ABCMdb

ABCA3 p.Arg20Leu

Predicted by SNAP2:	A: D (66%), C: D (63%), D: D (71%), E: D (71%), F: D (66%), G: D (71%), H: D (53%), I: D (63%), K: N (72%), L: D (66%), M: D (63%), N: N (53%), P: D (66%), Q: D (59%), S: D (53%), T: N (53%), V: D (63%), W: D (80%), Y: D (63%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Clinical, radiological and pathological features o... Thorax. 2008 Apr;63(4):366-73. Epub 2007 Nov 16. Doan ML, Guillerman RP, Dishop MK, Nogee LM, Langston C, Mallory GB, Sockrider MM, Fan LL
Clinical, radiological and pathological features of ABCA3 mutations in children.
Thorax. 2008 Apr;63(4):366-73. Epub 2007 Nov 16., [PMID:18024538]

Abstract [show]
BACKGROUND: Mutations in the ABCA3 gene can result in fatal surfactant deficiency in term newborn infants and chronic interstitial lung disease in older children. Previous studies on ABCA3 mutations have focused primarily on the genetic abnormalities and reported limited clinical information about the resultant disease. A study was undertaken to analyse systematically the clinical presentation, pulmonary function, diagnostic imaging, pathological features and outcomes of children with ABCA3 mutations. METHODS: The records of nine children with ABCA3 mutations evaluated at Texas Children's Hospital between 1992 and 2005 were reviewed and their current clinical status updated. Previous diagnostic imaging studies and lung biopsy specimens were re-examined. The results of DNA analyses were confirmed. RESULTS: Age at symptom onset ranged from birth to 4 years. Cough, crackles, failure to thrive and clubbing were frequent findings. Mean lung function was low but tended to remain static. CT scans commonly revealed ground-glass opacification, septal thickening, parenchymal cysts and pectus excavatum. Histopathological patterns included pulmonary alveolar proteinosis, desquamative interstitial pneumonitis and non-specific interstitial pneumonitis, and varied with age. Dense abnormalities of lamellar bodies, characteristic of ABCA3 mutations, were seen by electron microscopy in all adequate specimens. Outcomes varied with the age at which the severity of lung disease warranted open lung biopsy, and some patients have had prolonged survival without lung transplantation. CONCLUSIONS: The presentation and course of interstitial lung disease due to ABCA3 mutations are variable, and open lung biopsy and genetic testing are warranted early in the evaluation of children with a consistent clinical picture.

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45 Five patients eventually Table 1 Characteristics of nine children with ABCA3 mutations Patient no Age of onset, manifestation Clinical features (age at evaluation) CT imaging (age at examination) Mutational analysis Outcomes (current age) 1 Newborn, respiratory failure Ta, Cr, Wh, Cl, Hy (4 years) GGO, ST, PE (2 weeks) Nt622C.T (R208W) Nt2279T.G (M760R) Transplanted (died) (5 years)* 2 Newborn, respiratory failure Ta, Hy (1 month) None Nt289insA Nt4648C.T (R1550W) Transplanted (died) (3 months)* 3 3 months, acute respiratory distress Ta, FTT, Hy (3 months) GGO, ST (3 months) Nt2646insC Nt3757C.T (P1253S) Died (4 months)* 4 2 years, acute respiratory distress Ta, Cr, Cl, FTT, Hy (2 years) GGO, ST, PE (2 years) Nt4732G.A (E1578K) Nt4772A.C (Q1591P) Alive, ILD score 4 (15 years) 5 1 year, recurrent hypoxaemia Ta, Cl, FTT, Hy (3 years) GGO, ST, PE, cysts (2 years) Nt59G.T (R20L) Nt2879T.C (L960S) Alive, ILD score 4 (8 years) 6 Newborn, pneumonia Ta, Cr, Cl, FTT, Hy (10 years) GGO, ST, PE (4 years) Nt875A.T (E292V) Nt3341C.T (T1114M) Transplanted (alive) (12 years)* 7 Newborn, respiratory failure Ta, Cl, FTT (6 years) GGO, ST, PE, cysts (6 years) Nt875A.T (E292V) Nt4706delTCA (deltaI1569) Alive, ILD score 1 (18 years) 8 Newborn, pneumonia Ta, Cr, Cl, Hy (6 years) GGO, PE (6 years) Nt629G.T (G210V) Nt3609delCTT (deltaF1203) Alive, ILD score 3 (11 years) 9 4 years, recurrent hypoxaemia Ta, Cr, Hy (exertional) (8 years) GGO, ST (7 years) Nt128G.A (R43H) Nt1609 in/del (end exon 13) Alive, ILD score 2 (13 years) Ta, tachypnoea; Cr, crackles; Wh, wheezing; Cl, clubbing; Hy, hypoxaemia; FTT, failure to thrive; GGO, ground-glass opacification; ST, septal thickening; PE, pectus excavatum. Login to comment
83 Five of these mutations (R20L, DF1203, E292V, T114M, Q1591P) have been previously identified in subjects with chILD, whereas the remainder are novel. Login to comment

[hide] Persistent tachypnea and hypoxia in a 3-month-old ... J Pediatr. 2006 Nov;149(5):702-706. Prestridge A, Wooldridge J, Deutsch G, Young LR, Wert SE, Whitsett JA, Nogee L
Persistent tachypnea and hypoxia in a 3-month-old term infant.
J Pediatr. 2006 Nov;149(5):702-706., [PMID:17095348]

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66 No deviations from the known SFTPB or SFTPC sequences were identified; however, the sequence analysis of ABCA3 revealed 2 previously unreported mutations: a heterozygous G¡T transversion in exon 5 at cDNA position 59, resulting in a nonconservative substitution of leucine for arginine in codon 20 (R20L), and a heterozygous 25-base pair deletion in exon 29 (4483del25) resulting in a frame shift. Login to comment
67 Paternal DNA was not available for analysis; analysis of maternal DNA demonstrated heterozygosity for the R20L mutation but not for the 4483del25 mutation, indicating that these mutations were likely on separate alleles in the child. Login to comment
65 No deviations from the known SFTPB or SFTPC sequences were identified; however, the sequence analysis of ABCA3 revealed 2 previously unreported mutations: a heterozygous G&#a1;T transversion in exon 5 at cDNA position 59, resulting in a nonconservative substitution of leucine for arginine in codon 20 (R20L), and a heterozygous 25-base pair deletion in exon 29 (4483del25) resulting in a frame shift. Login to comment