X‐linked dominant protoporphyria: The first reported Japanese case

Abstract

A 12-year-old boy with photosensitivity since 3 years of age presented with small concavities on both cheeks, the nasal root and the dorsal surface of both hands. According to the clinical features, erythropoietic protoporphyria (EPP) was suspected. Urine and blood samples were tested for porphyrin derivatives, which revealed a markedly elevated level of erythrocyte protoporphyrin (EP) and a diagnosis of EPP was made. The patient's mother had no photosensitivity, however, lesions appearing slightly as small scars were found on the dorsum of her right hand; his elder sister and father showed no rash. The EP levels were elevated in samples from his mother and mildly elevated in those from his elder sister and father. To obtain a definitive diagnosis, genetic analyses were performed using samples from all family members, which revealed no mutations in the ferrochelatase-encoding gene (FECH), which is responsible for EPP. Instead, a pathological mutation of the 5-aminolevulinic acid synthase-encoding gene (ALAS2) was identified in samples from the patient, his mother and his elder sister, confirming a definitive diagnosis of X-linked dominant protoporphyria (XLDPP). This is the first Japanese family reported to have XLDPP, demonstrating evidence of the condition in Japan. In addition, because XLDPP is very similar to EPP in its clinical aspects and laboratory findings, a genetic analysis is required for the differential diagnosis.

X-linked dominant protoporphyria in a Chinese pedigree reveals a four-based deletion of ALAS2

“…Because females have two X chromosomes and one copy becomes randomly inactivated during early embryonic development, the proportion of mutant X-chromosome inactivation may explain phenotypic variability in X-linked dominant genetic diseases. This finding differs from that in an earlier study (7), which found that the proportion of X-chromosome inactivation may differ dramatically and also be associated with significant phenotypic variability.…”

“…This manifests clinically as a "weather-beaten" appearance, consisting of lichenification, a leather-like skin texture, pseudo-vesicles, perioral radial furrowing, and platonychia or koilonychia. Some patients develop liver disease, but their condition may not result in a reduced life expectancy (7). Fulminant hepatitis may, albeit rarely, develop and is the most severe outcome, potentially progressing to liver failure and liver transplantation (6).…”

Genome-wide microhomologies enable precise template-free editing of biologically relevant deletion mutations

“…4a). Patients with the rs387906472 variant have abnormally elevated levels of PPIX in erythroid cells causing photosensitivity of the skin and in extreme cases liver damage, a condition referred to as X-Linked Protoporphyria (XLP) 29,30 .

Fig. 4Erythropoietic protoporphyria disease models created by MMEJ display ALAS2 gain-of-function and FECH loss-of-function.

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