Persistent pulmonary arterial hypertension in the newborn (PPHN)

A frequent manifestation of TMEM70 defective patients

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)353-359
Number of pages7
JournalMolecular Genetics and Metabolism
Volume111
Issue number3
DOIs
Publication statusPublished - Mar 2014

Fingerprint

Pulmonary Hypertension
Newborn Infant
Hypertrophic Cardiomyopathy
Echocardiography
Mutation
Hyperammonemia
Lactic Acidosis
Muscle Hypotonia
Ventilation
Parturition
Nitric Oxide
Adenosine Triphosphate
Defects
High-Frequency Ventilation
Mitochondrial Diseases
Cardiomyopathies
Intubation
Milk
Phenotype
Sildenafil Citrate

Keywords

  • Mitochondrial diseases
  • Persistent pulmonary neonatal hypertension
  • TMEM70 defect

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

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title = "Persistent pulmonary arterial hypertension in the newborn (PPHN): A frequent manifestation of TMEM70 defective patients",
abstract = "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.",
keywords = "Mitochondrial diseases, Persistent pulmonary neonatal hypertension, TMEM70 defect",
author = "Michela Catteruccia and Daniela Verrigni and Diego Martinelli and Alessandra Torraco and Teresa Agovino and Luisa Bonaf{\'e} and Adele D'Amico and Donati, {Maria Alice} and Rachele Adorisio and Santorelli, {Filippo Maria} and Rosalba Carrozzo and Enrico Bertini and Carlo Dionisi-Vici",
year = "2014",
month = "3",
doi = "10.1016/j.ymgme.2014.01.001",
language = "English",
volume = "111",
pages = "353--359",
journal = "Molecular Genetics and Metabolism",
issn = "1096-7192",
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TY - JOUR

T1 - Persistent pulmonary arterial hypertension in the newborn (PPHN)

T2 - A frequent manifestation of TMEM70 defective patients

AU - Catteruccia, Michela

AU - Verrigni, Daniela

AU - Martinelli, Diego

AU - Torraco, Alessandra

AU - Agovino, Teresa

AU - Bonafé, Luisa

AU - D'Amico, Adele

AU - Donati, Maria Alice

AU - Adorisio, Rachele

AU - Santorelli, Filippo Maria

AU - Carrozzo, Rosalba

AU - Bertini, Enrico

AU - Dionisi-Vici, Carlo

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

KW - Mitochondrial diseases

KW - Persistent pulmonary neonatal hypertension

KW - TMEM70 defect

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U2 - 10.1016/j.ymgme.2014.01.001

DO - 10.1016/j.ymgme.2014.01.001

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SN - 1096-7192

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