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At a glance

Inability of the body to produce chylomicrons, low-density lipoproteins (LDL), and very-low-density lipoproteins (VLDL). Demyelination, peripheral sensory neuropathy, ataxia, retinopathy, coagulation disorders, acanthocytosis, and a diminished response to local anesthetics may be present.

Synonyms

Bassen-Kornzweig Syndrome; Microsomal Triglyceride Transfer Protein (MTP or MTTP) Deficiency.

Incidence

Estimated to be less than one in a million. Males are approximately 1.5 times more often affected than females.

Genetic inheritance

Autosomal recessive. Abetalipoproteinemia is caused by mutations in the gene encoding the MTP, which is responsible for the packaging and secretion of apolipoprotein (apo) beta–containing lipoprotein particles. Gene locus has been mapped to chromosome 4q23. Parental consanguinity is not uncommon.

Pathophysiology

Beta lipoproteins are lipoproteins of various molecular weights, with the longer apo-beta-100 (in hepatocytes, where it forms an essential component of VLDL and LDL) and the shorter apo-beta-48 (in enterocytes and mainly responsible for chylomicron formation) as their principal subtypes. Apo-beta-100 is the main structural protein of LDL and contains the LDL-receptor–binding domain. These lipoproteins bind to specific receptors on human cells, allowing for uptake and exchange of lipids. Virtual absence of VLDLs and LDLs results in low levels of plasma cholesterol and triglycerides. However, cholesterol delivery to individual cells remains normal due to an increased cholesterol-carrying capacity of the high-density lipoproteins (HDLs). The cholesterol required for the biosynthesis of steroids in the adrenal glands depends on de novo biosynthesis and on receptor-mediated LDL uptake from plasma. In abetalipoproteinemia, the basal secretion of adrenal corticosteroids is usually normal; however, the maximal production after stimulation with corticotropin or adrenocorticotropic hormone (ACTH) is typically reduced. In some female patients with abetalipoproteinemia, the progesterone production is reduced, but successful pregnancies without supplemental hormonal therapy have been reported.

Diagnosis

Based on the clinical course, combined with reduced plasma lipids (electrophoresis), and absent apo-beta lipoprotein. A peripheral blood smear shows approximately 50% acanthocytosis of red blood cells, which is associated with hyperbilirubinemia (secondary to reduced red cell lifespan). A sural nerve biopsy reveals loss of large myelinated fibers. Early diagnosis is crucial so that appropriate treatment (a low-fat diet with supplementation of essential fatty acids and high oral doses of fat soluble vitamins) can be initiated to avoid neurological complications.

Clinical aspects

The clinical expression is variable and characterized by profound hypocholesterolemia, hypotriglyceridemia, and complete absence of apo-beta–containing lipoproteins. Onset of symptoms is usually in the first 2 years of life (gastrointestinal manifestations, such as chronic diarrhea, severe steatorrhea from fat malabsorption, abdominal distention, vomiting, failure to thrive, and accumulation of triglycerides in enterocytes and hepatocytes). If left untreated, the disease progresses to spinocerebellar ataxia (fasciculi cuneatus and gracilis), dysmetria, loss of proprioception and deep tendon reflexes, peripheral neuropathy, and ceroid myopathy). Ocular manifestations (degenerative pigmentary ...

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