Abetalipoproteinaemia

Straight to the point of care

Last updated: Jul 22, 2022

 Table of Contents
Overview 3
Summary 3
Definition 3

Theory 4
Epidemiology 4
Aetiology 4
Pathophysiology 4
Case history 4

Diagnosis 6
Approach 6
History and exam 7
Risk factors 8
Investigations 9
Differentials 11

Management 13
Approach 13
Treatment algorithm overview 13
Treatment algorithm 14
Patient discussions 15

Follow up 16
Monitoring 16
Complications 16
Prognosis 16

Guidelines 17
Diagnostic guidelines 17
Treatment guidelines 17

References 18

Disclaimer 21
Abetalipoproteinaemia Overview

Summary
Abetalipoproteinaemia is a rare genetic disorder caused by impaired transport of intestinal and hepatic lipids
that typically presents in the first few months of life with symptoms of faltering growth and steatorrhoea.

OVERVIEW
Diagnosis is often missed due to vague symptoms more common to diseases such as viral gastroenteritis or
child abuse sequelae.

If untreated, the disorder is progressive. Deficiency of fat-soluble vitamins such as A, E, D, and K can lead to
clinical symptoms and neurological deterioration.

When treated early with high doses of vitamin E, sequelae such as retinal degeneration or ataxia may be
prevented.

Nutritional repletion, including a low-fat diet and ingestion of fat-soluble vitamins, is essential in management.

Definition
Abetalipoproteinaemia is a rare, inherited, autosomal-recessive disorder resulting from microsomal
triglyceride transfer protein deficiency in the liver and small intestine.[1] [2] [3] Fat transport is disrupted,
causing symptoms of fat malabsorption (i.e., steatorrhoea, diarrhoea, abdominal distension) and eventual
wasting, which often present by infancy or childhood.[2] [4] Fats, cholesterol, and fat-soluble vitamins
such as A, D, E, and K are poorly absorbed, leading to dietary deficiency.[1] [2] [5] [6] If discovered early
and treated, nutrition may be improved and sequelae prevented. If untreated, clinical findings of vitamin E
deficiency result from degeneration of the spinocerebellar and dorsal columns tracts. Irreversible effects
include ataxia, peripheral neuropathy, and retinal degeneration.[6]

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 Abetalipoproteinaemia Theory

Epidemiology
Abetalipoproteinaemia is a rare genetic disorder with an estimated prevalence of <1 in 1,000,000 people.[7]
Most case histories have been in patients of Ashkenazi Jewish descent, where the prevalence is much
THEORY

higher (1:69,000).[8] Males and females are equally affected and incidence is increased if born of
consanguineous parents.[2]

Aetiology
Mutations in the microsomal triglyceride transfer protein (MTTP) gene localised on chromosome 4 causes
abetalipoproteinaemia and results in low or absent plasma levels of apolipoprotein B and LDL-cholesterol.[1]
[3] [6] [7] [9] [10] [11] [12] As the disorder is recessive, both copies of the gene must be faulty in order
for the disease to present clinically. Genetic mutations of apolipoprotein B gene are seen in homozygous
hypobetalipoproteinaemia but not abetalipoproteinaemia.[3]

Pathophysiology
After ingestion, lipids are processed for absorption across intestinal cells into the blood through a process
that requires a chaperone protein (microsomal triglyceride transfer protein [MTTP]) and an acceptor
protein (apolipoprotein B [apo B]).[13] MTTP transfers lipids to apo B in enterocytes and hepatocytes
and promotes the assembly of lipoproteins that transport triglyceride, cholesterol ester, and fat-soluble
vitamins. In abetalipoproteinaemia, the gene coding for MTTP is abnormal and MTTP is either absent
or non-functional. As a result, lipoprotein assembly and secretion from the intestine is defective, leading
to fat malabsorption.[14] As bowel epithelial cells are unable to place fats into transfer complexes, lipids
accumulate in the intestinal lumen, and fat malabsorption results. Additionally, lipids may accumulate in liver
cells (hepatic steatosis). Defective lipoprotein secretion from the liver results in steatosis which may progress
to cirrhosis.[15] [16] [17] [18]

Fat-soluble vitamins found in ingested foods and vitamin supplements cannot be absorbed due to the same
faulty fat-transfer process. Consequently, calorie and vitamin deficiencies lead to poor weight gain and
faltering growth.[1] Vitamin E deficiency is particularly concerning due to the consequence of demyelinisation
of the peripheral nervous system and the posterior columns of the spinal cord. Neurological, muscular, and
ocular abnormalities result.[2] [3] [19]

Case history
Case history #1
A 4-month-old child presents with faltering growth associated with persistent foul-smelling stools. A stool
sample reveals steatorrhoea. A blood test indicates absent low-density lipoprotein (LDL) cholesterol
levels. Her parents are normocholesterolaemic.

Case history #2
A gaunt 27-year-old woman presents with progressively worsening balance and movement, and
deterioration of her vision. She reports habitually maintaining a low-fat diet to avoid diarrhoea. Blood tests

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Abetalipoproteinaemia Theory
reveal absent LDL cholesterol levels, a prolonged partial thromboplastin time, and low blood tocopherol
(vitamin E) levels.

THEORY

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 Abetalipoproteinaemia Diagnosis

Approach
Diagnosis is challenging as the disorder is rarely seen in clinical practice. Careful assessment of physical
signs and symptoms, with family history, are helpful, but laboratory and genetic analysis are essential for
definitive diagnosis.

History and physical examination

Patients typically are referred to a paediatrician following a visit to their primary care physician, as initial
signs and symptoms often are displayed in the first few months of life. Parents are phenotypically normal.
The diagnosis may still be unknown in other family members because heterozygous loss of microsomal
triglyceride transfer protein (MTTP) is tolerated with sufficient function from the wild type allele.

Parents will often note foul-smelling stools and a history of vomiting or abdominal distension. Regular
assessment of the patient's stool consistency, odour, and frequency are essential for diagnosis. Suspicion
of the diagnosis should arise if the child is displaying faltering growth or developmental delay on routine
growth charts (height, weight, head circumference).[1] [2]

If the disease is missed and the patient is older, more concerning and progressive symptoms may have
evolved, reflecting the deficiency of nutrients, fat-soluble vitamins, and free fatty acids.[2] Neurological
manifestations are due to vitamin A and E deficiencies and include peripheral neuropathy, movement
disorders, and ocular disorders such as ophthalmoplegia and retinitis pigmentosa.[1] [2] [5] Both central
and peripheral nervous systems are affected with patients having either upper or lower motor neuron
findings.[6] Patients can present with cerebellar dysfunction (e.g., ataxia, dysarthria, dysmetria), as well
as compromise of posterior column function with loss of proprioception and deep tendon reflexes.[2]
[21] The patient or family members may note poor vision, night blindness, ataxia, dysmetria, muscle
contractions, dysarthria, and muscle weakness.[2] [19] Atypical pigmentary retinopathy with bilateral optic
disc swelling has been reported.[22] Symptomatic neuromuscular problems are seen in approximately
one third of untreated patients by age 10 years; ataxia generally develops later. Additionally, if anaemia
has developed secondary to malnutrition, patients may complain of fatigue and may appear pale.
DIAGNOSIS

Hepatomegaly from hepatic steatosis may be present.[2]

The definitive diagnosis is likely to be obtained in the sub-specialist setting due to increased awareness
of the disease and familiarity with necessary testing. Referral to an ophthalmologist, a neurologist, and
a gastroenterologist is recommended. An ophthalmologist may find signs of retinal inflammation on
examination.[23]

Laboratory assessment
The initial work-up typically includes stool sampling, a blood smear, and a fasting lipid panel; however,
none of these tests are confirmatory. Due to the rarity of this disease, a genetics test is not usually done
initially but is necessary for diagnosis.

Tests to aid/confirm diagnosis include the following.

• A fasting lipid panel shows very low or absent levels of plasma triglycerides, total cholesterol, very
low-density lipoprotein, and low-density lipoprotein, and the absence of apolipoprotein B (apo B).[1]
• Vitamin A, E, and K levels should also be performed early, as low levels will help confirm diagnosis.
(Vitamin D is activated on the skin by ultraviolet rays from endogenously produced metabolites, but
levels may still be subnormal). Vitamin E levels are typically undetectable.

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Abetalipoproteinaemia Diagnosis
• A blood smear shows anaemia and acanthocytes (red blood cells with a star-like appearance).[2]
[24]
• Additionally, a stool sample shows increased fat composition.
• Liver transamininases may be elevated.[2]
• Clotting tests may display an increased partial thromboplastin time and iron studies may display low
iron.
• An intestinal biopsy is unnecessary for diagnosis; however, it may have been performed in the
process of identifying this rare diagnosis. The results may show a characteristic appearance of
villus tips with a lacy appearance and lipid droplets within enterocytes.
• The definitive diagnostic test is assessment of MTTP and requires a lipid disorders or genetic sub-
specialty laboratory.
• Genetic testing for mutations, deletions, or insertions in MTTP gene associated with
abetalipoproteinaemia confirms the diagnosis in a subject suspected to be affected.[7]
[10] The apolipoprotein B (apo B) gene should also be screened as homozygous familial
hypobetalipoproteinaemia can give a similar biochemical and clinical phenotype to
abetalipoproteinaemia.[7]

Other tests
If the disease has progressed, direct and indirect ophthalmoscopy by an ophthalmologist may identify
retinal degeneration.[23] If the patient begins showing neurological signs of damage, such as ataxia
or intention tremor, a neurologist may perform electrodiagnostic studies.[2] Evoked potentials may
display abnormal somatosensory conduction velocity. Conduction velocity may be slowed with
decreased amplitude of sensory potentials. Evidence of peripheral nerve demyelination may appear on
electromyelogram.[6]

History and exam

Other diagnostic factors

DIAGNOSIS
age 0 to 12 years (common)
• Patients typically present in infancy and childhood with faltering growth and malabsorption. If
presenting later in life, patients endure progressive neurological deterioration.[2]

steatorrhoea/diarrhoea (common)
• Often found in infancy and is usually pronounced, with foul-smelling stools that contain chunks of fat
and blood.[2]

low weight (common)

• Often found in infancy and childhood. The malabsorption and diarrhoea lead to faltering growth.[1]

muscle weakness (common)

• Often found in patients with progressive disease.[2] [19]

muscle contractions (common)

• Patients can have either upper or lower motor neuron findings or both.[2] [6] Often found in patients
with progressive disease. May lead to kyphoscoliosis.[19]

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 Abetalipoproteinaemia Diagnosis
loss of deep tendon reflexes (common)
• May be an early clinical sign.[19]

ataxia (common)
• Vitamin E deficiency culminates in spinocerebellar degeneration with ataxia. This generally develops in
the second decade if there has been no intervention.[2]

dysmetria (common)
• Vitamin E deficiency results in a compromise of posterior column function with loss of
proprioception.[2] [19] Often found in patients with progressive disease.
• Poor coordination resulting in over- or under-shooting the intended position of the hand, arm, leg,
or eye. On neurological examination, altered position and vibration senses and altered pinprick and
temperature sensations are found.

dysarthria (common)
• Vitamin E deficiency results in cerebellar dysfunction.[2] [19] Often found in patients with progressive
disease.

night blindness (common)

• Often reported as the first symptom of retinal degeneration.[2]

poor eyesight (common)

• Complete loss of vision can ultimately occur.[19]

ophthalmoplegia (common)
• Often found in patients with progressive disease. Presumably develops as a result of demyelination of
cranial nerves due to the vitamin E deficiency.[2]

fatigue (common)
• If anaemia has developed as a consequence of deficiencies of iron, folate, and other nutrients
DIAGNOSIS

secondary to fat malabsorption.[19]

pale skin (common)

• If anaemia has developed as a consequence of deficiencies of iron, folate, and other nutrients
secondary to fat malabsorption.[19]

optic disc swelling (uncommon)

• Atypical pigmentary retinopathy with bilateral optic disc swelling has been reported.[22]

hepatomegaly (uncommon)
• Hepatic steatosis may be present; in rare cases liver disease may progress to cirrhosis requiring liver
transplantation.[15] [17] [18]

Risk factors
Strong

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Abetalipoproteinaemia Diagnosis
genetic
• Patients with parents or other family members who are carriers for abetalipoproteinaemia are at
increased risk.[2]

consanguineous parents
• Abetalipoproteinaemia is inherited in a recessive pattern. As such, there is a higher frequency of this
disorder in populations with a high incidence of consanguineous marriages.[2] [20]

Investigations
1st test to order

Test Result
fasting lipid panel total cholesterol: <0.78
mmol/L (<30 mg/dL);
• Key to a clinical diagnosis for abetalipoproteinaemia.[1]
triglycerides: <0.34 mmol/
L (<30 mg/dL); low or
absent VLDL; absent LDL
and apolipoprotein B (apo
B) levels

vitamin A, D, E, K blood levels low or absent

• Vitamin D is activated on the skin by ultraviolet rays from
endogenously produced metabolites but levels may still be
subnormal.
blood smear contracted, dense, or
irregular acanthocytes
• Acanthocytosis or abnormal RBC morphology results from this
condition.[2] [24]
apo B and MTTP genetic testing abnormal MTTP or apo B
gene
• Genetic testing for mutations in microsomal triglyceride transfer

DIAGNOSIS
protein (MTTP) gene associated with abetalipoproteinaemia
confirms the diagnosis in a patient suspected to be affected. Over 30
variants in MTTP associated with abetalipoproteinaemia have been
described.[7]
• The apolipoprotein B (apo B) gene should also be screened as
homozygous familial hypobetalipoproteinaemia can give a similar
biochemical and clinical phenotype to abetalipoproteinaemia.[7]

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 Abetalipoproteinaemia Diagnosis

Other tests to consider

Test Result
stool smear increased fat
• Lack of MTTP facilitated lipidation of chylomicrons in the small
intestine causes lipid accumulation in enterocytes with associated
malabsorption, steatorrhoea, and diarrhoea.[1]
(aPTT) PTT may be prolonged
• A consequence of abetalipoproteinaemia is deficiency of fat-soluble
vitamins. Vitamin K deficiency can lead to a significant bleeding
diathesis.[1]
serum iron levels may be decreased
• Iron deficiency secondary to malabsorption.[1]
liver transaminases may be elevated
• Hepatic involvement includes steatosis and elevated serum
transaminase levels.[2]
intestinal biopsy villus tips with lacy
• Not necessary for diagnosis, but is often performed to identify causes appearance; lipid
droplets within
of fat malabsorption.
enterocytes; yellowish
discoloration of mucosa
(increased lipid content);
lack of apolipoprotein B
on immunofluorescence

direct or indirect ophthalmoscope retinal degeneration

• Not necessary for diagnosis, but may be found upon ophthalmologist
referral in progressive disease.[23]
electromyelogram evidence of peripheral
nerve demyelination
• Not necessary for diagnosis, but may be found upon neurologist
DIAGNOSIS

referral in progressive disease.

• Determines whether the neuropathy is primarily axonal or
demyelinating.
evoked potential electrodiagnostic test abnormal somatosensory
conduction velocity
• Not necessary for diagnosis, but may be found upon neurologist
referral in progressive disease.
nerve conduction study conduction velocity may
be#slowed with decreased
• Not necessary for diagnosis, but may be found upon neurologist
amplitude of sensory
referral in progressive disease.
potentials

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Abetalipoproteinaemia Diagnosis

Differentials

Condition Differentiating signs / Differentiating tests

symptoms
Coeliac disease • Family history of coeliac • Diagnosis is suggested by
disease or personal history positive immunoglobulin
of other autoimmune A tissue transglutaminase
diseases. Very similar serology, but must be
presentation of non-specific confirmed by duodenal
symptoms. Abdominal biopsy and histology.
pain, nausea or vomiting,
bloating, or excess
intestinal gas common in
coeliac disease. Gluten
intolerance is not present in
abetalipoproteinaemia.[4]

Crohn's disease • Both patient groups present • Ileocolonoscopy with

with a chronic course; biopsies should be
however, diarrhoea occurs performed in the assessment
with painful bouts in of suspected Crohn's
Crohn's disease, whereas disease.
abetalipoproteinaemia
is painless. Additionally,
patients with Crohn's
disease rarely present in
infancy.

Ulcerative colitis • Both patient groups present • Colonoscopy with biopsy

with a chronic course; helps differentiate ulcerative
however, diarrhoea occurs colitis.
with painful bouts in
ulcerative colitis, whereas
abetalipoproteinaemia

DIAGNOSIS
is painless. Additionally,
patients with ulcerative colitis
disease rarely present in
infancy.

Viral gastroenteritis • Abetalipoproteinaemia • Usually a clinical diagnosis.

is chronic while viral Responds to oral rehydration
gastroenteritis is time-limited therapy.
and occurs with fever.

Child abuse • Child abuse is generally • In child abuse, radiological

manifested by faltering studies may show multiple
growth without steatorrhoea healed fractures or
or ocular signs and suspicious spiral fractures.
symptoms.

Homozygotic • Hepatic steatosis, • In HHBL, the patient's

hypobetalipoproteinaemia while seen in both parents will have low plasma
(HHBL) abetalipoproteinaemia LDL and low apolipoprotein
and HHBL, seems to be B (apo B) levels.[7]
somewhat more prevalent in
patients with HHBL.[2]

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 Abetalipoproteinaemia Diagnosis

Condition Differentiating signs / Differentiating tests

symptoms
• The heterozygous parent of • Genetic testing shows
a patient with HHBL typically mutations in the apo B
has a reduced serum gene.[3]
cholesterol concentration
but is otherwise generally
normal with no signs or
symptoms.[7]
DIAGNOSIS

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Abetalipoproteinaemia Management

Approach
The goal for any patient is early treatment with dietary changes and vitamin supplementation to stave
off end-stage disease sequelae. Treatment is aided by referral to a gastroenterologist, a neurologist, an
ophthalmologist, and a dietician. Of note, due to the rarity of this disease, treatment studies are limited to
case report interventions.

General approach for all patients

All treatments may be initiated simultaneously. Patients must establish adequate caloric dietary intake
with a low-fat diet consisting of <20% fat from total calories (5-20 g fat per day). Referral to a nutritionist
may be advisable at this point. Long-chain triglycerides should be eliminated in favour of medium-chain
triglycerides. If fats are ingested, medium-chain triglycerides are least toxic, but still should be limited as
they may cause liver damage as well. A low-fat diet should be coupled with dietary supplementation of
essential fatty acids and fat-soluble vitamins, including vitamin A, (high-dose) vitamin E, vitamin D, and
vitamin K to prevent vitamin deficiency and its consequences of neurological deterioration.[1] [2] [7]

Vitamin K treats associated coagulopathy, vitamin A treats night blindness, and early vitamin E
supplementation can prevent or delay neurological manifestations and retinopathy. Vitamin E can, in
rare cases, reverse neurological and retinal sequelae. There are no significant side effects from this
intervention.

Vitamin D may be administered as well, but can be satisfied by non-dietary sources, such as sunlight from
outdoor exposure. Ultraviolet rays activate endogenously produced metabolites, producing vitamin D.
Supplementation may be given to individuals of all ages and incurs no risk of toxicity.

Iron, folate, or vitamin B12 (cyanocobalamin) supplementation may be necessary to reverse signs of
anaemia.[25]

Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

Ongoing ( summary )
all patients

1st dietary treatment + vitamin/mineral

supplementation
MANAGEMENT

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 Abetalipoproteinaemia Management

Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

Ongoing
all patients

1st dietary treatment + vitamin/mineral

supplementation
Primary options

» alpha tocopherol: (vitamin E) 100-300

international units/kg/day orally

OR

» vitamin A: (retinol) 100-400 international

units/kg/day orally

OR

» phytomenadione: (vitamin K1) 5-35 mg/

week orally

OR

» colecalciferol: (vitamin D3) 800-1200

international units/day orally

OR

» ferrous sulfate: 50-100 mg orally three

times daily

OR

» folic acid: (vitamin B9) 0.4 to 1 mg orally

once daily

OR

» cyanocobalamin: (vitamin B12) 1000

micrograms subcutaneously/intramuscularly
once daily for 1 week, followed by 1000
micrograms once weekly for 1 month, then
1000 micrograms once monthly thereafter

» The treatment goal for all patients is to

MANAGEMENT

maximise caloric intake and prevent the

sequelae of neuromuscular deterioration that
results from fat-soluble vitamin deficiency,
specifically from vitamin E (alpha-tocopherol).[1]
[2] [7]

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Abetalipoproteinaemia Management

Ongoing
» In addition to vitamin and mineral
supplements, the patient should begin a low-fat
diet consisting of <20% fat from total calories
(5-20 g fat per day). If fat is ingested, medium-
chain triglycerides are least toxic. However,
limitation of any fats is most favourable. A
diet containing essential fatty acids, found in
safflower oil, is recommended. No significant
complications arise from this intervention.

» Vitamin D (colecalciferol) can be given, but this

is not critical because it can also be activated on
the skin by ultraviolet rays from endogenously
produced metabolites; hence, requirements
in adults seem to be satisfied by non-dietary
sources. However, a supplement can be given
to individuals of all ages and incurs no risk of
toxicity, thus no need for monitoring.

» Iron, folate, or vitamin B12 (cyanocobalamin)

supplementation may be necessary to reverse
signs of anaemia.[25] Folic acid can be given,
though evidence for or against supplementation
is lacking. It can be taken indefinitely as it is non-
toxic.

Patient discussions
Patients should be strongly advised to adhere to their nutritional regimen.

MANAGEMENT

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 Abetalipoproteinaemia Follow up

Monitoring
Monitoring
FOLLOW UP

Depending on the severity of disease progression at diagnosis, the patient may require minor follow-up or
assessment by multiple specialists. If diagnosed early, the patient's nutritional status should be monitored
on a regular basis to ensure adequate growth and development.[1] [2] Regular weights and blood tests to
monitor vitamin levels (i.e., vitamin E, A, D, and K) are recommended.[21] If vitamin D supplementation is
given in the usual amount, there is no risk of toxicity, thus no need for monitoring.

If the disease has progressed, in addition to nutritional, laboratory, and weight assessments, referral to
an ophthalmologist is recommended with periodical evaluation for evidence of visual impairment.[21]
Additionally, a referral to a neurologist is advisable for assessment for disease progression exhibited
in the peripheral nervous system. If severe neuropathy has developed, the patient may benefit from
assessment by a gait disorder clinic and follow-up physiotherapy. A gastroenterologist referral may be
warranted, depending on disease progression. Serum transaminases should be monitored yearly. Hepatic
ultrasound should be monitored every 3 years for patients aged 10 years or older.[2]

Complications

Complications Timeframe Likelihood

retinitis pigmentosa long term high

Due to late diagnosis, patients may describe night blindness and poor vision, which are symptoms of
retinitis, a disease sequelae. Dietary supplementation is warranted to prevent worsening disease. Referral
to an ophthalmologist for assessment and treatment is necessary. Vitamin E can, in rare cases, reverse
neurological and retinal sequelae.

spinocerebellar disorder long term high

If undiagnosed and untreated, cerebellar and spinal cord degeneration may occur. Symptoms may include
ataxia and spasticity. Referral to a neurologist is essential, with physiotherapy evaluation and treatment as
well. Dietary supplementation is warranted. Vitamin E can, in rare cases, reverse neurological and retinal
sequelae.

hepatic complications long term low

In rare cases liver disease may progress to cirrhosis requiring liver transplantation.[15] [17] [18]

Prognosis

If initiated early in disease, treatment may rarely reverse neurological sequelae and prevent further
deterioration.[1] [2]

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Abetalipoproteinaemia Guidelines

Diagnostic guidelines

United Kingdom

Faltering growth: recognition and management of faltering growth in children

(ht tps://www.nice.org.uk/guidance/ng75)
Published by: National Institute for Health and Care Excellence (NICE) Last published: 2017

International

Child growth standards (ht tps://www.who.int/tools/child-growth-standards/

standards)
Published by: World Health Organization Last published: 2022

GUIDELINES
North America

The toddler who is falling off the growth chart (ht tps://cps.ca/en/documents)
Published by: Canadian Paediatric Society Last published: 2012 (re-
affirmed 2020)

Treatment guidelines

North America

Vitamin E: fact sheet for health professionals (ht tps://ods.od.nih.gov/

factsheets/VitaminE-HealthProfessional)
Published by: National Institutes of Health Office of Dietary Last published: 2021
Supplements

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 Abetalipoproteinaemia References

Key articles
• Shapiro MD, Feingold KR. Monogenic disorders causing hypobetalipoproteinemia. In: Feingold KR,
REFERENCES

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Contributors:

// Authors:

Nicholas Davidson, MD, DSc

Professor of Medicine
Washington University School of Medicine, Saint Louis, MO
DISCLOSURES: ND declares that he has no competing interests.

// Acknowledgements:
Professor Nicholas Davidson would like to gratefully acknowledge Professor David Leaf for his contribution
to this topic.
DISCLOSURES: DL declares that he has no competing interests.

// Peer Reviewers:

David Muller, PhD

Emeritus Professor of Biochemistry
UCL Institute of Child Health, London, UK
DISCLOSURES: DM is a co-author of an article referenced in this topic. He has previously received
research funding from F Hoffmann-La Roche and Co Ltd for research studies on vitamin E.

Katherine Wu, MD
Associate Professor of Medicine
Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD
DISCLOSURES: KW declares that she has no competing interests.