Abetalipoproteinemia

Clinical characteristics: Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiting, and malabsorption of fat. Hematologic manifestations may include acanthocytosis (irregularly spiculated erythrocytes), anemia, reticulocytosis, and hemolysis with resultant hyperbilirubinemia. Malabsorption of fat-soluble vitamins (A, D, E, and K) can result in an increased international normalized ratio (INR). Untreated individuals may develop atypical pigmentation of the retina that may present with progressive loss of night vision and/or color vision in adulthood. Neuromuscular findings in untreated individuals including progressive loss of deep tendon reflexes, vibratory sense, and proprioception; muscle weakness; dysarthria; and ataxia typically manifest in the first or second decades of life.

Diagnosis/testing: The diagnosis of abetalipoproteinemia is established in a proband with absent or extremely low LDL-cholesterol, triglyceride, and apolipoprotein (apo) B levels and biallelic pathogenic variants in MTTP identified by molecular genetic testing.

Management: Treatment of manifestations: Adequate caloric intake to alleviate growth deficiency; low-fat diet (10%-20% of total calories from fat); oral essential fatty acid supplementation (up to 1 teaspoon per day of oils rich in polyunsaturated fatty acids, as tolerated); supplementation with vitamin A (100-400 IU/kg/day), vitamin D (800-1,200 IU/day), vitamin E (100-300 IU/kg/day), and vitamin K (5-35 mg/week). Mild anemia rarely requires treatment, although occasionally vitamin B₁₂ or iron therapy may be considered. Dysarthria, ataxia, and hypothyroidism are treated in the standard fashion.

Prevention of primary manifestations: Most complications can be prevented through institution of a low-fat diet with supplementation of fat-soluble vitamins (A, D, E, and K).

Surveillance: Assessment of growth parameters at each visit. Complete blood count, INR, reticulocyte count, liver function tests (AST, ALT, GGT, total and direct bilirubin, alkaline phosphatase, and albumin), fat-soluble vitamin levels (vitamin A [retinol], 25-OH vitamin D, and plasma or red blood cell vitamin E concentrations), serum calcium, serum phosphate, serum uric acid, and TSH levels annually. Lipid profile (total cholesterol, triglyceride concentration, LDL-cholesterol, HDL-cholesterol, apo B, and apo A-I) every several years. Ultrasound of the liver every three years. Ophthalmology and neurology evaluations every six to 12 months.

Agents/circumstances to avoid: Fatty foods, particularly those rich in long-chain fatty acids.

Evaluation of relatives at risk: Sibs of a proband should undergo a full lipid profile and apolipoprotein (apo) B determination to allow for early diagnosis and treatment of findings. If the pathogenic MTTP variants in the family are known, molecular genetic testing may also be used to determine the genetic status of at-risk sibs. In classic abetalipoproteinemia, affected sibs will present shortly after birth with failure to thrive, diarrhea, vomiting, and malabsorption of fat.

Pregnancy management: Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum beta carotene levels throughout pregnancy is recommended. Because vitamin A is an essential vitamin, vitamin A supplementation should not be discontinued during pregnancy.

Genetic counseling: Abetalipoproteinemia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible if the pathogenic MTTP variants in the family are known.