Clinical and molecular characteristics of imerslund‐gräsbeck syndrome: First report of a novel Frameshift variant in Exon 11 of AMN gene

Abstract

Introduction Imerslund‐Gräsbeck syndrome (IGS) is a rare autosomal‐recessive disorder characterized by selective vitamin B12 malabsorption, megaloblastic anemia, and proteinuria. The precise incidence of this disorder is unknown in the Middle East and Arab countries. The disease is caused by a homozygous variant in either AMN or CUBN genes. In addition, some compound heterozygous variants are reported. Methods Clinical and laboratory data of patients diagnosed with IGS in Oman were retrospectively collected. Mutation analysis for all genes involved in vitamin B12/folic acid metabolism and megaloblastic anemia was conducted using next‐generation sequencing (NGS). Results Three siblings (2 girls and a boy) have been diagnosed with the condition. They exhibit a phenotypic variability with different age of presentation and different spectrum of disease. All patients harbor a novel biallelic frameshift mutation in exon 11 of AMN gene (p.Pro409Glyfs*), which was not reported previously in the literature. Both parents are heterozygotes for the same variant. All patients responded well to vitamin B12 parenteral therapy, but proteinuria persisted. Conclusion In communities with high incidence of consanguinity, cases of early‐onset vitamin B12 deficiency should be thoroughly investigated to explore the possibility of Imerslund‐Gräsbeck syndrome and other vitamin B12–related hereditary disorders. Further local and regional studies are highly recommended.

Síndrome de Imerslund-Gränsbeck: caso clínico.

“…El síndrome de Imerslund-Gräsbeck, también conocido como anemia megaloblástica juvenil o anemia megaloblástica hereditaria, es un síndrome en el cual se evidencia de manera concreta como característica representativa la deficiencia de vitamina B 12 , además de anemia megaloblástica y proteinuria (12) . Esta enfermedad se presenta con mayor frecuencia hacia la región europea, con una incidencia de 5 por cada millón de personas en países escandinavos (13) . El cuadro clínico se caracteriza por deficiencia de vitamina B 12 , anemia megaloblástica y proteinuria sin afectación renal como efecto secundario a esta deficiencia; también se pueden encontrar signos como palpitaciones, sudoración, mareo e insuficiencia cardiaca de instauración lenta (13) , y algunos pueden presentar anomalías anatómicas del tracto urinario, manifestaciones y retraso en el crecimiento (14) .…”

“…Esta enfermedad se presenta con mayor frecuencia hacia la región europea, con una incidencia de 5 por cada millón de personas en países escandinavos (13) . El cuadro clínico se caracteriza por deficiencia de vitamina B 12 , anemia megaloblástica y proteinuria sin afectación renal como efecto secundario a esta deficiencia; también se pueden encontrar signos como palpitaciones, sudoración, mareo e insuficiencia cardiaca de instauración lenta (13) , y algunos pueden presentar anomalías anatómicas del tracto urinario, manifestaciones y retraso en el crecimiento (14) . Entre las alteraciones digestivas se destacan la anorexia, diarrea, estomatitis angular, lengua lisa depapilada, dolorosa al tacto y de color rojo intenso, denominada glositis de Hunter (9) .…”

Megaloblastic anemia and benign proteinuria: Clues to the diagnosis of Imerslund–Gräsbeck syndrome

“…4 Imerslund-Gräsbeck syndrome is a rare autosomal recessive disorder characterized by vitamin B12 deficiency due to selective malabsorption of vitamin B12 and usually results in megaloblastic anemia in childhood. 1,2 The patient responded to the parenteral vitamin B12 therapy. It is clinically characterized by megaloblastic anemia, benign mild proteinuria, and other nonspecific symptoms.…”

“…Imerslund-Gräsbeck syndrome is a rare autosomal recessive disorder characterized by megaloblastic anemia secondary to selective vitamin B12 malabsorption and tubular proteinuria associated with preserved renal function.s 1,2 Herein, we describe the case of a 47-month-old male with Imerslund-Gräsbeck syndrome, macrocytic anemia, and mild but persistent proteinuria since the age of 22-month-old. Macrocytic anemia with a low vitamin B12 concentration was not corrected, although he had received oral vitamin B12 for more than 2 years.…”

“…It is clinically characterized by megaloblastic anemia, benign mild proteinuria, and other nonspecific symptoms. 1,2 Several pathogenic variants of the amnionless (AMN) or cubilin (CUBN)…”