NEWBORN SCREENING FOR PILOT STUDY FOR ADRENOLEUKODYSTROPHY (ALD)

新生儿筛查的目标是发现新生儿可能致命或致残的情况，从而为早期治疗提供机会之窗，通常是在儿童仍无症状的情况下。这种早期发现和治疗可能对受影响儿童的病情临床严重程度产生深远影响。如果不加以诊断和治疗，针对性疾病的后果可能是可怕的，许多疾病会导致不可逆转的神经损伤、智力、发育和身体残疾，甚至死亡。2006年，美国医学遗传学学会(ACMG)制定了新生儿筛查指南，建议对所有新生儿进行31种“核心疾病”的筛查，并报告在核心评估中发现的26种次要疾病。这些建议已被卫生与公众服务部新生儿和儿童遗传性疾病咨询委员会(经2000年《儿童健康法》授权)和卫生与公众服务部秘书接受。大多数州现在使用这种或非常类似的面板进行新生儿筛查。目前，已发现数千种罕见疾病，数百种可能从新生儿筛查中受益。 X连锁肾上腺脑白质营养不良(ALD)是一组名为脑白质营养不良的遗传性疾病之一，会损害髓鞘，髓鞘是包围大脑神经细胞的绝缘膜。女性有两条X染色体，是疾病的携带者，但由于男性只有一条X染色体，缺乏额外X染色体的保护作用，他们受到的影响更严重。患有X-ALD的人在大脑和肾上腺皮质积累了高水平的饱和超长链脂肪酸(VLCFA)。髓鞘丢失和肾上腺进行性功能障碍是X-ALD的主要特征。虽然几乎所有的X-ALD患者都患有肾上腺皮质功能不全，也被称为爱迪生病，但神经症状可以从儿童时期开始，也可以在成年后开始。儿童脑型最为严重，发病年龄在4岁至10岁之间。最常见的症状通常是行为变化，如异常的退缩或攻击性，记忆力差，学习成绩差。其他症状包括视力丧失、学习障碍、癫痫发作、说话不清晰、吞咽困难、耳聋、步态和协调障碍、疲劳、间歇性呕吐、皮肤色素沉着增加和进行性痴呆。较轻的成人起病形式也被称为肾上腺脊髓神经病(AMN)，通常在21岁至35岁之间开始。症状可能包括进行性僵硬、肢体无力或瘫痪，以及共济失调。虽然成人型ALD的进展慢于经典的儿童期ALD，但它也会导致大脑功能的恶化。几乎一半的X-ALS携带者会患上较轻微的X-ALD。 所有ALD患者必须定期检测肾上腺功能。用肾上腺激素治疗可以挽救生命。ALD的对症和支持治疗包括物理治疗、心理支持和特殊教育。除非及早进行骨髓移植，否则儿童大脑X-ALD患者的预后通常很差，这是由于神经功能的进行性恶化。死亡通常发生在症状出现后1至10年内。成人发病的AMN将在几十年内进展。

The goal of newborn screening is to detect potentially fatal or disabling conditions in newborns, thereby providing a window of opportunity for early treatment, often while the child is still asymptomatic. Such early detection and treatment can have a profound impact on the clinical severity of the condition in the affected child. If left undiagnosed and untreated, the consequences of the targeted disorders can be dire, many causing irreversible neurological damage, intellectual, developmental and physical disabilities, and even death. In 2006, the American College of Medical Genetics (ACMG) developed newborn screening guidelines that recommend that all newborn infants be screened for 31 "core conditions" and that 26 secondary conditions identified during the core evaluations be reported. These recommendations have been accepted by the Department of Health and Human Services (HHS) Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) (authorized by the Children's Health Act of 2000), and by the Secretary of HHS. Most states now use this or very similar panels for newborn screening. Currently, there are thousands of rare disorders that have been identified and hundreds that could potentially benefit from newborn screening. X-linked Adrenoleukodystrophy (ALD) is one of a group of genetic disorders called the leukodystrophies that cause damage to the myelin sheath, an insulating membrane that surrounds nerve cells in the brain. Women have two X chromosomes and are the carriers of the disease, but since men only have one X chromosome and lack the protective effect of the extra X chromosome, they are more severely affected. People with X-ALD accumulate high levels of saturated, very long chain fatty acids (VLCFA) in the brain and adrenal cortex. The loss of myelin and the progressive dysfunction of the adrenal gland are the primary characteristics of X-ALD. While nearly all patients with X-ALD suffer from adrenal insufficiency, also known as Addison's disease, the neurological symptoms can begin either in childhood or in adulthood. The childhood cerebral form is the most severe, with onset between ages 4 and 10. The most common symptoms are usually behavioral changes such as abnormal withdrawal or aggression, poor memory, and poor school performance. Other symptoms include visual loss, learning disabilities, seizures, poorly articulated speech, difficulty swallowing, deafness, disturbances of gait and coordination, fatigue, intermittent vomiting, increased skin pigmentation, and progressive dementia. The milder adult-onset form is also known as adrenomyeloneuropathy (AMN), which typically begins between ages 21 and 35. Symptoms may include progressive stiffness, weakness or paralysis of the lower limbs, and ataxia. Although adult-onset ALD progresses more slowly than the classic childhood form, it can also result in deterioration of brain function. Almost half the women who are carriers of X-ALS will develop a milder form of X-ALD. Adrenal function must be tested periodically in all patients with ALD. Treatment with adrenal hormones can be lifesaving. Symptomatic and supportive treatments for ALD include physical therapy, psychological support, and special education. Prognosis for patients with childhood cerebral X-ALD is generally poor due to progressive neurological deterioration unless bone marrow transplantation is performed early. Death usually occurs within 1 to 10 years after the onset of symptoms. Adult-onset AMN will progress over decades.