Retinitis Pigmentosa And Erythrocytic Microcytosis

A number sign (#) is used with this entry because of evidence that retinitis pigmentosa and erythrocytic microcytosis (RPEM) is caused by compound heterozygous mutation in the TRNT1 gene (612907) on chromosome 3p26.

Mutation in the TRNT1 gene also causes a more severe syndrome, consisting of sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD; 616084). Some patients with SIFD have retinitis pigmentosa.

Clinical Features

DeLuca et al. (2016) studied a 19-year-old man who presented after routine eye examination with pigmentary changes in the retina. He had first noted nyctalopia at age 16, when he began driving. Funduscopy revealed bilateral mild arteriolar attenuation and scant bone spicule-like pigmentary changes in the periphery of the retina, and optical coherence tomography (OCT) showed diffuse outer retinal atrophy with foveal preservation. Hematologic evaluation revealed low normal hemoglobin and hematocrit, with abnormally small red blood cells (RBCs) and significant anisocytosis. Peripheral blood smear showed microcytosis, hypochromia, anisocytosis, and poikilocytosis with numerous elliptocytes. Past medical history was significant for juvenile rheumatoid arthritis involving the hip and neck that started in the first year of life; he also experienced bouts of high fever that occurred 2 to 3 times per year. After a 3-year treatment with methotrexate, he had not had a recurrence of the fevers or arthritis for over a decade. DeLuca et al. (2016) also studied 2 similarly affected brothers. The older brother presented at age 21 with a history of poor night vision since childhood. Funduscopy showed mild optic disc pallor, significant macular edema, mild attenuation of retinal arterioles, and diffuse atrophy of the peripheral retinal pigment epithelium; visual field testing showed mild generalized depression bilaterally. OCT revealed significant intraretinal cystoid changes and diffuse outer retinal atrophy with extrafoveal preservation. On CBC he had a near-normal hemoglobin and low-normal hematocrit, with microcytosis and anisocytosis. The younger brother presented at age 18 years, with nyctalopia since age 13 years. Funduscopy, visual fields, OCT, and CBC findings were similar to those of his brother; electroretinography (ERG) showed absent scotopic responses and severely diminished photopic responses bilaterally. The brothers had no history of arthritis or unusual febrile illnesses, and none of the 3 patients had developmental delay, deafness, ataxia, seizures, or cardiac disease.

Molecular Genetics

In a 19-year-old man with retinitis pigmentosa and RBC microcytosis, DeLuca et al. (2016) performed exome sequencing and identified compound heterozygosity for 2 mutations in the TRNT1 gene, a 1-bp deletion (1246delA; 612907.0007) and a 3-bp in-frame deletion (E43del; 612907.0008). His unaffected parents were each heterozygous for 1 of the mutations. Analysis of TRNT1 in 1,729 patients with RP who were negative for mutation in known RP-associated genes revealed 2 brothers, similarly affected with RP and RBC microcytosis, who were compound heterozygous for a 1-bp insertion (1246insA; 612907.0009) and a splice site mutation (612907.0010). Whole-exome sequencing in 195 additional patients with RP did not reveal any other disease-causing mutations. Western blot analysis of protein extracted from patient fibroblasts showed significantly decreased levels of TRNT1 protein compared to controls, although the authors noted that the protein level was not as diminished as in published cases of SIFD (616084), consistent with the milder phenotype in their patients. Suppression of trnt1 expression in zebrafish recapitulated several features of human SIFD; however, when levels of trnt1 were titrated, visual dysfunction was observed in the absence of other phenotypes. DeLuca et al. (2016) concluded that hypomorphic TRNT1 mutations can cause a recessive disease that is almost entirely limited to the retina.