Megaloblastic anemia is a hematological disorder in which the bone marrow produces abnormally large nucleated cells, including immature erythrocytes, superlobulated polymorphic leukocytes and large platelets. At the cellular level, megaloblastic anemia 1 (MGA1), originally named Imerslund-Grasbeck syndrome (IGS), is caused by intestinal malabsorption of vitamin B12 (cobalamin) due to a defect in the vitamin B12/gastric intrinsic factor (GIF) complex receptor. Clinically, IGS is characterized by relatively early childhood onset (before age 5 years), failure to thrive, infections, low level of vitamin B12 in serum, mild and innocuous proteinuria, and variable neurological symptoms such as peripheral neuropathy, cognitive problems, and dementia.
Since poor absorption of vitamin B12 is the cause of MGA1, the diagnosis is established by measuring the absorption of radioactive vitamin B12 by using Schilling's urinary excretion test. The absorbed radioactivity is measured indirectly after it has been flushed into the urine by intramuscular injection of a large quantity of non-radioactive vitamin B12. Unfortunately, the radioactive vitamin B12 tests are no longer available in many countries. The treatment of the disease consists of intramuscular injections of vitamin B12 and continues a long life. When properly treated the disease is a fairly innocuous condition. However, the disease can be fatal without treatment.
MGA1 occurs worldwide, but it is more common in several Middle Eastern countries and Norway, and has highest prevalence in Finland.
MGA1 is genetically heterogeneous and can be caused by mutations in either the cubilin (CUBN) or the amnionless (AMN) gene. The products of both genes form a complex that acts as a receptor for vitamin B12 and gastric intrinsic factor (GIF).
All Finnish patients with MGA1 studied so far have mutations in CUBN gene and P1297L mutation is the most common mutation among Finnish patients, whereas all Norwegian patients have mutations in the AMN gene.
For the first time from Bahrain, Al-Ajmi et al. (2003) described a rare case of pernicious anemia (PA) in a young female.
Ismail et al. (1997) reported seven patients in two unrelated consanguineous Bedouin families with Grasbeck-Imerslund syndrome. In Family one, three affected male sibs, had a deceased brother, who died of severe anemia, and seven apparently healthy sisters. Family two had four affected and four healthy sibs hinting for a possible autosomal recessive mode of inheritance. However, pedigree analysis in Family one was suggestive of an X-linked mode of inheritance, since none of the seven female children was found to be affected, while all three males, and most probably their deceased brother, were found to have the disease. Intra-familial phenotypic heterogeneity was demonstrated in this study by the variable age of presentation in both families while inter-familial heterogeneity was illustrated by the absence of proteinuria in all cases of Family one vs. its detection in three patients in Family two. Two of the affected sibs in each family were found to have raised Hb A2 (>4%) while a third in Family one was found to have a raised level of Hb F before treatment. One of the patients developed subacute combined degeneration of the cord at the age of 17 years before the correct diagnosis was made. All abnormalities were corrected following the institution of parenteral cobalamin therapy.
Abdelaal and Ahmed (1991) reported a Saudi family affected by megaloblastic anemia. The proband was an 18 year old male suffering from anemia since early childhood. A physical examination found him to be severely anemic with signs of impending right side heart failure. His serum bilirubin was 34 micromol/l (RR 0-20) and his urine was positive for urobilinogen and protein. He was diagnosed with severe megaloblastic anemia and given 500 ml of packed red blood cells under diuretic cover. Due to his low B12 levels, he was given hydroxycobalamin injections. His 15 year old sibling and 6 year old first cousin shared a similar history; both had anemia since the age of 3 years and required recurrent blood transfusions. Both were found to be normal upon physical examination. The proband was administered cyanocobalamin labelled with two cobalt isotopes; urinary excretion of the isotopes proved that he suffered from vitamin B12 malabsorption. The finding that B12 malabsorption was uninfluenced by the administration of intrinsic factor, the lack of evidence for blind loop syndrome, the presence of normal TC-2 levels, normal renal function and persistent proteinuria confirmed the diagnosis of Imerslund-Grasbeck syndrome in these three patients.
Al Essa et al. (1998) described two Saudi sisters with this disorder. In children, early anemia usually leads to the diagnosis. In this case, however, the presence of hemoglobinopathy that required frequent transfusions masked the usual macrocytosis, and the older sister was not diagnosed until the age of 12 years when neurologic changes became apparent. Dementia and paralysis responded remarkably to treatment, despite the late diagnosis.
Tanner et al. (2004) conducted a study to explain the peculiar geographical distribution of CUBN and AMN mutations in 42 Imerslund-Gräsbeck patients. The study included an extended multiply consanguineous Saudi family, with seven male MGA patients belonging to six-generations. A homozygous missense mutation (c.434G>A), G145E in exon 5 of the CUBN gene was identified in the affected patients.
Bulut et al. (2012) described a case of Imersland-Grasbeck Syndrome in a 17-month-old Saudi Arabian boy. He was born prematurely at 31 weeks with a birth weight of 1.5kg, and exhibited growth retardation for 1.5 years. He had presented with recurrent apthous-stomatitis, upper respiratory tract infections, and gastrointestinal infections during the 6th and 15th months of age, as well as fatigue and failure to thrive. Hemoglobin, erythrocyte volume fraction, mean corpuscular volume, and white blood cell and platelet count levels were below the normal ranges for infants; Deficient levels of vitamin B12 were detected (33pg/mL), and bone marrow aspiration indicated megaloblastic erythroid hyperplasia and nuclear-cytoplasmic dissociation. Glomerular proteinuria was determined through urine protein electrophoresis, however tubular leakage was also suspected due to elevated levels of secreted N-acetyl-beta-D glucosaminidase and beta 2 microglobulin; no infection or malformation of the urinary tract was observed. He was treated intramuscularly with vitamin B12 1000µg/day for a course of 4 days, followed by twice a week, and once a month for 6 months. Treatment was effective with growth catch-up, weight gain, and increased hemoglobin levels; however non-progressive proteinuria persisted. Life-long vitamin B12 was prescribed.
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