Houlden Henry, Smith Stephen, De Carvalho Mamede, Blake Julian, Mathias Christopher, Wood Nicholas W, Reilly Mary M
Department of Clinical Neurology, Institute of Neurology, London, UK.
Brain. 2002 Dec;125(Pt 12):2681-90. doi: 10.1093/brain/awf270.
Triple A (Allgrove) syndrome is characterized by achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. Affected individuals have between two and four of these relatively common clinical problems; hence the diagnosis is often difficult in all but the classical presentation. The inheritance is autosomal recessive, and most cases of triple A have no family history. Using genetic linkage analysis in a small number of families, a locus on chromosome 12q13 was identified. The triple A gene was identified recently at this locus and called ALADIN (alacrima, achalasia, adrenal insufficiency neurologic disorder). Mutations in this gene were reported in families from North Africa and Europe. The majority of mutations were homozygous. We have identified 20 families with between two and four of the clinical features associated with the triple A syndrome. Sequencing of the triple A gene revealed five families that had a total of nine compound heterozygous mutations, and one Portuguese family (previously published) had two homozygous mutations; these changes were spread throughout the triple A gene in exons 1, 2, 7, 8, 10, 11, 12, 13 and 16, and the poly(A) tract. Those bearing mutations had the classical triple A syndrome of achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. We identified a spectrum of associated neurological abnormalities in these cases, including pupil and cranial nerve abnormalities, frequent optic atrophy, autonomic neuropathy and upper and lower motor neurone signs including distal motor neuropathy and amyotrophy with severe selective ulnar nerve involvement. In these families, we have made genotype-phenotype correlations. Mutations in the triple A gene are thus an important cause of this clinically heterogeneous syndrome, and sequencing represents an important diagnostic investigation. Identifying further mutations and defining their phenotype along with functional protein analysis will help to characterize this neuroendocrine gene.
三A（奥尔格罗夫）综合征的特征为贲门失弛缓症、无泪、肾上腺异常以及进行性神经综合征。受影响个体存在两到四种这些相对常见的临床问题；因此，除了典型表现外，诊断通常很困难。其遗传方式为常染色体隐性遗传，大多数三A综合征病例无家族病史。通过对少数家族进行基因连锁分析，确定了12号染色体长臂13区的一个位点。最近在该位点发现了三A基因，称为ALADIN（无泪、贲门失弛缓症、肾上腺功能不全神经障碍）。在来自北非和欧洲的家族中报告了该基因的突变。大多数突变是纯合的。我们鉴定出20个具有两到四种与三A综合征相关临床特征的家族。对三A基因进行测序发现，有五个家族共有九个复合杂合突变，还有一个葡萄牙家族（此前已发表）有两个纯合突变；这些变化分布在三A基因的外显子1、2、7、8、10、11、12、13和16以及聚腺苷酸尾中。携带突变的个体患有贲门失弛缓症、无泪、肾上腺异常以及进行性神经综合征的典型三A综合征。我们在这些病例中发现了一系列相关的神经异常，包括瞳孔和颅神经异常、频繁的视神经萎缩、自主神经病变以及上、下运动神经元体征，包括远端运动神经病变和肌萎缩，严重选择性累及尺神经。在这些家族中，我们进行了基因型与表型的关联分析。因此，三A基因的突变是这种临床异质性综合征的一个重要病因，测序是一项重要的诊断检查。识别更多突变并确定其表型以及进行功能性蛋白质分析将有助于明确这种神经内分泌基因的特征。
