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Please note that we are a research service provider, not a pharmacy or clinic, so we are unable to see patients and do not offer diagnostic and treatment services for individuals.

Refsum Disease

Refsum disease is an uncommon, autosomal recessive peroxisomal biogenesis disorder marked by the impaired alpha-oxidative metabolism of the branched-chain fatty acid, phytanic acid. Protheragen provides complete research service packages to assist in creating new and effective diagnostics and therapeutics for Refsum disease.

Overview of Refsum Disease

Refsum disease is a rare disorder with an autosomal recessive pattern that occurs due to the accumulation of phytanic acid, a branched-chain fatty acid, because of the defects in its catabolic pathway. This leads to a myriad of phytanic acid accumulation symptoms such as retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and cardiomyopathy. The main cause of this disorder is mutations in the PHYH gene, which is responsible for encoding the enzyme phytanoyl-CoA hydroxylase, or in the PEX7 gene, which is associated with the peroxisomal import of the enzyme.

Graph illustrating the frequency of adult refsum disease (ARD) symptoms at diagnosis and survey submission.

Fig. 1 The frequency of adult Refsum disease (ARD) symptoms at diagnosis and survey submission. (Li J. J., et al., 2023)

Pathogenesis of Refsum Disease

The pathogenesis of Refsum disease is largely due to the altered metabolism of phytanic acid, which is obtained from the diet, like dairy products and meats from ruminants or derived from the metabolism of chlorophyll in plants. In normal people, phytanic acid is metabolized in the peroxisomes by a series of enzyme-catalyzed steps, and one of the primary steps is carried out by phytanoyl-CoA hydroxylase (PAHX). Phyh mutations result in loss of this enzyme so that phytanic acid accumulates in tissues and plasma. Moreover, mutations in the gene PEX7, which encodes the receptor for PAHX in peroxisomes, also cause deficient metabolism of phytanic acid. The excess accumulation of phytanic acid is thought to be neurotoxic and interfere with the indispensable fatty acid metabolism, thus causing the symptoms of Refsum disease.

Diagnostics Development for Refsum Disease

Biochemical Analysis
Refsum disease can be diagnosed through biochemical examination of pumps phytanic acid level in a patient's plasma. Phytanic acid concentration is a hallmark of the disease as it is characteristically 50 to 150 times raised above the average. The technique employs sample collection from patients, wherein blood is extracted, and gas chromatography-mass spectrometry (GC-MS) is employed for phytanic acid quantification. The technique's sensitivity and specificity are remarkable and allow for prompt detection of the illness.

Genetic Testing
Examining the genetic profile of the PHYH and PEX7 genes is a very useful diagnostic tool. The NGS techniques allow for the detection of particular mutations within these genes, which in turn provides a molecular validation of the ailment. This technique is most helpful for those cases that present with unusual manifestations or when the analysis of their biochemistry does not yield clear results. Genetic testing also enables the screening for carriers and diagnosis before birth, thus aiding families to make appropriate choices.

Therapeutics Development for Refsum Disease

Enzyme Replacement Therapy

Enzyme replacement therapy (ERT) appears to be a developing therapeutic option for Refsum disease. This technique is based on giving phytanoyl-CoA hydroxylase to restore normal phytanic acid metabolism. Results from preclinical studies have been encouraging in that significant reductions in angiopathic acid were noticed along with improvement in symptoms. Further work is required regarding the method of delivery and for the evaluation of continuation and termination of efficacy and safety.

Gene Therapy

Gene therapy is one more elegant option for Refsum disease. It entails supplying the relevant cells with functioning PHYH or PEX7 genes through either viral or non-viral means. Preclinical trials have shown that correcting the gene defect through gene therapy is achievable and normal phytanic acid metabolism can be restored. Still, effective gene delivery and off-target complications present as hurdles that must be overcome.

Our Services

Protheragen provides extensive services focused on diagnostic and therapeutic development for Refsum disease. The capabilities of our diagnostics include biochemical tests, genetic assessments, and histopathological studies, which enable accurate and reliable diagnosis. We also specialize in the development of innovative therapeutic approaches, including enzyme replacement therapy and gene therapy, leveraging cutting-edge technologies and rigorous preclinical research.

Diagnostics Development

Therapeutic Development

Disease Models

Patient-Derived Fibroblasts
Induced Pluripotent Stem Cells (iPSCs)
PhyH Knockout Mice
PEX7 Knockout Mice
PhyH Knockout Zebrafish

Protheragen's preclinical research services are designed to support the development of novel diagnostics and therapeutics for Refsum disease. Our state-of-the-art facilities and experienced scientific team provide a robust platform for conducting comprehensive preclinical studies. If you are interested in our services, please feel free to contact us.

Reference

Li, Jeffrey J., Jane J. Kim, and Fauzia Nausheen. "Phytanic acid intake and lifestyle modifications on quality of life in individuals with adult Refsum disease: a retrospective survey analysis." Nutrients 15.11 (2023): 2551.