Introduction

Chanarin-Dorfman Syndrome (CDS) is a rare disorder that is inherited from both parents, also known as autosomal recessive inheritance.¹ It is a lipid storage disease, which means that it leads to the buildup of fatty materials in cells and tissues, affecting the way they function.² In CDS, these lipids are accumulating in neutrophils. This can lead to the following:³

• Lamellar Ichthyosis, which is the accumulation of dry and scaly skin
• Ectropion eyelids, lower eyelid droops and is slightly inverted
• Hepatomegaly, enlarged liver
• Cataracts, cloudy eye lens, causing blurred vision
• Hearing loss
• Short stature
• Myopathy, muscle weakness
• Intellectual disabilities

Therefore, as it affects multiple different parts of the body, including cognitive and developmental issues, it is characterised as a multiple-organ dysfunction syndrome.

Currently, there have been 150 cases reported worldwide, predominantly in the Mediterranean and West Asia (commonly known as the Middle East).⁴

Biological mechanism

1. Genetic mutation¹⁴
   • A mutation occurs in the ABHD5 gene.
2. Lack of protein¹⁵ 
   • This leads to a lack of the CGI-58 protein. 
3. Inactivation of an enzyme¹⁴
   • This protein is crucial for activating the enzyme adipose triglyceride lipase (ATGL), which breaks down any stored fats for energy. 
4. Lipid build-up¹⁴
   • As the stored fats are not being broken down and moved around the body, this means that they build up.
5. Lipid droplets¹⁴ 
   • As the fats build up in cells, they form what is known as lipid droplets. 
6. Body effects¹⁴
   • These lipid droplets build up in tissues such as the liver, muscle, blood cells, skin, and central nervous system. 
   • Specifically for cognitive impairment in CDS patients, these lipid droplets are found in the cerebral white matter, cortex and basal ganglia⁶

Understanding cognitive impairment

What is cognitive impairment?

Cognitive impairment is a medical term referring to problems with:⁵

• Memory 
• Understanding 
• Reasoning 
• Organising 
• Problem-solving
• Decision-making 
• Attention 
• Visual-spatial skills
• Speech and language

Cognitive impairment can range from mild to severe.⁶ Mild impairments mean that the individual can do day-to-day activities, whereas severe cognitive impairment is when an individual is incapable of living alone. 

Cognitive impairment in CDS  

Cognitive impairment in CDS has not been commonly described.⁷ These cases only show mild intellectual disability and mental retardation; severe cases are very rare.⁸ It has been noted that in some patients lipid accumulation can occur in the cerebral white matter, cortex and basal ganglia.⁷ Accumulation of lipids in the cerebral cortex can affect memory; this also occurs in patients with Alzheimer's.⁹ However, there is not enough research on large groups of individuals with lipid storage diseases, let alone CDS, to confirm memory loss as a symptom.¹⁰

Additionally, due to the common symptoms of hearing loss and visual problems, this could lead to further issues in cognitive development and educational progress, leading to developmental delays. 

Understanding developmental delay

What is a developmental delay?

Children reach milestones in playing, learning, speaking, behaving, and moving.¹² These different milestones are reached at different rates. Some children have developmental delays such as:

• Thinking skills
• Social and emotional skills
• Speech and language skills
• Muscle coordination

A delay can be isolated, meaning that it can affect only one area of development. Children with CDS tend to show developmental delays.

Features of developmental delay in CDS

Common symptoms of CDS that may cause developmental delay:¹¹

• Ataxia, problems with coordination, speech and balance
• Myopathic gait affects- problems with the way you walk
• Behavioural disturbances, such as anxiety and depression
• Cataracts and hearing loss- which can affect sensory input and communication skills

Additionally, diminished growth rate has also been reported. Therefore, patients with CDS tend to have a short stature.¹³

Other neurological disorder features in CDS patients¹¹

• Nystagmus, which is the involuntary movement of the eye
• Areflexia, problems with sudden reflexes
• Hypotonia, poor muscle strength
• Cranial nerve weakness, problems with the sensory nervous system

Diagnosis and evaluation

CDS Diagnosis 

CDS is a very rare disorder and can take up to 6 years to receive an accurate diagnosis.¹⁸ There are a few tests that need to be done before a patient can be diagnosed these include:³

1. Clinical examination
   1. Recognising any skin changes
2. Peripheral blood smear
   1. A sample of blood would be taken
   2. This blood sample is then analysed by looking at red and white blood cells and platelets 
   3. Assessing the presence of lipid droplets
3. Genetic testing 
   1. To confirm the diagnosis, a genetic test can detect the mutation in the ABHD5 gene

Radiology can occasionally be used to identify lipid droplets in the muscle or tissue. The type of screening is called magnetic resonance (MR).^{7, 17}

• MR imaging
  • This is used to identify lipid droplets in the muscle and liver
• MR spectroscopy
  • Identifying the accumulation of lipid droplets in the brain
• Ultrasound
  • Revealing any changes to the liver

Cognitive impairment diagnosis  

As cognitive impairment is not present in all CDS patients, an evaluation may be useful if any symptoms are present. There are different types of cognitive tests:¹⁶

1. Montreal Cognitive Assessment test (this takes 15 minutes)
   1. Memorising a short list of words
   2. Copy and draw shapes
   3. Identifying pictures of animals
2. Mini-Mental State Exam (this takes 10 minutes)
   1. Recognising the current date
   2. Counting backwards
   3. Identifying everyday objects
3. Mini-cog(this takes 3 minutes)
   1. Recall three objects
   2. Draw a clock showing a specific time

If your score is lower than normal, it means you may have a cognitive impairment, and the provider performing the clinical assessment may give you a diagnosis. 

Developmental delay 

Developmental delay is typically seen in CDS patients; however, it is still not seen in all.¹²

1. Developmental screening 
   1. This is seeing how your child learns, speaks, behaves and moves
   2. A questionnaire is normally given to the parent while the provider talks and plays with the child.
   3. No blood or lab tests involved
      1. In this case, as CDS would be the cause of the developmental delay, other tests would follow 

Management 

Currently, there is no specific treatment for CDS. 

However, to decrease liver enlargement, it has been suggested that patients have:¹⁷

1. Low-fat diet in fatty acids
2. Vitamin E supplements.
3. Ursodeoxycholic acid
4. Medium-chain triglycerides intake

This should be followed by a variety of therapies if needed:

1. Motor rehabilitation
2. Speech therapy
3. Special education
4. Occupational therapy

Early initiation of the treatment is important to achieve positive results and enhance developmental outcomes. 

Chance of recovery and support

Full recovery of CDS is impossible, but there are many places where you can seek support. 

Seeing multiple specialists when you have a rare disorder, such as CDS, can be effective, as having multiple doctors who specialise in different departments can lead to better care¹⁸. For this, you can visit a Multidisciplinary Care Centre. This is a collective of teachers, university and hospital researchers who are medical experts collaborating on providing diagnostic tests and knowledge for the patient.

Connecting with other patients and families with the same disorder may also be helpful. Specifically for CDS patients, the Foundation for Ichthyosis and Related Skin Types(FIRST) provides research and support for CDS patients. Connecting CDS patients and providing mental health support. 

Other services that may provide support include:

• Patient registries.
• Financial aid and travel resources.
• Up-to-date treatment and research information.

CDS life expectancy?

There is no evidence of CDS significantly reducing life expectancy. If symptoms are severe, it may affect quality of life; however, there are certain therapies and suggested dietary requirements that may help, as mentioned above.¹³

Summary 

CDS is a lipid-storage disease that causes dry and scaly skin, liver enlargement, visual and hearing problems, mobility issues, developmental problems and occasionally cognitive impairment. This multiple-organ dysfunction is caused by a mutation in the ABHD5 gene, which creates a domino effect resulting in lipid storage sites being unable to break down fat. Therefore, this leads to a build-up of lipids in cells, causing CDS. This lipid accumulation can further contribute to cognitive impairment by leading to visual and hearing problems, which can affect one's ability to learn. Additionally, it can affect the muscles, resulting in developmental delay in mobility. Not only does it affect mobility, but it can also hinder growth, as most individuals with CDS have a short stature. Although CDS cannot be cured, early intervention with certain therapies and dietary modifications can benefit developmental outcomes. Furthermore, specific foundations and care centres can provide support.