Current Diagnosis and Management of Abetalipoproteinemia.

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride transfer protein (MTTP) abrogates the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fat-soluble vitamins and severe hypolipidemia. Patients with ABL typically manifest steatorrhea, vomiting, and failure to thrive in infancy. The deficiency of fat-soluble vitamins progressively develops into a variety of symptoms later in life, including hematological (acanthocytosis, anemia, bleeding tendency, etc.), neuromuscular (spinocerebellar ataxia, peripheral neuropathy, myopathy, etc.), and ophthalmological symptoms (e.g., retinitis pigmentosa). If left untreated, the disease can be debilitating and even lethal by the third decade of life due to the development of severe complications, such as blindness, neuromyopathy, and respiratory failure. High dose vitamin supplementation is the mainstay for treatment and may prevent, delay, or alleviate the complications and improve the prognosis, enabling some patients to live to the eighth decade of life. However, it cannot fully prevent or restore impaired function. Novel therapeutic modalities that improve quality of life and prognosis are awaited. The aim of this review is to 1) summarize the pathogenesis, clinical signs and symptoms, diagnosis, and management of ABL, and 2) propose diagnostic criteria that define eligibility to receive financial support from the Japanese government for patients with ABL as a rare and intractable disease. In addition, our diagnostic criteria and the entry criterion of low-density lipoprotein cholesterol (LDL-C) ＜15 mg/dL and apoB ＜15 mg/dL can be useful in universal or opportunistic screening for the disease. Registry research on ABL is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.

Alectinib induces marked red cell spheroacanthocytosis in a near-ubiquitous fashion and is associated with reduced eosin-5-maleimide binding.

We reviewed haematological investigations for 43 patients treated at a single centre with alectinib, an inhibitor of anaplastic lymphoma kinase (ALK) which is considered standard first-line treatment for patients with ALK-rearranged advanced non-small cell lung cancer. Ninety-five percent of patients developed marked acanthocytosis, echinocytosis and/or spheroacanthocytosis, not observable with prior treatment with other ALK-inhibitors. Anaemia developed in 73% of patients (38% <100 g/L, 8% <80 g/L), though definite new haemolysis was present in only 11%. Eosin-5-maleimide binding was reduced in all assessed patients, and increased membrane cholesterol was identified in one patient assessed with lattice light sheet microscopy. We have identified a previously undescribed phenomenon whereby alectinib induces red cell membrane abnormalities in nearly all patients through an unclear, but likely ALK-independent, mechanism, resulting in mild anaemia without universal haemolysis.

An Unusual Presentation of Hemorrhagic Disease in an Infant: A Probable Case of Abetalipoproteinemia.

We report a probable case of abetalipoproteinemia in an infant who presented with unusual symptoms of late-onset vitamin K deficiency. Abetalipoproteinemia is a rare autosomal recessive disease caused by mutation of the microsomal triglyceride transfer protein gene, resulting in the absence of microsomal triglyceride transfer protein function in the small bowel. It is characterized by the absence of plasma apolipoprotein B-containing lipoproteins, fat malabsorption, hypocholesterolemia, retinitis pigmentosa, progressive neuropathy, myopathy, and acanthocytosis. A biopsy of the small intestine characteristically shows marked lipid accumulation in the villi of enterocytes. Large supplements of fat-soluble vitamins A, D, E, and K have been shown to limit neurologic and ocular manifestations. Dietary fat intake is limited to medium-chain triglycerides.

Novel MTTP Gene Mutation in a Case of Abetalipoproteinemia with Central Hypothyroidism

Abetalipoproteinaemia (ABL) is an autosomal recessive disorder characterized by very low plasma concentrations of total cholesterol and triglyceride (TG). It results from mutations in the gene encoding microsomal TG transfer protein (MTTP). A nine-month-old girl was admitted to hospital because of fever, cough, diarrhea and failure to thrive. She had low cholesterol and TG levels according to her age. The peripheral blood smear revealed acanthocytosis. Thyroid function test showed central hypothyroidism. Cranial magnetic resonance imaging revealed the retardation of myelination and pituitary gland height was 1.7 mm. A homozygous novel mutation [c.506A>T (p.D169V)] was detected in the MTTP gene. Vitamins A, D, E, and K and levothyroxine were started. The coexistence of ABL and central hypothyroidism has not previously been reported. A homozygous novel mutation [c.506A>T (p.D169V)] was detected in the MTTP gene.

Acanthocytosis and the c.680 A>G Mutation in the PANK2 Gene: A Study Enrolling a Cohort of PKAN Patients from the Dominican Republic.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a form of Neurodegeneration with Brain Iron Accumulation (NBIA) associated with mutations in the pantothenate kinase 2 gene (PANK2). Pantothenate kinases catalyze the rate-limiting step of coenzyme A synthesis and Pank2 is the only pantothenate kinase isoform in humans that is localized to mitochondria. Acanthocytosis, the occurrence of spiculated erythrocytes, is observed in about 10% of the PKAN patients. Therefore PKAN is also classified together with other rare neurodegenerative diseases like Chorea Acanthocytosis (ChAc) and McLeod syndrome (MLS) into the Neuroacanthocytosis (NA) syndromes. It has not been investigated yet whether acanthocytosis in PKAN is associated with a specific subset of Pank2 mutations. In this study, we analyzed acanthocytosis of a cohort of 25 PKAN patients from the Dominican Republic that are homozygous for the c.680 A>G mutation in the PANK2 gene as compared to control donors that are heterozygous or wild-type with respect to this mutation. 3D modeling of this mutation indicated that the replacement of a tyrosine by a cysteine at position 227 in Pank2 disrupts a polar interaction within the A domain of the enzyme. Mean acanthocyte count was elevated in the cohort of patients, however, acanthocytosis varied among the patients with nearly half of them showing high (>20%) or elevated acanthocytosis and the rest showing mild (6-10%) or no (<6%) acanthocytosis. Heterozygous control donors revealed a tendency to mild acanthocytosis. Based on the insight that Pank2 is a normal constituent of red blood cells and de novo biosynthesis of coenzyme A is likely to take place in the erythrocyte cytosol we propose a hypothetical model that accounts for the variability in the occurrence of acanthocytic cells in PKAN.

HYPERGLYCAEMIC HEMIBALLISMUS: IMPLICATIONS FROM CONNECTIVITY ANALYSIS FOR COGNITIVE IMPAIRMENTS.

Hyperglycaemia induced movement disorders, such as hemiballism are rare disorders. The syndrome is characterised by the triad of hemiballism, contralateral T1-hyperintense striatal lesion and non-ketotic hyperglycaemia. Here we report a patient with untreated diabetes presenting with acute onset of hemiballism. MRI revealed T1 hyperintensity of the head of the caudate nucleus and the anterior putamen. The patient also had acantocytosis. Based on the detailed examination of the neuroradiological results and earlier findings we will discuss the pathomechanism. Based on previous findings microhemorrhages, extensive mineralisation, gemistocytic astrocytosis might play a role in the development of the imaging signs. The connectivity pattern of the striatal lesion showed extensive connections to the frontal cortex. In coexistence with that the most severe impairment was found on the phonemic verbal fluency task measuring frontal executive functions.

Clinical features and molecular genetics of two Tunisian families with abetalipoproteinemia.

Abetalipoproteinemia (ABL) is a rare monogenic disease characterized by very low plasma levels of cholesterol and triglyceride and almost complete absence of apolipoprotein B (apoB)-containing lipoproteins. Typically, patients present with failure to thrive, acanthocytosis, pigmented retinopathy and neurological features. It has been shown that ABL results from mutations in the gene encoding the microsomal triglyceride transfer protein (MTTP). Sanger sequencing of MTTP was performed for two unrelated consanguineous Tunisian families with two affected individuals each, presenting a more severe ABL phenotype than previously reported in the literature. The patients were found to be homozygous for two novel mutations. In the first family, a nonsense mutation, c.2313T>A, leading to a truncated protein (p.Y771X) was identified. In the second family, a splice mutation, IVS 9+2T>G, was found. These mutations are believed to abolish the assembly and secretion of apoB-containing lipoproteins.

Disease distribution in canine patients with acanthocytosis: 123 cases.

BACKGROUND: An acanthocyte is an abnormally shaped erythrocyte. In veterinary medicine, acanthocytes have historically been associated with canine hemangiosarcoma. In human medicine, acanthocytes are rarely observed with neoplastic disease and are more commonly associated with a variety of hereditary and acquired diseases. OBJECTIVES: The purpose of the study was to determine what disease processes are associated with the presence of acanthocytes in the peripheral blood of dogs. METHODS: Medical records for dogs presented to the Veterinary Teaching Hospital of Colorado State University during January 2004 through June 2008 with acanthocytes documented in their CBCs were retrospectively reviewed. RESULTS: A total of 123 dogs were included, 66 of which were diagnosed with neoplastic disease, most commonly hemangiosarcoma (n = 12), osteosarcoma (n = 11), and lymphoma (n = 11). The remaining 57 dogs had nonneoplastic disease, most commonly observed were gastrointestinal (n = 13), musculoskeletal (n = 8), renal (n = 8), and immune-mediated diseases (n = 7). No statistically significant difference was detected between percent acanthocytes present in dogs with neoplastic and nonneoplastic diseases. CONCLUSION: Acanthocytosis was observed with a variety of neoplastic and nonneoplastic diseases. While clearly commonly associated, the presence of acanthocytes in a blood smear should not be considered pathognomonic for hemangiosarcoma in dogs.

Microsome-associated lumenal lipid droplets in the regulation of lipoprotein secretion.

PURPOSE OF REVIEW: Liver is the major organ in mammals that possesses the capacity to release triglyceride within VLDL. VLDL assembly requires apolipoprotein (apo) B-100 with the assistance of microsomal triglyceride transfer protein (MTP), which facilitates the mobilization of triglyceride into the microsomal lumen. Recent experimental evidence has suggested that the lumenal triglyceride associated with endoplasmic reticulum (ER)/Golgi may represent an entity serving as precursors for large VLDL1. RECENT FINDINGS: Under lipid-rich conditions, discrete triglyceride-rich lipidic bodies, termed lumenal lipid droplets, are accumulated in association with ER/Golgi microsomes. Formation of the microsome-associated lumenal lipid droplets (MALD) is dependent on the activity of MTP, and the resulting apoB-free lipidic body is associated with a variety of proteins including apolipoproteins that are components of VLDL. Formation and utilization of MALD during the assembly and secretion of VLDL1 have a profound influence on hepatic cell physiology, such as ER stress responses. SUMMARY: This review summarizes current understanding of hepatic triglyceride homeostasis in general, and highlights the functional significance of triglyceride compartmentalization between cytosol and microsomes in particular. Understanding of MALD metabolism may shed new light on the prevention and treatment of liver diseases associated with abnormally elevated intracellular triglycerides.

Neuroacanthocytosis syndromes.

Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis and progressive degeneration of the basal ganglia. NA syndromes are exceptionally rare with an estimated prevalence of less than 1 to 5 per 1'000'000 inhabitants for each disorder. The core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome which have a Huntington's disease-like phenotype consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. In addition, cardiomyopathy may occur in McLeod syndrome. Acanthocytes are also found in a proportion of patients with autosomal dominant Huntington's disease-like 2, autosomal recessive pantothenate kinase-associated neurodegeneration and several inherited disorders of lipoprotein metabolism, namely abetalipoproteinemia (Bassen-Kornzweig syndrome) and hypobetalipoproteinemia leading to vitamin E malabsorption. The latter disorders are characterized by a peripheral neuropathy and sensory ataxia due to dorsal column degeneration, but movement disorders and cognitive impairment are not present. NA syndromes are caused by disease-specific genetic mutations. The mechanism by which these mutations cause neurodegeneration is not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basal ganglia, however, suggests a common pathogenetic pathway. Laboratory tests include blood smears to detect acanthocytosis and determination of serum creatine kinase. Cerebral magnetic resonance imaging may demonstrate striatal atrophy. Kell and Kx blood group antigens are reduced or absent in McLeod syndrome. Western blot for chorein demonstrates absence of this protein in red blood cells of chorea-acanthocytosis patients. Specific genetic testing is possible in all NA syndromes. Differential diagnoses include Huntington disease and other causes of progressive hyperkinetic movement disorders. There are no curative therapies for NA syndromes. Regular cardiologic studies and avoidance of transfusion complications are mandatory in McLeod syndrome. The hyperkinetic movement disorder may be treated as in Huntington disease. Other symptoms including psychiatric manifestations should be managed in a symptom-oriented manner. NA syndromes have a relentlessly progressive course usually over two to three decades.

Identification of a novel mutation of MTP gene in a patient with abetalipoproteinemia.

Abetalipoproteinemia (ABL), or Bassen-Kornzweig syndrome, is a rare autosomal recessive disorder of lipoprotein metabolism, characterized by fat malabsorption, hypocholesterolemia retinitis pigmentosa, progressive neuropathy and acanthocytosis from early infancy. We describe the clinical and molecular characterization of a 6-month-old infant born of consanguineous, apparently healthy parents from Iran. The patient was hospitalized because of failure to thrive, greasy stool and vomiting. The patient's serum lipid profile, the clinical phenotype and the duodenal histology suggested the clinical diagnosis of ABL. The MTP gene analysis by direct sequencing revealed a novel homozygous mutation (c.1586 A > G-H529R). The parents were heterozygotes for the same mutation and interestingly the father showed a lipid profile characterized by a slight reduction of total and LDL-cholesterol plasma levels.

A severe form of abetalipoproteinemia caused by new splicing mutations of microsomal triglyceride transfer protein (MTTP).

Abetalipoproteinemia is a rare autosomal recessive disease characterized by low lipid levels and by the absence of apoB-containing lipoproteins. It is the consequence of microsomal triglyceride transfer protein (MTTP) deficiency. We report two patients with new MTTP mutations. We studied their functional consequences on the triglyceride transfer function using duodenal biopsies. We transfected MTTP mutants in HepG2 and HeLa cells to investigate their association with protein disulfide isomerase (PDI) and their localization at the endoplasmic reticulum. These children have a severe abetalipoproteinemia. Both of them had also a mild hypogammaglobulinemia. They are compound heterozygotes with c.619G>T and c.1237-28A>G mutations within the MTTP gene. mRNA analysis revealed abnormal splicing with deletion of exon 6 and 10, respectively. Deletion of exon 6 (Δ6-MTTP) introduced a frame shift in the reading frame and a premature stop codon at position 234. Despite the fact that Δ6-MTTP and Δ10-MTTP mutants were not capable of binding PDI, both MTTP mutant proteins normally localize at the endoplasmic reticulum. However, these two mutations induce a loss of MTTP triglyceride transfer activity. These two mutations lead to abnormal truncated MTTP proteins, incapable of binding PDI and responsible for the loss of function of MTTP, thereby explaining the severe abetalipoproteinemia phenotype of these children.

Rickets and dysmorphic findings in a child with abetalipoproteinemia.

Abetalipoproteinemia (ABL) is characterized by acanthocytosis, hypocholesterolemia, and steatorrhea. Here, we describe a case of ABL associated with rickets and dysmorphic findings and the subsequent therapeutic course in an 18-month-old male referred for evaluation for failure to thrive and chronic fatty diarrhea. Examination revealed a pale child, dysmorphic face, and signs of rickets. Laboratory examination revealed low hemoglobin (3.7 gm/dl), low albumin (28 gm/L), low cholesterol and triglyceride levels. The blood smear showed acanthocytes while the small bowel histology showed the enterocytes were distended with lipid droplets. He was diagnosed with ABL and treated with fat-soluble vitamins (ADEK), and hydrolyzed protein formula containing medium chain triglycerides. Three months later, his fatty diarrhea becomes normal stool, his serum fat-soluble vitamins normalized, and his weight increased from 4.1 kg to 5.9 kg.

Abetalipoproteinemia induced by overexpression of ORP150 in mice.

ORP150 is an endoplasmic-resident, hypoxic stress-induced protein, but little is known about the effects of its systemic overexpression. We have produced a transgenic strain of mice that overexpress ORP150 (ORP-Tg mice). These mice exhibit severe growth retardation concomitant with vacuolar degeneration in the heart. To investigate the cause of the observed growth retardation in response to ORP150 overexpression, we conducted a clinical evaluation of the ORP-Tg mice. Blood analysis showed significantly lower concentrations of serum triglyceride, cholesterol, glucose and insulin. The triglyceride components that were reduced in ORP-Tg mice were localized mainly at the origin and in the pre-beta fraction on agarose gel electrophoresis, corresponding to chylomicrons and very low-density lipoproteins. A lipid-loading test of ORP-Tg mice revealed reduced triglyceride uptake, which mainly was due to suppressed uptake of very low-density lipoproteins. An intraperitoneal glucose tolerance test indicated that the ORP-Tg mice have a significantly higher rate of glucose degradation. These findings suggest that overexpression of ORP150 in mice leads to abetalipoproteinemia with alteration of glucose and lipid metabolism. These data could provide clues for a therapeutic target of dyslipidemia or diabetes.

CD1d function is regulated by microsomal triglyceride transfer protein.

CD1d is a major histocompatibility complex (MHC) class I-related molecule that functions in glycolipid antigen presentation to distinct subsets of T cells that express natural killer receptors and an invariant T-cell receptor-alpha chain (invariant NKT cells). The acquisition of glycolipid antigens by CD1d occurs, in part, in endosomes through the function of resident lipid transfer proteins, namely saposins. Here we show that microsomal triglyceride transfer protein (MTP), a protein that resides in the endoplasmic reticulum of hepatocytes and intestinal epithelial cells (IECs) and is essential for lipidation of apolipoprotein B, associates with CD1d in hepatocytes. Hepatocytes from animals in which Mttp (the gene encoding MTP) has been conditionally deleted, and IECs in which Mttp gene products have been silenced, are unable to activate invariant NKT cells. Conditional deletion of the Mttp gene in hepatocytes is associated with a redistribution of CD1d expression, and Mttp-deleted mice are resistant to immunopathologies associated with invariant NKT cell-mediated hepatitis and colitis. These studies indicate that the CD1d-regulating function of MTP in the endoplasmic reticulum is complementary to that of the saposins in endosomes in vivo.

Clinical features and molecular bases of neuroacanthocytosis.

The term acanthocytosis is derived from the Greek for "thorn" and is used to describe a peculiar spiky appearance of erythrocytes. Acanthocytosis is found to be associated with at least three hereditary neurological disorders that are generally referred to as neuroacanthocytosis. Abetalipoproteinaemia is an autosomal recessive condition, characterised by absence of serum apolipoprotein B containing lipoproteins leading to fat intolerance and fat-soluble vitamin deficiency. This results in a progressive spinocerebellar ataxia with peripheral neuropathy and retinitis pigmentosa. Chorea-acanthocytosis is also an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysphagia, dysarthria, areflexia, seizures and dementia. Some of its features, including choreic movements, peripheral neuropathy with areflexia, elevated serum creatine kinase levels and myopathy are shared by another form of neuroacanthocytosis, McLeod syndrome. Patients affected by this X-linked disorder also show abnormal expression of Kell blood group antigens and a permanent haemolytic state. In addition to these cases, acanthocytosis is occasionally associated with other neurological disorders, such as Hallervorden-Spatz disease. For each of the neuroacanthocytosis syndromes we review the main clinical features and their molecular bases. The recent molecular genetics findings are the first step towards the understanding of the pathogenetic mechanisms and eventually the search for effective treatments.