[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.

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.

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.

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.

Molecular characterization of Tunisian families with abetalipoproteinemia and identification of a novel mutation in MTTP gene.

BACKGROUND: Abetalipoproteinemia (ABL; OMIM 200100) is a rare monogenic disorder of lipid metabolism characterized by reduced plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and almost complete absence of apolipoprotein B (apoB). ABL results from genetic deficiency in microsomal triglyceride transfer protein (MTP; OMIM 157147). In the present study we investigated two unrelated Tunisian patients, born from consanguineous marriages, with severe deficiency of plasma low-density lipoprotein (LDL) and apo B. METHODS: Intestinal biopsies were performed and The MTTP gene was amplified by Polymerase chain reaction then directly sequenced in patients presenting chronic diarrhea and retarded growth. RESULTS: First proband was homozygous for a novel nucleotide deletion (c. 2611delC) involving the exon 18 of MTTP gene predicted to cause a non functional protein of 898 amino acids (p.H871I fsX29). Second proband was homozygous for a nonsense mutation in exon 8 (c.923 G > A) predicted to cause a truncated protein of 307 amino acids (p.W308X), previously reported in ABL patients. CONCLUSIONS: We discovered a novel mutation in MTTP gene and we confirmed the diagnosis of abetalipoproteinemia in new Tunisian families. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8134027928652779.

Autosomal recessive cerebellar ataxias.

Autosomal recessive cerebellar ataxias (ARCA) are a heterogeneous group of rare neurological disorders involving both central and peripheral nervous system, and in some case other systems and organs, and characterized by degeneration or abnormal development of cerebellum and spinal cord, autosomal recessive inheritance and, in most cases, early onset occurring before the age of 20 years. This group encompasses a large number of rare diseases, the most frequent in Caucasian population being Friedreich ataxia (estimated prevalence 2-4/100,000), ataxia-telangiectasia (1-2.5/100,000) and early onset cerebellar ataxia with retained tendon reflexes (1/100,000). Other forms ARCA are much less common. Based on clinicogenetic criteria, five main types ARCA can be distinguished: congenital ataxias (developmental disorder), ataxias associated with metabolic disorders, ataxias with a DNA repair defect, degenerative ataxias, and ataxia associated with other features. These diseases are due to mutations in specific genes, some of which have been identified, such as frataxin in Friedreich ataxia, alpha-tocopherol transfer protein in ataxia with vitamin E deficiency (AVED), aprataxin in ataxia with oculomotor apraxia (AOA1), and senataxin in ataxia with oculomotor apraxia (AOA2). Clinical diagnosis is confirmed by ancillary tests such as neuroimaging (magnetic resonance imaging, scanning), electrophysiological examination, and mutation analysis when the causative gene is identified. Correct clinical and genetic diagnosis is important for appropriate genetic counseling and prognosis and, in some instances, pharmacological treatment. Due to autosomal recessive inheritance, previous familial history of affected individuals is unlikely. For most ARCA there is no specific drug treatment except for coenzyme Q10 deficiency and abetalipoproteinemia.

Abetalipoproteinemia: monitoreo del tratamiento / Abetalipoproteinemia: monitoring of therapy

La abetalipoproteinemia es causada por un defecto en la síntesis de β-lipoproteínas plasmáticas, VLDL y quilomicrones. Cursa con desnutrición grave, diarrea crónica mal absortiva, polineuritis, ataxia, retinitis pigmentaria y acantocitosis. Se presenta un niño de cinco años de edad que consultó por un cuadro compatible con esta enfermedad. El diagnóstico se hizo por biopsia de intestino delgado y laboratorio. Se inició tratamiento con dieta hipograsa y triglicéridos de cadena mediana, formas hidrosolubles de vitaminas A y D, altas dosis de vitaminas E y K intramuscular y lípidos endovenosos en forma periódica para la provisión de ácidos grasos esenciales ante evidencias de deficiencia. Recibió lípidos endovenosos quincenalmente durante cinco años hasta que comenzó con reacciones de intolerancia durante las infusiones, que hubo que espaciar. La recuperación fue excelente. Hoy, a los catorceaños, es un adolescente normal, con desarrollo y tamaño corporal normales para su edad. Ante la imposibilidad de monitorear el estado nutricional (deficiencia o exceso) en ácidos grasos esenciales y vitaminas, eventualidad posible por lo atípico de la dieta, el síndrome mal absortivo y debido a los valores no dosables en plasma se obtuvieron tres biopsias de tejido adiposo. Los resultados demostraron la dependencia de las infusiones y una composición diferente del tejido adiposo, según los distintos momentos del tratamiento y en comparación con la de los adultos normales de nuestro país. Consideramos que la determinación de ácidos grasos en el tejido adiposo es una herramienta útil en el monitoreo del tratamiento de esta grave enfermedad.

Importance of screening the peripheral smear.

A 5-year-old boy presented with history of failure to thrive from infancy. There was a history of one sibling death due to similar problems and history of severe abortions in the mother. Routine examination of peripheral smear revealed more than 50% acanthocytes. Based on this tests were streamlined to doing lipid profile and Lipo protein electrophoresis which revealed hypolipidemia and absent beta hypo protein band. Jejunal mucosal biopsy confirmed the diagnosis of A Beta Lipo proteinemia which revealed lipid laden enterocytes. This case illustrates the importance of simple tests like peripheral smear examination in streamlining further tests in the diagnosis of major diseases.

Abetalipoproteinemia: a case report.

Abetalipoproteinemia is a rare autosomal recessive disorder characterized by steatorrhea, poor weight gain, acanthocytosis and retinitis pigmentosa. Here we peresent a six-month-old patient with abetaliporoteinemia. He had a history of chronic diarrhea from the first month of life. He was cachectic and his motor development was delayed. Microscopic examination of the stool revealed fat. Mild anemia with reticulocytosis, acanthocytosis, low triglyceride, low cholesterol, low-density lipoprotein, high-density lipoprotein, and apolipoprotein A and B were detected. Ophthalmological examination was normal. Peroral jejunal capsule biopsy revealed normal villi and significant lipid deposition in the cytoplasm of affected cells. The patient was given large doses of vitamins E and A.

[Role of the electrophysiologic examination in the diagnosis of Bassen-Kornzweig syndrome]. / Apport de l'examen électrologique au diagnostic de maladie de Bassen-Kornzweig. A propos de deux observations.

An autosomal recessive disorder, abetalipoproteinemia or Bassen-Kornzweig disease, concerning two sisters are described. This disorder, clinically similar to Friedreich ataxia, should be examined by electrophysiological and laboratory procedures because of the possibility of treatment by high doses of vitamin A and E. The routine electrophysiological examination of the two sisters revealed a degenerative spinocerebellar and peripheral nervous process which confirmed the damage of large myelinated fibers, as reported in the literature: neurogenic muscular atrophy of distal muscles, polyphasic motor unit potentials, moderately decrease of lower motor and sensory nerve conduction rates, and reduced amplitude of evoked responses in sensory nerves and muscles. We stress out the diagnostic value of the heterogenous conduction decrease in the distal motor fibers, signs of processes of demyelination or distal regeneration.

[Abetalipoproteinemia. Apropos of 2 cases]. / L'abêtalipoprotéinémie. A propos de deux cas.

The cases of two sisters with abetalipoproteinemia are reported. Both presented the complete clinical and biological features of the disease: ataxia, retinitis pigmentosa, lack of apolipoprotein B, chylomicrons, LDL and VLDL, reduced titers of serum cholesterol and triglycerides, acanthocytosis, very low levels of serum vitamin A and E. Abetalipoproteinemia is a rare autosomal inherited disease. It is usually revealed during early childhood by steatorrhea and failure to thrive; ataxia and retinitis pigmentosa appear later. The originality of these two cases stems from: 1) their late and fortuitous diagnosis: the first sister was investigated at the age of 42 after the discovery of a vitamin K induced coagulation disorder. The other sister was 39 when she was routinely examined as a family member; 2) the presence of constipation without any other suggestive digestive complaint. However, white discoloration of the duodenal mucosa seen at endoscopy and lipid droplets within the intestinal absorptive cells at biopsy were characteristic. Barium studies showed diffuse involvement of the small bowel which was displaced by an enlarged sigmoid. Treatment consists of administration of vitamin A and vitamin E which prevent or delay ocular and neurologic symptoms. Vitamin K is associated whenever necessary.

[Ophthalmoplegia-plus (multisystem mitochondrial cytopathy) in childhood]. / Oftal'moplegiia-plius (multisistemnaia mitokhondrial'naia tsitopatiia) v detskom vozraste.

Two cases of ophthalmoplegia-plus are described for the first time in the national literature. The clinical picture of both patients aged 7 and 15 years exhibited a characteristic triad: external ophthalmoplegia, retinitis pigmentosa and heart conduction impairments. In one patient, this triad was supplemented by neurosensory deafness, torsion dystonia and the myopathic syndrome, and in the other one, by ichthyosis, cerebellar symptomatology, the myopathic syndrome and a marked elevation of protein in the cerebrospinal fluid. In both patients, the diagnosis was supported by electron microscopic studies of a muscular biopsy-specimen which disclosed pronounced changes in the number, structure, size and form of mitochondria as well as the presence of glycogen and lipid drops accumulating near mitochondria.

[Abetalipoproteinemia (author's transl)]. / Abetalipoproteinämie.

A 21/2-years-old Greek girl with marked failure to thrive and steatorrhea diagnoses to suffer from abetalipoproteinemia by the dissecting microscope appearance of a white intestinal mucosa. This specific finding is due to storage of lipids in the enterocytes. Another typical finding is the acanthocytosis in blood smears. Serum lipids were studied in detail in the patient and her relatives; there was a marked reduction of the low and very low density lipoproteins in the patient only (LDL/VLDL). The most characteristic finding is the lack of apolipoprotein B.

[Hypolipidemias]. / Hypolipidämien

Hypolipidemias can be divided in primary, familial and hereditary forms and symptomatic forms which may accompany other diseases. The primary hypolipidemias (abetalipoproteinemia, hypobetalipoproteinemia and analphalipoproteinemia) are very rare. Severe hypolipidemia can be found in some peoples (e.g. the Masai). This article is chiefly devoted to secondary hypolipidemias such as those associated with malabsorption, malnutrition and maldigestion including protein-losing gastroenteropathy, with liver diseases, endocrine diseases (hyperthyroidism, hirsutism) and anemia. Finally, the hypolipidemias secondary to the formation of autoantibodies against HDL and LDL in M-gradient, carcinoma and rheumatoid arthritis are briefly reviewed.