J Inherit Metab Dis DOI 10.1007/s10545-013-9665-4
REVIEW
Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management Jooho Lee & Robert A. Hegele
Received: 16 September 2013 / Revised: 12 November 2013 / Accepted: 14 November 2013 # SSIEM and Springer Science+Business Media Dordrecht 2013
Abstract Abetalipoproteinemia (ABL; OMIM 200100) and homozygous hypobetalipoproteinemia (HHBL; OMIM 107730) are rare diseases characterized by hypocholesterolemia and malabsorption of lipid-soluble vitamins leading to retinal degeneration, neuropathy and coagulopathy. Hepatic steatosis is also common. The root cause of both disorders is improper packaging and secretion of apolipoprotein (apo) B-containing lipoprotein particles due to mutations either in both alleles of the MTP (alias MTTP) gene encoding microsomal triglyceride transfer protein (MTP) or both alleles of the APOB gene itself in the case of ABL and HHBL, respectively. Clinical diagnosis is based on signs and symptoms, acanthocytosis on blood smear, and virtually absent apo B-containing lipoproteins, including chylomicrons, very low density lipoprotein and low density lipoprotein. Obligate heterozygote parents of ABL patients usually have normal lipids consistent with autosomal recessive inheritance, while heterozygous parents of HHBL patients typically have half normal levels of apo B-containing lipoproteins consistent with autosomal co-dominant inheritance. Definitive diagnosis involves sequencing the MTP and APOB genes, for which >30 and >60 mutations have been described for ABL and HHBL, respectively. Follow-up includes monitoring for ophthalmologic, neurologic, Communicated by: Robert Steiner J. Lee : R. A. Hegele Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada R. A. Hegele Department of Medicine, University of Western Ontario, London, Ontario, Canada R. A. Hegele (*) Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, Room 4288A, 1151 Richmond Street North, London, Ontario, Canada N6A 5B7 e-mail:
[email protected]
hematologic, and hepatic complications, as well as compliance with treatment. Investigations include lipid profile, serum transaminases, markers for lipid-soluble vitamins, and periodic instrumental assessment of ocular and neurological function. Mainstays of treatment include adherence to a low-fat diet, and supplementation with essential fatty acids and high oral doses of fat soluble vitamins. Prognosis is variable, but early diagnosis and strict adherence to treatment can recover normal neurological function and halt disease progression.
Introduction The proper absorption and trafficking of lipids and lipidsoluble nutrients is an essential function of the digestive system. Almost all of this trafficking is done via lipoprotein particles. The predominant family of lipoprotein particles contains apolipoprotein (apo) B, which is expressed in enterocytes and hepatocytes. In enterocytes, RNA editing produces the shorter apo B-48 form, which pulls together long-chain triglyceride (TG) and fatty acids into chylomicrons (Abumrad and Davidson 2012), whereas in hepatocytes the unedited APOB RNA produces the longer apo B-100, which becomes the backbone of very low-density lipoprotein (VLDL), and its metabolic product low-density lipoprotein (LDL). In addition to proper synthesis of the APOB gene product, post-translational processing of apo B in the endoplasmic reticulum is critical to normal trafficking of these particles. Thus, mutations affecting the processing of apo Bcontaining lipoproteins can lead to impaired lipid absorption and transport. Microsomal triglyceride transfer protein (MTP) is a 97 kDa protein encoded by the MTP (alias MTTP ) gene on chromosome 4q22-24. It forms a heterodimer with protein disulfide isomerase (PDI) and transfers lipids onto nascent apo B in the rough endoplasmic reticulum. This step is also necessary for
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proper folding of apo B. Consequently, MTP dysfunction causes severely impaired apo B processing and secretion, ultimately leading to defective secretion and transport of lipids and fat soluble vitamins that are carried within lipoprotein particles. Homozygous or compound heterozygous mutations in MTP cause abetalipoproteinemia (ABL; OMIM 200100), an autosomal recessive disorder characterized by a virtual absence of apo B-containing lipoproteins in serum. A virtually identical clinical and biochemical phenotype is seen with homozygous or compound heterozygous mutations in the APOB gene that affect structure and stability of apo B, and are the cause of homozygous hypobetalipoproteinemia (HHBL; OMIM 107730). ABL, also known as Bassen-Kornzweig syndrome (Bassen and Kornzweig 1950) and HHBL, clearly illustrate the range of clinical effects of dysfunctional processing of apo Bcontaining lipoproteins. The incidences of both ABL and HHBL are reported as less than 1 in 1,000,000 (Burnett et al 2012a, b). For both disorders, in keeping with their autosomal inheritance pattern - autosomal recessive in the case of ABL and autosomal co-dominant in the case of HHBL - males and females are equally affected, and consanguinity is often found (Berriot-Varoqueaux et al 2000; Tarugi et al 2007). While cases have reported patients being first diagnosed well into adulthood, especially for HHBL, the age of onset or first diagnosis is often within the first 24 months of life (Burnett et al 2012a, b). Both ABL and HHBL have profound consequences if left untreated. Patients can develop atypical retinitis pigmentosa, severe ataxia, dysarthria, and absent reflexes, leading to dramatic neurological functional impairment and reduced lifespan. Early recognition and treatment of the nutritional deficiencies caused by ABL can delay or even prevent deterioration of multi-system function. However, the time between initial presentation and diagnosis of this disease is sometimes lengthy, for various reasons. First, the initial clinical findings of both disorders are nonspecific and lead to other, more common diagnoses such as celiac disease. Additionally, there is a scarcity of long-term follow-up of ABL and HHBL patients in the literature. Furthermore, there is no standardized management protocol for ABL or HHBL, which might affect long term outcomes. Here, we describe the clinical presentations and diagnosis of ABL and HHBL, and suggest a framework for longer term management and follow-up.
Clinical findings Key clinical features in ABL and HHBL patients in the first years of life are steatorrhea from fat malabsorption, and failure to thrive. This is often accompanied by digestive symptoms, such as vomiting and abdominal distention. The digestive and malabsorptive symptoms subside once the patient eats a low-
fat diet. Other symptoms can involve many organ systems due to the resultant malnutrition and deficiencies in essential fatty acids (EFAs) and lipid-soluble vitamins. Most commonly, cases are complicated by retinal degeneration and ataxia beginning in the second decade if there has been no intervention. Neurological findings often have the greatest impact on quality of life for the patient with ABL and HHBL. Patients can present with cerebellar dysfunction in the form of ataxia and dysmetria, as well as compromise of posterior column function with loss of proprioception and deep tendon reflexes. These clinical changes are associated with demyelination of spinocerebellar axons (Zamel et al 2008). If left untreated, impaired mobility can gradually progress to immobility. Early treatment with vitamin E has been shown to delay or prevent development of neurological dysfunction in ABL (Hegele and Angel 1985; Muller et al 1985; Zamel et al 2008). Hepatic involvement includes steatosis and elevated serum transaminase levels. While the exact mechanism underlying these findings is unclear, one possibility is impaired lipid efflux from the liver due to failure to assemble VLDL particles, resulting in chronic lipid retention. Hepatic steatosis, while seen in both ABL and HHBL, seems to be somewhat more prevalent in HHBL patients (Burnett et al 2012a, b; Tarugi et al 2007; Tarugi and Averna 2011). However, hepatic involvement in either condition frequently has no major pathological consequence; in some patients who have been followed clinically for three decades or more it does not seem to progress to inflammation (steatohepatitis) or fibrosis (Hegele, unpublished data). However, a few adult patients had developed hepatosteatosis by the time a diagnosis of ABL was made (Berriot-Varoqueaux et al 2000; Collins et al 1989; Suarez et al 1987), and in a few cases of ABL, hepatic injury progressed to fibrosis and cirrhosis, requiring transplantation (Black et al 1991; Illingworth et al 1980; Suarez et al 1987). Ophthalmologic findings are variable in ABL and HHBL, but the general pattern mimics the natural history of retinitis pigmentosa. Loss of night vision is often reported as the first symptom of retinal degeneration, while some patients first report loss of colour vision (Chowers et al 2001; Runge et al 1986; Segal and Sharma 2005; Zamel et al 2008). Fundoscopic examination reveals atypical dark pigmentation irregularly distributed on the retina, which can eventually lead to progressively expanding scotomas. Without intervention, retinal degeneration can eventually lead to blindness (Runge et al 1986). The precise mechanism for this process remains unclear. Deficiencies in vitamins A and E are thought to underlie other less consistently observed ophthalmic findings, such as ptosis, ophthalmoplegia and corneal ulcers. Ptosis and ophthalmoplegia presumably develop as a result of demyelination of cranial nerves due to the vitamin E deficiency, while corneal ulcers can be the end result of vitamin A deficiency
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causing dysfunction of the lacrimal glands, as these and other ocular tissues depend on vitamin A and its metabolites for cell differentiation, growth and normal function.
Diagnosis The initial presentation in ABL and HHBL is often chronic diarrhea and failure to thrive in infancy, suggesting malabsorption syndromes such as celiac disease. Endoscopic examination performed in the context of a normal fat diet reveals a “gelee blanche” or "white hoar frosting" appearance of the intestinal epithelium and microscopy of biopsied specimens shows distended enterocytes with a clarified cytoplasm that stains strongly positive with oil red O due to the presence of intracellular neutral lipid (Berriot-Varoqueaux et al 2000). The presence of acanthocytes on the peripheral blood film in the context of neurological involvement might prompt consideration of other neuroacanthocytosis syndromes, such as Xlinked McLeod syndrome (Jung et al 2011). In adult patients, where neurological features are often the most prominent clinical findings, differential diagnoses can include Friedreich’s ataxia and isolated vitamin E deficiency. The list of differential diagnoses can be considerably shortened by obtaining the patient’s lipid profile, particularly triglycerides (TG), low density lipoprotein-cholesterol (LDL-C), and apo B. With virtually undetectable or extremely low levels of TG, apo B and LDL-C, the diagnosis can be narrowed to either ABL or HHBL. If the parents of the proband are screened, ABL and HHBL can be differentiated clinically, as obligate heterozygote parents of HHBL typically have half-normal levels of apo B and LDL-C, while the obligate heterozygote parents of ABL usually have normal lipid profiles, consistent with autosomal co-dominant and recessive inheritance patterns, respectively. Patients with other inherited disorders of lipid trafficking, such as chylomicron retention disease (CRD; OMIM 246700) and heterozygous hypobetalipoproteinemia may variably show some of these clinical features, but have relatively higher TG and LDL-C levels, although still around 5th -10th percentile for age and sex. A clinical diagnosis can be made for ABL based on lipid profile, blood smear, and symptoms. As mentioned, all ABL patients have steatorrhea due to fat malabsorption. Additionally, depending on the age at first presentation, the majority of patients also present with neurological abnormalities due to profound vitamin E deficiency. Symptoms involving other organ systems can be used to support clinical suspicion of ABL or HHBL. Among laboratory investigations, a blood smear shows acanthocytosis, and the lipid profile would reveal nearly absent LDL-C (
