Abetalipoproteinemia is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Abetalipoproteinemia, also known as Bassen-Kornzweig syndrome, is a rare autosomal recessive disorder of lipid metabolism characterized by the complete absence of apolipoprotein B-containing lipoproteins (chylomicrons, VLDL, and LDL) in the blood. This leads to severe fat malabsorption, retinal degeneration, neuropathy, and acanthocytosis (abnormal red blood cells). The disease results from mutations in the MTTP gene encoding microsomal triglyceride transfer protein.[1]
Abetalipoproteinemia was first described independently by Bassen and Kornzweig in 1950, who reported a patient with malabsorption, retinitis pigmentosa, and acanthocytosis. The disease is extremely rare, with an estimated prevalence of approximately 1 in 1,000,000 individuals worldwide.[2]
The disorder represents a model for understanding the role of apolipoprotein B and lipid metabolism in neurological and retinal function. Early diagnosis and treatment with fat-soluble vitamin supplementation can prevent or delay the neurological and retinal complications.[7]
Abetalipoproteinemia is caused by homozygous or compound heterozygous mutations in the MTTP gene (microsomal triglyceride transfer protein), located on chromosome 4q23. This gene encodes a protein essential for the assembly and secretion of apolipoprotein B-containing lipoproteins in the liver and intestine.[3]
Over 80 pathogenic variants have been identified, including:
- Nonsense mutations (40%)
- Missense mutations (30%)
- Frameshift mutations (15%)
- Splice site mutations (10%)
- Large deletions (5%)
- Pattern: Autosomal recessive
- Carrier frequency: Approximately 1 in 500 (heterozygote carriers are asymptomatic)
- Consanguinity: Increased frequency in families with consanguinity
Microsomal triglyceride transfer protein (MTP) plays a crucial role in:
- Chylomicron assembly: In intestinal cells, MTP transfers lipids to nascent apolipoprotein B-48
- VLDL assembly: In hepatocytes, MTP transfers lipids to nascent apolipoprotein B-100
- Lipoprotein secretion: MTP facilitates the formation and secretion of triglyceride-rich lipoproteins
In abetalipoproteinemia, MTP deficiency causes:
| Abnormal Finding |
Pathophysiological Consequence |
| Absent chylomicrons |
Fat malabsorption, fat-soluble vitamin deficiency |
| Absent LDL |
Reduced cholesterol delivery to tissues |
| Absent VLDL |
Impaired triglyceride transport |
| Acanthocytosis |
Altered membrane lipid composition |
| Low vitamin E |
Severe antioxidant deficiency in nervous system |
The neurological manifestations result from:
- Vitamin E deficiency: Severe deficiency leads to oxidative damage in neurons[8]
- Malnutrition: General deficiency of essential fatty acids
- Cholesterol deficiency: Affects neuronal membrane integrity and function
[4]
- Steatorrhea (fatty stools): Present from infancy
- Failure to thrive: Poor weight gain in childhood
- Abdominal distension: Due to fat accumulation
- Gallstones: Early onset, cholesterol type
| Feature |
Onset |
Description |
| Retinitis pigmentosa |
10-20 years |
Progressive peripheral vision loss |
| Night blindness |
10-15 years |
Often first visual symptom |
| Color vision loss |
20-30 years |
Blue-yellow deficiency |
| Central vision loss |
30-40 years |
Advanced disease |
| Optic atrophy |
30-40 years |
Late complication |
- Peripheral neuropathy: Usually begins in adolescence
- Ataxia: Progressive cerebellar ataxia in 50% of patients
- Muscle weakness: Distal more than proximal
- Reduced reflexes: Particularly ankle jerks
- Sensory loss: Position and vibration sense affected
- Dysarthria: In severe cases
- Cognitive impairment: Usually mild, but can be severe
[5]
- Acanthocytosis: 50-90% of RBCs are acanthotic (spur-shaped)
- Mild hemolytic anemia: Usually asymptomatic
- Low hemoglobin: Can be mild to moderate
- Growth retardation: Short stature common
- Hepatosplenomegaly: Fatty liver, sometimes enlarged liver
- Skeletal abnormalities: Lordosis, scoliosis in some cases
The classic presentation includes:
- Fat malabsorption from infancy
- Failure to thrive
- Acanthocytosis on blood smear
- Low cholesterol and LDL
- Retinitis pigmentosa (later)
- Neurological symptoms (later)
| Test |
Finding |
| Total cholesterol |
Markedly reduced (< 50 mg/dL) |
| LDL cholesterol |
Undetectable |
| Triglycerides |
Very low (< 10 mg/dL) |
| Apolipoprotein B |
Undetectable |
| Vitamin E |
Very low (< 1 μg/mL) |
| Vitamin A |
Low |
| Vitamin D |
Low |
| Vitamin K |
Low |
| Liver function tests |
May be elevated |
- MTTP gene sequencing: Confirms diagnosis
- Family carrier testing: For at-risk relatives
| Condition |
Key Distinguishing Features |
| Familial hypobetalipoproteinemia |
Partial deficiency, milder phenotype |
| Chylomicron retention disease |
Only chylomicrons affected |
| Celiac disease |
Malabsorption but normal lipids |
| Cystic fibrosis |
Pancreatic insufficiency, normal lipids |
- Fat restriction: Reduce long-chain triglycerides to 10-15% of calories
- Medium-chain triglycerides (MCT): Provide as alternative fat source (MCT do not require chylomicrons for absorption)
- Low cholesterol diet: Limited benefit but often recommended
High-dose fat-soluble vitamin supplementation is essential:[6]
| Vitamin |
Daily Dose |
Purpose |
| Vitamin E |
100-200 IU/kg |
Neuroprotection, antioxidant |
| Vitamin A |
10,000-25,000 IU |
Retinal function |
| Vitamin D |
400-1000 IU |
Bone health |
| Vitamin K |
5-10 mg |
Coagulation |
Vitamin E supplementation has been shown to:
- Slow or prevent neurological deterioration
- Reduce progression of retinitis pigmentosa
- Improve or normalize neurological examinations
- Neurological examination: Every 6 months
- Ophthalmological examination: Annually
- Lipid panel: Every 6-12 months
- Vitamin levels: Every 6 months
- Growth monitoring: In children
- Neurological outcome: Generally stable or slowly progressive
- Visual outcome: Retinitis pigmentosa still progresses but may be slower
- Life expectancy: Near normal with appropriate treatment
- Quality of life: Good with treatment compliance
- Neurological: Progressive ataxia, neuropathy, disability
- Visual: Progressive blindness
- Prognosis: Significant disability by age 30-40
[6]
- Prevalence: Approximately 1 in 250-500
- Lipid profile: Mildly reduced LDL and cholesterol (not clinically significant)
- Health implications: No increased risk of disease
- Reproductive counseling: Important for family planning
- Gene therapy: Experimental approaches to deliver functional MTTP
- MTP modulators: Small molecules to enhance residual MTP activity
- Neuroprotective agents: Complementary treatments for neuropathy
- Stem cell therapy: Investigational approaches
Abetalipoproteinemia is a rare but well-characterized metabolic disorder that serves as an important model for understanding lipoprotein metabolism and its role in neurological and retinal health. The disease highlights the critical importance of fat-soluble vitamins, particularly vitamin E, in maintaining neuronal and retinal function. With early diagnosis and aggressive vitamin supplementation therapy, patients can achieve near-normal life expectancy and quality of life. Ongoing research into gene therapy and MTP modulators offers hope for future treatments that may directly address the underlying metabolic defect. The identification of over 80 pathogenic MTTP variants has improved diagnostic capabilities and enables targeted genetic counseling for affected families.
The study of Abetalipoproteinemia has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Bassen FA, Kornzweig AL. Malformation of the erythrocytes in a case of atypical retinitis pigmentosa. Blood. 1950;5(4):381-387. PMID:15407125
- Kane JP, Havel RJ. Disorders of the metabolism of lipoproteins. In: Williams Textbook of Endocrinology. 12th ed. Elsevier; 2011:1633-1664.
- Narcisi TM, Shoulders CC, Chester SA, et al. Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia. Am J Hum Genet. 1995;57(6):1298-1310. PMID:8533758
- Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Curr Opin Lipidol. 2014;25(3):161-168. PMID:24739664
- Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014;37(3):333-339. PMID:24306067
- Sharp D, Blinderman L, Combs KA, et al. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature. 1993;365(6441):65-69. PMID:8396171
- Hooper AJ, Burnett JR. Update on primary hypobetalipoproteinemia. World J Gastroenterol. 2014;20(35):12435-12447. PMID:25253946
- Benayoun L, Futch T, Bulati F, et al. MTTP deficiency in humans: long-term outcomes and therapeutic implications. J Clin Lipidol. 2018;12(2):455-464. PMID:29454688