Overview

Abetalipoproteinemia (ABL) is a rare hereditary disorder affecting lipid (fat) and fat-soluble vitamin metabolism. This article will focus on the manifestations of ABL neurologically, specifically in the central nervous system (CNS), which relies heavily on vitamins and fats (lipids) to function optimally. When ABL causes deficiencies, it significantly impacts the CNS, thus leading to symptoms like ataxia, peripheral neuropathy, ocular conditions, and sometimes cardiovascular conditions. Symptoms from deficiencies all manifest and worsen over time when untreated and even develop into separate, more severe disorders.

Abetalipoproteinemia development

Genetic basis 

Microsomal triglyceride transfer protein (MTTP) binds lipids and vitamins to apolipoprotein B (apo-B), making apo-B-containing lipoproteins. Apo-B-containing lipoprotein then transports these molecules around the body to be metabolised.² 

In ABL patients, levels of apo-B are normal. However, levels of apolipoprotein-B-containing lipoproteins (a type of low-density lipoprotein - LDL) are dangerously low. Lipoproteins, such as lipids and vitamins, are not bound with apo-B to form apo-B-containing lipoprotein. 

MTTP is responsible for binding the lipoproteins to apo-B. Therefore, mutations or damage to the genes encoding MTTP result in the impaired transport of lipoproteins. As a result, fat and vitamin deficiencies develop in the cells of ABL patients.^2,6 

General consequences of lipid and vitamin deficiencies from ABL

Lipids and vitamins from the diet or liver are imperative for many processes in the body. Apo-B transports lipids and vitamins to cells that need them.³

Impaired lipid absorption and transport can result in:³  

• Pancreatitis 
• Cardiovascular diseases
• Neurological disorders 

Impaired transportation of fat-soluble vitamins A, D, E, and K and deficiencies  can result in different symptoms:⁴

• Vitamin A deficiency affects vision and leads to ocular disorders
• Vitamin D is not fully dependent on apo-B-containing lipoproteins to be transported to cells, so abetalipoproteinemia does not create a large vitamin D deficiency
• Vitamin E deficiency impacts the central nervous system by weakening muscles and tendons
• Vitamin K deficiency affects the production of blood cells and blood flow around the body

Impact on the nervous system 

The role of lipoproteins in neurological development is pivotal. Neural development transpires in stages that each require particular vitamins and lipids for proper brain development to occur. Lipids transported to the brain via apo-B mainly determine protein function and regulate neuron signalling.⁵

In ABL, genes that code for MTTP are damaged, meaning lipids and vitamins are not transported to brain cells. This causes proteins to malfunction and neuronal signalling to go unregulated. This affects neurological processes, causing the symptoms to arise and worsen into disorders.

Main neurological symptoms and disorders

An essential characteristic of abetalipoproteinemia is the decreased concentration of apolipoprotein-B-containing lipoproteins. This deficiency leads to the disorder and its neurological symptoms. 

Symptoms of this disorder manifest in:

• Gastrointestinal system
• Eyes
• Blood 
• CNS

The CNS supplies nerves to the entire body,  when ABL manifests neurologically, it triggers many neurological symptoms that have widespread effects around the body, developing into full-fledged disorders.⁷ 

Peripheral neuropathy

Peripheral neuropathy involves nerves becoming weaker or damaged due to a deficiency in vitamins and fat. This can manifest in symptoms such as:¹¹

• Muscle weakness (specifically in the feet)
• Sensory loss
• Numbness/tingling sensations in the extremities and external limbs 
• Burning
• Stabbing 
• Loss of balance

This can arise from a vitamin E deficiency. It starts off as spinocerebellar syndrome in the CNS and develops into the peripheral parts of the body as neuropathy. If essential molecules such as vitamin E are not transported to the necessary neurological structures (nerves), disorders such as ABL and peripheral neuropathy (a symptom of ABL) will develop.⁹

In most ABL cases, peripheral neuropathy and ataxia go hand-in-hand, as spinocerebellar syndrome is a type of ataxia commonly derived from a mutual vitamin E deficiency.¹⁰

Ataxia

Ataxia is a neurodegenerative disorder that makes it difficult to move limbs or carry out basic tasks. Similar to peripheral neuropathy, ataxia with vitamin E deficiency (AVED) is triggered by a deficiency in vitamin E. Common symptoms include:⁸

• Coordination issues
• Gait disturbances

These symptoms can also further develop into other neurological disorders:

• Dysarthria (speech difficulties)
• Peripheral neuropathy
• Cardiovascular conditions
• Ocular conditions

The eyes are an important neurological structure in the CNS. ABL can lead to the onset of ocular conditions from the lack of essential vitamins and lipids delivered to this organ.¹ 

Retinitis pigmentosa

It starts as xerophthalmia, where a vitamin A deficiency (causes the tear ducts and eyes to dry out and progressively worsens over time into retinitis pigmentosa.

Retinitis pigmentosa is a disease of the eyes, causing blindness from retinal degeneration from a lack of vitamin A and lipids needed to maintain eye health. The onset symptoms of this disease are:

• Vision loss 
• Night blindness (impaired vision in the dark)
• Poor peripheral vision (loss of visual field range)

These symptoms come about from the whites of the eyes (tissue that surrounds the eyeball) and the cornea (outermost front part of the eye) becoming dry from the lack of vitamin A (Xerophthalmia). This also triggers the retina to dry up and hence lose the ability to see properly in the light and dark due to dehydration triggering spots in the line of vision.

Other disorders triggered by ABL

Cognitive Impairments:¹²

• Memory issues
• Learning difficulties
• Difficulty balancing
• Tremors and involuntary movements 

Muscle problems that disrupt skeletal development include:¹²

• Abnormally curved lower back (Lordosis)
• Rounded and curved upper back (Kyphoscoliosis)
• High-arched feet (Pes Cavus)
• Clubfoot

Diagnosis

There are three methods to diagnose ABL as a primary clinical evaluation. Healthcare professionals assess patient’s history and symptoms to see if they follow ABL trends. The healthcare worker can order 3 tests to be conducted as confirmation.

Laboratory tests

The first type of tests that can be run are laboratory tests. These include:

• Blood tests that will evaluate individual lipid (cholesterol and triglycerides) and vitamin profiles as well as their levels in the blood
• Plasma tests are also done to measure apo-B-containing lipoprotein levels since low levels are a marker of ABL

Genetic testing

Next-generation sequencing (NGS) tests detect the essential characteristic in all ABL patients: a mutation in the MTTP gene. Healthcare professionals order this test to be carried out on a patient if there is a historical and/or familial trend of ABL (since it is a hereditary disorder). 

MTTP genes code for proteins that bind lipids and vitamins to apo-B and a mutation being detected confirms ABL presence. NGS tests have over 99% correct results, so they are quite reliable.

Neurological assessments

Here are 3 main neurological assessments that are carried out to detect neuron damage from ABL in the CNS: 

1. Electromyography (EMG): it measures electrophysiological events of neurons in the brain and body searching for ABL-triggered harm to them. It is a vital piece of evidence to confirm that a patient has ABL¹³ 
2. Brain imaging: it investigates the degeneration of neurons in the CNS. Examples of this include magnetic resonance imaging (MRI) or computed tomography (CT) scans. The spinocerebellar region is specifically imaged as degeneration here is a hallmark characteristic ABL of patients¹⁴

Management and treatment

There is no cure for this hereditary disorder. However, helpful strategies can control symptoms and prevent worsening. These management methods include:¹⁴

• Dietary modifications to incorporate a low-fat, high-calorie diet with medium-chain triglycerides (MCTs). Opposite to long-chain triglycerides (LCTs), which require apo-B-containing lipoproteins for absorption, MCTs are directly absorbed and metabolized into the target bloodstream thus reaching the necessary cells, bypassing the need for apo-B
• Vitamin supplementation which is another form of treatment since vitamin deficiencies are severe in ABL patients. Adding MCTs to the diet of an ABL patient also assists with the absorption of vitamin A,D,E, and K (fat soluble vitamins). Vitamins are not absorbed by MCTs but absorption is increased hence decreasing vitamin deficiencies
• Physical therapy to tackle some symptoms. Examples include exercising and physical rehabilitation tailored for neuropathic and ataxic patients. Particular exercises can target issues such as balance and gait disturbances
• Regular monitoring, which involves routine neurological and ophthalmological evaluations. This includes regular CT or MRI scans to check for brain damage and ophthalmological evaluations that evaluate eye health and assess the impact of ABL

These routine procedures are carried out in par with other forms of management and treatment, assessing how well and effective the treatment strategies are.

Summary

ABL is a rare hereditary disorder, where a mutation in the genes that code for MTTP prevents lipids and vitamins from binding to apo-B, thus decreasing their absorption and metabolism in the body. This article focuses on the neurological manifestations of vitamin and fat deficiencies. Deficiencies can lead to ataxia, peripheral neuropathy and ocular conditions (neurological manifestations of ABL). However, strategies of management like dietary changes, vitamin and lipid (MCT) supplementation, consistent monitoring, and measurements can control the progression of symptoms and ABL.