukocyte arylsulfatase activity was low, confirming the diagnosis of juvenile-onset MLD.

Are there behavioral markers and/or historical caveats that clinicians can use to distinguish between ASD/ID with coexisting ADHD and a neurodegenerative disorder with an insidious onset of regression?

中文翻译：

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诊断的阴影：模仿自闭症谱系障碍的隐匿神经退化表现

案件： 

扎克 (Zac) 是一名 13 岁的男孩，他与父母一起前往发育行为儿科寻求明确的诊断。他是在一次简单的怀孕后足月通过阴道分娩出生的。他在正常年龄就达到了发育里程碑，直到 4 岁时进入学前班时发现他有语言迟缓、过度活跃和冲动。尽管他在言语中使用了一些短语，但他经常使用体力从其他孩子那里拿走玩具，而不是使用言语。

4 岁时进入学前班时，他被发现有语言发育迟缓（即仅持续使用短语言语）并且过度活跃和冲动。一项确定个人化教育计划 (IEP) 资格的评估已经完成，发现他在认知、接受性语言、表达性语言、社交情感和适应技能方面存在延迟。他的精细运动技能处于较低的平均范围，而他的粗大运动技能处于平均范围。他被录取进入一个幼儿特殊教育项目，在结构化的课堂上，攻击性行为和多动行为减少了。

扎克 7 岁时，学区对他进行了重新评估，发现他患有中度智力障碍 (ID)。染色体微阵列分析和脆性 X 综合征检测均正常。人们注意到他喜欢与其他儿童和成人互动，但他的游戏非常不成熟（例如，偏爱因果玩具）。当被问及他的姓名和年龄时，他能够做出适当的回应，但他也经常表现出模仿的样子。他的初级保健医生还对他进行了评估，结果发现他符合注意力缺陷/多动障碍合并表现（ADHD）的标准。开始使用哌醋甲酯治疗，但由于攻击行为增加，短时间内就停止了。

由于持续严重发脾气、攻击性倾向和无法表达自己的基本需求，扎克在 10 岁时在当地区域中心（为发育障碍人士提供资源和服务的全州系统）接受了评估，结果发现符合标准患有自闭症谱系障碍 (ASD)，并且之前的 ID 诊断得到证实。扎克接受了应用行为分析 (ABA)，但由于保险提供者发生变化以及家长认为该疗法没有效果，一年后就停止了。

随着年龄的增长，扎克不再那么活跃和精力充沛。当扎克 13 岁时到发展行为诊所就诊时，他已经持续使用大约 30 个单词，并且不再将单词组合成短语。他对言语和非言语暗示的反应有很长的潜伏期，而且似乎很孤僻。体检发现在执行精细运动任务时脊柱侧弯和手部颤抖。没有报告癫痫发作，但从检查和病史中可以看出神经运动退化。包括促甲状腺激素、游离 T4、肌酸激酶、极长链脂肪酸、乳酸、丙酮酸、尿液有机酸和血浆氨基酸在内的实验室检查均正常。头颅磁共振成像显示脑室周围和大脑深部白质以及小脑周围白质异常 T2 高信号，与异染性脑白质营养不良 (MLD) 和其他白质神经退行性疾病中观察到的“老虎”模式一致。通过扩展的 ID/ASD 检测组检测到芳基硫酸酯酶 A 突变，并且白细胞芳基硫酸酯酶活性较低，证实了青少年发病的 MLD 的诊断。

临床医生是否可以使用行为标记和/或历史警告来区分患有 ADHD 的 ASD/ID 和隐匿性退化的神经退行性疾病？