NEWBORN SCREENING FOR PILOT STUDY FOR ADRENOLEUKODYSTROPHY (ALD)

新生儿肾上腺脑白质营养不良 (ALD) 试点研究筛查

• 批准号: 9360162
• 负责人: WILLIAM WILCOX
• 金额: $ 66.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-03-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9360162
• 关键词: 21 year old; Addison' s disease; Adrenal Cortex; Adrenal Glands; Adrenal gland hypofunction; Adrenal hormone preparation; Adrenoleukodystrophy; Adrenomyeloneuropathy; Adult; Advisory Committees; Affect; Age; Aggressive behavior; American; Area; Behavioral; Biogenesis; Blindness; Blood specimen; Bone Marrow Transplantation; Brain; Cerebrum; Cessation of life; Characteristics; Child; Child health care; Childhood; Clinical; Contractor; Data; Deglutition; Dementia; Detection; Deterioration; Development; Developmental Disabilities; Diagnostic tests; Disease; Early Diagnosis; Early treatment; Environment; Evaluation; Fatigue; Female; Functional disorder; Gait abnormality; Goals; Guidelines; Health; Hereditary Disease; Human; Infantile Refsum Disease; Intellectual functioning disability; Laboratories; Learning Disabilities; Left; Limb Ataxia; Medical Genetics; Membrane; Memory; Methodology; Methods; Myelin; Myelin Sheath; National Institute of Child Health and Human Development; Neonatal Adrenoleukodystrophy; Neonatal Screening; Nervous System Trauma; Neurologic; Neurons; Newborn Infant; Paralysed; Patients; Performance; Physical therapy; Physically Handicapped; Pilot Projects; Randomized; Rare Diseases; Recommendation; Reporting; Research Infrastructure; Resources; Schools; Seizures; Services; Severities; Skin Pigmentation; Special Education; Speech; Symptoms; Testing; Translational Research; United States Dept. of Health and Human Services; Very Long Chain Fatty Acid; Vomiting; Withdrawal; Woman; X Chromosome; Zellweger Syndrome; college; common symptom; deafness; follow-up; leukodystrophy; male; men; new technology; outcome forecast; programs; protective effect; psychologic; screening; support network; technology validation

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.

新生儿筛查的目的是发现新生儿潜在的致命或致残状况，从而为早期治疗提供机会（通常是在孩子还没有症状时）。这种早期发现和治疗可以对受影响儿童病情的临床严重程度产生深远的影响。如果不及时诊断和治疗，目标疾病的后果可能是可怕的，许多会导致不可逆的神经损伤、智力、发育和身体残疾，甚至死亡。 2006年，美国医学遗传学学院（ACMG）制定了新生儿筛查指南，建议对所有新生儿进行31种“核心病症”筛查，并报告核心评估期间发现的26种次要病症。这些建议已被美国卫生与公众服务部 (HHS) 新生儿和儿童遗传性疾病咨询委员会 (ACHDNC)（经 2000 年《儿童健康法》授权）和 HHS 部长接受。现在大多数州都使用此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，还有数百种可能受益于新生儿筛查。 X 连锁肾上腺脑白质营养不良 (ALD) 是一组称为脑白质营养不良的遗传性疾病之一，会导致髓鞘损伤，髓鞘是大脑中神经细胞周围的绝缘膜。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，因此受到的影响更为严重。患有 X-ALD 的人会在大脑和肾上腺皮质中积累高水平的饱和超长链脂肪酸 (VLCFA)。髓磷脂缺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 X-ALD 患者都患有肾上腺功能不全（也称为艾迪生氏病），但神经系统症状可能在儿童期或成年期开始出现。儿童脑型最为严重，发病年龄为 4 至 10 岁。最常见的症状通常是行为改变，如异常退缩或攻击性、记忆力差和学习成绩差。其他症状包括视力丧失、学习障碍、癫痫、言语不清、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。成人发病的较温和形式也称为肾上腺脊髓神经病 (AMN)，通常在 21 至 35 岁之间开始。症状可能包括进行性下肢僵硬、虚弱或瘫痪以及共济失调。尽管成人发病的 ALD 进展速度比典型的儿童期 ALD 慢，但它也会导致大脑功能恶化。几乎一半的 X-ALS 携带者女性会患上较温和的 X-ALD。 所有 ALD 患者都必须定期检测肾上腺功能。肾上腺激素治疗可以挽救生命。 ALD 的对症治疗和支持治疗包括物理治疗、心理支持和特殊教育。儿童脑部 X-ALD 患者的预后通常较差，因为神经功能进行性恶化，除非及早进行骨髓移植。死亡通常发生在症状出现后 1 至 10 年内。成人发病的 AMN 将在几十年内发展。