Neonatal cholestasis

Gene: LIPA

Comment when marking as ready: 3 unrelated cases with plausible disease causing mutations for Wolman disease which is neonatal onset and shows cholestasis phenotype.

Created: 25 Jul 2018, 2:08 p.m.

Comment on phenotypes: Added relevant phenotypes from Jane Hartley and from OMIM.

Created: 25 Jul 2018, 2:07 p.m.

Comment on publications: Added publications relating to cases.

Created: 25 Jul 2018, 2:05 p.m.

Comment on mode of inheritance: All reports are of homozygous or compound heterozgous mutations.

Created: 25 Jul 2018, 2 p.m.

Comment on list classification: More than 3 cases of variants in LIPA associated with Cholesteryl ester storage disease and 3 cases associated with the more severe neonatal onset Wolman disease so rating this gene as green.

Created: 25 Jul 2018, 1:59 p.m.

In OMIM LIPA is associated with Cholesteryl ester storage disease/Wolman disease. Cholestasis is listed as a common extrahepatic finding in patients with Cholesteryl ester storage disease by Bernstein et al 2013 (PMID: 23485521). Wolman disease (also known as lysosomal acid lipase deficiency) is a rare, neonatal-onset, fulminant subtype of CESD which may also manifest as neonatal cholestasis (Götze et al. (2015)(PMID: 26137452). OMIM reports findings by Aslanidis et al. (1996) (PMID: 8617513) who describe a CESD patient heterozygous for a variant in a splice donor site that results in a skipping of exon 8 and 97% of the mRNA originating from this allele. The other allele of the patient carried a premature termination mutation as well as a L179P mutation They also describe two siblings that are homozygous for a G-to-A mutation at position +1 of the splice donor site following exon 8 of the LIPA gene. Maslen and Illingworth (1993) (PMID: none) and Maslen et al. (1995) (PMID: 8598644) identified compound heterozygosity for this splice site mutation in the LIPA gene, inherited from their father, and the L179P mutation. The affected children were a sister and brother who presented with idiopathic hepatomegaly at ages 6 and 8 years, respectively. Muntoni et al. (1995)(PMID: 7759067) observed homozygosity for the splice site mutation (Klima et al., 1993)(PMID: 8254026) in a Spanish kindred with cholesterol ester storage disease. Exon 8 of the LIPA gene was deleted. A PubMed search finds Tinsa et al (2018)(PMID: 29702543) with a severe lysosomal acid lipase deficiency phenotype report an individual with a homozygous mutation in exon 3which interrupted the reading frame by a premature STOP codon and confirmed the diagnosis of Wolman disease. The parents were heterozygous for this mutation. Ikari et al 2018 (PMID: 29731497) report on two siblings with early onset lysosomal acid lipase deficiency or Wolman disease. Their parents had a consanguineous marriage. LIPA gene showed a single substitution within exon 3 which changed a tyrosine codon to a termination codon and lead to unstable mRNA and very low levels of enzyme activity.

Created: 25 Jul 2018, 1:47 p.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
lysosomal acid lipase deficiency; cholestasis; cirrhosis; liver failure