title: TMEM70 deficiency: long-term outcome of 48 patients.
abstract: OBJECTIVE
  TMEM70 deficiency is the most common nuclear-encoded defect affecting the ATP synthase. In this multicentre retrospective study we characterise the natural history of the disease, treatment and outcome in 48 patients with mutations in TMEM70. Eleven centers from eight European countries, Turkey and Israel participated.
  
  
  RESULTS
  All 27 Roma and eight non-Roma patients were homozygous for the common mutation c.317-2A > G. Five patients were compound heterozygotes for the common mutation and mutations c.470 T > A, c.628A > C, c.118_119insGT or c.251delC. Six Arab Muslims and two Turkish patients were homozygous for mutations c.238C > T, c.316 + 1G > T, c.336 T > A, c.578_579delCA, c.535C > T, c.359delC. Age of onset was neonatal in 41 patients, infantile in six cases and two years in one child. The most frequent symptoms at onset were poor feeding, hypotonia, lethargy, respiratory and heart failure, accompanied by lactic acidosis, 3-methylglutaconic aciduria and hyperammonaemia. Symptoms further included: developmental delay (98%), hypotonia (95%), faltering growth (94%), short stature (89%), non-progressive cardiomyopathy (89%), microcephaly (71%), facial dysmorphism (66%), hypospadias (50% of the males), persistent pulmonary hypertension of the newborn (22%) and Wolff-Parkinson-White syndrome (13%). One or more acute metabolic crises occurred in 24 surviving children, frequently followed by developmental regression. Hyperammonaemic episodes responded well to infusion with glucose and lipid emulsion, and ammonia scavengers or haemodiafiltration. Ten-year survival was 63%, importantly for prognostication, no child died after the age of five years.
  
  
  CONCLUSIONS
  TMEM70 deficiency is a panethnic, multisystemic disease with variable outcome depending mainly on adequate management of hyperammonaemic crises in the neonatal period and early childhood.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, 12808, Prague 2, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Magner
authors.forename: Veronika
authors.initials: V
authors.lastname: Dvorakova
authors.forename: Marketa
authors.initials: M
authors.lastname: Tesarova
authors.forename: Stella
authors.initials: S
authors.lastname: Mazurova
authors.forename: Hana
authors.initials: H
authors.lastname: Hansikova
authors.forename: Martin
authors.initials: M
authors.lastname: Zahorec
authors.forename: Katarina
authors.initials: K
authors.lastname: Brennerova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bzduch
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Horovitz
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.forename: Fatma Tuba
authors.initials: FT
authors.lastname: Eminoğlu
authors.forename: Johannes Adalbert
authors.initials: JA
authors.lastname: Mayr
authors.forename: Johannes
authors.initials: J
authors.lastname: Koch
authors.forename: Diego
authors.initials: D
authors.lastname: Martinelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Konstantopoulou
authors.forename: Joél
authors.initials: J
authors.lastname: Smet
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
authors.forename: Alexander
authors.initials: A
authors.lastname: Broomfield
authors.forename: Vesna
authors.initials: V
authors.lastname: Stojanović
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Rudy
authors.initials: R
authors.lastname: van Coster
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Eva
authors.initials: E
authors.lastname: Morava-Kozicz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.forename: Jiri
authors.initials: J
authors.lastname: Zeman
authors.forename: Tomas
authors.initials: T
authors.lastname: Honzik
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics; D000293:Adolescent; D000328:Adult; D009202:Cardiomyopathies / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019468:Disease Management; D005060:Europe; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D022124:Hyperammonemia / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007557:Israel; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D008661:Metabolism, Inborn Errors / Q000235:genetics; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology*; D009154:Mutation; D012189:Retrospective Studies; D014421:Turkey; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C533106:TMEM70 protein, human