Alternative titles; symbols
SNOMEDCT: 15346004, 723579009; ICD10CM: E78.6; ORPHA: 31150; DO: 1388;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q31.1 | Tangier disease | 205400 | Autosomal recessive | 3 | ABCA1 | 600046 |
A number sign (#) is used with this entry because of evidence that Tangier disease (TGD) is caused by homozygous or compound heterozygous mutation in the ABCA1 gene (600046) on chromosome 9q31.
A more common form of genetic HDL deficiency, familial HDL deficiency (604091), is allelic to Tangier disease.
Tangier disease (TGD) is an autosomal recessive disorder characterized by markedly reduced levels of plasma high density lipoproteins (HDL) resulting in tissue accumulation of cholesterol esters. Clinical features include very large, yellow-orange tonsils, enlarged liver, spleen and lymph nodes, hypocholesterolemia, and abnormal chylomicron remnants (Brooks-Wilson et al., 1999).
Tangier disease was originally described and named on the basis of a kindred living in Tangier Island in the Chesapeake Bay (Fredrickson et al., 1961), most of whom were descendants of first settlers of 1686. Other affected families have been discovered in Missouri and Kentucky. The 2 hallmarks of the disease, enlarged lipid-laden tonsils and low serum HDL, were based on the initial description of the original kindred. Engel et al. (1967) observed that patients with Tangier disease had recurrent peripheral neuropathy, intestinal lipid storage, and decreased serum alpha-lipoproteins. Obligate heterozygotes also had decreased serum alpha-lipoproteins.
Kocen et al. (1967) described a 37-year-old British air force corporal with Tangier disease who showed widespread loss of pain and temperature sensation and progressive muscle wasting and weakness. They commented that, whereas the characteristic pharyngeal appearance had been the presenting feature in children, adolescents tended to present with relapsing peripheral neuropathy, and adults with hypersplenism or precocious coronary artery disease.
Hypocholesterolemia was a tip-off to the diagnosis in a 38-year-old patient with Tangier disease described by Brook et al. (1977). Assmann et al. (1977) reported cases in Germany.
Pietrini et al. (1985) reported a case they alleged to be the thirty-third in the 'world literature' and the second in Italy. A complete tabulation of the 33 cases was given. Age at diagnosis varied from 2 years to 67 years. The patient of Pietrini et al. (1985) had widespread neuropathy with facial diplegia, bilateral wasting of the hand muscles, and dissociated loss of pain and temperature sensation sparing the distal parts of the limbs, known as a 'syringomyelia-like' syndrome. First neurologic symptoms appeared at age 37; he burned the base of the neck by application of an excessively hot heating pad and noted induced sensation to heat and pain in some areas of the shoulder and later in the hand and arm. Levels of apoA-I (107680) and HDL cholesterol were very low and triglycerides were high.
Pressly et al. (1987) described a 66-year-old man with Tangier disease and discussed the ocular complications, including corneal clouding, decreased corneal sensation, cicatricial ectropion, and slowly progressive visual impairment. The authors noted that ectropion and incomplete eyelid closure may precede corneal clouding. The combination of exposure keratopathy and corneal infiltration was responsible for the visual impairment in their patient.
Dyck et al. (1978) studied a 67-year-old woman with typical biochemical features of Tangier disease and a syringomyelia-like syndrome that has been observed in other patients with adult onset. Over a period of 17 years, she had developed progressive facial diplegia, bilateral wasting of hand muscles, and loss of sensation over cranial, cervical, and brachial dermatomes.
Schaefer et al. (1980) presented data consistent with increased risk for premature vascular disease in Tangier disease. However, the strikingly accelerated atherosclerosis of familial hypercholesterolemia (143890) was not seen, possibly because of the normal or reduced LDL cholesterol levels.
Cheung et al. (1993) described a 48-year-old Caucasian female of central European origin with very low apoprotein A-I and A-II (107670) and low HDL cholesterol. She had most of the clinical features typical of Tangier disease, including early corneal opacities, yellow-streaked tonsils, hepatomegaly, and variable degrees of peripheral neuropathy, but no splenomegaly. She had a myocardial infarction at the age of 46.
Schippling et al. (2008) reported a 49-year-old Afghan Caucasian patient with Tangier syndrome who presented with a 15-year history of a progressive syringomyelia-like syndrome with episodes of appendicular stabbing pain. He had tonsillectomy at age 14. Physical examination revealed marked distal atrophic weakness with absent tendon reflexes, loss of pain and temperature sensation, trophic changes of nails and skin, distal loss of facial hair, and mild splenomegaly. He had proximal internal carotid artery stenosis (60% left, 50% right) on color coded duplex sonography, left ventricular hypertrophy with reduced left ventricular function on echocardiography, and severe coronary artery disease with proximal LAD stenosis on coronary angiography. Laboratory studies showed undetectable serum HDL and decreased total cholesterol and apoA-I. Electrophysiologic studies demonstrated a predominantly axonal sensorimotor polyneuropathy with signs of chronic and active denervation and mild to moderate demyelination. Sural nerve biopsy showed de- and remyelination, endoneurial fibrosis, and deposition of fat droplets in axons and Schwann cells. Relatively low levels of HDL were also found in the patient's mother and the 2 daughters, consistent with heterozygosity. Genetic analysis identified a homozygous truncating mutation in the ABCA1 gene, consistent with complete loss of protein function.
Schmitz et al. (1985) showed that in macrophages, subsequent to receptor-mediated binding, HDL is internalized and then resecreted. Studying human monocytes from normal subjects and from patients with Tangier disease, Schmitz et al. (1985) found that HDL was internalized but only a minor amount, most of which was degraded, was resecreted from Tangier monocytes. They postulated that Tangier disease is a disorder of intracellular membrane traffic in which HDL is diverted into the lysosomal compartment and degraded instead of being secreted through its regular transcellular route.
In contrast to 2 other monogenic HDL deficiencies in which defects in the plasma proteins APOA1 and LCAT (606967) interfere primarily with the formation of HDL, Tangier disease shows a defect in cell signaling and the mobilization of cellular lipids (Rust et al., 1998).
Studies of cultured cells from the original Tangier kindred and others were pivotal in confirming the importance of the apolipoprotein-mediated pathway in cholesterol and phospholipid cellular efflux in the reverse cholesterol transport pathway (Remaley et al., 1999).
Rust et al. (1998) mapped the Tangier disease phenotype to chromosome 9q31 using a genomewide graphical linkage exclusion strategy in 1 large pedigree complemented by classic lod score calculations at that region in a total of 3 pedigrees. The results yielded a combined lod score of 10.05 at D9S1784. The studies of a mentally retarded boy with a heterozygous de novo deletion of 9q22-q32 showed an HDL cholesterol level below the 2.5 percentile. The HDL cholesterol in the parents of the boy was normal. The findings in this boy were taken to support assignment of the Tangier disease locus, and suggested that the disorder results from a loss-of-function defect.
The transmission pattern of TGD in the family reported by Fredrickson et al. (1961) and Remaley et al. (1999) was consistent with autosomal recessive inheritance.
In 2 probands with Tangier disease, Brooks-Wilson et al. (1999) identified compound heterozygous or homozygous mutations in the ABCA1 gene (600046.0001-600046.0003). One of the patients had presented with acute myocardial infarction at 38 years of age; the second patient was born of consanguineous parents and had been reported by Frohlich et al. (1987).
Bodzioch et al. (1999) analyzed 5 kindreds with Tangier disease and identified 7 different mutations in the ABCA1 gene, including 3 that were predicted to impair the function of the gene product (see, e.g., 600046.0005-600046.0008). Rust et al. (1999) likewise identified mutations in the ABCA1 gene in Tangier disease (600046.0009-600046.0010).
Remaley et al. (1999) demonstrated that in the original Tangier disease family (Fredrickson et al., 1961) the disorder was caused by homozygosity for a dinucleotide deletion in exon 22 of the ABCA1 gene (600046.0011).
Exclusion of a Defect in the Apolipoprotein A-I Gene
HDL is the designation of lipoproteins derived from density properties revealed by ultracentrifugation; alphalipoprotein is the designation based on mobility in an electrophoretic system. The apoproteins of the lipoproteins are named by their C-terminal amino acid (Schaefer et al., 1978). Lux et al. (1972) demonstrated a marked reduction in 1 of the 2 major apoproteins of high density lipoprotein, 'Apo-Gln-I' (Apo-I). Because no immunochemical difference could be demonstrated between this apoprotein of Tangier disease and that of normals, they concluded that Tangier disease could be caused by a mutation in a gene that regulates the synthesis of Apo-Gln-I.
Schaefer et al. (1978, 1981) presented evidence suggesting that the deficiency of apolipoproteins in Tangier disease was largely due to increased rapid catabolism. Heterozygotes showed normal catabolism. Kay et al. (1982) concluded that apoA-I in Tangier disease is abnormal in amino acid composition, electrophoretic mobility, apparent molecular weight on sodium dodecyl sulfate/polyacrylamide gel electrophoresis, and heterogeneity of isoforms on isoelectric focusing. Schmitz et al. (1983) suggested that the underlying defect in Tangier disease is a faulty conversion of pro-apoA-I to mature apoA-I, either because of a defect in the converting enzyme activity or a specific structural defect in Tangier apoA-I. Thus, the failure of Tangier pro-apoA-I to associate with HDL may be at least partially responsible for the HDL deficiency in Tangier subjects.
Bojanovski et al. (1987) found that both proapolipoprotein A-I and the mature protein are metabolized abnormally rapidly in Tangier disease.
By restriction enzyme analysis, Rees et al. (1984) could demonstrate no major deletion or insertion in the apoA-I gene in a patient with Tangier disease. Law and Brewer (1985) derived the complete amino acid sequence from the nucleic acid sequence of a cloned apoA-I cDNA from liver of a patient with Tangier disease. The structure of Tangier preproapoA-I was identical to the normal preproapoA-I except for a single base substitution (G-to-T) that resulted in the isosteric substitution of aspartic acid for glutamic acid at position 120. These results were interpreted as indicating that there is no major structural defect in Tangier apoA-I and that the rapid rate of catabolism must be from a posttranslational defect in apoA-I metabolism. Specifically, a structural defect at the propeptide cleavage site, as suggested by Zannis et al. (1982), was excluded. Makrides et al. (1988) likewise concluded that the APOA1 gene is structurally normal in patients with Tangier disease. They isolated and characterized the gene from a lambda-L47.1 genomic library constructed with DNA from lymphocytes of a Tangier disease patient. The DNA-derived protein sequence of Tangier apoA-I was found to be identical to normal apoA-I. Transfection into mouse cells resulted in synthesis of a protein that was indistinguishable from the apoA-I secreted by cultured normal human cells.
Young and Fielding (1999) stated that the inhabitants of Tangier Island in the Chesapeake Bay 'still speak a unique Elizabethan dialect, and three-quarters of them bear one of four surnames from the original group of founders.'
By identifying heterozygotes for Tangier disease, Suarez et al. (1982) excluded close linkage to RH, MN, GPT, and GLO.
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Assmann, G., Simantke, O., Schaefer, H.-E., Smootz, E. Characterization of high density lipoproteins in patients heterozygous for Tangier disease. J. Clin. Invest. 60: 1025-1035, 1977. [PubMed: 198431] [Full Text: https://doi.org/10.1172/JCI108853]
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Bojanovski, D., Gregg, R. E., Zech, L. A., Meng, M. S., Bishop, C., Ronan, R., Brewer, H. B., Jr. In vivo metabolism of proapolipoprotein A-I in Tangier disease. J. Clin. Invest. 80: 1742-1747, 1987. [PubMed: 3119665] [Full Text: https://doi.org/10.1172/JCI113266]
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