Clinical and Molecular Characteristics of Mitochondrial DNA Depletion Syndrome Associated with Neonatal Cholestasis and Liver Failure

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• 作者：Abdulrahman Al-Hussaini ; MD¹ ; ^{aa_alhussaini@yahoo.com" class="auth_mail} ; Eissa Faqeih ; MD² ; Ayman W. El-Hattab ; MD² ; Majid Alfadhel³ ; Ali Asery ; MD¹ ; Badr Alsaleem ; MD¹ ; Eman Bakhsh ; MD⁴ ; Ashraf Ali ; MD⁵ ; Ali Alasmari ; MD² ; Khurram Lone ; MD¹ ; Ahmed Nahari ; MD¹ ; Wafaa Eyaid ; MD³ ; Mohammed Al Balwi ; MD⁵ ; ⁶ ; Kate Craig ; PhD⁷ ; Anna Butterworth ; BSc⁷ ; Langping He ; PhD⁷ ; Robert W. Taylor ; PhD ; FRCPath⁷
• 关键词：ATP ; Adenosine triphosphate ; DGUOK ; Deoxyguanosine kinase ; MDS ; Mitochondrial DNA depletion syndrome ; MRI ; Magnetic resonance imaging ; mtDNA ; Mitochondrial DNA
• 刊名：The Journal of Pediatrics
• 出版年：March, 2014
• 年：2014
• 卷：164
• 期：3
• 页码：553-559.e2
• 全文大小：1264 K

文摘

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Objective

To determine the frequency of mitochondrial DNA depletion syndrome (MDS) in infants with cholestasis and liver failure and to further clarify the clinical, biochemical, radiologic, histopathologic, and molecular features associated with MDS due to deoxyguanosine kinase (DGUOK) and MPV17 gene mutations.

Study design

We studied 20 infants with suspected hepatocerebral MDS referred to our tertiary care center between 2007 and 2013. Genomic DNA was isolated from blood leukocytes, liver, and/or skeletal muscle samples by standard methods. Mitochondrial DNA copy number relative to nuclear DNA levels was determined in muscle and/or liver DNA using real-time quantitative polymerase chain reaction and compared with age-matched controls. Nuclear candidate genes, including polymerase 纬, MPV17, and DGUOK were sequenced using standard analyses.

Results

We identified pathogenic MPV17 and DGUOK mutations in 11 infants (6 females) representing 2.5% of the 450 cases of infantile cholestasis and 22% of the 50 cases of infantile liver failure referred to our center during the study period. All of the 11 patients manifested cholestasis that was followed by a rapidly progressive liver failure and death before 2 years of life. Mitochondrial DNA depletion was demonstrated in liver or muscle for 8 out of the 11聽cases where tissue was available. Seven patients had mutations in the MPV17 gene (3 novel mutations), 4 patients had DGUOK mutations (of which 2 were novel mutations).

Conclusion

Mutations in the MPV17 and DGUOK genes are present in a significant percentage of infants with liver failure and are associated with poor prognosis.