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


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.
Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy. Electronic address: michela.catteruccia@gmail.com.
Michela
M
Catteruccia
Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy.
Daniela
D
Verrigni
Unit of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy.
Diego
D
Martinelli
Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy.
Alessandra
A
Torraco
Metabolic and Muscular Unit, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.
Teresa
T
Agovino
Division of Molecular Pediatrics, Lausanne University Hospital, 1011 Lausanne, Switzerland.
Luisa
L
Bonafé
Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy.
Adele
A
D'Amico
Metabolic and Muscular Unit, Neuroscience Department, Meyer Children's Hospital, Florence, Italy.
Maria Alice
MA
Donati
Heart Failure Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital, Rome Italy.
Rachele
R
Adorisio
UOC Neurogenetica e Malattie Neuromuscolari, IRCCS Fondazione Stella Maris, Pisa, Italy.
Filippo Maria
FM
Santorelli
Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy.
Rosalba
R
Carrozzo
Unit for Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy.
Enrico
E
Bertini
Unit of Metabolism, Bambino Gesù Children's Hospital, Rome, Italy.
Carlo
C
Dionisi-Vici
D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D005260:Female; D006801:Humans; D022124:Hyperammonemia / Q000378:metabolism / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009569:Nitric Oxide / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D011687:Purines / Q000008:administration & dosage; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010879:Piperazines; D011687:Purines; D013450:Sulfones; C533106:TMEM70 protein, human; D009569:Nitric Oxide; D000068677:Sildenafil Citrate
Mitochondrial diseases; Persistent pulmonary neonatal hypertension; TMEM70 defect