Persistent pulmonary arterial hypertension in the newborn (PPHN): A frequent manifestation of TMEM70 defective patients

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• 作者：Michela Catteruccia^a ; ^{michela.catteruccia@gmail.com" class="auth_mail} ; Daniela Verrigni^a ; Diego Martinelli^b ; Alessandra Torraco^a ; Teresa Agovino^c ; Luisa Bonaf&eacute ; ^d ; Adele D'Amico^a ; Maria Alice Donati^c ; Rachele Adorisio^e ; Filippo Maria Santorelli^f ; Rosalba Carrozzo^a ; Enrico Bertini^a ; Carlo Dionisi-Vici^b
• 关键词：HCMP ; hypertrophic cardiomyopathy ; 3-MGA ; 3-methylglutaconic aciduria ; PPHN ; persistent neonatal pulmonary hypertension ; NO ; Nitric Oxide ; HFO ventilation ; High Frequency Oscillatory Ventilation ; IMV ; Intubation and Mechanical Ventilation ; ICU ; Intensive Care Unit ; TTE ; transthoracic echocardiogram
• 刊名：Molecular Genetics and Metabolism
• 出版年：March, 2014
• 年：2014
• 卷：111
• 期：3
• 页码：353-359
• 全文大小：258 K

文摘

Introduction

Mutations in the TMEM70 are the most common cause of nuclear ATP synthase deficiency resulting in a distinctive phenotype characterized by severe neonatal hypotonia, hypertrophic cardiomyopathy (HCMP), facial dysmorphism, severe lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria (3-MGA).

Methods and results

We collected 9 patients with genetically confirmed TMEM70 defect from 8 different families. Six were homozygous for the c.317-2A>G mutation, 2 were compound heterozygous for mutations c.317-2A>G and c.628A>C and 1 was homozygous for the novel c.701A>C mutation. Generalized hypotonia, lactic acidosis, hyperammonemia and 3-MGA were present in all since birth. Five patients presented acute respiratory distress at birth requiring intubation and ventilatory support. HCMP was detected in 5 newborns and appeared a few months later in 3 additional children. Five patients showed a severe and persistent neonatal pulmonary hypertension (PPHN) requiring Nitric Oxide (NO) and/or sildenafil administration combined in 2 cases with high-frequency oscillatory (HFO) ventilation. In 3 of these patients, echocardiography detected signs of HCMP at birth.

Conclusions

PPHN is a life-threatening poorly understood condition with bad prognosis if untreated. Pulmonary hypertension has rarely been reported in mitochondrial disorders and, so far, it has been described in association with TMEM70 deficiency only in one patient. This report further expands the clinical and genetic spectrum of the syndrome indicating PPHN as a frequent and life-threatening complication regardless of the type of mutation. Moreover, in these children PPHN appears even in the absence of an overt cardiomyopathy, thus representing an early sign and a clue for diagnosis.