Chylomicron Retention Disease

A number sign (#) is used with this entry because chylomicron retention disease (CMRD), also referred to as Anderson disease, is caused by homozygous or compound heterozygous mutation in the SAR1B gene (607690) on chromosome 5q31.

Description

Chylomicron retention disease is an autosomal recessive disorder of severe fat malabsorption associated with failure to thrive in infancy (Dannoura et al., 1999).

Clinical Features

Anderson et al. (1961), Lamy et al. (1967) and Silverberg et al. (1968) described infants with severe steatorrhea. An intestinal defect in lipid transport and a failure of chylomicron formation was suggested, similar to that observed in abetalipoproteinemia (200100). However, neither acanthocytosis nor neuroocular symptoms occurred in Anderson disease.

Bouma et al. (1986) described 7 cases (3 young adults and 4 children) in 5 kindreds with Anderson disease. Several of the patients were of Algerian descent. All presented with severe diarrhea in childhood and had a varying degree of growth retardation. The diagnosis was established by the finding of fat-laden enterocytes in small bowel biopsies. The transmission pattern was consistent with autosomal recessive inheritance. Enterocytes isolated from intestinal biopsies of patients after an overnight fast show numerous fat droplets, as in abetalipoproteinemia. Immunoenzymatic staining of enterocytes showed large amounts of material that reacted with a polyclonal antiserum to apolipoprotein B (107730) and a monoclonal antibody to B48.

Roy et al. (1987) and Kane and Havel (1989) described chylomicron retention disease. Roy et al. (1987) reported 8 affected infants and distinguished the disorder from abetalipoproteinemia. One of the patients had mild acanthocytosis and 3 patients in their teens had mild peripheral neuropathy with diminished or absent deep tendon reflexes and diminished vibratory sense, and definite or borderline mental retardation. All showed severe growth retardation, steatorrhea, and malnutrition with hypoalbuminemia in 3 and undetectably low plasma vitamin E levels in 5. Although none had retinitis pigmentosa, some showed mild defects in color vision.

Nemeth et al. (1995) described 2 sibs with fat malabsorption and jejunal chylomicron retention. Plasma lipoproteins were studied in the patients and their first-degree Relatives. The patients were a 14-year-old girl and her 8-year-old brother. Compared to healthy controls, they both had low fasting plasma concentrations of plasma total, HDL, and LDL cholesterol, as well as of apolipoproteins A-I (107680) and B. No increase in plasma lipoprotein levels or detectable apo B-48 was observed following an oral fat load. Histologic studies of jejunal biopsy specimens obtained during fasting and 1 hour postprandially showed severe steatosis, and an apparent block of chylomicron secretion from the endoplasmic reticulum into the Golgi apparatus was observed by electron microscopy. Liver biopsy specimens showed moderate steatosis and ultrastructural changes similar to those in the enterocytes. One healthy sister had a normal plasma lipoprotein pattern, and showed increased plasma triglyceride levels as well as the presence of apo B-48 following an oral fat load. Both parents had normal plasma total cholesterol levels, but clearly reduced fasting concentrations of HDL cholesterol and apo A-I. Nemeth et al. (1995) suggested that at least in this family, determination of plasma apo A-I levels might thus prove useful in the identification of heterozygotes.

Clinical Variability

Aguglia et al. (2000) described 2 Italian brothers, aged 19 and 12 years, who presented with a clinical diagnosis of Marinesco-Sjogren syndrome (MSS; 248800). They also had very low serum vitamin E concentrations and an absence of postprandial chylomicrons. Ataxia with isolated vitamin E deficiency (277460), abetalipoproteinemia, and hypobetalipoproteinemia (605019) were ruled out. Findings on electron microscopy of the intestinal mucosa were consistent with chylomicron retention disease. Aguglia et al. (2000) postulated that both CMRD and MSS were related to defects in a gene crucial for the assembly or secretion of chylomicron particles. In the brothers reported by Aguglia et al. (2000), Jones et al. (2003) identified a mutation in the SAR1B gene (607690.0006), responsible for CMRD, and Annesi et al. (2007) identified a mutation in the SIL1 gene (608005.0004), responsible for MSS. The findings indicated that the patients had 2 distinct diseases due to mutations in 2 different genes, rather than defects in a single gene leading to both disorders.

Other Features

Silvain et al. (2008) reported increased serum creatine kinase in 8 CMRD patients between the ages of 13 and 39 years. Two patients had mild clinical symptoms suggestive of mechanical muscle irritability, but none had frank muscle weakness. A 38-year-old woman had increased CK-MB, but no evidence of cardiac dysfunction. A 35-year-old woman had normal serum CK-MB, but decreased cardiac ejection fraction.

Inheritance

Lamy et al. (1967) reported 2 affected brothers, and Silverberg et al. (1968) noted parental consanguinity, both suggesting autosomal recessive inheritance.

Pathogenesis

By in vitro studies of small intestinal explants from CMRD patients, Levy et al. (1987) found normal apoB-48 protein synthesis, but deficient glycosylation. The authors postulated a defect in the formation and secretion of chylomicrons resulting from a defect in glycosylation.

Dannoura et al. (1999) studied 8 patients with Anderson disease from 7 unrelated families of North African origin after treatment with a low-fat diet. Lipid loading of intestinal biopsies persisted, but the pattern and the extent of loading varied among the patients. Electron microscopy showed lipoprotein-like particles in membrane-bound compartments, the densities and mean diameters of which were, in general, significantly larger than in normal-fed subjects. There were also large lipid particles with diameters up to 7,043 nm that were not surrounded by a membrane. Rarely, lipoprotein-like particles were observed in the intercellular spaces. All of these changes could be seen in all patients. Intestinal organ cultures showed that apolipoprotein B and apolipoprotein A-IV (APOA4; 107690) were synthesized with apparently normal molecular masses and that small amounts were secreted in lipid-bound forms. Normal microsomal triglyceride transfer protein (MTP; 157147) and activity were also detected in intestinal biopsies. Segregation analyses of 4 families excluded involvement of significant regions of the genome surrounding the genes encoding the apolipoproteins expressed in the intestine, as well as the genes encoding 3 intracellular lipid transport proteins, MTP, FABP1 (134650), and FABPZ (134640). The results suggested that factors other than apolipoproteins and MTP are important for human intestinal chylomicron assembly and secretion.

Duden (2003) noted that although endoplasmic reticulum-to-Golgi trafficking has been well characterized by both genetic and biochemical methods, few human disorders have been attributed to defects in its individual components. It is likely that the functional redundancy of the COPII pathway leads to nonlethal phenotypes that have escaped classification. Three disorders due to defects in this system are CMRD disease, X-linked spondyloepiphyseal dysplasia tarda (313400), and combined deficiency of clotting factors V and VIII (277300).

Molecular Genetics

Mutations in the SAR1B Gene

Jones et al. (2003) identified a region of apparent homozygosity on chromosome 5q31.1 that segregated with affected status in 4 families with CMRD. In 10 affected individuals from 7 families with chylomicron retention disease, Jones et al. (2003) identified homozygous or compound heterozygous mutations in the SAR1B gene (see, e.g., 607690.0001-607690.0005). Several of the patients had previously been reported (Bouma et al., 1986), Roy et al. (1987), Nemeth et al. (1995), and Dannoura et al. (1999).

Exclusion Studies

Pessah et al. (1991) provided clear genetic evidence that Anderson disease is not due to a defect in the APOB gene: RFLP studies in 2 families indicated that affected children inherited different APOB alleles from at least 1 parent. Strich et al. (1993) arrived at the same conclusion from study of a family in which 3 of 7 children with consanguineous parents were affected. All 3 suffered from diarrhea, failure to thrive, and recurrent infections during infancy. Although the symptoms disappeared later in life, biochemical disorders (e.g., low plasma levels of apolipoproteins A1 (107680) and B as well as cholesterol, resulting in avitaminosis E, plus failure to secrete chylomicrons after a fat meal) persisted. Electron microscopy of enterocytes in 1 of the patients showed accumulation of lipid vacuoles. A VNTR polymorphism linked to the APOB locus excluded that gene as the site of the mutation.