Clinicopathological Phenotype of Autosomal Recessive Cholesterol Deficiency in Holstein Cattle

Mock, T.; Mehinagic, K.; Menzi, F.; Studer, E.; Oevermann, A.; Stoffel, M.H.; Drögemüller, C.; Meylan, M.; Regenscheit, N.

ves in CD animals as soon as they start ruminating. In humans, truncation mutations in APOB affecting the APOB-48 protein were shown to result in defective chylomicron formation in the small intestine. 4, 5 This protein is exclusively synthesized in enterocytes of the small intestine. 12 The histologically visible accumulation of lipid vacuoles within the enterocytes in the CD-affected cattle indicates that the enterocytes of these animals are capable of resorbing fat from the ingesta. The hypocholesterolemia and low triglycerides concentrations, however, demonstrate that the transfer of these lipids from the enterocytes into the blood is impaired or even absent. Thus, these histological findings further support a chylomicron formation defect due to the lack of the APOB-48 protein, as it has been described in FHBL. 4, 12 In human patients, FHBL is additionally characterized by malabsorption of lipid-soluble vitamins (A, D, E, K), leading to retinal degeneration, neuropathy, and coagulopathy. 6 These neurologic disorders are associated with cerebellar dysfunction and compromising of the posterior column function with demyelination in the CNS and peripheral nervous system (PNS). 5, 6 We assume that the examined calves were too young to present clinical and pathological signs of chronic cholesterol and lipid deficiency and/or chronic lipid-soluble vitamin deficiencies. In contrast, the hypermetria observed in the heifer, which was first interpreted as a sign of cortical dysfunction in combination with abnormal gait (pacing), might also have been due to cerebellar dysfunction. 13 In the heifer, the histological lesions were mild in general, but were most prominent in the PNS and only minimal in the CNS. Peripheral neuropathy has been described in humans in association with abetalipoproteinemia (ABL), a similar genetic fat metabolism disorder. 14 However, this needs further study of additional older affected animals, including examination of semithin sections and ultrastructural studies. We assume that the mild changes in the sciatic nerve observed in the heifer might be a consequence of APOB mutation. Therefore, it represents a possible further histological feature of APOBassociated CD in cattle. Because no clinical PNS symptoms were present, the question whether the histological lesions are of clinical relevance remains open. Severe demyelination within the CNS as described in FHBL in humans 5, 6 was not visible by light microscopy in the heifer. Therefore, we cannot exclude a functional cause of the clinical CNS symptoms. Calves with CD are described to usually die within the first 6 months of life. 1 Thus, the case of the 2.5-yearold heifer is a rare example of an adult animal surviving the initial phase of CD. The heifer may have established chronic cholesterol and lipid deficiency and/or chronic lipid-soluble vitamin deficiencies as described in FHBL. Upon treatment, young human patients with FHBL can expect to return to a normal growth rate, although they may not reach their full growth potential. 4 In fact, it is proposed that FHBL might be a longevity syndrome, as a result of low LDL cholesterol in the bloodstream, 15 leading to absence of atherosclerosis. 16 The treatment described for humans, ie, total fat restriction and lipid-soluble vitamin supplementation, 5, 6 is not applicable in cattle. Exceptionally older CD cattle, like the heifer in our study, are particularly interesting animals for further investigation concerning the