A rare case of nephrotic syndrome and Tangier disease.

Rarely, disorders of lipid metabolism cause nephrotic syndrome with progressive kidney disease. Tangier disease is a rare condition belonging to this family of lipid disorders; however, it is not associated with kidney disease. We report a patient presenting with nephrotic syndrome, leading to the unmasking of Tangier disease. A 34-year-old man presented with ankle oedema, nephrotic-range proteinuria and hypoalbuminaemia. Kidney biopsy demonstrated membranous nephropathy with features of immunoperoxidase staining, suggesting a secondary aetiology. Acute serology was negative. Imaging showed lymphadenopathy with splenomegaly suggestive of lymphoproliferative disorder. Bone marrow biopsy revealed foamy macrophages with widespread lipid deposition. Genomic sequencing revealed a pathological homozygous variant for ATP-binding cassette subfamily A member 1 (ABCA1) c.1510-1G > A, consistent with Tangier disease. Review of the ultrastructural kidney biopsy features demonstrated, in addition to membranous subepithelial and intramembranous usual-type electron-dense deposits, intramembranous osmiophilic lipid deposits similar to those in LCAT deficiency. The patient's renal function gradually declined (serum creatinine 133 µmol/L); therefore, he was started on rituximab. Metabolic disorders causing nephrotic syndrome are rare and even more so their association with membranous nephropathy. These should be considered in cases with unexplained persistent nephrotic syndrome with progressive kidney disease and lipid deposits on renal biopsy.

A case of mesenteric panniculitis in a patient with Tangier disease.

Mesenteric panniculitis is a rare disease caused by idiopathic inflammation of adipose tissue, most commonly affecting the mesentery of the small bowel. We present a unique case of mesenteric panniculitis in a patient with Tangier disease; a rare genetic disorder caused by mutations in the ABCA1 gene, leading to deficiency of high-density lipoprotein in the blood and accumulation of cholesterol esters within various tissues. The accumulation of cholesterol esters in body tissues in patients with Tangier disease may contribute to the pathogenesis of mesenteric panniculitis; although there is limited evidence to support this hypothesis due to the rarity of concurrent disease.

A case of premature and recurrent myocardial infarction associated with ABCA.1 gene mutation.

Coronary heart disease (CHD) is the most important cause of cardiovascular death and when premature, it affects the most productive population of the community. Premature CHD usually has a specific etiology, which on diagnosis, might help in the secondary prevention in that individual. We report a case of young adult with recurrent myocardial infarction, who on evaluation had mildly reduced HDL and Protein C levels with elevated serum homocysteine. Clinical exome identified a possibly pathogenic variant of ABCA1 gene, associated with Tangier disease.

Tangier disease may cause early onset of atherosclerotic cerebral infarction: A case report.

RATIONALE: The present study explored the relationship between the adenosine triphosphate (ATP)-binding cassette A1 (ABCA1) gene, atherosclerosis, and cerebral infarction. The diagnosis and treatment ideas of stroke caused by Tangier disease via the summary of the diagnosis and treatment process of one case with juvenile stroke were explored. The relevant literature on the clinical manifestations, laboratory examinations, and treatment of Tangier disease was reviewed. PATIENT CONCERNS: The brain magnetic resonance imaging (MRI) of a juvenile man with acute onset of sudden right limb weakness and speechlessness revealed infarct lesions. The laboratory tests found low serum high-density lipoprotein (HDL), while further genetic testing identified ABCD1 gene mutation. The mother also carried the mutant gene. DIAGNOSES: Tangier disease was diagnosed. INTERVENTIONS: Statin treatment was administered for platelet aggregation. OUTCOMES: After 3 years of follow-up, the patient was declared to be in a stable condition. LESSONS: ABCA1 gene mutation caused early onset of atherosclerosis, leading to the occurrence of cerebral infarction. The cerebral infarction associated with reduced high-density lipoprotein (HDL), was under intensive focus with respect to ABCA1 gene. Child and Juvenile stroke patients with low HDL should not be excluded from the possibility of Tangier disease.

Peripheral neuropathy in Tangier disease: A literature review and assessment.

Tangier disease (TD) (OMIM#205400) is a rare cause of inherited metabolic neuropathies characterized by marked deficiency of high-density lipoproteins and accumulation of cholesterol esters in various tissue resulting from reverse cholesterol transport deficiency. We report a case of a patient with TD with multifocal demyelinating neuropathy with conduction block who presents with winging scapula, tongue, and asymmetric extremity weakness. We also present a review of all studies published from 1960 to 2017 regarding peripheral neuropathy in TD. Our search identified 54 patients with TD with peripheral neuropathy. Syringomyelia-like neuropathy subtype (52.4%) was more frequent than multifocal sensorial and motor neuropathy subtype (26.2%), focal neuropathy subtype (19.1%), and distal symmetric polyneuropathy subtype (2.4%). Splenomegaly was the most common (40.7%) clinical manifestation in these patients. The pattern of electrodiagnostic abnormalities are: (1) demyelinating abnormalities were more predominant in the upper extremities than in the lower extremities and (2) slowing of motor nerve conduction was more prominent in the intermediate segment than in distal nerve segments. The sural-sparing pattern was present in 34.6% and conduction block was present in 11.5% of the patients. Our literature review and our case showed the clinical spectrum of TD neuropathy is quite wide and that it should be considered in the differential diagnosis of non-uniform demyelinating neuropathies.

Accelerated Atherogenicity in Tangier Disease.

We report a case of Tangier disease with Leriche syndrome and bleeding tendency. In this male patient, nasal hemorrhage had been observed frequently throughout childhood. At 46 years old, he experienced effort angina, and coronary angiography demonstrated 75% stenosis in the right coronary artery. Orange-colored tonsils, mild hepatosplenomegaly and very low levels of serum high-density lipoprotein cholesterol (HDL-C) were observed, and the patient was diagnosed with Tangier disease. At 52 years old, effort angina recurred. Coronary angiography revealed 75% stenosis of the left main trunk, left anterior descending, and right coronary arteries. Stenosis of the brachiocephalic and right common iliac arteries was also recorded. Stents were implanted, and coronary artery bypass surgery was performed. At 53 years old, 15 months after surgery, the patient reported intermittent claudication, coldness of feet, and impotence. Aortic angiography showed progression of the stenosis at the bifurcation of the common iliac artery. The patient was diagnosed with Leriche syndrome, and aorta-left external iliac artery graft bypass surgery was performed. After surgery, oozing from subcutaneous tissue and leaking from the anastomotic region were observed. Additional analysis revealed two single-nucleotide polymorphisms (V825I and N935T) in the ATP-binding cassette transporter A1 (ABCA1) gene, and accumulation of small dense low-density lipoprotein together with low levels of HDL-C. In Tangier disease, HDL-C is markedly decreased because of ABCA1 deficiency. However, this is the first reported case to exhibit extensive atherosclerosis and bleeding tendency. This patient had atypical extensive and multiple atherosclerotic lesions, accompanied by Leriche syndrome and uncontrollable bleeding.

Can Tangier disease cause male infertility? A case report and an overview on genetic causes of male infertility and hormonal axis involved.

Tangier disease is an autosomal recessive disorder caused by mutations in the ABCA1 gene and characterized by the accumulation of cholesteryl ester in various tissues and a near absence of high-density lipoprotein. The subject in this investigation was a 36-year-old Italian man with Tangier disease. He and his wife had come to the In Vitro Fertilization Unit, Pesaro Hospital (Azienda Ospedaliera Ospedali Riuniti Marche Nord) seeking help regarding fertility issues. The man was diagnosed with severe oligoasthenoteratozoospermia. Testosterone is the sex hormone necessary for spermatogenesis and cholesterol is its precursor; hence, we hypothesized that the characteristic cholesterol deficiency in Tangier disease patients could compromise their fertility. The aim of the study was to therefore to determine if there is an association between Tangier disease and male infertility. After excluding viral, infectious, genetic and anatomical causes of the subject's oligoasthenoteratozoospermia, we performed a hormonal analysis to verify our hypothesis. The patient was found to be negative for frequent bacteria and viruses. The subject showed a normal male karyotype and tested negative for Yq microdeletions and Cystic Fibrosis Transmembrane Conductance Regulator gene mutations. A complete urological examination was performed, and primary hypogonadism was also excluded. Conversely, hormonal analyses showed that the subject had a high level of follicle stimulating hormone and luteinizing hormone, low total testosterone and a significant decline in inhibin B. We believe that the abnormally low cholesterol levels typically found in subjects with Tangier disease may result in a reduced testosterone production which in turn could affect the hormonal axis responsible for spermatogenesis leading to a defective maturation of spermatozoa.

[Valve Replacement for Severe Aortic Stenosis in a Patient with Tangier Disease].

We report a case of severe aortic valve stenosis in a patient with Tangier disease. A 64-year-old female was diagnosed with Tangier disease on the basis of gene mutation. The serum levels of total cholesterol and high-density lipoprotein were 124 mg/dl and 4.3 mg/dl, respectively. She had a symptom of dyspnea and echocardiography revealed severe aortic valve stenosis with the maximum gradient of 60.5 mmHg. Chest computed tomography showed severe calcification of the ascending aorta and the aortic root. Aortic valve replacement using a bioprosthetic valve was performed. Several reports have been made on coronary artery revascularization in Tangier disease patients, but one on surgical treatment for aortic valve stenosis is extremely rare.

Platelet activating factor levels and metabolism in Tangier disease: a case study.

BACKGROUND: Tangier disease (TD) is a phenotypic expression of rare familial syndrome with mutations in the ABCA1 transporter. The risk of coronary artery disease in patients with TD is variable. On the other hand the pivotal role of Platelet-Activating Factor (PAF) mediator in atheromatosis was found. Plasma lipoproteins are transporters of the PAF acetylhydrolase (PAF-AH) in cells and known as lipoprotein-phospholipase A2 (Lp-PLA2) in plasma and regulators of PAF levels in blood. In addition, PAF can be biosynthesized from the remodeling and the de novo pathways in which Lyso-platelet activating factor-acetyltransferase (Lyso-PAF-AT) and platelet activating factor-cholinephosphotransferase (PAF-CPT) are the regulatory enzymes. The aim of this study is to investigate in a TD patient with a unique mutation (C2033A), the concentration of PAF in blood, the Equivalent Concentration for 50% aggregation (EC50) values of platelet rich plasma (PRP) toward PAF, adenosine diphosphate (ADP) and thrombin, and the activities of PAF metabolic enzymes Lp-PLA2, PAF-AH, Lyso-PAF-AT and PAF-CPT. METHODS: The EC50 value of PRP was measured by an aggregometer. The determination of the specific activity of PAF-CPT and Lyso-PAF-AT was made after in vitro enzymatic assay, chromatographic separation and measurement of the produced PAF in a biological assay with washed rabbit platelets. The determination of PAF-AH and Lp-PLA2 was made after an in vitro enzymatic assay from the decay of radioactive PAF. RESULTS: The TD patient had lower bound-PAF values in blood, decreased specific activity of PAF-CPT and Lyso-PAF-AT, increased specific activity of PAF-AH in platelets and leukocytes and Lp-PLA2 activity in plasma compared to healthy women. The EC50 of PAF and Thrombin were higher compared to healthy women. CONCLUSION: The increased Lp-PLA2 activity, as well as, the decreased activities of PAF-CPT and Lyso-PAF-AT, explain the decreased bound-PAF level in TD patient and the EC50 of PAF. However, total PAF is in a normal range and this probably can explain one of the reasons this TD patient has no CAD.

Clinical and electrophysiological characteristics of neuropathy associated with Tangier disease.

Tangier disease (TD) (OMIM#205400) is a rare autosomal recessive disorder resulting from mutations in the ABCA1 gene, leading to decreased levels of plasma high-density lipoproteins (HDL). Peripheral neuropathy is a common finding in this disease, and may present as relapsing/remitting mono/polyneuropathies or as syringomyelia-like neuropathy. We retrospectively analyzed four patients, and report here their clinical, biological, electrophysiological, imaging, and genetic findings. Three patients had a typical pseudosyringomyelic neuropathy including facial diplegia, but asymmetrical onset was observed in one patient who had first been misdiagnosed with Lewis-Sumner syndrome. Electrophysiological pattern was heterogeneous, showing both signs of demyelination and axonal degeneration. Truncating mutations of the ABCA1 gene, including two previously undescribed mutations, were constantly found. Atypical symptom onset and demyelinating features on electrophysiological examination can be misleading in case of pseudosyringomyelic neuropathy. These reports illustrate two different neurological phenotypes in TD, namely the pseudosyringomyelic type and the Lewis-Sumner-like type, and advocate for a systematic assessment of lipid profile including HDL cholesterol in demyelinating neuropathies.

Recurrent lobar intracerebral hemorrhage in Tangier disease.

We report a patient with familial α-lipoprotein deficiency (Tangier disease) who presented with recurrent lobar intracerebral hemorrhages and accumulating microbleeds on T*2-weighted magnetic resonance imaging, suggestive of probable cerebral amyloid angiopathy. This case provides new insight into the links between the adenotriphosphate-binding cassette A1 (ABCA1) transporter gene mutation in Tangier disease and apolipoprotein-E expression in the brain and supports further investigation of the potential role of ABCA1 transporter in cerebral amyloid angiopathy.

A novel ABCA1 nonsense mutation, R1270X, in Tangier disease associated with an unrecognised bleeding tendency.

The ATP binding cassette transporter A1 (ABCA1) is involved in the regulation of lipid trafficking and export of cholesterol from cells to high density lipoprotein (HDL). ABCA1 gene defects cause Tangier disease, an autosomal recessive disorder characterised by the absence of HDL-cholesterol in plasma, abnormal deposition of cholesteryl esters in the reticuloendothelial system, defective platelet dense and lysosomal granule release, and disordered cellular cholesterol efflux. We describe the case of a 62-year-old man with Tangier disease who presented with severe anaemia secondary to a spontaneous splenic haematoma. He underwent elective splenectomy without haemorrhage and his thrombocytopaenia resolved with a platelet count rising from 97 to 560 x 10(9)/L. Macroscopically, the resected spleen was enlarged with evidence of splenic haematoma. Histologic analysis of sections of spleen revealed lipid histiocytosis consistent with the diagnosis of Tangier disease. DNA sequence analysis revealed the subject to be a homozygote for a novel ABCA1 mutation c.4121C>T, which changes arginine 1270 to a stop codon (R1270X). In conclusion, we describe a case of Tangier disease in association with an unrecognised bleeding tendency, in a man homozygous for a novel ABCA1 gene mutation, R1270X.

Lewis-Sumner syndrome and Tangier disease.

OBJECTIVE: To report unusual electrophysiologic data in a patient with Tangier disease in an effort to better understand the pathophysiologic features of the peripheral nerve lesions in this disease. DESIGN: Case report. PATIENT: A 15-year-old girl had subacute onset of asymmetric neuropathy with persistent conduction block, resembling Lewis-Sumner syndrome. MAIN OUTCOME MEASURES: Electrophysiologic data in Tangier disease. RESULTS: After initially unsuccessful treatment with intravenously administered immunoglobulins, the finding of an abnormal lipid profile led to the diagnosis of Tangier disease due to the R587W mutation in the adenotriphosphate-binding cassette transporter-1 gene (ABCA1) (OMIM 9q22-q31). CONCLUSIONS: Conduction block, which is the electrophysiologic hallmark of focal demyelination, can be present in Tangier disease. It could be induced by focal nerve ischemia or by preferential lipid deposition in the paranodal regions of myelinated Schwann cells. The presence of a conduction block in Tangier disease may lead to a misdiagnosis of dysimmune neuropathy.

An unusual presentation of Tangier disease with gallbladder involvement.

Tangier disease is a rare, autosomally inherited disorder of lipoprotein metabolism characterized by absence or marked deficiency of normal high density lipoprotein (HDL) cholesterol in plasma resulting in the accumulation of cholesterol esters in various organs. A 57-year old male with a past medical history of hypertension, coronary artery disease and splenectomy admitted to our hospital for rectal bleeding. In routine laboratory tests thrombocytopenia, hypocholesterolemia and low HDL levels were detected. Colonoscopy revealed 1-3 mm sized, brownish, spotty lesions spread throughout the colonic mucosa. Histopathologically accumulation of foam cells which showed lipid vacuoles and myeline figures on electron microscopy were observed. Bone marrow biopsy was also suggestive of lipid storage disease. The laparoscopic operation performed for acute cholecystitis showed similar appearances in the gall bladder and liver. The case was diagnosed as rare presentation of Tangier disease with gallbladder involvement in view of the low HDL cholesterol level and systemic lipid deposition.

Manifestaciones anatomoclínicas de las enfermedades cutáneas metabólicas y sistémicas misceláneas: Parte II / Anatomoclinical manifestations of metabolic and systemic diseases: Part II

Numerosas enfermedades sistémicas y metabólicas tienen manifestaciones cutáneas, muchas de estas manifestaciones pueden favorecer su diagnóstico. Dado el gran número de estas patologías, esta revisión no pretende ser un análisis exhaustivo de todas ellas, sino que presenta un análisis clínico-patológico de algunas enfermedades metabólicas y sistémicas seleccionadas.

Numerous systemic and metabolic diseases have coetaneous manifestations, many of these manifestations can favor diagnosis Due to the great number of these conditions, this review does not try to be a comprehensive analysis of all of them, but present a clinicopathological analysis of some selected metabolic and systemic diseases.