Abetalipoproteinemia

Lipid Disorders Main Page
Overview
Causes
Classification Abetalipoproteinemia Hypobetalipoproteinemia Familial hypoalphalipoproteinemia LCAT Deficiency Chylomicron retention disease Tangier disease Familial combined hypolipidemia
Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Synonyms and keywords: Acanthocytosis, Bassen-Kornzweig syndrome, apolipoprotein B deficiency, microsomal triglyceride transfer protein deficiency, MTP deficiency

Overview

Abetalipoproteinemia (APOB) is a disease with autosomal recessive inheritance, affecting the etc. Abetalipoproteinemia (ABL; OMIM200100) and hypobetalipoproteinemia (HHBL; OMIM107730) together are reffered to as familial hypolipoproteinemia. These are a set of diseases which specifically have low Low density lipoprotein (LDL) levels.

Historical Perspective

• The first clinical association of peripheral blood acanthocytosis with atypical retinitis pigmentosa and ataxia was first reported by Bassen and Kornzweig in 1950.
• In 1958, Jampel and Falls observed low serum cholesterol values in affected individuals.
• In 1960, Salt noticed the absence of serum beta-lipoprotein in a patient with the syndrome.
  • Consequently the name of the disease was changed to ABL.
  • Eventually, the fundamental biochemical defect was determined to be a complete absence of plasma apolipoprotein (apo) B-containing lipoproteins, namely chylomicrons, very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL).
• In 1986, the APOB gene, its mRNA and the apo B content of the hepatocytes were found to be normal in ABL patients, suggesting that defective post-translational processing and secretion of apo B was the cause of ABL.
• In 1992, a deficiency of microsomal triglyceride transfer protein (MTP) activity was suggested to be the proximal cause of ABL.
• In 1993, the region on chromosome 4q22-24 that encodes the large subunit of MTP was cloned and sequenced, and human MTP mutations in ABL patients were reported.

Pathophysiology

Pathogenesis

• The defect in the MTP causes accumalation of lipid in the intestine leading to Steatorrhea and malabsorption of fat soluble vitamins.
• Accumalation of lipid in the liver causes hepatic steatosis.
• The result of this excessive accumulation causes very low LDL C and VLDL.
• Vitamin E deficiency features are more prominent because the absorption and transport of vitamin E is parallel to the total body lipid levels due to its hydrophobic nature.
  • Spinocerebellar and posterior columns are affected as only minimal amount of vitamin E was transported in HDL C resulting in neurological symptoms.

Genetics

• Autosomal Recessive Inheritance..
• Mutation of MTP (aka MTTP) gene which codes for the Microsomal Trigyceride transfer Protein, MTP.
• MTTP gene mutation occurs on chromosome 4q 22-24, leads to the failure of formation and secretion of apolipoprotein B( Apo B) containing lipoproteins which include chylomicrons, LDL and VLDL from the intestine and liver.
• Patients with heterozygous expression have normal lipoprotein levels indicating that both the alleles of the gene coding for MTTP must be defective.

Microscopic Findings

• Intestinal biopsy : Distended enterocytes strongly positive to oil red O indicates presence of intracellular lipid.
• Liver Biopsy: Hepatic Steatosis

Screening

• Screening of parents of affected individuals show normal Apo B levels and LDL C levels consistent with autosomal recessive inheritance.

Epidemiology and Demographics

Incidence

The incidence of ABL is reported less than 1 in 1,000,000.

Natural History, Complications, and Prognosis

• If left untreated, patients can develop atypical retinitis pigmentosa, severe ataxia, dysarthria, and absent reflexes, leading to significant neurological functional impairment and reduced lifespan.

• Early identification and treatment with vitamin E can delay or prevent progression of the disease.

Differential Diagnosis

• Differentiate from congenital causes of diarrhea.
• Hypobetalipoproteinemia: Homozygous patients have similar presentation and laboratory results.
• Severe Vitamin E deficiency: Neurological Symptoms improve significantly with supplementation of Vitamin E.
• Friedrich Ataxia.
• X-Linked McLeod Disease: Presence of acanthocytes and ataxia. Additionally movement disorders and cognitive impairment are present.

Diagnosis

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

History and Symptoms

• Patients present in infancy with symptoms of chronic diarrhea, steatorrhea, failure to thrive.
• The most serious symptoms are neurological due to demyelination, which begins in the first or second decade of life and include progressive ataxia and peripheral neuropathy.
• Less common symptoms due to long term fat soluble vitamin deficiency are:
  • Easy bruising
  • Osteomalacia
  • Impaired Vision

Physical Examination

Specific physical exam findings include as follows:

• Reduced Visual Acuity and degenerative changes in the retina are seen.Fundoscopic examination reveals atypical dark pigmentation irregularly distributed on the retina, which left untreated will progress to expanding scotomas leading to blindness.
• Hepatomegaly
• Neurological: The symptoms are secondary to demyleination.
  • Truncal Ataxia due to the effect on spinocerebellar tracts.
  • Sensory Motor neuropathy presenting with weakness and muscular atrophy.
  • Loss of proprioception, vibration and temperature can be affected when the disease affects the posterior column.
  • Deep Tendon reflexes are diminished.

Laboratory Findings

Laboratory findings consistent with the diagnosis of abetalipoproteinemia include :

• Lipid Profile: Low Triglyceride and LDL C.(LDL-C (<0.1 mmol/L), TG (<0.2 mmol/L).
• Absent Beta-lipoprotien on electrophoresis.(apo B (<0.1 g/L)
• Gold Standard test : Molecular testing by sequencing the MTTP gene.
• Peripheral Smear shows 50 to 90% of acanthocytes.
• Nerve conduction studies show reduced or absent action potential.
• Very low or Undetectable vitamin E levels.
• Elevated LFT's due to hepatic steatosis.

Treatment

Medical Therapy

• High dose oral vitamin E Supplementation therapy, 150-300mg/kg/day helps in preventing or reversal of the neurological symptoms. Dosing and efficacy can be assessed by checking the Vitamin E levels in the adipose tissue needle aspiration biopsy.
• Oral supplementation of Vitamin A 100–400 IU/kg/day -Vitamin D 800–1200 IU/day -Vitamin K 5–35 mg/week.
• Diet modification to control gastrointestinal symptoms.Low fat (<30 % of total calories), with reduced long-chain fatty acids and oral essential fatty acids.
• Parenteral supplementation is avoided due to the risk of hepatic steatosis.

Surgery

Surgical intervention is not recommended for the management of ABL.

Primary Prevention

There are no primary preventive measures available for ABL.

Secondary Prevention

• Goal is to monitor growth in children and to delay neurological complications.
• Assesment for ataxia, dysarthria, visual changes every 6 to 12 months.
• As vitamin levels dont return to normal even after years of treatment, its recommended to assess for deficiencies.

Hypobetalipoproteinemia

It shares similar clinical and lab features with abetalipoproteinemia.

Pathophysiology and Lab Findings

• Mutations in the gene coding for Apolipoprotein B resulting in malabsorption, hepatic steatosis and fat souble vitamin deficiency.
• Genetics:
  • Based on a Study which involved genetic analysis in 2010, showed

• Patients commonly have low levels of plasma ApoB and LDL cholesterol.

References

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