Rare Diseases and Medical Genetics Unit, Academic Department of Pediatrics (DPUO), Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio, 4, 00165, Rome, Italy.
Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Orphanet J Rare Dis. 2021 Mar 1;16(1):112. doi: 10.1186/s13023-021-01731-6.
Adenylosuccinate lyase deficiency (ADSLD) is an ultrarare neurometabolic recessive disorder caused by loss-of-function mutations in the ADSL gene. The disease is characterized by wide clinical variability. Here we provide an updated clinical profiling of the disorder and discuss genotype-phenotype correlations.
Data were collected through "Our Journey with ADSL deficiency Association" by using a dedicated web survey filled-in by parents. Clinical and molecular data were collected from 18 patients (12 males, median age 10.9 years ± 7.3), from 13 unrelated families. The age at onset ranged from birth to the first three years (median age 0.63 years ± 0.84 SD), and age at diagnosis varied from 2 months to 17 years, (median age 6.4 years ± 6.1 SD). The first sign was a psychomotor delay in 8/18 patients, epilepsy in 3/18, psychomotor delay and epilepsy in 3/18, and apneas, hypotonia, nystagmus in single cases. One patient (sibling of a previously diagnosed child) had a presymptomatic diagnosis. The diagnosis was made by exome sequencing in 7/18 patients. All patients were definitively diagnosed with ADSL deficiency based on pathogenic variants and/or biochemical assessment. One patient had a fatal neonatal form of ADSL deficiency, seven showed features fitting type I, and nine were characterized by a milder condition (type II), with two showing a very mild phenotype. Eighteen different variants were distributed along the entire ADSL coding sequence and were predicted to have a variable structural impact by impairing proper homotetramerization or catalytic activity of the enzyme. Six variants had not previously been reported. All but two variants were missense.
The study adds more details on the spectrum of ADSLD patients' phenotypes and molecular data.
腺嘌呤琥珀酸裂解酶缺乏症（ADSLD）是一种超罕见的神经代谢隐性遗传疾病，由 ADSL 基因的功能丧失突变引起。该疾病的临床表现具有广泛的变异性。本文提供了该疾病的最新临床特征分析，并讨论了基因型-表型相关性。
通过使用专门的网络调查，由父母填写，我们通过“ADSL 缺乏症协会的旅程”收集数据。我们从 13 个无关的家庭中收集了 18 名患者（12 名男性，中位年龄 10.9 岁±7.3 岁）的临床和分子数据。发病年龄从出生到三岁（中位年龄 0.63 岁±0.84 标准差），诊断年龄从 2 个月到 17 岁不等（中位年龄 6.4 岁±6.1 标准差）。18 名患者中有 8 名首发表现为精神运动发育迟缓，3 名首发表现为癫痫，3 名首发表现为精神运动发育迟缓伴癫痫，1 名首发表现为呼吸暂停、低张力、眼球震颤。1 名患者（先前诊断患儿的同胞）存在无症状期诊断。7 名患者通过外显子组测序确诊，其余 11 名患者则基于致病性变异和/或生化评估明确诊断。1 名患者存在致命性新生儿型 ADSLD，7 名患者表现为 I 型特征，9 名患者表现为更轻的 II 型特征，其中 2 名表现为非常轻微的表型。18 种不同的变异分布在 ADSL 编码序列的全长上，通过影响酶的正确同源四聚化或催化活性，预测具有不同的结构影响。其中 6 种变异尚未见报道。除了 2 种变异之外，所有变异均为错义变异。
该研究增加了关于 ADSLD 患者表型和分子数据谱的更多细节。
