Clinical and electrophysiological characteristics of neuropathy associated with Tangier disease

Abstract

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.

Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency

“…For example, in our series of 9 adult TD patients only four had overt coronary heart disease (CHD) while three had peripheral sensory neuropathy in the absence of CHD (present study and [13,17,18,22,23]). Recently among four TD patients with neuropathy and ABCA1 truncating mutations (ABCA1 negative mutations) only two were found to have cardiovascular disease and yellow orange tonsils [21]. On the other hand, in our TD children (from 6 months to 16 years of age) (present study and Refs.…”

“…In four of them bone marrow biopsy had revealed the presence of lipid loaded macrophages, providing further support to the clinical diagnosis of TD [1,2]. One adult patient had peripheral sensory neuropathy [1,21], while clinical manifestations of premature coronary artery disease [1,2] were documented in one adult patient (# Mo-2) and in his twin brother.…”

“…[13,22]), splenomegaly, thrombocytopenia and anemia with or without orange yellow tonsils were the most prominent clinical features. It is reasonable to assume, therefore, that, besides the effect of the ABCA1 mutations, the clinical manifestations of TD are affected by other genes (such as those affecting cell cholesterol efflux) [24], age (sensory neuropathy appears to be a late onset disorder) [21] as well as nutritional/metabolic factors such as the high level of plasma TG which is an independent risk factor for cardiovascular disease (see below).…”

Mitochondrial regulation of macrophage cholesterol homeostasis

“…Loss of the endosomal cholesterol trafficking protein, Niemann-Pick type C1 (NPC1), leads to cholesterol accumulation in mitochondria of NPC1-deficient cells, decreased mitochondrial respiration, increased reliance on glycolysis, and enhanced expression of antioxidant response factor Nrf2 [189]. It has also been suggested that loss of function mutations in ABCA1, which cause the peripheral neuropathies found in patients with Tangier disease [190], can also increase mitochondrial cholesterol levels, preventing apoptosis and promoting the "Warburg effect," a term which describes the reliance of cancer cells on aerobic glycolysis rather than mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes [191,192].…”

Diagnosis and Management of Pediatric Peripheral Neuropathies In Resource-Poor Settings

“…Peripheral neuropathy in children with HIV has not been extensively studied, but is also described in the form of AIDP at the time of seroconversion as an immune reconstitution phenomenon, and in relation to secondary infection with Cytomegalovirus [25][26][27][28][29]. In differentiating between AIDP in children who are not infected with HIV and those undergoing seroconversion, the former future science group Special Report Wilmshurst CME [106,107] Patients can suffer painful radiculoneuropathy [108] Vasculitis Tangier disease Rare autosomal recessive mutation of ABCA1 gene leading to reduced levels of plasma high-density lipoprotein: children tend to present with large yellow-orange tonsils [109] Adults are more likely to have neuropathy that can be remitting/relapsing mono-/poly-neuropathy or a syringomyelia-like neuropathy [110] Acute intermittent porphyria…”