Clinical features

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The first symptoms of AD/CMRD, which most frequently occurr within a few months after birth, consist of failure to thrive, diarrhea with steatorrhea and abdominal distension. Of the 62 patients described in the literature, only 4 were diagnosed as adults; two sisters presented with diarrhea that was found to have begun in infancy [21, 23], the third adult had severe neurological signs in infancy [6] and the past medical history of the last adult revealed some clumsiness in walking and running and very loose bowel movements in infancy [7]. These patients may have spontaneously avoided the fat in their diets to minimize symptoms. Non specific malabsorptive diarrhea is present in almost all cases with steatorrhea, even when a low fat diet is observed [28]. The diagnosis is sometimes delayed (often for several years) because the symptoms are non-specific and are attributed to chronic diarrhea (cystic fibrosis or coeliac disease). Thus, 39/45 patients exhibited the first symptoms before one year of age, whereas only 21/52 received the proper diagnosis without undue delay. As consequence of diarrhea, failure to thrive (-1 to -4DS for height and/or weight) is also frequent (45/51 patients) and persists if a low fat diet is not instituted. Other digestive symptoms, such as vomiting or a grossly distended abdomen are commonly observed. Usually, if a low fat diet supplemented with lipid soluble vitamins is instituted, the growth starts again; however, some patients with a delayed diagnosis do not attain a normal height and weight [29]. Tolerance to fat in the diet has been reported in a few cases [14, 16, 22, 24, 27]; however, in most instances, diarrhea begins again when fat is reintroduced in the diet [29].

Hepatic and neurological abnormalities, although sometimes reported in young patients, generally are tardive manifestations, particularly when the diagnosis and the implementation of dietary vitamin supplements are delayed. Several cases of transient hepatomegaly have been described [6, 9, 11, 16, 17, 22] and one or both amino-transaminases (ASAT and ALAT) are frequently reported to be increased (13/15 patients of Charcosset [22]) but confirmed hepatic steatosis are infrequent (three cases described) [11, 25]. However, no instance of cirrhosis has been reported. In young adults or older patients, neurological abnormalities consist mainly of areflexia [11, 12, 14, 22]. In some cases, more severe neurological degeneration consisting of ataxia, sensory neuropathy and/or tremor has been reported [6, 7, 11, 19]. Mild defects in color vision and retinal function also have been observed [11, 14, 28] but no retinis pigmentosa has been reported. Acanthocytosis is very rare and usually transient [6, 12, 17, 27].

Mild muscular abnormalities have been described in several patients and consist mainly of muscular pain and cramps; one patient was described with myopathy [6]. Creatine kinase (CK) levels are often found to be elevated (1,5-2,5 times normal) [23, 27]. Jones et al (2003) have shown that high levels of SAR1B mRNA expression occurs in tissues other than intestine [2] and, therefore, extra-intestinal clinical manifestations might occurr in AD/CMRD. Silvain et al have described a cardiomyopathy in an adult and documented the accumulation of lipids in some muscle fibers [23]. Consequently, clinical evaluation and follow-up of these patients should include CK levels and cardiac examination.

Poor mineralization and delayed bone maturation may be present and vitamin D levels may be normal or decreased [5, 12, 18, 21, 23, 28]. Several patients also have exhibited associated infectious diseases [14, 16].

AD/CMRD patients exhibit a particular recessive hypocholesterolemia which differs from other familial hypocholesterolemias. The hypocholesterolemia manifests itself by a decrease of plasma LDL (LDLc) and HDL (HDLc) cholesterol (both by approximately 50%) associated with a normal level of triglycerides (Table 1). The severe decrease of HDLc (the mean level in patients is 0,49mM) associated with a normal triglyceride level is pathognomonic of AD, if all the secondary causes of malabsorption such as celiac disease, exocrine pancreatic insufficiency (cystic fibrosis or Shwachman-Diamond syndrome), and the Mc Kusick syndrome (small height and malabsorption with exactly the same lipid profile as AD) have been ruled out. Further, other causes of familial hypocholesterolemias must be carefully ruled out; for example, some patients with AD/CMRD have low levels of triglycerides and high levels of HDLc that are similar to those found in atypical abetalipoproteinemia [30, 31] or homozygous hypobetalipoproteinemia (data not shown). Plasma levels of vitamin E, measured before supplementation in patients diagnosed during the last decade, are usually low or very low (but detectable, from 0,5 to 6,8 |M, 3 of 19 patients had undetectable levels). In patients described previously, the undetectable levels were probably due to technical limitations (reported values range from 0, 23 to 11,3 |M, and 13 of 28 patients had undetectable levels). Mild decreases of vitamin A have also been found [5, 6, 11, 12, 18, 21, 24, 27] but there are normal levels of other fat soluble vitamins in most of the AD/CMRD patients.

Patients data

All published cases

Published cases with mutations

N

62

34

age at onset

56% < 3 mths, 87% < 1 year

53% < 3 mths, 84% < 1 year

age at diagnosis

60% > 1 year, 23% > 10 years

50% > 1 year, 23% > 10 years

major clinical data

90% diarrhea, 88% failure to thrive

90% diarrhea, 57% failure to thrive

TC mM

n=54 M=1,75 (0,86-3,38)

n=34 M=1,81 (1,11-2,82)

TG mM

n=48 M=0,87 (0,36-2,06)

n=33 M=0,92 (0,36-1,98)

HDLc mM

n=26 M=0,49 (0,32-0,83)

n=23 M=0,50 (0,32-0,83)

LDLc mM

n=26 M=0,87 (0,26-1,61)

n=23 M=0,88 (0,31-1,61)

apoB g/l

n=37 M=0,44 (0,20-0,82)

n=21 M=0,49 (0,20-0,82)

apoAl g/l

n=31 M=0,52 (0,26-0,90)

n=18 M=0,52 (0,38-0,90)

Vitamin E ||M

n=43 M=2,74 (0 - 11,3)

n=23 M=2,81 (0 - 7,6)

(TC: total cholesterol, TG: triglycerides, HDLc: HDL cholesterol, LDLc: LDL cholesterol)

Table 1. Mean data for all the published cases

(TC: total cholesterol, TG: triglycerides, HDLc: HDL cholesterol, LDLc: LDL cholesterol)

Table 1. Mean data for all the published cases

In most cases, an essential fatty acid (FA) deficiency has been not investigated, nevertheless, a decrease of linoleic acid (C18:2 n-6) and normal levels of n-3 FA have been found in two files of patients [10, 28]. For all the patients, the lipid profiles of the heterozygous parents were normal.

Four new cases of AD/CMRD in 3 families have recently been discovered (Table 2, 3). All the individuals presented with diarrhea and failure to thrive (4/4 patients). Interestingly, one of the patients presented with tremor at diagnosis (Table 2). The plasma lipids and vitamin E exhibit a wide range of levels and, in particular, the triglycerides and total and LDL cholesterol values which is an other characteristic of AD.

The inability of the enterocytes to secrete chylomicrons and apoB 48 after a fat load is a common clinical feature of AD/CMRD, ABL (abetalipoproteinemia) and, generally, homozygous FHBL (familial hypobetalipoproteinemia). When observed with video-endoscopy, the intestine of AD/CMRD patients shows a white mucosa ("gelée blanche"). This typical white stippling, like hoar frosting, covers the mucosal surface of the small intestine (Fig 1A, B) even in the fasted state in contrast to healthy individuals. When intestinal biopsies from patients who have fasted are observed by light microscopy, they appear to have a normal number of villi of appropriate length. However, the enterocytes are overloaded with birefringent droplets in the cytoplasm (Fig 1 C, D) [1, 5, 6, 8, 9, 11, 12, 14, 16-18, 20, 25, 27]. These droplets are present, mainly, in the upper one-third of the villus of the enterocyte and they stain positively with oil red O indicating that they are fat droplets (mainly triglyceride) (Fig 1D, E). In some cases, the droplets are seen to be present preferentially on one side of the villus as opposed to both sides, whereas, in other cases (or sometimes in the same case), they may be present on both sides [32]. When the biopsies are examined by electron microscopy, two types of lipid-containing structures, in fact, are observed in the cytoplasm which alter the normal architecture of the cells.Very large lipid droplets (1025 nm average diameter), not in a membrane-bound compartment, are present along with smaller lipoprotein-sized particles (305 nm average diameter) which are present in membrane-bound structures (Fig 2 A, B) [32]. This is in contrast to enterocytes in biopsies

Intestinal endoscopy after a 12-hour fast. In contrast to what is observed in a normal subject (A), video-endoscopy of the duodenum (D) of patient AD2 (B), shows the typical « white hoary frosting » on the small intestinal mucosa. In contrast with a normal subject(C), light microscopy of the duodenal biopsy from AD2 (D) shows the typical vacuolated enterocytes (black arrows) that stain positively with oil red O (E, black arrows). Note the typical heterogeneous aspect of the villi either fat loaded (black arrows) or without lipid droplets (white arrows). Goblet cells are normal (D, arrow g). (C *100; D x400; E x200).

Intestinal endoscopy after a 12-hour fast. In contrast to what is observed in a normal subject (A), video-endoscopy of the duodenum (D) of patient AD2 (B), shows the typical « white hoary frosting » on the small intestinal mucosa. In contrast with a normal subject(C), light microscopy of the duodenal biopsy from AD2 (D) shows the typical vacuolated enterocytes (black arrows) that stain positively with oil red O (E, black arrows). Note the typical heterogeneous aspect of the villi either fat loaded (black arrows) or without lipid droplets (white arrows). Goblet cells are normal (D, arrow g). (C *100; D x400; E x200).

Figure 1. Intestinal endocopy after a 12-hour fast (A, B, C, D, E) (from A. Georges [27])

from patients with ABL which exhibit only (or predominantly) the very large lipid droplets whereas the smaller lipoprotein-sized particles, in membrane bound structures, are absent. In the enterocytes of both AD/CMRD and ABL patients, the Golgi apparatus is often distended but it is, generally, empty and free of lipoprotein-like particles. Further, in AD/CMRD, lipoprotein-like particles are observed, although in only a few cases, in the intercellular spaces between the enterocytes in contrast to ABL where they are never observed in intercellular spaces.

In addition to the lipid profiles of the patient and the parents, the diagnosis is supported by the absence of secretion of chylomicrons after a fat load, the presence of white duodenal mucosa upon endoscopy, the presence of cytosolic lipid droplets and lipoprotein-sized particles in the enterocytes of the intestinal biopsy and, finally, the discovery of a mutation in SAR1B gene. It should be noted, however, that the AD/CMRD phenotype has been observed in patients for which there is no mutation in the coding sequence of the SAR1B gene ([33] and unpublished data).

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