Abetalipoproteinemia


Article Author:
Zeenat Junaid


Article Editor:
Krunal Patel


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
12/13/2018 11:45:11 AM

Introduction

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder marked by low or absent levels of plasma cholesterol, low-density lipoproteins (LDLs), and very-low-density lipoproteins (VLDLs). It should not be confused with a deficiency in beta-lipoproteins. Hallmark symptoms include fat malabsorption, spinocerebellar degeneration, acanthocyte red blood cells, and retinitis pigmentosa. [1],[2]

Treatment aims to arrest the neuropathy and efficiency-induced complications in patients.

Etiology

Abetalipoproteinemia is caused by a homozygous autosomal recessive mutation in the MTTP gene. More than 33 mutations that cause the disease have been identified. The gene codes for microsomal triglyceride protein (MTP) that mediates intracellular chylomicron or VLDL assembly and transport in the intestinal mucosa and hepatocytes. Most of the signs and symptoms of the disease result from a severe deficiency of fats and fat-soluble vitamins, especially vitamin E. It usually presents in infants as failure to thrive, steatorrhea, and abdominal distension and results in spinocerebellar degeneration and retinitis pigmentosa.[3]

Epidemiology

Abetalipoproteinemia occurs in less than 1 in 1 million persons. Consanguineous marriages are strongly implicated. Because it is autosomal recessive, both copies of the gene must be faulty to cause the disease. It occurs in females and males equally. [4]

One particular mutation is more common in people of Ashkenazi (eastern and central European) Jewish descent. This mutation substitutes the protein building block, or amino acid, glycine with a stop signal at position 865 (written as Gly865X or G865X). As a result of this amino acid change, an abnormally small, nonfunctional version of the protein is made. [5]

Pathophysiology

Beta apolipoproteins are very large apolipoproteins. They are critically important for the secretion and formation of chylomicrons (CMs) and VLDL. Abnormalities that impede this process result in abetalipoproteinemia and hypobetalipoproteinemia. [6],[7],[8]

MTP acts as a chaperone that facilitates the transfer of lipids onto apo B. MTP is found within the lumen of microsomes in the liver and intestinal mucosa and catalyzes the transfer of triglyceride, cholesteryl esters, and phosphatidylcholine between membranes. Lipid transport rates decrease in the order of triglyceride to cholesteryl ester to diglyceride to cholesterol to phosphatidylcholine. Unlike other lipid transfer proteins, MTP is a heterodimer containing subunits of molecular mass 58 and 97 kDa. The large 97-kDa subunit possesses the lipid transfer activity or confers lipid transfer activity on the complex. The large subunit of MTP may be missing in abetalipoproteinemia.

Initial assembly occurs in the endoplasmic reticulum where apolipoproteins, cholesterol, phospholipid, and triacylglycerides are synthesized and incorporated into lipoprotein particles. The particles are subsequently transported to Golgi and secreted. Each lipoprotein is specific in its lipid composition and type of apolipoproteins it possesses.

The two beta apolipoproteins are B-100 and B-48. ApoB-100 is carried on VLDL. ApoB-100, synthesized by the liver, is larger than apoB-48, which is made up of 4536 amino acids. Unlike apoB-48, apoB-100 contains the binding site essential for LDL uptake by hepatocyte LDL receptors. ApoB-48 is carried on CMs, is derived from the same gene as apoB-100. [1] 

Gastrointestinal Manifestations

These manifestations include diarrhea and fat-soluble vitamin deficiency. They are evident from infancy. Diarrhea may not be a prominent symptom later though because patients learn to avoid fatty foods. However, the deficits in fat-soluble vitamins continue, because their assimilation and transport depend heavily on the integrity of the apoB pathway. It is worth noting that high dose vitamin-E supplementation only results in marginally increased serum vitamin levels. In contrast, high doses of vitamin-A therapy can achieve normal serum levels. This shows that despite the damaged intestinal absorption, the transport of vitamin A by retinol-binding proteins in serum is not impaired in abetalipoproteinemia.

Hepatic Manifestations

  • Hepatomegaly due to hepatic steatosis.
  • Possible increase in serum ALTs and ASTs
  • Reports of cirrhosis in some patients

Hematologic Manifestations

Acanthocytosis is a hallmark feature of this disease. Acanthocytes are abnormally spiked RBCs due to the defective phospholipid cell membrane. They are also seen in liver dysfunction. Because of their inability to form rouleaux, erythrocyte sedimentation rates could be very low. Fat malabsorption could lead to deficiencies in iron, folic acid, among others and lead to anemia. Vitamin E is involved in protection from free radical damage. Its deficiency could potentiate lipid peroxidation of cells and lead to hemolysis. This exacerbates anemia. Vitamin K is involved in the gamma decarboxylation of clotting factors, an indispensable step in coagulation. Its deficiency could lead to bleeding disorders.

Neurological Involvement

Peripheral neuropathy, delayed intellectual development, tremor, nystagmus, loss of deep tendon reflexes

These may be myriad and variable in their severity. The primary pathophysiology is demyelination due to deficiency of lipid-soluble vitamins. The central and peripheral nervous systems are both affected.

Muscle Involvement

Weakness and increased degeneration

Ophthalmic Involvement

Retinitis pigmentosa, decreased night and color vision, blindness

Histopathology

Acanthocytes on the peripheral blood smear are pathognomonic for abetalipoproteinemia.

History and Physical

Failure to thrive in infancy may cause gastroenterologic, neurologic, and ophthalmologic symptoms, including the following:

Gastroenterology Symptoms

  • Steatorrhea and diarrhea 
  • Abdominal distention

Neurologic Symptoms 

  • Slow mental growth
  • Deep tendon reflexes are absent
  • Ataxia
  • Slurred speech
  • Peripheral neuropathy.
  • Intention tremors.

Ophthalmologic Symptoms

  • Retinitis pigmentosa by adolescence (due to deficiency of vitamin A)
  • Decreased night and color vision.
  • Blindness may occur

Evaluation

Complete Blood Count

Complete blood count shows anemia, thrombocytopenia, or pancytopenia.[1]

Blood Smear

Blood smear shows acanthocytes (Burr cells).

Fasting Lipid Profile

Fasting lipid profile shows low VLDLs, LDLs, and total cholesterol.

Stool Study

Stool studies show fat malabsorption and absence of evidence for other possible causes.

Imaging Studies

  • Hepatic scan or ultrasonography to assess changes of fatty liver
  • Magnetic resonance imaging (MRI) of the spinocerebellar region may show degeneration
  • Eye and retinal examination and imaging to check for retinal damage

Treatment / Management

Dietary Manipulation[9]

  • Strict restriction of long-chain fatty acids

Vitamin Supplementation

  • Very large doses of oral vitamin E
  • Vitamin A supplementation is instituted if an elevated prothrombin time suggests vitamin K depletion.

Physiotherapy

Occupational Therapy

Differential Diagnosis

  • Chronic cholestatic liver disease
  • Combined neuropathy and ataxia
  • Familial vitamin E deficiency
  • Hereditary sensorimotor neuropathies·
  • Retinal degeneration
  • Secondary cancers
  • Spinocerebellar disorders

Prognosis

Prognostic Factors

  • Age at diagnosis
  • The onset of treatment with low-fat diet and vitamin replacement therapy
  • Type of MTP mutation and APOE genotype with the long-term outcome of patients with abetalipoproteinemia

Enhancing Healthcare Team Outcomes

Abetalipoproteinemia is a relatively rare genetic and acquired disorder that is characterized by acanthocytic red blood cells, fat malabsorption, spinocerebellar degeneration and pigmented retinopathy. The condition is associated with very high morbidity and thus it is vital to have an integrated pathway of management with close interaction with a number of health professionals. Besides a gastroenterologist, an interprofessional approach is essential if one is to improve outcomes:

  • Ophthalmologist to regularly assess for retinal degeneration and ophthalmoplegia
  • Internist to assess the cholesterol profile and the abetalipoproteinemia.
  • Neurologist: to assess and monitor the patient for spinocerebellar degeneration
  • Hematologist to assess the anemia and acanthocytosis
  • Pharmacist to determine the need for pyridoxine and total parenteral nutrition or supplementation with vitamins
  • Dietitian to assess the patient for failure to thrive, assess malabsorption of fat-soluble vitamins and the need to change diet
  • Genetic counseling for patients and their first-degree relatives
  • Social worker and nurse to assess the patients for nutritional needs, failure to thrive and referral to a specialist.

Evidence-based Medicine

Because of the rarity of the disorder, there is a lack of randomized clinical trials on the long-term benefits of vitamins. However, small case series and anecdotal reports indicate that when patients are diagnosed and referred early to a clinic which specializes in the management of this lipid disorder, the outcomes are improved.[10] There is ample evidence indicating that prompt supplementation with vitamins can improve the prognosis and outcome.[11] (Level III) However, the long-term outlook for many of these patients is guarded as many go on to develop vision loss and permanent blindness.


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Abetalipoproteinemia - Questions

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A 12-year-old male is seen for fatigue. A blood smear indicates the presence of acanthocytes. Which of the following disorders may be the cause of this finding?



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An 11-year-old boy has developed progressive neuropathy, diarrhea, and fatty stools, and he has a history of short stature. Deep tendon reflexes are decreased. Proprioception and vibratory sensation are impaired. There is spastic gait and ataxia. Pigmentary retinal degeneration is noted and the patient has decreased night vision. The lipid profile is markedly abnormal with a cholesterol of 30 mg/dL, triglycerides of 0, and HDL of 28 mg/dL. What gene mutation is most likely?



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Which of the following is not a common feature of abetalipoproteinemia?

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Which of the following about abetalipoproteinemia is FALSE?



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Which of the following conditions most likely results in very low levels of serum cholesterol and triglyceride?



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A patient is diagnosed with abetalipoproteinemia. There is absence of low-density lipoprotein, very low-density lipoprotein, and chylomicrons. Which gene has mutated?



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A 5-year-old boy develops loss of Achilles reflexes. By age 10 years he has limb ataxia and then peripheral neuropathy. At age 15 he has retinitis pigmentosa and acanthocytosis. What is the most likely diagnosis?



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Which of the following mutations is responsible for abetalipoproteinemia?



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A 2 week old infant is noted to have ongoing vomiting, loose stool, and failure to thrive. The infant is currently hospitalized for strict calorie counts which have not helped weight gain. Standard initial failure to thrive workup is negative. An expanded workup is ordered. Which of the following laboratory findings would NOT be consistent with abetalipoproteinemia?



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A 7-year-old female has developed progressive neuropathy, fatty stools, diarrhea, and failure to thrive. A neurology exam reveals absent deep tendon reflexes and impaired proprioception and vibratory sensation. There are spastic gait and ataxia. Pigmentary retinal degeneration is seen, and the child has diminished night vision. The lipid profile is markedly abnormal with cholesterol of 37 mg/dL, triglycerides are 0, and HDL is 23 mg/dL. What disease is most likely?



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A 6-month-old child presents with poor growth and loose malodorous stools since birth. Stool studies are significant for an increased amount of fecal fat. Cystic fibrosis was initially considered, but the chloride sweat tests were negative. Celiac sprue was also suspected, and the child underwent colonoscopy. Intestinal biopsy, however, revealed normal-appearing villi. What is the diagnosis?



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A 3-year-old child presents with malabsorption of fats and neuropathy and has an absence of chylomicrons, VLDL, and LDL in the plasma. Which disorder does the child have?



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Abetalipoproteinemia - References

References

Boltshauser E,Weber KP, Laboratory investigations. Handbook of clinical neurology. 2018     [PubMed]
Mushtaq I,Cheema HA,Malik HS,Waheed N,Hashmi MA,Malik HS, Causes Of Chronic Non-Infectious Diarrhoea In Infants Less Than 6 Months Of Age: Rarely Recognized Entities. Journal of Ayub Medical College, Abbottabad : JAMC. 2017 Jan-Mar     [PubMed]
Strain JE,Vigilante JA,DiGeorge NW, Hypolipidemia in a Special Operations Candidate: Case Report and Review of the Literature. Journal of special operations medicine : a peer reviewed journal for SOF medical professionals. 2015 Winter     [PubMed]
Hentati F,El-Euch G,Bouhlal Y,Amouri R, Ataxia with vitamin E deficiency and abetalipoproteinemia. Handbook of clinical neurology. 2012     [PubMed]
Wang LR,McIntyre AD,Hegele RA, Complex genetic architecture in severe hypobetalipoproteinemia. Lipids in health and disease. 2018 Mar 14     [PubMed]
Ramasamy I, Update on the molecular biology of dyslipidemias. Clinica chimica acta; international journal of clinical chemistry. 2016 Feb 15     [PubMed]
Yilmaz BS,Mungan NO,Di Leo E,Magnolo L,Artuso L,Bernardis I,Tumgor G,Kor D,Tarugi P, Homozygous familial hypobetalipoproteinemia: A Turkish case carrying a missense mutation in apolipoprotein B. Clinica chimica acta; international journal of clinical chemistry. 2016 Jan 15     [PubMed]
Walsh MT,Iqbal J,Josekutty J,Soh J,Di Leo E,Özaydin E,Gündüz M,Tarugi P,Hussain MM, Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal β-Barrel in Microsomal Triglyceride Transfer Protein Function. Circulation. Cardiovascular genetics. 2015 Oct     [PubMed]
Cuerq C,Henin E,Restier L,Blond E,Drai J,Marcais C,Di Filippo M,Laveille C,Michalski MC,Poinsot P,Caussy C,Sassolas A,Moulin P,Reboul E,Charriere S,Levy E,Lachaux A,Peretti N, Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease. Journal of lipid research. 2018 Jul 18     [PubMed]
Gaudet LM,MacKenzie J,Smith GN, Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2006 Aug     [PubMed]
Chardon L,Sassolas A,Dingeon B,Michel-Calemard L,Bovier-Lapierre M,Moulin P,Lachaux A, Identification of two novel mutations and long-term follow-up in abetalipoproteinemia: a report of four cases. European journal of pediatrics. 2009 Aug     [PubMed]

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