Overview

Tangier disease is a rare familial disorder of lipoprotein metabolism which is characterised by extremely low levels of plasma high-density lipoprotein (HDL) and its major protein constituents, apolipoproteins (apo) A-I and A-II.^1,2 This rare familial disorder occurs due to mutations in the ATP-binding cassette transporter A1 (ABCA1) gene, leading to impaired cholesterol transport.¹ Individuals with Tangier disease often present with severe reduction in HDL cholesterol and accumulation of cholesterol ester-rich lipids in various macrophage-laden tissues of the body, particularly those at lower body temperatures, such as the tonsils. The tonsils of people with Tangier disease tend to enlarge and obtain a yellow/orange appearance over time. Anaemia, thrombocytopenia, corneal opacification, accelerated atherosclerosis, hepatosplenomegaly, and lymphadenopathy are other symptoms these individuals present with.³

Notably, neurological complications, particularly peripheral neuropathy and sensory deficits, are significant manifestations associated with Tangier disease.⁴ These manifestations arise due to impaired handling of cholesterol esters in Schwann cells, which are essential for the myelination of peripheral nerves.  The defect in cholesterol efflux causes morphological and functional alterations in these cells, potentially disrupting the normal environment necessary for nerve conduction (speed at which electrical impulses travel through nerves) and resulting in peripheral neuropathy. This presents as a spectrum of symptoms ranging from nonspecific sensory loss to more severe forms, including both demyelination and axonal neuropathy (a condition that damages the axons of peripheral nerves).⁴

Pathophysiology of tangier disease

Mutations in the ATP-binding cassette transporter A1 (ABCA1) gene result in Tangier disease. ABCA1 is a membrane transporter that plays a pivotal role in lipid metabolism, particularly in the process of reverse cholesterol transport, which is essential for the efflux of cholesterol from peripheral tissues to the liver for excretion. It mediates the transfer of cellular phospholipid and free (unesterified) cholesterol to lipid-poor apolipoproteins (mainly apoA-I) and related proteins present in the extracellular medium, forming nascent HDL particles.^5,6 This implies that when newly synthesised apolipoproteins lack the ability to acquire cellular lipids by the ABCA1 pathway, it leads to their rapid degradation and an over-accumulation of cholesterol in macrophages.⁵

The variants of the ABCA1 gene associated with Tangier disease lead to defects in cholesterol efflux from cellular membranes, resulting in the pathological accumulation of cholesterol esters in tissues. This defect is compounded by a low plasma concentration of apoA-I caused by a pathologically rapid catabolism, resulting in a low level of HDL in plasma, and thus making it unable to scavenge cholesterol from tissues.⁷

In patients with Tangier disease, lipids also accumulate within Schwann cells, which synthesise and maintain the myelin sheaths of peripheral nerves. This accumulation contributes to Schwann cell dysfunction⁸. Impaired lipid metabolism may significantly affect nerve integrity, which mostly manifests in patients as neurological deficits like facial weakness and non-length-dependent demyelinating neuropathy.⁹ The abnormal lipid metabolism resulting from ABCA1 dysfunction can disrupt the balance of myelin formation, leading to axonal degeneration and demyelination, which exacerbates nerve-related symptoms.^8,10

Peripheral neuropathy and sensory deficits in tangier disease

Neuropathy is the most debilitating feature of Tangier disease, affecting approximately 50% of individuals with the condition.⁸ Peripheral neuropathies are frequently encountered in the course of Tangier disease, manifesting in different forms with varying degrees of sensory deficits.⁴

Peripheral neuropathy in tangier disease

Peripheral neuropathy in Tangier disease has presented in multiple forms, with two primary subtypes: syringomyelia-like neuropathy and multifocal neuropathy subtypes.^4,11

Syringomyelia-like neuropathy (SMLN)

This is a slowly progressive symmetric neuropathy characterised by proximal dissociated sensory loss, especially in the face, upper trunk and arms, sparing the lower limbs. It mostly presents as faciobrachial muscle wasting and weakness (wasting of distal upper-extremity muscles), loss of temperature sensation and pain. Progressive autonomic involvement has also been reflected by increased sweating and later anhidrosis. By contrast, the underlying pathology involves prominent axonal degeneration, primarily affecting small myelinated and unmyelinated nerve fibres. However, there is no evidence of demyelination or remyelination in the syringomyelia-like neuropathy of Tangier disease.^4,11

Multifocal neuropathy

The multifocal mono or polyneuropathy subtype presents a relapsing-remitting multifocal pattern of motor and sensory loss. Patients with this subtype often experience fluctuating limb weakness, numbness, and tingling, with symptoms typically appearing distally in a "glove and stocking" pattern (nerve damage to the hands and feet). The pathology in multifocal neuropathy is predominantly demyelination and remyelination, with lipid vacuoles accumulating in Remak Schwann cells. These houses have unmyelinated nerve fibres, but there is no increased incidence of degenerating fibres. In multifocal neuropathy, unmyelinated fibre loss is selective, and motor function can partially recover during remission​, unlike SMLN.^4,11

Sensory deficits in tangier disease

Sensory deficits in Tangier disease vary depending on the peripheral neuropathy subtype.

Syringomyelia-like neuropathy, sensory deficit

In this type, there is loss of pain and temperature sensation due to the involvement of small myelinated and unmyelinated fibres in the upper limbs and trunk. The sensory loss here is dissociated. This means that pain and temperature perception are lost, but touch, vibration, and proprioception remain intact.

In SMLN, the sensory deficits are usually progressive, starting in the face, arms, and upper trunk while sparing the lower limbs in the early stages​. Some cases report autonomic dysfunction, such as anhidrosis (inability to sweat), which may relate to sensory nerve damage ^4,11.

Multifocal mononeuropathy sensory deficit

Here, there is a patchy, asymmetric loss of all sensory modalities (temperature, pain, proprioception, vibration), affecting both small and large myelinated fibres, unlike in SMLN. Most cases report that patients experience intermittent numbness, tingling, and burning pain, often in a "glove and stocking" pattern, where symptoms begin distally in the hands and feet before progressing proximally. This form of sensory deficit is relapsing-remitting, meaning sensory deficits can fluctuate or partially recover between episodes​. Some patients may also exhibit lancinating pain attacks, possibly due to dorsal root ganglion involvement​.^4,11

Diagnosis of neurological complications of tangier disease

The diagnosis of neurological complications of Tangier disease requires a high index of suspicion. This involves genetic testing, histopathological analysis, clinical examination, electrophysiological studies, and biochemical tests.

Genetic testing

• ATP-binding cassette transporter A1 (ABCA1) molecular gene sequencing is the gold standard for the diagnosis of Tangier disease¹²
• Identification of pathogenic mutations in the ABCA1 gene confirms the diagnosis of Tangier disease
• Whole-exome sequencing or targeted sequencing of ABCA1 is recommended when neuropathy is present with low levels of high-density lipoproteins (HDL)⁴

Clinical examination

Patients may present with progressive limb weakness, sensory loss, muscle wasting or cranial nerve involvement. Syringomyelia-like neuropathy (SMLN) presents with proximal sensory loss (pain and temperature) and muscle atrophy, while multifocal mononeuropathy shows asymmetric weakness with fluctuating sensory deficits​. Autonomic symptoms, such as sweating abnormalities (anhidrosis), orthostatic hypotension, and gastrointestinal issues, may indicate small fibre involvement.​^4,11

Electrophysiological studies

Nerve conduction studies reveal patterns of demyelination, conduction block, and sural nerve sparing, which differentiate Tangier disease neuropathy from other neuropathies. Patients with multifocal neuropathy show reduced motor nerve conduction velocities and prolonged distal latencies, consistent with segmental demyelination​. Sural nerve action potentials may be preserved, despite severe sensory deficits, which is a diagnostic clue.​^4,11

Biochemical tests

Lipid profile analysis is essential for diagnosing Tangier disease, as patients exhibit the following:

• Extremely low HDL cholesterol levels (<5 mg/dL)
• Decreased apolipoprotein A-I (ApoA-I), the major protein in HDL
• Low to normal total cholesterol levels
• Elevated triglycerides in some cases​^4,11

Histopathology

• Nerve biopsy reveals lipid-laden Schwann cells, demyelination, and axonal degeneration
• Electron microscopy shows vacuolated Remak cells, indicating cholesterol accumulation in peripheral nerves​
• Tonsil biopsy may also show cholesterol ester deposits, which are characteristic of Tangier disease​^4,11

Management and treatment

There is no curative treatment yet established for Tangier disease. Currently, no clinical trials have been conducted to check the efficacy of gene therapy for the ABCA1 gene, although gene therapy has been proposed to have potential in treating Tangier disease.¹³

The attempts made focus on increasing high-density lipoprotein (HDL) through lifestyle modifications like:

• Replacing mono-unsaturated fatty acids with saturated fatty acids to raise HDL cholesterol
• Maintaining a healthy weight
• Maintaining regular aerobic exercise
• Smoking cessation

The above interventions could alleviate symptoms, particularly peripheral neuropathies.¹³ 

Future therapeutic approach

A future therapeutic approach is suggested either through cholesterol uptake upregulation by hepatocytes or by downregulating HDL metabolism. This approach can be made possible by targeted gene therapy, which causes ABCA1 overexpression, leading to increased cholesterol uptake within the cells.¹³

Summary

Tangier disease is a rare familial disorder of lipoprotein metabolism caused by mutations in the ABCA1 gene. It is characterised by extremely low levels of plasma high-density lipoprotein. Enlarged tonsils with a yellow/orange appearance, anaemia, thrombocytopenia, and corneal opacification are some symptoms of the disorder.

Peripheral neuropathy and sensory deficits are significant manifestations associated with Tangier disease; they arise due to impaired handling of cholesterol esters in Schwann cells, essential for the myelination of peripheral nerves. Peripheral neuropathies manifest in different forms with varying degrees of sensory deficits. Two primary subtypes are syringomyelia-like neuropathy and multifocal neuropathy.

Syringomyelia-like neuropathy is a slowly progressive symmetric neuropathy characterised by proximal dissociated sensory loss (face, upper trunk and arms), loss of temperature sensation and pain, and faciobrachial muscle wasting. The underlying pathology involves prominent axonal degeneration but no demyelination; it affects small myelinated and unmyelinated nerve fibres. The sensory loss here is dissociated (pain and temperature perception are lost, but touch, vibration, and proprioception remain intact).

Multifocal neuropathy presents a relapsing-remitting multifocal pattern of motor and sensory loss with weakness and numbness. The pathology is predominantly demyelination and remyelination. It affects both small and large myelinated fibres. There is patchy, asymmetric loss of all sensory modalities.

Diagnosis of the neurological complications of Tangier disease involves genetic testing, histopathological analysis, clinical examination, electrophysiological studies, and biochemical tests. Additionally,  no cure is available, and management focuses on lifestyle changes (healthy diet, exercise, etc). However, targeted gene therapy is a possible future therapeutic approach.