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

It 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 LDL C 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 accumalation 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 MTTP gene which codes for the Microsomal Trigyceride transfer Protien, 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

Epidemiology and Demographics

The incidences 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 reduce lifespan.
• Early indentification 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.

Overview

Abetalipoproteinemia is a rare autosomal recessive genetic disorder that interferes with the normal absorption of fat and fat soluble vitamins from food. The syndrome causes the body not to make lipoproteins, including low-density lipoproteins, very-low-density lipoproteins, and chylomicrons. It is an autosomal recessive inherited disorder, which affects both sexes. It predominantly affects males. It is caused by mutations in the genes: apolipoprotein B (APOB) or microsomal triglyceride transfer protein (MTP).

Pathophysiology

Abetalipoproteinemia is an inherited disorder that affects the absorption of dietary fats, cholesterol, and certain vitamins. People affected by this disorder are not able to make certain lipoproteins, which are molecules that consist of proteins combined with cholesterol and particular fats called triglycerides. This leads to a multiple vitamin deficiency, affecting the fat soluble vitamin A, vitamin D, vitamin E, and vitamin K. However, many of the observed effects are due to vitamin E deficiency in particular.

Two genes have been identified in which mutations are associated with this disorder: microsomal triglyceride transfer protein (MTTP) and apolipoprotein B (ApoB).

The MTTP gene provides instructions for making a protein called microsomal triglyceride transfer protein, which is essential for creating beta-lipoproteins. These lipoproteins are necessary for the absorption of fats, cholesterol, and fat-soluble vitamins from the diet and the efficient transport of these substances in the bloodstream. Most of the mutations in this gene lead to the production of an abnormally short microsomal triglyceride transfer protein, which prevents the normal creation of beta-lipoproteins in the body. MTTP associated mutations are inherited in an autosomal recessive pattern, which means both copies of the gene must be faulty to produce the disease.

There is an absence of apolipoprotein B. On intestinal biopsy, vacuoles containing lipids are seen in enterocytes. Since there is no or little assimilation of chylomicrons, their levels in plasma remains low. This disorder may also result in fat accumulation in the liver (hepatic steatosis). Because the epithelial cells of the bowel lack the ability to place fats into chylomicrons, lipids accumulate at the surface of the cell, crowding the functions that are necessary for proper absorption.

Clinical History, Complications and Prognosis

This normally results in the affected person being extremely thin, and is normally, if untreated, fatal. It is usually diagnosed in infancy, and sometimes can develop later in life. The signs and symptoms of abetalipoproteinemia appear in the first few months of life. They can include failure to gain weight and grow at the expected rate (failure to thrive); diarrhea; abnormal star-shaped red blood cells (acanthocytosis); and fatty, foul-smelling stools (steatorrhea). Specifically the stool may contain large chunks of fat and or blood. Other features of this disorder may develop later in childhood and often impair the function of the nervous system. They can include poor muscle coordination, difficulty with balance and movement (ataxia), and progressive degeneration of the light-sensitive layer (retina) at the back of the eye that can progress to near-blindness. Adults in their thirties or forties may have increasing difficulty with balance and walking. Many of the signs and symptoms of abetalipoproteinemia result from a severe vitamin deficiency, especially vitamin E deficiency which typically results in eye problems with degeneration of the spinocerebellar and dorsal columns tracts.

Signs and Symptoms

Often symptoms will arise that indicate the body is not absorbing or making the lipoproteins that it needs. These symptoms usually appear en masse, meaning that they happen all together, all the time. These symptoms come as follows:

• Failure to grow in infancy
• Fatty, pale stools
• Frothy stools
• Foul smelling stools
• Protruding abdomen
• Mental retardation/developmental delay
• Dyspraxia, evident by age ten
• Muscle weakness
• Slurred speech
• Scoliosis (curvature of the spine)
• Progressive decreased vision
• Balance and coordination problems

Diagnosis

The inability to absorb fat in the ileum will result in steatorrhea, or fat in the stool. As a result, this can be clinically diagnosed when foul smelling stool is encountered. Low plasma chylomicron levels are also characteristic. Acanthocytes are seen on blood smear.

Shown below is an image depicting acanthocytes on blood smear.

Acanthocytes (Abetalipoproteinemia)

Treatment

• Treatment normally consists of rigorous dieting, involving mass amounts of vitamin E. Vitamin E helps the body restore and produce lipoproteins, which people with abetalipoprotenimia usually lack. Vitamin E also helps keep skin and eyes healthy, which studies show that many males whom are affected will have vision problems later on in life. Dyspraxia and muscle weakness is usually combated with psysiotherapy, or occupational therapy.
• Dietary restriction of triglycerides has also been useful.