5th February 2024

Other lipid metabolism and storage disorders

Introduction

Apart from lipid metabolism disorders affecting plasma lipids, other lipid metabolism disorders affect lipoproteins, sphingolipids and others.

Syndromes affecting lipoproteins include abetalipoproteinemia.

Syndromes affecting sphingolipids include GM1 gangliosidosis, Tay-Sachs disease, Sandhoff disease, Gaucher disease, Niemann-Pick disease, Fabry disease, Batten’s disease, Zellweger syndrome and Refsum disease. There are many rare syndromes secondary to inborn errors of lipid metabolism; however, these are MRCP Part 1 favourites, as they can come up in the answer options!

Lipoprotein disorders

Abetalipoproteinemia

This is also known as Bassen-Kornzweig syndrome. A microsomal triglyceride transfer protein deficiency causes it. It is seen most commonly in the Ashkenazi Jews (Eastern Europeans) population, often inherited in an autosomal recessive fashion. 

It results in lipid malabsorption, causing fat-soluble vitamin deficiency. Fat-soluble vitamins cannot be normally put into chylomicrons for transportation from the intestine to the liver. 

Symptoms include steatorrhea, abdominal distension, failure to thrive and malnutrition. Patients may also present with spinocerebellar degeneration (ataxia, areflexia, weakness), myopathy, pigmentary retinopathy, cataracts, and pale optic disc.

The blood film will show acanthocytosis. Serum apolipoprotein B and apo-LDL levels will be absent. Treatment includes fat-soluble vitamin supplementation.

Fatty acid oxidation disorders

These are disorders caused by a lack or deficiency of enzymes needed to metabolise lipids. This leaves the body short of energy and allows breakdown products such as Acyl-CoA to accumulate. The enzyme most commonly deficient is the medium-chain acyl-CoA dehydrogenase (MCAD). Other enzyme deficiencies include:

• short-chain acyl-CoA dehydrogenase (SCAD) deficiency
• long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency
• very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency
• glutaric acidemia type II
• mitochondrial trifunctional protein (TFP) deficiency

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

It is an autosomal recessive condition that prevents the body from converting certain fats to energy, particularly during fasting or periods of acute illness. Symptoms include lethargy, hypoglycaemia, vomiting, seizures, breathing difficulties, and liver problems.

It is more common in people of northern European ancestry. It can be diagnosed through newborn screening by looking at acylcarnitine levels.

Lysosomal storage disorders

Lysosomes are cytoplasmic organelles in which various macromolecules are degraded by different acid hydrolase enzymes (lysosomal enzymes). If these enzymes are absent or have reduced activity, the macromolecules usually degraded by lysosomes will accumulate, causing abnormal storage of various compounds.

GM1 gangliosidosis

It is an autosomal recessive caused by mutations in beta-glucosidase/beta-galactosidase-1 gene) causing accumulation of GM1 ganglioside, keratan sulphate and oligosaccharides. It can be divided into three types:

• Type 1- hypotonic from birth, then spasticity, psychomotor retardation, hyperreflexia within six months, dermal melanocytosis (formerly known as Mongolian spots), skeletal dysplasia, frontal bossing, enlarged tongue, hirsutism, coarse skin, cherry red spot, corneal clouding, nystagmus, strabismus.
• Type 2- Juvenile. Associated with later onset of psychomotor deterioration.
• Type 3- Adult-onset. Associated with dystonia, speech and gait difficulties, neurodegeneration (dementia, parkinsonian, extrapyramidal disease).

Tay-Sachs disease

It is an autosomal recessive condition caused by a mutation in the hexosaminidase alpha gene, causing failure to break down GM2-ganglioside, resulting in its abnormal accumulation in the central nervous system.

Most commonly seen as its infantile form. This presents with reduced vision, cherry red spot, seizures, exaggerated startle response, gradual loss of skills and early death.

Juvenile form presents with clumsiness, incoordination, ataxia, optic atrophy and pigmentary retinopathy.

Late-onset cases are associated with neurogenic muscle atrophy, ataxia, dysarthria, dysphagia and other cognitive disorders.

Sandhoff disease

It is an autosomal recessive condition. It is associated with mutations in beta-hexosaminidase A and beta-hexosaminidase B genes. Due to the lack of these enzymes to break down fatty substances called GM2 gangliosides and globosides, accumulating those molecules causes a rapidly progressive mental and motor decline in infancy.

Symptoms include neurodegeneration, visceromegaly, cherry-red spot and macrocephaly with unique facial features.

Juvenile and adult forms present with muscle atrophy, balance problems, dystonia, autonomic neuropathy and cognitive dysfunction.

Gaucher disease

This is an autosomal recessive caused by a deficiency of glucocerebrosidase enzyme. This causes accumulation of glucocerebroside throughout the body, especially within the bone marrow, spleen and liver. Patients typically present with visceromegaly and skeletal abnormalities. Three main types of the condition exist:

• Type 1: absence of neurological complications (non-neuronopathic): most common form, thrombocytopenia, anaemia, hepatosplenomegaly, bone pain, avascular necrosis.
• Type 2: neurological complications (acute neuronopathic): occurs in newborns and infants, splenomegaly, hypotonia, spasticity, strabismus, supranuclear palsy, dysphagia, and laryngeal spasm.
• Type 3: chronic neuronopathic: neurological complications with ataxia and myoclonic seizures that develop and progress slower than in type 2, horizontal and vertical gaze palsy.

Other forms: perinatal-lethal form and cardiovascular form

Niemann-Pick

This is an autosomal recessive condition caused by mutations in the gene-producing sphingomyelinase, which converts sphingomyelin to ceramide (another type of fat). Sphingomyelin accumulates, causing cells to malfunction.

This is divided into four main types: type A, B, C1 and C2

• Type A: hepatosplenomegaly, failure to thrive, psychomotor regression, interstitial lung disease, cherry red spot, optic atrophy, do not survive past early childhood
• Type B: symptoms and signs not as severe as type A, hepatosplenomegaly, recurrent lung infections, thrombocytopenia, delayed bone age, some have a cherry red spot or neurological impairment
• Type C1 & C2: similar, only differ in genetic cause, ataxia, vertical supranuclear palsy, dystonia, interstitial lung disease, problems with speech and swallowing, progressive cognitive dysfunction

Fabry disease

This is an X-linked recessive condition caused by mutations in the alpha-galactosidase A gene, causing its deficiency and glycolipids cannot be broken down easily. 2 types exist:

• Type 1: “classic”- acroparaesthesia, angiokeratoma, anhidrosis/hypohidrosis, abdominal pain and cramping, vortex keratopathy, arrhythmias, hypertrophic cardiomyopathy, renal failure, transient ischaemic attacks and strokes.
• Type 2: “late onset”- essentially normal childhood and adolescence, present with renal and cardiac diseases in adulthood.

Batten’s disease

It is also known as neuronal ceroid lipofuscinoses. It is an autosomal recessive condition caused by abnormal accumulation of pigmented lipids, ceroid and lipofuscin within neurons, causing progressive deterioration.

Symptoms include progressive vision loss, optic atrophy, pigmentary retinopathy, seizures, neurological degeneration, clumsiness, balance and behavioural problems.

Peroxisomal disorders

Peroxisomes are cytoplasmic organelles that play a central role in the catabolism of very long-chain fatty acids and other compounds via beta-oxidation, essential in the biosynthesis of crucial cellular membrane constituents, cholesterol and bile acids. 

Zellweger’s syndrome

It is an autosomal recessive condition caused by gene mutations involved in peroxisome function.

It is considered a collective spectrum of disease, with the most severe form referred to as Zellweger syndrome. Its intermediate form is known as neonatal adrenoleukodystrophy, and infantile Refsum disease is milder.

• Symptoms: neurological deficits, progressive liver and renal dysfunction, optic nerve hypoplasia, pigmentary retinopathy, hypotonia, developmental delay, failure to thrive, flat brows

Refsum’s disease

It is an autosomal recessive condition. It is caused by a mutation in the gene that transports phytanoyl-CoA hydroxylase enzymes into peroxisomal compartments. Phytanic acid cannot be broken down and accumulates in the cell. Patients usually develop normally, and symptoms start at 10-20 years old, including nyctalopia, retinitis pigmentosa, cerebellar ataxia, anosmia, ichthyosis, and hearing impairment.

Diagnosis is made with raised phytanic acid in blood, low pristanic acid and molecular genetic diagnosis.

Treatment is done by minimising intake of phytanic acid and plasmapheresis.

References

National Institute of Neurological Disorders and Stroke. (2023). Lipid storage diseases. National Institute of Neurological Disorders and Stroke. Retrieved Mar 26, 2023, from https://www.ninds.nih.gov/health-information/disorders/lipid-storage-diseases