Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure.
Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure.
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DOI：
10.1007/s13353-010-0008-y
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发表时间：
2011-02
影响因子：
2.4
通讯作者：
Wegrzyn, Grzegorz
中科院分区：
文献类型：
--
作者：
Pronicka, Ewa;Weglewska-Jurkiewicz, Anna;Taybert, Joanna;Pronicki, Maciej;Szymanska-Debinska, Tamara;Karkucinska-Wieckowska, Agnieszka;Jakobkiewicz-Banecka, Joanna;Kowalski, Pawel;Piekutowska-Abramczuk, Dorota;Pajdowska, Magdalena;Socha, Piotr;Sykut-Cegielska, Jolanta;Wegrzyn, Grzegorz
关键词：
脱氧鸟苷激酶缺乏 (dGK) 是肝脑型线粒体耗竭综合征 (MDS) 的常见原因。招募了 28 名患有原因不明的严重进行性肝功能衰竭的婴儿进行尸检，以寻找脱氧鸟苷激酶 (DGUOK) 基因突变。确定了四名受影响的患者（占研究组的 14%）、两名纯合子、一名复合杂合子和一名仅在一个等位基因上发现 DGUOK 突变的杂合子。检测到 DGUOK 基因中的三种已知致病突变：c.3G>A (p.Met1Ile)、c.494A>T (p.Glu165Val) 和 c.766_767insGATT (p.Phe256X)，以及一种未知致病性的新分子变异 c.813_814insTTT (p.Asn271_Thr272insPhe)。肝脏样本（正常值的 4%、15% 和 10%）和肌肉样本（分别为正常值的 4%、23%、45% 和 6%）证实线粒体 DNA 严重缺失。这些患者出生时体重较胎龄低，并且在出生后的最初几天就出现了适应问题。随后出现肝功能衰竭，分别导致 18 个月、6 个月、5.5 个月和 2.25 个月时死亡。所有儿童均观察到轻度神经系统受累（肌张力减退、精神运动迟缓和上睑下垂）。低血糖（酮症）和乳酸性酸中毒是持续的实验室检查结果。在两个病例中，转铁蛋白饱和度升高、铁蛋白和甲胎蛋白水平升高类似于新生儿血色素沉着症。肝脏组织病理学显示严重的肝损伤，从微结节形成和肝硬化到肝脏结构完全丧失，伴有弥漫性纤维化和新胆管增殖。在两名尸检婴儿中均发现胰岛细胞增生，并伴有大量汇合的巨大胰岛。通过对患者疾病自然史和文献数据的分析，我们得出以下观察结果：(i) 胰岛细胞增生（和高胰岛素血症）可能导致 MDS 相关的低血糖； (ii) 铁超载还可能损害 mtDNA 耗尽的组织； (iii) dGK 缺乏的新生儿经常出现低出生体重、适应困难和新生儿筛查中氨基酸异常等情况。
Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogeneity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDS-associated hypoglycemia; (ii) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates.
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DOI：
10.1097/00005176-200402000-00022
发表时间：
2004-02-01
影响因子：
2.9
作者：
Rabinowitz, SS;Gelfond, D;DiMauro, S
通讯作者：
DiMauro, S
影响因子：
5.1
作者：
Sarzi, Emmanuelle;Bourdon, Alice;Rotig, Agnes
通讯作者：
Rotig, Agnes
影响因子：
12.7
作者：
Filosto, M;Mancuso, M;Simonati, A
通讯作者：
Simonati, A
影响因子：
--
作者：
Mancuso, M;Filosto, M;DiMauro, S
通讯作者：
DiMauro, S
影响因子：
4.2
作者：
Spinazzola, A.;Invernizzi, F.;Zeviani, M.
通讯作者：
Zeviani, M.