Refsum Disease via the PHYH Gene

Refsum disease, also known as adult Refsum disease (ARD), is usually late childhood onset. The first set of clinical symptoms includes anosmia, night blindness, and progressive retinitis pigmentosa. Other symptoms may occur in the following 10-15 years, including peripheral neuropathy, nerve deafness, cerebellar ataxia, ichthyosis, and skeletal dysplasia. Premature death is often due to cardiac arrhythmias. Unexplained remission has been observed in some patients. 90% of ARD cases are caused by PHYH mutations which lead to a peroxisomal single enzyme defect that results from deficiency of phytanoyl-CoA hydroxylase. The remaining 10% of all reported ARD patients are due to defects in PEX7, which is a peroxisome biogenesis disorder. For patients with PHYH mutations, the elevated phytanic acid in plasma and deficiency of phytanoyl-CoA hydroxylase enzyme activity are the diagnostic biochemical markers. Elevated pipecolic acid levels were found in about 20% of patients. Plasmalogen synthesis and VLCFA metabolism are normal. Elevated phytanic acid is thought to be toxic and also related to phenotypic variation. A phytanic acid restricted diet has been found to be effective treatment especially for children (Wanders et al. 2010; Jansen et al. 2004; Mihalik et al. 1997).

Refsum disease is inherited in an autosomal recessive manner. The PHYH gene encodes phytanoyl-CoA hydroxylase, which is a key enzyme for α-oxidation of branched-chain lipids. PHYH mutations have been found in more than 90% of individuals with Refsum disease. Reported PHYH mutations are loss-of-function variants including missense, nonsense, splicing site mutations, small deletion/insertions and a gross deletion. No clear phenotype-genotype correlation has been observed (Jansen et al. 2004).

PHYH mutations are the major cause for Refsum disease and were found in more than 90% of patients (Wanders et al. 2010; Jansen et al. 2004).

Clinical sensitivity for del/dup testing is expected to be low. Only one gross deletion affecting PHYH exons 5-6 has been reported so far (Chahal et al. 1998).

This test provides full coverage of all coding exons of the PHYH gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).