What is the most likely explanation for a mother and two adult sons all having a chronic serum vitamin B12 deficiency?

Familial Vitamin B12 Deficiency: Most Likely Explanation

The most likely explanation for a mother and two adult sons all having chronic serum vitamin B12 deficiency is a genetic disorder affecting vitamin B12 absorption, such as Imerslund-Gräsbeck disease (selective vitamin B12 malabsorption with proteinuria) or hereditary intrinsic factor deficiency. 1

Genetic Causes of Familial B12 Deficiency

When multiple family members present with the same nutritional deficiency, genetic factors should be strongly considered. The familial pattern described suggests:

1. Inherited disorders of B12 absorption:

   • Mutations in genes encoding cubilin or amnionless (components of the ileal receptor for B12-intrinsic factor complex) 1
   • Hereditary intrinsic factor deficiency 1
   • Transcobalamin gene polymorphisms affecting B12 transport 2

2. Alternative explanations (less likely given the familial pattern):

   • Shared dietary patterns (strict vegetarian/vegan diet) 2
   • Shared environmental exposures affecting B12 absorption

Diagnostic Approach

To confirm the genetic basis of familial B12 deficiency:

1. Initial testing:

   • Serum B12 levels (already known to be low)
   • Methylmalonic acid (MMA) and homocysteine levels to confirm metabolic B12 deficiency 3
   • Complete blood count to assess for megaloblastic anemia 4, 5

2. Specialized testing:

   • Intrinsic factor antibodies (to rule out pernicious anemia)
   • Genetic testing for mutations in cubilin, amnionless, or transcobalamin genes 1
   • Urinalysis to check for proteinuria (present in Imerslund-Gräsbeck syndrome)

Clinical Implications

B12 deficiency left untreated can lead to serious complications:

• Neurological damage: Permanent degenerative lesions of the spinal cord may occur if deficiency persists longer than 3 months 4, 5
• Hematologic abnormalities: Megaloblastic anemia 6
• Cardiovascular risk: Elevated homocysteine levels increasing risk of atherosclerotic vascular disease 3
• Cognitive impairment: Memory loss and other neurological deficits 6

Management Recommendations

Treatment should be initiated promptly:

1. Vitamin B12 supplementation:

   • For genetic causes of malabsorption: 1000-2000 μg daily oral supplementation or 1000 μg intramuscularly monthly 3, 4
   • Higher doses may be needed for patients with malabsorption disorders 3

2. Monitoring:

   • Check B12 levels after 3 months of supplementation 3
   • Monitor MMA levels if B12 levels remain indeterminate (180-350 ng/L) 3
   • Regular follow-up to ensure adequate treatment response

3. Family counseling:

   • Genetic counseling for affected family members
   • Lifelong supplementation will likely be required 4, 5

Important Caveats

• Do not substitute folic acid: While folic acid may correct anemia, it will not prevent neurological damage from B12 deficiency 4, 5
• Early intervention is crucial: Neurological damage becomes irreversible if treatment is delayed 4
• Genetic causes often underdiagnosed: The genetic causes of B12 malabsorption are probably underestimated in adult cases with B12 deficiency 1
• Consider testing other family members: Siblings and children of affected individuals may also carry genetic mutations

The familial pattern strongly suggests a genetic basis for the vitamin B12 deficiency, requiring lifelong treatment and monitoring to prevent serious neurological and hematological complications.