Introduction 

Chanarin-Dorfman Syndrome (CDS) is a very rare genetic disease that has widespread effects throughout the body, with the influence on liver function being particularly significant for the course of the disease.¹ It is characterised as a lipid storage disease, caused by the accumulation of lipid droplets in different cells of the body, including leukocytes, skin cells, blood cells, central nervous system cells and liver cells. 

The disease is caused by inheriting recessive mutations in the abhydrolase domain containing 5 (ABHD5 gene.¹ There are a range of mutations that are associated with this disease, and the clinical symptoms of CDS patients depend on which mutations are present, highlighting a possible genotype and phenotype correlation.¹ 

Identifying the various mutations in the ABHD5 gene and the relationship of these mutations with the different clinical symptoms seen in CDS is important to understand the course of this disease better and to develop targeted therapies. This article will give a clear overview of the genetics underlying CDS and how the different mutations of the ABHD5 gene influence the observable characteristics of CD patients. 

Genetic Basis of CDS

Approximately 78 different mutations associated with the ABHD5 gene have been identified in individuals with CDS, including splice-site changes, insertions, deletions, as well as nonsense and missense mutations.¹ 

One of the most common mutations is p.N209X, and it has been reported frequently in Turkey.¹ It was identified that around half of the people diagnosed with CDS around the world were born to intra-family marriages. Due to these types of marriages being more common in regions such as the Middle East and Turkey, the probability of inheriting these disease-causing mutations was higher, meaning the incidence of CDS was higher.¹ 

The product of the ABHD5 gene belongs to the alpha/beta-hydrolase protein group. It plays a key role in activating the enzyme adipose triglyceride lipase, which is involved in breaking down lipid (fat) molecules within cells.¹ Thus, mutations in the ABHD5 gene interfere with the function of this enzyme, leading to the build-up of lipid droplets in cells and a deficiency of fatty acid molecules within cells due to decreased lipid breakdown.¹ 

The ABHD5 protein contains multiple regions that are crucial for its function and role in lipid metabolism.² These regions include the alpha/beta-hydrolase domain, which is commonly found in enzymes that break down fats, the pseudo-catalytic domain, the HX4D motif within the hydrolase domain, along with the lipid-binding motif.² Importantly, the reported mutations in CDS affect one or more of these regions of the ABHD5 protein.² 

Phenotypes of CDS

CDS affects multiple organs in the body, with symptoms being widespread and varied among different patients. The most common symptoms of CDS include congenital ichthyosiform erythroderma, a skin disease which causes scaly skin, and fatty liver disease.¹ 

Other symptoms of CDS can include muscle weakness, enlarged spleen, hearing loss, uncontrolled eye movements, loss of coordination and possibly defects in mental and physical development. Alongside ichthyosis, which impacts the skin’s protective layer, if lipid droplets are identified inside white blood cells by microscopy, the patient can be diagnosed with CDS.¹ Thus, CDS is a disease where various health problems occur simultaneously. The specific symptoms and their onset often depends on the type of mutation present on the ABHD5 gene in different patients.¹

A summary of the multiple organ symptoms of CDS that can be seen in patients is  described as follows: 

• Skin: ichthyosis, dryness, redness
• Liver: cirrhosis, hepatomegaly and fatty liver disease
• Spleen: splenomegaly 
• Muscle: high levels of creatine kinase (associated with muscle damage), weakness
• Eyes: cataract, keratopathy, ectropion, uncontrolled eye movement
• Ears: hearing loss
• Nervous system: ataxia, intellectual disability³ 

Genotype-Phenotype Correlations

It is essential to note that the relationship between the genotype and phenotype of CDS patients cannot be easily defined.⁴ The clinical symptoms of patients with the most common N209X mutation and with the other ABHD5 mutations did not show significant differences, which undermines the genotype-phenotype correlation.⁴ It has been stated that a combination of multiple mutations across different genes is responsible for the diversity of clinical symptoms, highlighting the significance of intra-family marriage in increasing the risk of CDS.

 Despite there being a large array of clinical symptoms ranging in severity, ichthyosis and liver problems were the key elements reported in almost all cases. Since the degree of liver disease plays a significant role in determining the severity of CDS, it has been suggested that the onset of cirrhosis in patients could be related to the type of mutation in their ABHD5 gene, therefore proposing a certain genotype-phenotype correlation.⁴ 

Currently, 45 different mutations of the ABHD5 gene have been identified, with the N209X mutation being the most frequent.⁴ Another mutation was identified in a Chinese CDS patient, and the resulting clinical features were determined. The L154R mutation was reported to alter the characteristics of the ABHD5 protein, thus affecting its function in lipid metabolism in cells.⁴ 

Furthermore, mutations in the adipose triglyceride lipase (ATGL) gene are also responsible for lipid accumulation in CDS, and it was identified that patients with altered ATGL function have a higher degree of muscle disease.⁵ It was also reported that patients with ABHD5 mutations always have ichthyosis, as this is a defining feature for CDS diagnosis. In a study focusing on different mutations associated with CDS, it was observed that all of the patients with the N209X mutation presented similar clinical features. Almost all had liver problems, with cirrhosis and spleen problems in some patients. These findings can be present in both N209X and other mutations.⁵ 

Around a quarter of patients were reported to have cognitive impairments, along with a tendency to develop psychiatric disorders. Around 40% of CDS cases had eye problems, with cataracts being the most common, seen equally in N209X and non-N209X mutation groups. Hearing loss was also seen in around a quarter of patients, with no notable difference between different mutation types. Furthermore, muscle weakness and increased levels of creatine kinase were seen in similar frequencies across different mutation groups.⁵ These findings revealed no definitive genotype-phenotype correlation in CDS. 

Another study focusing on an Afghan family with consanguineous parents who had four children with CDS identified a novel nonsense mutation, causing the ABHD5 protein to be truncated (shortened).² This mutation resulted in the loss of 14 amino acids, shorterning the hydrolase domain of the protein. These changes to the protein structure n lead to serious symptoms, including early cirrhosis and severe liver disease. All of the affected children had ichthyosis from birth, but the extent of other clinical symptoms varied between siblings. One developed early liver problems, and another one had no liver disease but only skin and eye problems. All of the affected children had cataracts and other rare eye symptoms, suggesting this ABHD5 mutation could be associated with new ophthalmic findings. Overall, despite all the siblings having the same homozygous nonsense mutation, their symptoms and severity varied.² This suggests, even a single mutation can produce a range of clinical features in different people, indicating other components, such as genetic and environmental factors, could influence  the phenotype of CDS patients.^2,5 

In addition, another study also proposed that the same ABHD5 mutation, namely the homozygous ABHD5 splice-site mutation classified as the founder mutation in Tunisian island populations, can result in a wide range of phenotypes in different CDS patients.⁶ For instance, even though the patients analysed had the same mutation, their clinical symptoms and extent of organ involvement differed. Some older patients had thyroid dysfunction, while others had kidney abnormalities. Thus, besides genotype, age and environmental factors could play a significant role in determining the phenotype of CDS patients.⁶ 

Summary 

Chanarin-Dorfman Syndrome (CDS) is an extremely rare autosomal recessive condition that is genetically inherited and caused by mutations in the ABHD5 gene. These mutations interfere with the function of the ABHD5 protein, leading to problems in lipid metabolism and the accumulation of lipid molecules in cells. 

CDS has a wide range of effects on the body, including skin issues, muscle weakness, liver disease, vision and central nervous system problems. Many different mutations in the ABHD5 gene have been identified in CDS patients, with the N209X mutation being the most common. 

This disease is seen more frequently in regions of the Middle East and Turkey, where its association to consanguineous marriages has been established. 

Overall, studies indicate that the clinical symptoms of CDS patients cannot be predicted using their genotype alone. This means that currently the genotype-phenotype correlations of CDS are not well characterised, and future studies are needed to further define this relationship.