ABL is a rare, autosomal recessive disorder with an estimated prevalence in North America of < 1 per 100,000 [9] and for which worldwide there were about 50 cases with defined MTTP mutations reported as of 2012 [10–15]. There is strong evidence for a founder effect in Ashkenazi Jewish patients, where a conserved haplotype with a common truncating mutation (p.G865X) was discovered in Israel with a carrier frequency of 1:131 and an estimated ABL incidence of 1:69,000 [16]. Some but not all of the reported ABL probands are the offspring of consanguineous marriage, an observation replicated across different national registries [12, 16]. While a range of mutations and deletions have been described in the MTTP gene in association with ABL, affected subjects may be either homozygous for a single mutation or compound heterozygous for different mutations and there appears to be no relationship between the site and nature of these mutations and the clinical phenotypes observed [17].

Although typically ABL presents in infancy with failure to thrive, there is a wide age range of presentation (from infancy to > 20 years) suggesting that there are either environmental or other genetic modifiers that influence some of the clinical features. Infants typically present with diarrhea and malabsorption and the hallmark features including extremely low plasma cholesterol and TG levels, very low or undetectable levels of APOB, low to absent levels of fat-soluble vitamins and red blood cell acanthacytosis [9, 11].

The clinical phenotypes of low to undetectable levels of cholesterol and TG and APOB reflect the virtual complete block in lipoprotein secretion from both enterocytes and hepatocytes , which reflects the inability to lipidate the nascent APOB protein as it traverses the ER membrane (Fig. 38.1). The very low levels of fat-soluble vitamins (particularly vitamins A and E) reflect fat malabsorption and defective CM production. Among the neurological sequelae of unrecognized ABL is retinal degeneration, which may be progressive and result in visual impairment and which is likely a consequence of continued fat-soluble vitamin A and E deficiency [9]. The observation that ABL subjects treated upon diagnosis with long-term high-dose supplementation with vitamins A (10–15,000 IU/day) and E (100 mg/kg/day, equivalent to 150 IU/kg) [18], maintain retinal function and neurological function provides indirect but strong evidence that deficiency of these vitamins is responsible for the phenotypic outcomes, although the exact mechanisms linking ABL to neurologic deficits are yet to be fully elucidated [19]. Importantly, there was no evidence for increased oxidative stress in the plasma of ABL patients receiving long-term vitamin A and E supplementation [19]. For clinical monitoring purposes, it is worth noting that even with high-dose vitamin E supplementation, plasma levels rarely return to the normal range. This is because of the dual defect that exists in vitamin E metabolism, reflecting a block in intestinal absorption of vitamin E and also a defect in hepatic alpha tocopherol transfer to circulating lipoproteins [20]. Because circulating plasma lipid levels are so low in ABL subjects, plasma levels of alpha and gamma tocopherol may not reflect tissue (particularly adipose) concentrations, but nevertheless may be a useful surrogate to monitor long-term compliance [9].

ABL subjects require lifelong maintenance on a low-fat diet (to minimize steatorrhea) and supplementation with fat-soluble vitamins as noted above and in addition supplementation with 1000 IU/day vitamin D (which is available in a water-soluble form). Longer term, ABL subjects should be monitored for development of steatohepatitis (transaminases, liver magnetic resonance spectroscopy) which has been associated with progressive liver disease requiring liver transplantation [21] .

FHBL is an autosomal codominant disorder whose molecular basis (where known) most commonly resides in mutations in the APOB gene on chromosome 2 [22]. Unlike ABL, heterozygous FHBL subjects exhibit low circulating levels of plasma cholesterol, triglyceride, and APOB and are generally discovered in routine plasma lipid level screening tests. Heterozygous FHBL, recognized through population-based plasma lipid screening for subjects at or below the fifth percentile, is present in ~ 1:500–1:1000 [22, 23]. Homozygous FHBL by contrast is extremely rare, with perhaps 20 index cases whose molecular genetic basis is known [24]. FHBL associated with structural defects in the APOB gene represent the majority of known cases [22, 23]. The known mutations generally produce truncated forms of APOB (i.e., smaller proteins than APOB100) which are defective in undergoing lipidation despite adequate levels of MTTP (Fig. 38.1). These truncated forms of APOB may be detected using denaturing gel electrophoresis and are present at very low levels in plasma, and notably even in heterozygous subjects are found at lower abundance than those encoded by the wild-type allele. This observation implies that transcription or translation of the mutant allele in FHBL is also defective [25]. In addition, FHBL is genetically heterogeneous with several kindreds described in whom the trait is inherited in an autosomal dominant manner without mutations in the APOB gene but rather with linkage to a locus on chromosome 3p21, between D3S2407 and D3S1767 [25]. The molecular basis for the defects in FHBL subjects linking to chromosome three remains unknown.

The clinical manifestations of homozygous FHBL are heterogeneous with severely affected individuals presenting in infancy or early childhood with failure to thrive and steatorrhea, while yet other affected homozygous individuals may present in adulthood with incidentally discovered hepatic steatosis and very low levels (< fifth percentile) of plasma lipids and undetectable levels of APOB100 [24]. In general, the clinical manifestations and management of severe homozygous FHBL subjects follows the same principles as alluded to above for ABL subjects, including acanthocytosis, very low levels of plasma lipids and fat-soluble vitamins, and neurologic deficits with macular degeneration and steatorrhea [26]. A more sinister concern longer term for FHBL subjects is the development of cirrhosis [27, 28] and hepatocellular carcinoma [24, 29]. The observations in relation to hepatic lipid accumulation in subjects with FHBL due to APOB truncations were not replicated in homozygous FHBL subjects linked to chromosome 3p21, reinforcing the concept that the clinical phenotypes among FHBL subjects is very variable [30, 31]. Homozygous FHBL subjects should therefore undergo regular evaluation of fat-soluble vitamin sufficiency (as outlined above) and also periodic monitoring for progressive hepatic steatosis and steatohepatitis (transaminases, liver magnetic resonance spectroscopy), again as alluded to above for ABL subjects.

CRD was identified by Roy and colleagues in 1987 [32]. Although this disorder appears to be the same as that described by Anderson in 1961 [33], the term “CRD” is preferred nowadays, as it is more indicative of the pathology. CRD is a very rare, autosomal recessive disorder with fewer than 50 cases described worldwide [7], and whose molecular genetic defect resides in the SAR1-ADP ribosylation factor , type B (SAR1B), which belongs to the Ras superfamily of guanosine triphosphatase (GTPases). SAR1B mutations induce an accumulation of pre-CM transport vesicles [7], as seen on intestinal biopsies and illustrated schematically in Fig. 38.2.

SAR1B is a single polypeptide of 198 amino acids and functions as molecular switch controlled by the exchange of guanosine diphosphate (GDP) and GTP. SAR1 is cytosolic in its GDP form and is recruited to the ER by the exchange of GDP for GTP to initiate COPII-coated vesicle formation. SAR1-GTP forms a coating protein complex (COPII) with two heterodimers SEC23/24 and SEC13/31. COPII initiates budding and captures cargo to eject vesicles from the ER to the Golgi apparatus [34]. The SAR1B GTPase cycle then allows cytosolic COPII proteins to exchange on and off the membrane at specific sites on the ER to regulate cargo exit. As a result, genetic defects in SAR1B affect the transport of pre-CM cargo from the ER to the Golgi apparatus where they usually undergo additional glycosylation before being released from the enterocyte. CMs are transported from the ER to Golgi, probably inside the pre-CM transport vesicle or PCTV [35]. PCTV share several proteins including COPII (SEC13–31, SEC24 and SAR1) [36]. Siddiqi et al. [37] earlier showed that PCTV formation can occur in the absence of SAR1 and later showed that PCTV fusion with Golgi requires the presence of SAR1 [38].

The first investigation of genetic defects in eight families disclosed three frameshift (75–76 delTG, 555–558 dupTTAC, 349–1 G > C) and five missense mutations (109 G > A, 409 G > A, 537 T > A, 536 G > T, 542 T > C) [5]. The second exploration of the genetic abnormalities from eight families identified three new molecular aberrations: a stop codon mutation (364 G > T), a 5946 bp deletion (total exon 2) and a missense mutation (554 G > T) [39]. Thereafter, a new mutation G19T (changing a glutamic acid to a STOP codon) was found in the seventh exon [40] while two additional mutations were detected in exon 2 (G11D) and exon 4 (D75G) [41]. Recently, a novel homozygous deletion at position 142 (c.142delG) led to the replacement of the aspartic acid at position 48 by a threonine and gave rise to a frameshift-derived premature stop codon 17 amino acids further on (p.Asp48ThrfsX17), thereby resulting in a truncated protein (only 32 % of the length of the normal protein and 24 % of the normal sequence) [7]. Finally, the analysis of SAR1B gene mutations in Tunisian children revealed a proband homozygous for a novel nucleotide transition in exon 4 (c.184G > A), resulting in a nonconservative amino acid substitution (p.Glu62Lys) [42]. In order to provide a unifying explanation for the functional impairment of SAR1B mutated proteins, investigators have turned to information gleaned from the SAR1B crystal structure, computational analysis, and sequence alignment [43]. For example, the nonsense mutations and whole deletion of exon 2 in SAR1B yields truncated proteins that are predicted to modify the affinity of SAR1B for GDP and GTP, thereby affecting its interaction with the endoplasmic ER and other components of COPII machinery. In addition, the missense mutations in SAR1B likely yield nonfunctional proteins that alter the conformational and/or structural properties of SAR1B. Because SAR1B expression is detected in multiple different tissues, there are frequent clinical manifestations of CRD in organs beyond the gastrointestinal tract. As an example, cardiac abnormalities, myolysis, increased CK levels and cardiac abnormalities were associated with the G19T mutation [40].