A number sign (#) is used with this entry because of evidence that X-linked erythropoietic protoporphyria (XLEPP) is caused by gain-of-function mutations in the ALAS2 gene (301300) on chromosome Xp11.

Loss-of-function mutations in the ALAS2 gene cause X-linked sideroblastic anemia (300751).

X-linked erythropoietic protoporphyria (XLEPP) is a metabolic disorder of heme biosynthesis characterized by onset in early childhood of severe photosensitivity associated with decreased iron stores and increased erythrocyte zinc- and metal-free protoporphyrin. Some patients may develop liver disease or gallstones (summary by Ducamp et al., 2013).

For a discussion of genetic heterogeneity of erythropoietic protoporphyria, see EPP1 (177000).

In a subgroup of families with FECH (612386) mutation-negative protoporphyria, Whatley et al. (2008) studied 8 families in which at least 1 member had acute photosensitivity clinically indistinguishable from that seen in autosomal recessive erythropoietic protoporphyria-1 (EPP1; 177000). Four families were of western European ancestry, and the others were of Jewish, North African, Indo-Asian, and Sudanese ancestry. In these 8 families, both sexes were affected. Patients had neither anemia nor iron overload. Instead there was some evidence of diminished iron stores, particularly in males. Five patients (17%) had overt liver disease, which was more common in males (0.008), and 1 obligate carrier was asymptomatic. These families showed an apparent X-linked pattern of inheritance with an absence of father-to-son transmission.

Ducamp et al. (2013) reported 5 XLEPP patients from 4 unrelated families referred for a history of skin photosensitivity associated with increased levels of zinc- and metal-free protoporphyrin in erythrocytes. Two patients had elevated liver enzymes and 1 had gallstones. Most had evidence of iron deficiency, but only some patients had anemia.

Brancaleoni et al. (2016) reported 6 unrelated families of European descent with XLP confirmed by genetic analysis. Five of the families carried the common ALAS2 4-bp deletion (c.1706_1709delAGTG; 301300.0015). Among the families, there were 7 affected males with a hemizygous mutation and 10 females who had the mutation in the heterozygous state. In 1 family (family C), there was only 1 affected male who had a de novo mutation; his mother was not a carrier. There was heterogeneity among the females with the mutation: 2 were fully affected with photosensitivity from childhood and increased erythrocyte protoporphyrin IX (PPIX), 7 had later onset of symptoms and/or only mildly increased PPIX, and 1 was completely asymptomatic with normal laboratory values. X-chromosome inactivation studies on the females with mutations were consistent with the clinical and biochemical heterogeneity: the 2 photosensitive females had a skewed pattern with over 73% of the wildtype allele inactivated, the asymptomatic female had 88.4% inactivation of the mutant allele, and the 7 females with no or late-onset photosensitivity and/or mildly increased PPIX values had relatively balanced X-inactivation patterns with preferential expression of the wildtype ALAS2 allele.

Balwani et al. (2023) performed a phase 2 clinical trial in 93 patients with erythropoietic protoporphyria (177000) and 9 patients with X-linked protoporphyria aged 18 to 75 years who were randomly assigned in a 1:1:1 ratio to placebo or dersimelagon 100 mg or 300 mg once daily for 16 weeks. The primary endpoint was the change from baseline to 16 weeks in the time to first prodromal symptom associated with sunlight exposure. Daily sunlight exposure and symptoms were recorded in an electronic diary. Quality of life and safety were also assessed. Among enrollees, 90% completed the treatment period. There was a significant change in time to the first prodromal symptom compared with the placebo group for the 100 mg dersimelagon group (53.8 minutes, p = 0.008) and for the 300 gm dersimelagon group (62.5 minutes, p = 0.003). Quality of life improved in both treatment groups. The most common adverse events that occurred or worsened during treatment were nausea, freckles, headache, and skin hyperpigmentation.

The transmission pattern of erythropoietic porphyria in the families reported by Whatley et al. (2008) was consistent with X-linked dominant inheritance.

Ducamp et al. (2013) reported a French girl with XLEPP whose mother was mildly affected and was demonstrated to be germline and somatic mosaic for an ALAS2 mutation (301300.0015).

Brancaleoni et al. (2016) determined that clinical and biochemical heterogeneity in females who are heterozygous for pathogenic ALAS2 mutations is associated with X-chromosome inactivation patterns. Females with full symptoms of the disorder tend to have a skewed pattern with most of the wildtype allele inactivated, whereas those without symptoms have most of the mutant allele inactivated. Those with intermediate or mild symptoms have relatively balanced X-inactivation patterns with preferential expression of the wildtype ALAS2 allele. The findings indicated that the disorder should be considered to have X-linked inheritance with penetrance and severity in females related to the level of X-chromosome inactivation, and that the term 'X-linked dominant' inheritance be discontinued.

The observation of apparent X linkage of EPP in 8 families prompted Whatley et al. (2008) to investigate 2 candidate genes on the X chromosome that are involved in heme formation, GATA1 (305371) and ALAS2 (301300). Protoporphyrin accumulation segregated with an X chromosome haplotype defined by microsatellite markers around ALAS2 in 3 families. Sequencing of genomic DNA identified 2 different deletions in the last exon (exon 11) of ALAS2. The frameshifts produced by these deletions led to replacement or deletion of the approximately 20 C-terminal amino acids of the ALAS2 enzyme. These mutations segregated with photosensitivity (lod score 7.8) and were absent from 129 unrelated EPP patients (106 with dominant EPP, 23 with FECH mutation-negative EPP), and 100 normal chromosomes. The delAGTG mutation (301300.0015), present in 6 families, occurred on 5 different haplotypes, indicating that it had arisen on at least 5 separate occasions, whereas the 2 families with delAT (301300.0016), both from southwest England, had the same background haplotype and may have come from a single extended family. The ALAS2 gene encodes erythroid-specific mitochondrial aminolevulinate synthase-2, which catalyzes the first committed step of heme biosynthesis. Expression studies showed that both deletions markedly increased ALAS2 activity and that some of the 5-aminolevulinate (ALA) that was produced was further metabolized to porphyrin. Whatley et al. (2008) concluded that deletions in ALAS2 cause a theretofore unrecognized X-linked protoporphyria that, in contrast to autosomal dominant porphyrias, has close to 100% penetrance.

In 4 unrelated girls with X-linked dominant erythropoietic protoporphyria, Ducamp et al. (2013) identified 3 different heterozygous mutations in the ALAS2 gene. One was recurrent (delAGTG; 301300.0015) and the other 2 were novel (301300.0019 and 301300.0020). All occurred in the last exon of the ALAS2 gene, and all were shown in vitro to result in increased ALAS2 catalytic activity, consistent with a gain of function. By generating a series of ALAS2 variants, Ducamp et al. (2013) found that the 'gain-of-function domain' contains a minimum of 33 amino acids between residues 544 and 576 in the C terminus of the protein.