Maternal uniparental disomy 14 revealed by alpha 1 antitrypsin deficiency

Summary

Alpha 1 antitrypsin deficiency (AATD) is an autosomal co-dominant disease linked to a mutation of the SERPINA1 gene localized to chromosome 14q32. Uniparental disomy (UPD) is known to be a genetic mechanism that causes various syndromes. Maternal UPD14 presents with a Prader-Willi syndrome-like phenotype. No publications to date have dealt with the association of these two syndromes. In this article, we report on two cases of AATD (from different families), which lead to the diagnosis of maternal UPD14. AATD was diagnosed early in both children. Their clinical presentations were typical (chronic cytolysis in patient 1 and neonatal cholestasis in patient 2); serum alpha 1 antitrypsin levels were low (P1 0.33 g/L and P2 0.35 g/L), and both patients had a Z phenotype. A pedigree study of both families showed that the father had an M phenotype and the mother an MZ phenotype, which was unexpected. On the other hand, both children were born before term and presented with symmetrical growth retardation, early eating difficulties, moderate hypotonia, understated dysmorphic features and moderate psychomotor retardation, suggestive of a Prader-Willi syndrome-like phenotype. Genotyping was performed to explain gene transmission inconsistencies, and highlighted maternal UPD 14 in both families.

Conclusion

Logically, maternal UPD 14 can induce AATD. In light of these observations, it seems appropriate to search for AATD in patients with maternal UPD 14 in order to prevent a progression of the disease. These cases also underline the significance of maternal UPD 14, which should be suspected in AATD in view of the discordance with Mendel's allelic transmission law.

Introduction

Uniparental disomy (UPD) is a genetic phenomenon that was first described by Engel [1] in 1980. It may involve any maternal or paternal chromosome. When the genes involved are imprinted, various syndromes may appear, such as Angelman syndrome (paternal UPD15), Prader-Willi syndrome (maternal UPD15) or Silver-Russel syndrome (UPD7) [2], [3]. Maternal UPD14 is known to present a Prader-Willi syndrome-like phenotype (growth retardation, neonatal hypotonia, hypoglycemia, joint hyperlaxity, eating difficulties, and precocious puberty [2], [4], [6], [7]), but pedigrees may be misinterpreted in other UPD cases.

Alpha-1 antitrypsin (AAT) is a protein which is encoded by a gene (SERPINA1) located on chromosome 14q32.1 whose alleles are co-dominant. Gene mutations can cause alpha-1 antitrypsin deficiency (AATD);, an inherited autosomal co-dominant disease.

We report on two cases (from different families) of AATD that revealed maternal UPD14. This association of maternal UPD14 and AATD has never been described previously.