Abetalipoproteinemia

What is Abetalipoproteinemia?

Abetalipoproteinemia is also known as Bassen-Kornzweig Syndrome. It is a metabolic disorder with an autosomal recessive pattern of inheritance. It causes abnormalities in fat metabolism. It results in impaired absorption of lipid and lipid-soluble vitamins. If untreated, it can cause significant morbidity related to fat-soluble vitamin deficiencies.

How does Abetalipoproteinemia Occur?

There is a genetic defect causing mutations in the microsomal triglyceride transfer protein gene (MTP). MTP participates in the process of transfer of lipids as follows:

Lipoproteins, VLDL (Very-Low-Density Lipoproteins), and CM (chylomicrons) facilitate the transport of nonpolar lipids (cholesterol and Triglycerides-TGs) to plasma and assist in the function of the digestive system. Apo B is an essential structural component of these lipoproteins. The synthesis and manufacture of VLDL and CM occur in the endoplasmic reticulum (ER) of hepatocytes and enterocytes respectively. The first step in this is the formation of ApoB-containing lipoprotein particle (primordial lipoprotein) by the fusion of nascent ApoB with TG in the ER lumen. MTP mediates the transfer of TG from the ER membrane to the ApoB in the ER lumen. The second step involves the addition of another TG to this particle to form matured lipoprotein, likely mediated by MTP again. ApoB is present as ApoB-100 in VLDL and as ApoB-48 in CM. After the assembly, lipoproteins CM and VLDL are secreted into plasma where they are converted to CM remnants and low-density lipoproteins (LDL) respectively by plasma lipases. They carry the lipids and lipid-soluble nutrients to the tissues.

MTP mutation causes no availability of lipids at the initial phase of lipoprotein formation. Apo-B then gets degraded. There is subsequent impairment in the formation of lipoproteins and the associated lipid transfer to tissues. It leads to a deficiency of fat and fat-soluble vitamins, especially Vitamin E, which is almost entirely dependent on the lipoprotein pathway while vitamins A, D and K also have alternative pathways.

This is the reason that the serum levels of vitamin E rise only up to about 30% even after administering greater doses, while vitamin A and K levels can normalize and their deficiencies are relatively easily corrected in ABL.

Clinical Presentation

The manifestations of abetalipoproteinemia are multisystemic. The salient features are fat malabsorption during infancy and neuro-ocular complications during adolescence.

The presentation during infancy includes poor growth, steatorrhea, nausea and abdominal pain. These symptoms respond to a reduction in dietary fat.

During adolescence, features due to complications of fat-soluble vitamin deficiencies (mainly vitamin E) predominate. The proposed pathogenesis is lipid peroxidation.

There is a demyelination of the central and peripheral nervous systems. The presentation resembles spinocerebellar ataxia. It includes the signs of posterior column neuropathy, cerebellar ataxia, pyramidal tract involvement, and myopathy. Musculoskeletal complications like kyphoscoliosis and lordosis can result in eventually leading to severe disability and immobilization by the second decade.

Ocular Manifestations like ptosis, nystagmus, strabismus, anisocoria and ophthalmoplegia can be present. The unique presentation is retinitis pigmentosa which can show by ten years of age. The patient presents with nyctalopia, color blindness, tunnel vision. There is a progressive loss of peripheral vision. The pathogenesis is related to mainly vitamin E and also vitamin A deficiency. Untreated patients can develop blindness.

Other systems can be involved as follows: Rarely hepatic involvement in the form of steatosis and elevated transaminases can occur. Chronic hepatic damage is not characteristic, although it has been described in few abetalipoproteinemia patients. Hematological features like anemia and acanthocytosis can be the initial presentation of the disease. Coagulation abnormalities can also be present. Very rarely sudden cardiac death can occur. Overall fertility is reduced although pregnancies have occurred in patients with abetalipoproteinemia. Also, gastrointestinal and neurological malignancies have been diagnosed in a few patients with abetalipoproteinemia. The hypothesis here is chronic deficiencies of vitamins A and E with supposed antineoplastic properties.

Investigations

Biochemical

• Screening test: Lipid profile. An abnormal lipid profile showing extremely low levels of the lipoproteins, lipids (cholesterol and TG) and lipid-soluble vitamins. A typical picture is:
  
  • Nearly absent LDL-Cholesterol (<0.1 mmol/L),
  • TG (<0.2 mmol/L),
  • Apo B (<0.1 g/L),
  • Low-fat soluble vitamins A, D, E and K

• Absent beta-lipoprotein band on agarose electrophoresis
• Liver Function tests: Serum transaminases baseline and regular monitoring for hepatic involvement

Hematological

• Full Blood Count for anemia
• Peripheral smear for acanthocytosis
• Erythrocyte sedimentation rate: reduced

Supportive Investigations

Ophthalmic:

• Funduscopy
• Electroretinogram and
• Fluoroscein angiography

Electrophysiological:

• SSEP- Somatosensory evoked potentials
• VEPs -Visual Evoked Potentials

GI endoscopy

Confirmatory Tests

Genetic testing is primarily used for confirmation of the diagnosis where abetalipoproteinemia is suspected in a patient. It has no role in predictive testing or prenatal diagnosis.

Diagnosis

The characteristic features seen in almost all patients with abetalipoproteinemia are the abnormal lipid profile, acanthocytosis on peripheral smear, and symptoms of fat malabsorption.

The typical neurological and ophthalmic manifestations are present in most patients with abetalipoproteinemia if not all and can support the diagnosis.

Summmary Of Management Regime

• Special diet:
• Low fat diet:
• Start with 5 grams/day,
• Grade up fat in diet as tolerated up to 20 grams/day
• EFA supplementation: vegetable oils
• High dose vitamin therapy:
• Vitamin E:
  Dose: 100-300 mg/kg/day

  Route: oral (intramuscular also available)

• Vitamin A:
  Dose: 100-400 IU/kg/day

  Route: oral

• Vitamin K:
  Dose: 5-35 mg per week

  Route: either oral or parenteral

• Vitamin D:
  Dose: 800-1200 IU/day

  Route: oral

Disease Surveillance

Screening and monitoring the multisystem involvement with regular clinical and laboratory assessment is vital. It also assists in reviewing patient compliance with the management regime. Adherence to treatment can significantly reduce disease morbidity. Support from allied health mainly dietician and psychological is desirable. Family education and participation should be encouraged.

6-12 monthly dietary and clinical evaluation:
Main focus should be:

• gastrointestinal symptoms

• diet review

• growth,

• neurological and

• ophthalmic signs.

Annual laboratory investigations:

• monitoring for vitamins A(beta-carotene), vitamin D (D25-OH vitamin D), vitamin E (vitamin E/serum cholesterol ratio) and vitamin K (INR)

• Other nutritional bloods

• Serum transaminases

Additional evaluation during adolescence:

• Abdominal ultrasound (for hepatic steatosis) and echocardiogram.

Teratogenicity: Close surveillance is required in periconceptional females due to the risk of teratogenicity.

Treatment

A low-fat diet and high dose supplementation of fat-soluble vitamins, especially vitamins E and A are the principal aspects of management. The treatment is lifelong. Commencing the treatment as soon as after diagnosis can minimize the severe complications of the disease. Supplementing the diet with essential fatty acids (EFA) in the form of vegetable oils containing polyunsaturated fatty acids is also recommended. It is suggested to avoid MCT supplementation given the risk of hepatic fibrosis with prolonged use.