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.

Current Diagnosis and Management of Tangier Disease.

Tangier disease is a genetic disorder characterized by an absence or extremely low level of high-density lipoprotein (HDL)-cholesterol (HDL-C). It is caused by a dysfunctional mutation of the ATP-binding cassette transporter A1 (ABCA1) gene, the mandatory gene for generation of HDL particles from cellular cholesterol and phospholipids, and it appears in an autosomal recessive hereditary profile. To date, 35 cases have been reported in Japan and 109 cases outside Japan. With dysfunctional mutations in both alleles (homozygotes or compound heterozygotes), the HDL-C level is mostly less than 5 mg/dL and there is 10 mg/dL or less of apolipoprotein A-I (apoA-I), the major protein component of HDL. In patients with Tangier disease, major physical findings are orange-colored pharyngeal tonsils, hepatosplenomegaly, corneal opacity, lymphadenopathy, and peripheral neuropathy. Although patients tend to have decreased low-density lipoprotein (LDL)-cholesterol (LDL-C) levels, premature coronary artery disease is frequently observed. No specific curative treatment is currently available, so early identification of patients and preventing atherosclerosis development are crucial. Management of risk factors other than low HDL-C is also important, such as LDL-C levels, hypertension and smoking. Additionally, treatment for glucose intolerance might be required because impaired insulin secretion from pancreatic beta cells has occasionally been reported.

A novel homozygous ABCA1 variant in an asymptomatic man with profound hypoalphalipoproteinemia.

Low high-density lipoprotein cholesterol (HDL-C) can be caused by several acquired secondary causes as well as primary genetic disorders. However, only a few conditions are associated with profoundly reduced levels below 10 mg/dL. We present an unusual case of a healthy man with severely decreased HDL-C because of a novel homozygous variant causing a Proline > Arginine amino acid change at position 1412 in the ATP-binding cassette transporter A1 gene. Homozygous variations in ATP-binding cassette transporter A1 typically cause Tangier disease, a rare autosomal recessive condition linked with several other abnormalities (eg, enlarged discolored tonsils). Despite having an HDL-C below 10 mg/dL, our patient presented without any other clinical symptoms or physical signs suggestive of Tangier disease. This case of presumptive Tangier disease adds support to the growing body of evidence that this genetic disorder may have greater phenotypic heterogeneity along with a more varied presentation than traditionally considered.

Clinical, Electrodiagnostic, and Genetic Features of Tangier Disease in an Adolescent Girl with Presentation of Peripheral Neuropathy.

Tangier disease (TD) is a rare, autosomal recessive inherited disorder caused by a mutation in the adenosine triphosphate-binding cassette transporter 1 (ABCA1) gene, which results in a decrease in plasma high-density lipoprotein (HDL) levels. Peripheral neuropathy can be seen in approximately 50% of patients with TD, which usually occurs after the age of 15 years, and is characterized by relapsing-remitting mono- or polyneuropathy or syringomyelia-like neuropathy. Herein, we report a 16-year-old female patient who was initially diagnosed with peripheral neuropathy at the age of 13 years. Whole exome sequencing was performed, and a nonsense mutation (p.Arg1817X) in ABCA1 was identified. The patient was investigated for systemic findings of TD after the genetic diagnosis was made, and low (< 5 mg/dL) levels of HDL cholesterol were detected by lipid electrophoresis. Other family members were reexamined after the diagnosis of the proband, and asymptomatic sister of the proband was diagnosed with TD. We would like to emphasize that TD should be considered in the differential diagnosis of pediatric patients presenting with peripheral neuropathy; furthermore detection of HDL levels by lipid electrophoresis is a simple but indicative diagnostic test.

Whole exome sequencing combined with integrated variant annotation prediction identifies asymptomatic Tangier disease with compound heterozygous mutations in ABCA1 gene.

OBJECTIVE: Molecular diagnosis for subjects with extremely low HDL-C through candidate-gene approaches requires huge effort. Whole exome-sequencing (WES) has already shown approximately ∼30% success in the diagnosis of Mendelian disorders. Moreover, novel in silico prediction software for the pathogenicity of novel missense variants named Combined Annotation Dependent Depletion (CADD) has recently been developed, enabling the objective integration of many diverse annotations into a single measure (C-score) for each variant. Here, we investigated whether WES combined with integrated variant annotation prediction could facilitate the molecular diagnosis of this rare condition. METHODS: WES was performed on 8 individuals including 2 individuals exhibiting extremely low HDL-C (2 mg/dl and 6 mg/dl), 2 unaffected family members, and 4 unrelated individuals as controls. We filtered out the following variants: 1) Benign variants predicted by SnpEff; 2) Minor allele frequency (MAF) > 1%; 3) Segregation unmatched for the recessive form of inheritance; 4) C-score < 10. RESULTS: Among 305,202 variants found in those individuals, we found 21,708 nonsense, missense, or splice site variants, of which 5192 were rare (MAF ≤ 1% or not reported). Filtering assuming a recessive pattern of inheritance, combined with the use of the C-score, successfully narrowed down the candidates to compound heterozygous mutations in the ABCA1 gene (c.6230C > A or p.P2077H/c.6137G > A or p.S2046N, and c.2842G > A or p.G948R/c.1130C > T or p.P377L). CONCLUSIONS: WES combined with integrated variant annotation prediction successfully identified asymptomatic Tangier disease with novel ABCA1 mutations. This comprehensive approach is useful to determine causative variants, especially in recessive inherited diseases.

The curious case of the orange coloured tonsils.

Tangier disease is an extremely rare and severe form of high density lipoprotein deficiency. Even though there is no specific therapy for patients with Tangier disease, it is important to recognize the clinical presentation as patients are at an increased risk of developing atherosclerosis and subsequent CVD. The case discussed in this report, illustrates the importance of recognizing that orange discoloured tonsils are an indication that the patient could be suffering from Tangier's disease.

Tangier disease in a Turkish family.

In this report we describe the upper gastrointestinal tractus involvement in a rare genetic disease of lipid metabolism. A 12-year-old boy presented with sore throat and fever. On physical examination, orange-yellow tonsils and adenoid tissue were noted. Mild hepatosplenomegaly was present. Lipid profile was compatible with Tangier disease (TD). Endoscopy of the upper gastrointestinal tract showed white-yellowish fatty deposits on the gastric mucosa. Microscopically, biopsy specimens contained numerous histiocytes with a foamy cytoplasm packed in the lamina propria of the gastric mucosa and at the crypt basement of the duodenum. His sister, 8 years old, was also diagnosed with TD based on abnormal lipid profile and orange-yellow tonsils. TD is a rare familial disorder of lipid metabolism, characterized by deposition of cholesteryl esters, probably involving the entirety of the gastrointestinal tract from the mouth to the anus.

Effects of miglustat treatment in a patient affected by an atypical form of Tangier disease.

BACKGROUND: Tangier disease (TD) is a rare autosomal recessive disorder, resulting from mutations in the ATP binding cassette transporter (ABCA1) gene. The deficiency of ABCA1 protein impairs high density lipoprotein (HDL) synthesis and cholesterol esters trafficking. CASE REPORT: A 58 year-old female, presenting with complex clinical signs (splenomegaly, dysarthria, dysphagia, ataxia, tongue enlargement, prurigo nodularis, legs lymphedema, pancytopenia and bone marrow foam cells), was misdiagnosed as Niemann-Pick C (NPC) and treated with miglustat (300 mg/day), normalizing neurological symptoms and improving skin lesions and legs lymphedema. Subsequently filipin-staining and molecular analysis for NPC genes were negative. Lipid profiling showed severe deficiency of HDL, 2 mg/dl (n.v. 45-65) and apoAI, 5.19 mg/dl (n.v. 110-170), suggesting TD as a probable diagnosis. Molecular analysis of ABCA1 gene showed the presence of a novel homozygous deletion (c.4464-486_4698 + 382 Del). Miglustat treatment was then interrupted with worsening of some neurological signs (memory defects, slowing of thought processes) and skin lesions. Treatment was restarted after 7 months with neurological normalization and improvement of skin involvement. CONCLUSIONS: These results suggest miglustat as a possible therapeutic approach in this untreatable disease. The mechanisms by which miglustat ameliorates at least some clinical manifestations of TD needs to be further investigated.

A novel mutation in the ABCA1 gene causing an atypical phenotype of Tangier disease.

Tangier disease is a rare autosomal-recessive disorder caused by mutation in the ATP binding cassette transporter 1 (ABCA1) gene. Typically, Tangier disease manifests with symptoms and signs resulting from the deposition of cholesteryl esters in nonadipose tissues; chiefly, in peripheral nerves leading to neuropathy and in reticulo-endothelial organs, such as liver, spleen, lymph nodes, and tonsils, causing their enlargement and discoloration. An association with early cardiovascular disease can be variable. We describe a patient with a unique phenotype of Tangier disease from a novel splice site mutation in the ABCA1 gene that is associated with a central nervous system presentation resembling multiple sclerosis, and the presence of premature atherosclerosis.

Approach to the patient with extremely low HDL-cholesterol.

Patients with extremely low high-density lipoprotein-cholesterol (HDL-C) pose distinct challenges to clinical diagnosis and management. Confirmation of HDL-C levels below 20 mg/dl in the absence of severe hypertriglyceridemia should be followed by evaluation for secondary causes, such as androgen use, malignancy, and primary monogenic disorders, namely, apolipoprotein A-I mutations, Tangier disease, and lecithin-cholesterol acyltransferase deficiency. Global cardiovascular risk assessment is a critical component of comprehensive evaluation, although the association between extremely low HDL-C levels and atherosclerosis remains unclear. Therapeutic interventions address reversible causes of low HDL-C, multiorgan abnormalities that may accompany primary disorders and cardiovascular risk modification when appropriate. Uncommon encounters with patients exhibiting extremely low HDL-C provide an opportunity to directly observe the role of HDL metabolism in atherosclerosis and beyond the vascular system.

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.

[Heart without HDL.Tangier disease]. / Un cuore senza HDL.

A 37-year-old man was referred to our lipid clinic because of profound plasma lipid alteration. He presented large and orange tonsils, hepatosplenomegaly. No corneal opacities or other ocular abnormalities as well as no nervous system abnormalities were evident. Haematologic alterations included thrombocytopenia and stomatocytes. HDL and apolipoprotein A-I concentrations were 4 and 3.9 mg/dL, respectively. Because of a severe coronary atherosclerosis documented by coronary angiography, he underwent percutaneous revascularization. Nine months later, he experienced restenosis of the proximal anterior descending coronary artery and was referred for CABG. The patient was diagnosed with Tangier disease on the basis of the pathognomonic triad of the disease: HDL deficiency, low plasma cholesterol concentration accompanied by normal (or even elevated) triglyceride levels and hyperplastic orange tonsils.

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.

Enfermedad de Tangier: apariencia gástrica endoscópica / Gastric mucosa appearance in a patient with Tangier disease

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