Imerslund–Gräsbeck syndrome

Overview

Imerslund–Gräsbeck syndrome (IGS) is a rare inherited disorder characterized by selective vitamin B12 (cobalamin) malabsorption that leads to megaloblastic anemia and, in some cases, proteinuria (excess protein in urine). It typically presents in early childhood and is distinct from other causes of vitamin B12 deficiency due to its genetic basis and lack of response to oral supplementation. The condition was first described by Norwegian and Finnish physicians Imerslund and Gräsbeck in the 1960s and is most commonly reported in individuals of Scandinavian, Middle Eastern, or North African descent.

Causes

Imerslund–Gräsbeck syndrome is caused by mutations in either the AMN (amnionless) gene or the CUBN (cubilin) gene. These genes are responsible for encoding proteins involved in the absorption of vitamin B12 in the ileum of the small intestine. Specifically, these proteins form part of the receptor complex required for the uptake of the vitamin B12-intrinsic factor complex. Mutations in either gene disrupt this process, leading to impaired absorption of vitamin B12 despite normal levels of intrinsic factor. The disorder is inherited in an autosomal recessive pattern.

Symptoms

Symptoms of IGS typically begin in infancy or early childhood and are primarily related to vitamin B12 deficiency:

• Megaloblastic anemia: Fatigue, pallor, weakness, and shortness of breath due to impaired red blood cell production.

• Failure to thrive: Poor growth and developmental delays in affected infants.

• Neurological symptoms: Irritability, developmental delay, hypotonia, and, in severe cases, neuropathy or cognitive issues.

• Proteinuria: Non-progressive and usually asymptomatic, but detectable on routine urinalysis.

• Gastrointestinal issues: Diarrhea or poor appetite in some cases.

Diagnosis

Diagnosis of Imerslund–Gräsbeck syndrome involves identifying vitamin B12 deficiency and confirming the underlying cause through clinical and genetic evaluation:

• Blood tests: Reveal macrocytic anemia, elevated mean corpuscular volume (MCV), low serum vitamin B12, and elevated homocysteine and methylmalonic acid levels.

• Urinalysis: Detects mild proteinuria without signs of kidney disease.

• Schilling test (historical): Formerly used to assess vitamin B12 absorption; now largely obsolete.

• Genetic testing: Confirms diagnosis by identifying mutations in CUBN or AMN genes.

• Exclusion of other causes: Important to rule out pernicious anemia, dietary deficiency, or gastrointestinal malabsorption conditions.

Treatment

The mainstay of treatment for IGS is lifelong parenteral vitamin B12 supplementation:

• Intramuscular vitamin B12 injections: Usually administered monthly to maintain adequate levels and prevent recurrence of symptoms.

• Monitoring: Regular follow-up to assess hematologic response and monitor vitamin B12 levels.

• Nutritional support: In cases with growth or developmental delays, dietary evaluation and support may be necessary.

• Management of proteinuria: Typically no treatment is required, as it is non-progressive and does not affect kidney function.

Prognosis

With early diagnosis and consistent treatment, the prognosis for individuals with Imerslund–Gräsbeck syndrome is excellent. Most patients respond well to parenteral vitamin B12 therapy, with resolution of anemia and prevention of neurological complications. Growth and development usually normalize with proper management. Lifelong adherence to treatment is essential, as discontinuation of therapy can lead to relapse of symptoms. Long-term outlook is favorable, and quality of life is typically not affected with appropriate care.