ABL is a rare autosomal recessive metabolic disorder with multi-system manifestations. All reported patients have fat malabsorption, acanthocytosis, low serum cholesterol and deficiency of serum apo B. Retinitis pigmentosa, spinocerebellar ataxia and myopathy have complicated most of the cases. Two reports of possible association with certain cancers like ileal adenocarcinoma and metastatic spinal cord glioblastoma [9
] have been reported and fatty liver was reported in 4 cases. The clinical presentation is very heterogeneous and previous reports had suggested that MTP deficiency is not the sole cause of ABL [11
ABL is characterized by absent plasma apo B-containing lipoproteins that results from MTP
]. To date at least 33 MTP
mutations have been identified in 43 ABL patients (Figure ). Absorption of fats and fat-soluble vitamins are compromised, leading to failure to thrive and fat-soluble vitamin deficiency [13
]. Vitamin E deficiency is associated with hyporeflexia, reduced proprioception and vibratory sensation, muscle weakness and a Friedrich's-like ataxia [14
]. Before the use of high-dose oral fat-soluble vitamin treatment, many ABL patients developed neurological complications before the second decade and some did not survive past the third decade [13
Figure 2 Genetic map of MTP mutations in patients with abetalipoproteinemia. The map shows the genomic structure of MTP gene. Black boxes represent exons; dotted lines point to mutation positions. Above the map are single-nucleotide and small insertion-deletion (more ...)
Homozygous dysfunctional mutations in APOB lead to a clinically similar disorder called homozygous hypobetalipoproteinemia (HHBL, OMIM 107730). While obligate heterozygote parents of HHBL patients have half-normal plasma levels of apo B and LDL-cholesterol, obligate heterozygote parents of ABL patients have normal plasma lipoprotein profiles. HHBL patients receive similar treatment advice as ABL patients.
Muller and co-workers [15
] first reported in 1974 that high dose oral vitamin E (100 IU/kg) could increase undetectable serum vitamin levels in ABL patients. Thereafter, short-term efficacy of high-dose oral vitamin supplements was noted [8
]. Reports of longer-term treatment in ABL have been limited. For instance, combined vitamin E and A therapy initiated before age 2 was reported to markedly attenuate retinal degeneration 10 years later [17
]. Twelve-year follow-up indicated that high dose oral vitamin E (100 IU/kg) slowed retinal degeneration [18
]. Long-term high dose vitamin E reduced neurological sequelae in other vitamin E-deficient diseases, such as chronic cholestasis [19
], autosomal-recessive vitamin E deficiency (AVED) [20
] and short-bowel syndrome [21
]. Our observations over more than a quarter-century suggest that ultra-long-term high-dose oral vitamin therapy including vitamin E is associated with arrest of the neurological complications in at least some patients with ABL. Such long-term experience in ABL is relevant particularly since pharmacological MTP inhibition has recently been proposed as a therapeutic option for patients with severe hypercholesterolemia [22
]. Interestingly, coronary arteries of ABL patients appear to be free of atherosclerotic lesions [23
Gastrointestinal manifestations of ABL include diarrhea and fat soluble vitamin deficiency, which are consistent features in all reported cases. These manifestations usually develop during infancy and are worsened with a diet rich in fat. The diarrhea subsides later in part because patients learn to avoid fatty foods. However, the low serum levels of fat soluble vitamins continue, because the plasma transport and delivery of these vitamins to tissues depends almost exclusively (for vitamin E and beta-carotene) or in part (for vitamins A, D, and K) on intact synthesis and secretion of apo B-containing lipoproteins. Supplementation with high dose vitamin E results in increased serum vitamin levels to not more than 30% of the lower limit of normal. On the other hand, high doses of vitamin A therapy can normalize serum levels. This reflects the fact that despite impaired absorption and transport from the intestine, subsequent transport of vitamin A in plasma by retinol-binding protein is not impaired in ABL.
Hepatic manifestations of ABL include elevated serum transaminases with hepatomegaly due to hepatic steatosis [24
], although neither of the two patients reported here had these findings. Cirrhosis has been reported in a few cases and one patient required transplantation for hepatic cirrhosis; post transplantation the serum lipoprotein profile increased to normal levels, however the fat absorption defect continued as the mutant MTP remains expressed in the intestine [26
]. Liver biopsies in patients with ABL have shown marked steatosis that may be reflected in raised serum transaminase concentrations [27
Hematologic manifestations of ABL include acanthocytosis. These abnormal shaped cells comprise 50% or more of circulating erythrocytes and were among the earliest laboratory features of the disorder (see Figure ). Their structure inhibits rouleaux formation, leading to extremely low erythrocyte sedimentation rates. Anemia has been reported in some cases of ABL [28
]. The likely cause was deficiencies of iron, folate, and other nutrients secondary to fat malabsorption. Hemolysis which appears to result from accelerated hydroperoxidation of fatty acids secondary to tocopherol deficiency may also contribute to anemia [24
]. Elevated prothrombin time, and international normalized ratio due to vitamin K deficiency, was reported in several cases [24
]. In two cases, significant gastrointestinal bleeding associated with severe vitamin K deficiency was present in infancy or childhood [24
Neurological involvement in ABL may be the most serious clinical manifestation. In ABL both central and peripheral nervous systems are affected; patients can have either upper or lower motor neuron findings or both. The primary driving pathology is demyelination [25
]. The onset of neurologic disease usually begins in the first or second decade of life and in the past often progressed to catastrophic disability, although some patients inexplicably escaped serious affliction until much later in life [25
]. The long-term clinical results of vitamin E therapy from multiple previous studies show improvement in neurologic dysfunction with vitamin E treatment and early therapy before the age of 16 months prevents neurologic dysfunction [8
]. In both cases we have presented, high-dose oral vitamin E replacement appeared to be associated with long-term stabilization of neurologic status, although we appreciate the anecdotal – and perhaps non-generalizable – nature of this observation.
Muscle involvement in ABL affecting both striated and smooth muscle has been reported in some patients, and furthermore was the cause of premature death cases among a few ABL patients [28
]. While the etiology of myopathy is unclear, myositis appeared to be related to ceroid pigment deposition, while muscle weakness could possibly be related to vitamin E deficiency and neuropathy. A quadriceps muscle biopsy performed on a 26 year old male ABL patient who presented with sudden onset of severe weakness revealed ceroid pigment in the muscle fibers [30
]. The etiology of myopathy in that case remains unclear due to preserved myofilaments, a feature not consistent with myopathy due to vitamin E deficiency [30
]. Death related to cardiomyopathy has been reported in a 10 year old male ABL patient and a 36 year old female ABL patient [28
]. Autopsy of the male patient showed perinculear deposits of lipochrome pigment in cardiomyocytes, suggesting tocopherol deficiency. A male patient of Northern European descent (Patient 8 in Additional file 1
), died at the age of 18 due to respiratory failure related to neuropathy/myopathy; no autopsy findings were reported.
Ophthalmic involvement in ABL is variable and appears to cover a wide range of symptoms and ophthalmic manifestations [31
]. The most prominent abnormality is pigmentary retinal degeneration. Most patients have loss of night vision early in the course of disease, while some patients also present with loss of color vision. The retinopathy often produces slowly enlarging annular scotomas with macular sparing, such that patients are relatively unaware of the progression of the disease. Complete loss of vision can ultimately occur [31
]. Fundoscopic examination reveals an atypical pigmentation of the retina characterized by small, irregularly distributed, white spots. Electroretinogram and fluorescein angiography investigations have shown the retina to be affected in asymptomatic ABL patients [31
The mechanism underlying the retinopathy in ABL is not clear. Results from previous studies are inconsistent. A report of results of up to 18 years of follow-up of six ABL patients showed that high dose oral vitamin E therapy (47–172 mg/kg/day) not only prevented the development of retinopathy but also appeared to arrest the progression of retinopathy [18
]. In 2001, another study of 10 ABL patients followed for a mean of 11.7 years showed that combined vitamin A and E supplementation that was initiated prior to 2 years of age markedly attenuated the severe retinal degeneration. Yet, fundoscopic and functional retinal changes can occur despite early treatment. Of note, all ABL patients who received vitamin therapy prior to 2 years of age were free of the neurologic and systemic complications that are usually associated with untreated ABL [17
]. Other reported abnormalities include, ophthalmoplegia, anisocoria, nystagmus, strabismus and ptosis. Although the pathogenetic mechanism for these symptoms is unclear, a neurological basis was suggested.
In addition to ptosis, case #1 developed a unilateral corneal ulcer after oral vitamin A was discontinued. However, her symptoms did not improve following re-institution of vitamin A supplementation. A previous report described an ABL patient with mild xerophthalmia [32
]. Corneal ulceration is unusual among ABL patients.
It is of interest that reproductive system manifestations seem to be rather minimal in ABL, indicating that in the absence of LDL, there is sufficient capacity for synthesis and secretion of steroid hormones, including sex steroids, provided by HDL. One study evaluating the endocrine function in a 37 year old female ABL patient of Greek origin who was diagnosed at age 5 years after instituting dietary modifications, found that serum progesterone and 17 (OH) progesterone are low at both exams as well as serum progesterone at day 21 of the menstrual cycle was below normal [33
]. In addition, in context of low serum cholesterol one might expect a low fertility rate among ABL patients. However, successful pregnancy has been reported on several occasions, as seen with case #1 [31
Prognostic factors predicting disease course
Previous case reports have variably suggested links between age at diagnosis, onset of treatment with low fat diet and vitamin replacement therapy, type of MTP mutation and APOE genotype with the long-term outcome of patients with ABL.
Regarding prognosis based upon age at diagnosis, many ABL patients present in the 2nd to 4th decades, while a few others present in the 1st and 6th decades. It is possible that an earlier presentation is due to a more severe phenotype and perhaps a worse outcome, which would be more refractory to treatment. However, a later presentation might also be associated with a more severe outcome due to a longer period of untreated vitamin deficiency, especially during growth and development.
Regarding the potential relationship between the type of MTP
mutation and long-term outcome, the current paucity of information makes it difficult to predict outcomes based on MTP
genotype (Additional file 1
). Also, regarding a possible relationship between APOE
genotype and clinical progression of disease, a recent meta-analysis identified a linear relationship of APOE
genotype with plasma LDL cholesterol [36
]. On the background of APOE
E2 homozygosity, some missense mutations of MTP
with mild to moderate effects on protein structure and function have been suggested to lower plasma LDL cholesterol levels more dramatically (see patient 19 in Additional file 1
]. In another report that included information about APOE
genotype in six ABL patients, the E4/E2 genotype seemed to be associated with less favourable outcomes [7
Long term treatment and follow-up of ABL
The current standard treatment for ABL is dietary modification and replacement of fat soluble vitamins. A low fat diet has been shown to improve steatorrhea associated with fat malabsorption and allow absorption of other nutrients essential for growth and development. High dose oral fat soluble vitamin supplementation has anecdotally been associated with improved clinical outcomes. High dose oral vitamins are thought to bypass the intestinal chylomicron assembly pathway via the portal circulation (medium-chain triglyceride pathway).
Oral vitamin E is typically given in daily doses ranging from 2400 to 12000 IU. Plasma vitamin E levels might not accurately reflect the whole body content of vitamin E and thus the adequacy of vitamin replacement may be difficult to gauge from serum concentrations [38
]. In one study, serum vitamin E concentrations, which were initially undetectable in all ABL patients, became measurable after oral supplementation, although they never reached the normal range [16
]. Furthermore, needle aspiration of adipose tissue showed that high doses of vitamin E (150 mg/kg body weight daily) were associated with increased tissue levels of α-tocopherol in almost all ABL patients. This was associated with ameliorated neurologic symptoms in older subjects and possible protection from neurologic pathology, if supplement is started early enough [38
]. Therefore, the serum vitamin E level can be used to monitor compliance and adequacy of therapy.
High doses of vitamin A (100–400 IU/kg/day) are needed to alleviate the deficiencies; the dosing can be variable and titration can be guided by serum carotene concentrations. Vitamin A toxicity was reported in one patient. This patient developed papilledema a few days after introduction of vitamin A therapy, while her serum vitamin A level was within normal limits [39
Vitamin D deficiency is not consistently described among ABL patients. However, low serum ionized calcium, vitamin D and bony abnormalities have been described [33
], and thus vitamin D replacement (1000 mg daily) should be considered in all ABL patients. An abnormal coagulation profile with prolonged prothrombin time and increased international normalized ratio has been reported in many ABL patients: two patients had severe gastrointestinal bleeding. In addition vitamin E absorption can exacerbate the deficit in vitamin K therefore, replacement of vitamin K is necessary (5 mg daily). Other supplementary nutrients like iron, folic acid can also be considered. Patients need to be followed regularly for evaluation of symptoms and complications, and to monitor compliance with therapy.