Marked Acanthocytosis Associated With Klipple Trenaunay Syndrom.

Klipple-Trenaunay syndrome (KTS) is an extremely rare congenital vascular disorder with poorly defined incidence and prevalence. We report a case of a patient who presented after road traffic accident with primary complaints of poor wound healing and persistent bleeding from wound site. Discernible presence of arteriovenous malformation and skin hypertrophy since birth lead to the diagnosis of Klipple-Trenaunay syndrome (KTS). There was an incidental finding of acanthocytosis on peripheral film of blood which remained elevated even after clinical improvement of the patient. This case report highlights a close association of marked acanthocytosis of red blood cells and Klipple-Trenaunay syndrome.

[Homozygous familial hypobetalipoproteinemia caused by APOB gene variations: a case report and review of literature].

Objective: To summarize the genotypes and clinical characteristics of homozygous family hypobetalipoproteinemia (Ho-FHBL) caused by apolipoprotein B (APOB) gene variations. Methods: The clinical, laboratory, genetic, and liver histology data of a boy with Ho-FHBL managed in the hepatology ward of the Children's Hospital of Fudan University in May 2021 were retrospectively analyzed. The literature was searched from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China VIP database, China Biology Medicine disc and PubMed database (up to May 2022) with "familial hypobetalipoproteinemia" or "hypobetalipoproteinemias" or "hypo beta lipoproteinemia" or "hypolipoproteinemias" as the search terms. All relevant literatures were reviewed to summarize the clinical and genetic features of Ho-FHBL caused by APOB gene variations. Results: The male patient was admitted to the hospital due to abnormal liver function tests for 8 months at the age of 4 years and 6 months. Blood biochemistry showed transaminitis and abnormally low serum levels of lipids. Liver biopsy revealed fatty liver with inflammation and early cirrhosis (Brunt score was F3G2S4). Whole exome sequencing revealed two novel variants of APOB gene (c.3745C>T, p.Q1249 * from the father and c.4589_4592delinsAGGTAGGAGGTTTAACTCCTCCTACCT, p.T1530Kfs * 12 from the mother). He was diagnosed as Ho-FHBL caused by APOB gene compound heterozygous variations. Literature search retrieved 36 English literatures and 0 Chinese literature. A total of 55 (23 males and 32 females) Ho-FHBL cases, including this one, were caused by 54 APOB gene pathogenic variants (23 frameshift, 15 nonsense, 7 missense, 8 splice and 1 gross deletions). The age of the last follow-up was between 1 month and 75 years. Among them, 28 cases had lipid malabsorption, 19 cases had early dysplasia, 12 cases had no symptoms. Twenty-one patients had symptoms related to fat soluble vitamin deficiency, including 14 cases of acanthocytosis, 10 cases of neurological symptoms, and 6 cases of ocular lesions. Thirty-four patients had liver involvement, including 25 cases of elevated transaminase, 21 cases of fatty liver, 15 cases of hepatomegaly, 9 cases of liver fibrosis, 3 cases of liver cirrhosis, 1 case of hepatic hemangioma and 1 case of liver neoplastic nodule. Conclusions: The variants of APOB gene in Ho-FHBL are mainly frameshift and nonsense variations. Patients may have lipid malabsorption and (or) early dysplasia, or symptom-free. Liver involvement is common.

Homozygous familial hypobetalipoproteinemia caused by APOB gene variations: a case report and review of literature / 中华儿科杂志

Objective: To summarize the genotypes and clinical characteristics of homozygous family hypobetalipoproteinemia (Ho-FHBL) caused by apolipoprotein B (APOB) gene variations. Methods: The clinical, laboratory, genetic, and liver histology data of a boy with Ho-FHBL managed in the hepatology ward of the Children's Hospital of Fudan University in May 2021 were retrospectively analyzed. The literature was searched from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, China VIP database, China Biology Medicine disc and PubMed database (up to May 2022) with "familial hypobetalipoproteinemia" or "hypobetalipoproteinemias" or "hypo beta lipoproteinemia" or "hypolipoproteinemias" as the search terms. All relevant literatures were reviewed to summarize the clinical and genetic features of Ho-FHBL caused by APOB gene variations. Results: The male patient was admitted to the hospital due to abnormal liver function tests for 8 months at the age of 4 years and 6 months. Blood biochemistry showed transaminitis and abnormally low serum levels of lipids. Liver biopsy revealed fatty liver with inflammation and early cirrhosis (Brunt score was F3G2S4). Whole exome sequencing revealed two novel variants of APOB gene (c.3745C>T, p.Q1249 * from the father and c.4589_4592delinsAGGTAGGAGGTTTAACTCCTCCTACCT, p.T1530Kfs * 12 from the mother). He was diagnosed as Ho-FHBL caused by APOB gene compound heterozygous variations. Literature search retrieved 36 English literatures and 0 Chinese literature. A total of 55 (23 males and 32 females) Ho-FHBL cases, including this one, were caused by 54 APOB gene pathogenic variants (23 frameshift, 15 nonsense, 7 missense, 8 splice and 1 gross deletions). The age of the last follow-up was between 1 month and 75 years. Among them, 28 cases had lipid malabsorption, 19 cases had early dysplasia, 12 cases had no symptoms. Twenty-one patients had symptoms related to fat soluble vitamin deficiency, including 14 cases of acanthocytosis, 10 cases of neurological symptoms, and 6 cases of ocular lesions. Thirty-four patients had liver involvement, including 25 cases of elevated transaminase, 21 cases of fatty liver, 15 cases of hepatomegaly, 9 cases of liver fibrosis, 3 cases of liver cirrhosis, 1 case of hepatic hemangioma and 1 case of liver neoplastic nodule. Conclusions: The variants of APOB gene in Ho-FHBL are mainly frameshift and nonsense variations. Patients may have lipid malabsorption and (or) early dysplasia, or symptom-free. Liver involvement is common.

Guidance for the diagnosis and treatment of hypolipidemia disorders.

The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals.

Forty year follow-up of three patients with complete absence of apolipoprotein B-containing lipoproteins.

Complete deficiency of apolipoprotein (apo) B-containing lipoproteins can result from both abetalipoproteinemia (ABL) and homozygous hypobetalipoproteinemia (HoHBL), caused by bi-allelic loss-of-function variants in the MTTP and APOB genes encoding microsomal triglyceride transfer protein and apolipoprotein (apo) B, respectively. Both conditions are associated with failure to assemble and secrete apo B-containing lipoproteins from intestine and liver, resulting in absence of chylomicrons, very low-density lipoproteins and remnants, and low-density lipoproteins. Because absorption and transport of fat soluble vitamins requires intact production of apo B-containing lipoproteins, untreated patients develop fat soluble vitamin deficiencies, with associated clinical features including atypical retinitis pigmentosa, osteopenia, neuromyopathy and coagulopathy. Other features include acanthocytosis on the peripheral blood film, fat malabsorption and hepatosteatosis. We describe two patients with ABL and one with HoHBL who have each been on high dose oral fat soluble vitamin replacement under the care of the same physician for more than four decades. Each patient has remained clinically stable. A recent liver biopsy from an ABL patient showed mild macrovesicular steatosis, patchy microvesicular steatosis and mild fibrosis. These observations add to our understanding of the long term trajectory of ABL and HoHBL, and emphasize the importance of compliance to treatment and follow up.

Abetalipoproteinemia Due to a Novel Splicing Variant in MTTP in 3 Siblings.

Abetalipoproteinemia (ABL) is a rare recessive condition caused by biallelic loss-of-function mutations in the MTTP gene encoding the microsomal triglyceride transfer protein large subunit. ABL is characterized by absence of apolipoprotein B-containing lipoproteins and deficiencies in fat-soluble vitamins leading to multisystem involvement of which neurological complications are the most serious. We present 3 siblings with ABL who were born to non-consanguineous parents of Filipino and Chinese background. Identical twin boys with long-standing failure to thrive and malabsorption were diagnosed at age 2 years. ABL therapy with vitamins and a specialized diet was initiated, replacing total parenteral nutrition at age 3 years. Their younger sister was diagnosed from a blood sample taken at birth; treatment was instituted shortly thereafter. We observed in the twins reversal and in their sister prevention of ABL systemic features following early implementation of fat restriction and high doses of oral fat-soluble vitamins. A targeted sequencing panel found that each affected sibling is homozygous for a novel MTTP intron 13 -2A>G splice acceptor site mutation, predicted to abolish splicing of intron 13. This variant brings to more than 60 the number of reported pathogenic mutations, which are summarized in this article. The twin boys and their sister are now doing well at 11 and 4 years of age, respectively. This experience underscores the importance of early initiation of targeted specialized dietary and fat-soluble vitamin replacements in ABL.

Normal plasma apoB48 despite the virtual absence of apoB100 in a compound heterozygote with novel mutations in the MTTP gene.

"Normotriglyceridemic abetalipoproteinemia (ABL)" was originally described as a clinical entity distinct from either ABL or hypobetalipoproteinemia. Subsequent studies identified mutations in APOB gene which encoded truncated apoB longer than apoB48. Therefore, "Normotriglyceridemic ABL" can be a subtype of homozygous familial hypobetalipoproteinemia. Here, we report an atypical female case of ABL who was initially diagnosed with "normotriglyceridemic ABL", because she had normal plasma apoB48 despite the virtual absence of apoB100 and low plasma TG level. Next generation sequencing revealed that she was a compound heterozygote of two novel MTTP mutations: nonsense (p.Q272X) and missense (p.G709R). We speculate that p.G709R might confer residual triglyceride transfer activity of MTTP preferentially in the intestinal epithelium to the hepatocytes, allowing production of apoB48. Together, "normotriglyceridemic ABL" may be a heterogenous disorder which is caused by specific mutations in either APOB or MTTP gene.

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.

Lipids Responsible for Intestinal or Hepatic Disorder: When to Suspect a Familial Intestinal Hypocholesterolemia?

ABSTRACT: Familial intestinal hypocholesterolemias, such as abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, are rare genetic diseases that result in a defect in the synthesis or secretion of lipoproteins containing apolipoprotein B.In children, these conditions present with diarrhoea and growth failure, whereas adults present with neuromuscular, ophthalmological, and hepatic symptoms. Simple laboratory investigations have shown that diagnosis can be made from findings of dramatically decreased cholesterol levels, deficiencies in fat-soluble vitamins (mostly vitamin E), endoscopic findings of the characteristic white intestinal mucosa, and fat-loaded enterocytes in biopsy samples. Genetic analysis is used to confirm the diagnosis. Treatment is based on a low-fat diet with essential fatty acid supplementation, high doses of fat-soluble vitamins, and regular and life-long follow-up.The present study examines cases and literature findings of these conditions, and emphasises the need to explore severe hypocholesterolemia and deficiencies in fat-soluble vitamins to not miss these rare, but easy to diagnose and treat, disorders.

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.

A novel p.Gly417Valfs*12 mutation in the MTTP gene causing abetalipoproteinemia: Presentation of the first patient in Mexico and analysis of the previously reported cases.

BACKGROUND: Our aims were to describe the first Mexican patient with abetalipoproteinemia and to perform a comparative analysis of biochemical, clinical, and genetic characteristics of 100 cases reported in the literature. METHODS: We performed biochemical and molecular screenings in a Mexican girl with extremely low lipid levels and in her family. Further, we integrated and evaluated the characteristics of the cases with abetalipoproteinemia described in the literature. RESULTS: Our patient is a six-year-old girl who presented vomiting, chronic diarrhea, failure to thrive, malabsorption, acanthocytosis, anemia, transaminases elevation, and extremely low lipid levels. MTTP gene sequencing revealed homozygosity for a novel mutation p.Gly417Valfs*12 (G deletion c.1250). With the analysis of the reported cases, 60 clinical features (14 classical and 46 non-classical) were observed, being the most common acanthocytosis (57.5%), malabsorption (43.7%), and diarrhea (42.5%); 48.8% of the patients presented only classic clinical features, while the remaining 51.2% developed secondary effects due to a fat-soluble vitamin deficiency. An odds ratio analysis disclosed that patients diagnosed after 10 years of age have an increased risk for presenting clinical complications (OR = 18.0; 95% CI 6.0-54.1, p < 0.0001). A great diversity of mutations in MTTP has been observed (n = 76, being the most common p.G865X and p.N139_E140) and some of them with possible residual activity. CONCLUSION: The first Mexican patient with abetalipoproteinemia presents a novel MTTP mutation p.Gly417Valfs*12. Three factors that could modulate the phenotype in abetalipoproteinemia were identified: age at diagnosis, treatment, and the causal mutation.

Microsomal Triglyceride Transfer Protein: From Lipid Metabolism to Metabolic Diseases.

Microsomal triglyceride transfer protein (MTP) was first identified as an endoplasmic reticulum (ER) resident protein that helps in the transfer of neutral lipids to nascent apolipoprotein B (apoB). Its critical role in the assembly and secretion of apoB-containing lipoproteins was identified in abetalipoproteinemia patients who have mutations in MTP and completely lack apoB-containing lipoproteins in the circulation. It has been established now that MTP not only is involved in the transfer of neutral lipids but also plays a role in cholesterol ester and cluster of differentiation 1d (CD1d) biosynthesis. Besides neutral lipids, MTP may also help in the transfer of sphingolipids such as ceramides and sphingomyelin to the apoB-containing lipoproteins. MTP is a multifunctional protein, and its deregulation during pathophysiological conditions gives rise to different metabolic conditions. This book chapter discusses the physiological role and regulation of MTP to maintain the homeostasis of lipids and lipoproteins. It also reviews the regulation of MTP during certain pathophysiological conditions and provides a brief overview of therapeutic interventions that can be possibly used to target its activity or expression to alleviate some of these metabolic diseases.

Consideraciones clínicas de la abetalipoproteinemia: revisión de la literatura / Clinical considerations of abetalipoproteinemia: literature review

La abetalipoproteinemia es una enfermedad rara que se suele presentarse en la primera década de la vida; sus principales manifestaciones son esteatorrea, alteración en el desarrollo y niveles plasmáticos lipídicos onsiderablemente disminuidos. Sin embargo, este cuadro suele ser confuso, puesto que existe un grupo de desórdenes genéticos que conllevan a mala absorción lipídica, que requieren un exhaustivo diagnóstico diferencial desde el punto de vista clínico, bioquímico y molecular. Este artículo expone una revisión actualizada sobre la abetalipoproteinemia, enfocándose en su fisiopatología, manifestaciones sistémicas, diagnóstico y abordaje en general, para facilitar su comprensión integral. La estrategia de búsqueda y los métodos de selección de estudios se realizó con base en elementos de la declaración prisma y guías Cochrane, utilizando términos de búsqueda tales como "abetalipoproteinemia" ,"bioquímica" y sinónimos, los cuales fueron combinados con los operadores "and" y "or", en las bases de datos PubMed, Science Direct, Clinical Key y Ebsco. No existe mucha literatura específica sobre esta condición, lo cual explica que sea una entidad subvalorada y poco conocida. Es fundamental realizar más investigaciones en torno al tema, pues en caso de no establecerse un diagnóstico y manejo adecuado, las complicaciones serán muchas y severas..Au

Abetalipoproteinemia is a rare disease that occurs predominantly in the first decade of life, having as main manifestations, steatorrhea, alteration in development and considerably decreased lipid plasma levels. However, this clinical presentation is often confusing, since there is a group of genetic disorders that lead to poor lipid absorption, requiring the need to make a comprehensive differential diagnosis from a clinical, biochemical and molecular point of view. This article will provide an updated review on Abetalipoproteinemia, focusing on its pathophysiology, systemic manifestations, diagnosis and general approach, allowing easy access to an integral knowledge. The search strategy and study selection methods were based on elements of the prisma statement and Cochrane guidelines, using search terms such as "Abetalipoproteinemia" and "Biochemistry", in addition to synonyms, which were combined with "and" and "or" operators, in the PubMed, Science Direct, Clinical Key and Ebsco databases. It is necessary to highlight that there is not much specific literature on this condition, which would support the fact that it is an undervalued and little-known entity, it is essential to carry out more research on the subject, taking into account that if a diagnosis is not established proper management, the complications are many and severe..Au

Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series.

BACKGROUND: X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype. METHODS: We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types. RESULTS: The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well. CONCLUSION: This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.