Current Diagnosis and Management of Abetalipoproteinemia

Abstract

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride transfer protein (MTTP) abrogates the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fat-soluble vitamins and severe hypolipidemia. Patients with ABL typically manifest steatorrhea, vomiting, and failure to thrive in infancy. The deficiency of fat-soluble vitamins progressively develops into a variety of symptoms later in life, including hematological (acanthocytosis, anemia, bleeding tendency, etc.), neuromuscular (spinocerebellar ataxia, peripheral neuropathy, myopathy, etc.), and ophthalmological symptoms (e.g., retinitis pigmentosa). If left untreated, the disease can be debilitating and even lethal by the third decade of life due to the development of severe complications, such as blindness, neuromyopathy, and respiratory failure. High dose vitamin supplementation is the mainstay for treatment and may prevent, delay, or alleviate the complications and improve the prognosis, enabling some patients to live to the eighth decade of life. However, it cannot fully prevent or restore impaired function. Novel therapeutic modalities that improve quality of life and prognosis are awaited. The aim of this review is to 1) summarize the pathogenesis, clinical signs and symptoms, diagnosis, and management of ABL, and 2) propose diagnostic criteria that define eligibility to receive financial support from the Japanese government for patients with ABL as a rare and intractable disease. In addition, our diagnostic criteria and the entry criterion of low-density lipoprotein cholesterol (LDL-C) ＜15 mg/dL and apoB ＜15 mg/dL can be useful in universal or opportunistic screening for the disease. Registry research on ABL is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.

Keywords: Abetalipoproteinemia; Chylomicron; Fat-soluble vitamin; Hypolipidemia; MTTP; VLDL.

Fig.1. Overview of abetalipoproteinemia

(A) MTTP is a prerequisite for the assembly and secretion of VLDL and CM by the liver and small intestine, respectively. Homozygous MTTP deficiency causes fat malabsorption, steatorrhea, vomiting, failure to thrive, hypolipoproteinemia, fatty liver, as well as symptoms related to deficiencies of fat-soluble vitamins. (B, C) Endoscopic examination and histological analysis of the duodenal mucosa of an ABL patient and a non-ABL control. Accumulation of intracellular lipids in epithelial cells (C) results in a snowy appearance (B), called snow-white duodenum, a gelee blanche, or white hoar frosting. (D) Acanthocytes of an ABL patient (Patient 1 in Ref 29). Figures 1B, 1C, and 1D are reproduced with permission from Ishibashi S and Ohashi K (The Lipid, 2014; 25: 200-203).

Fig.2. Mutations in the MTTP gene

At least 74 MTTP mutations have been reported. The type of mutation may influence the severity of the disease . The exon-intron structure of the MTTP gene encoded by exons 1a to 18 has been described . Gray boxes represent exons. Lines represent the position of each mutation and polymorphism. Adapted from Zamel R, et al. , Narcisi TM et al. , and Suzuki T et al.