Abetalipoproteinemia is a very rare autosomal recessive disease due to mutation in MTP gene on chromosome 4q23. MTP encodes for microsomal triglyceride transport protein, which catalyses the intracellular transport of triglyceride, cholesterol esters and phospholipids from the cytosol onto the apolipoprotein B present in the endoplasmic reticulum. Mutation in MTP gene results in the failure of formation and secretion of chylomicrons, LDL and VLDL which accumulate in the intestine and liver. Characteristic features of abetalipoproteinemia include steatorrhea, retinitis pigmentosa, ataxia, acanthocytosis, low or undetectable LDL and apolipoprotein B. Patients present in infancy with steatorrhea and failure to thrive. Asymptomatic patients in infancy are usually diagnosed in adulthood with symptoms of neuropathy. Fat malabsorption results in the deficiency of fat soluble vitamins and essential fatty acids, features of vitamin E deficiency are seen early in the disease, as the vitamin E levels are dependent on the total lipid levels in the body. Early diagnosis and initiation of vitamin E supplementation is helpful to stop the progression of disease and in reversal of neurological damage.

• The first clinical association of peripheral blood acanthocytosis, atypical retinitis pigmentosa and ataxia was reported by Bassen and Kornzweig in 1950.^[1]
• In 1958, Jampel and Falls observed low serum cholesterol values in affected individuals.^[2]
• In 1960, Salt noticed the absence of serum beta-lipoprotein in the patient on electrophoresis.^[3]
• The biochemical defect was determined to be a complete absence of apolipoprotein B-containing lipoproteins: chylomicrons, very-low density lipoprotein (VLDL), and low-density lipoprotein (LDL).^[4]
• In 1986, apolipoprotein B content of the hepatocytes, APOB gene and mRNA were found to be normal in patients with abetalipoproteinemia, suggesting a defective post-translational processing and secretion of apolipoprotein B as the cause of abetalipoproteinemia.^[5]
• In 1992, microsomal triglyceride transfer protein (MTP) a deficiency due to the mutation reported as the primary cause of abetalipoproteinemia.^[6]
• In 1993, the region on chromosome 4q 22-24 that encodes the large sub-unit of MTP was cloned and sequenced, and various human MTP mutations in abetalipoproteinemia patients were reported.^[7]

• MTTP catalyzes the transfer of triglycerides from the cytosol to apolipoprotein B in the endoplasmic reticulum, essential step for the formation and secretion of LDL, VLDL, and chylomicrons.^[8]
• Abetalipoproteinemia is a defect in the MTP, the mutation causes defective intracellular lipid transport resulting in the accumulation of lipids in the intestine, leading to steatorrhea, malabsorption of fat soluble vitamins and accumulation of lipids in the liver causing hepatic steatosis.
• Excessive accumulation of lipid in the liver and intestine results in very low LDL and VLDL.
• Vitamin E deficiency features are more prominent because the absorption and transport of vitamin E are parallel to the total body lipid levels, due to its hydrophobic nature. Spinocerebellar and posterior columns of the spinal cord are affected as only minimal amount of vitamin E is transported in HDL causing demyelination.^[9]

• Abetalipoproteinemia is transmitted in an autosomal recessive inheritance pattern.^[10][11]
• Abetalipoproteinemia is caused by a mutation in MTP (aka MTTP) gene which codes for the microsomal trigyceride transfer protein on chromosome 4q 22-24.^{[7] [6][12]}
• MTTP gene mutation results in defective intracellular transport leading to the failure of formation and secretion of apolipoprotein B containing lipoproteins which include chylomicrons, LDL and VLDL from the intestine and liver.^[13]
• Patients with heterozygous expression have normal lipoprotein levels indicating that both the alleles of the gene must be defective to cause the disease.

On microscopic examination:

• Intestinal biopsy demonstrates distended enterocytes strongly positive to oil red O indicating the presence of intracellular lipid.^[8]
• Liver biopsy demonstrates hepatic steatosis.

• Screening for the disease is advised for prenatal diagnosis who are known heterozygous carriers for the disease.^[14]

• Worldwide, the prevalence of abetalipoproteinemia is reported to be less than 1 in 1,000,000.^[15]
• Males and females are affected equally.

• If left untreated, patients can develop atypical retinitis pigmentosa, severe ataxia, dysarthria, and absent reflexes, leading to significant neurological functional impairment and reduced lifespan.^[14]
• Early identification and treatment with vitamin E can delay and prevent progression of the disease.^{[16] [17]}
• The prognosis is poor with a significantly reduced life expectancy.^[18]

Clinical diagnosis is made based on the symptoms, lipid profile and peripheral blood smear findings.

• Patients present in infancy with symptoms of chronic diarrhea, steatorrhea, failure to thrive.
• The neurological symptoms due to demyelination, which begins in the first or second decade of life and include:
  • Progressive truncal ataxia : Presents as instability
  • Peripheral neuropathy causing numbness, tingling, weakness and parasthesias.^[19]
• Less common symptoms in abetalipoproteinemia due to long term fat soluble vitamin deficiency include:
  • Easy bruising
  • Loss of night vision is the first symptom of retinal degeneration which progresses to blindness.
  • Osteomalacia

Physical examination of patients with abetalipoproteinemia is remarkable for:

• Ophthalmologic findings, include reduced visual acuity and degenerative changes in the retina.
  • Fundoscopic examination reveal expanding scotomas, which left untreated will result in blindness. ^[20]
• Hepatomegaly
• Neurological findings include:
  • Truncal ataxia due to the effect on spinocerebellar tracts.
  • Muscle atrophy and weakness due to motor neuropathy.
  • Loss of proprioception, vibration and temperature when the disease affects the posterior column.
  • Deep tendon reflexes are diminished.

Laboratory findings consistent with the diagnosis of abetalipoproteinemia include :

• Lipid profile after a 12 hour fast will demonstrate a low LDLC less than 0.1 mmol/L and triglyceride level of <0.2 mmol/L.^[4]
• Very low or undetectable vitamin E levels.
• Elevated liver function tests due to hepatic steatosis.
  • Hepatomegaly can be demonstrated on abdominal ultrasound.^[21]
• Peripheral blood smear demonstrates 50 to 90% of acanthocytes, with increased erythrocyte fragility.
• Absent beta-lipoprotein is demonstrated on 2D electrophoresis.(apo B (<0.1 g/L)^[5]
• Gold standard test for diagnosing abetalipoproteinemia is molecular gene sequencing for MTTP gene.

The following algorithm helps to diagnose patients with low LDL C:

Initial approach to a patient with steatorrhea requires a general approach to rule out the congenital causes of diarrhea and then consider the rarer causes like abetalipoproteinemia.^{[22] [23]}

The table below summarizes the diseases that have similar presentation as abetalipoproteinemia^[24]:

The main stay of medical therapy for abetalipoproteinemia is fat soluble vitamin supplementation, monitoring the progression of growth, and early identification and treatment of complications.

• High dose oral vitamin E supplementation therapy, 150-300mg/kg/day helps in preventing and reversal of neurological symptoms.
  • Dosing and efficacy can be assessed by checking the Vitamin E levels in the adipose tissue needle aspiration biopsy.^{[27] [28]}
• Oral supplementation of Vitamin A 100–400 IU/kg/day; Vitamin D 800–1200 IU/day; Vitamin K 5–35 mg/week.^[29]
• Parental supplementation of fat soluble vitamins is not preferred due to the risk of hepatic steatosis.^[30]
• Diet modification is advised for control gastrointestinal symptoms, low fat diet consisting of less than 30 % of daily requirement with reduced long-chain fatty acids and oral essential fatty acids is recommended.

Surgical intervention is not recommended for the management of abetalipoproteinemia.

There are no primary preventive measures available for abetalipoproteinemia.

Secondary prevention strategies following abetalipoproteinemia include:

• Monitoring growth in children and to delay neurological complications.^[29]
• Assessment for ataxia, dysarthria, visual changes every 6 to 12 months.
• As vitamin levels do not return to normal even after years of treatment, it’s recommended to assess for features of deficiency regularly.^[31]