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Identification of novel pathogenic variants in the PHYH gene and extending the phenotypic range in Refsum disease
Cheryl Y Gregory-Evans1,2, Anna Lehman2, Andre Mattman3
1Departments of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada.
Insights
Genetic testing identified novel variants in PHYH and PHYN, confirming Refsum disease in two patients with inherited retinal dystrophy. Early diagnosis and dietary changes are crucial for managing Refsum disease complications.
Area of Science:
- Ophthalmology
- Medical Genetics
- Metabolic Disorders
Background:
- Inherited retinal dystrophies (IRDs) encompass a group of genetic disorders affecting vision.
- Refsum disease is a rare metabolic disorder characterized by the accumulation of phytanic acid.
- Ocular manifestations are common in Refsum disease, but specific associations with macular dystrophy are less understood.
Purpose of the Study:
- To investigate the genetic basis of suspected inherited retinal dystrophy in two patients.
- To identify novel genetic variants associated with retinal disease.
- To establish a potential link between macular dystrophy and Refsum disease.
Main Methods:
- Ophthalmological examination and referral for genetic testing.
- Molecular genetic analysis to identify pathogenic variants in relevant genes.
- Biochemical testing to measure phytanic acid levels for Refsum disease diagnosis.
Main Results:
- Patient 1 (P1) presented with retinitis pigmentosa and was found to have novel pathogenic variants in PHYH.
- Patient 2 (P2) presented with macular pigmentary changes and had novel variants in PHYN.
- Both patients exhibited elevated phytanic acid levels, confirming Refsum disease, and shared systemic features.
Conclusions:
- This study reports, for the first time, an association between macular dystrophy and Refsum disease.
- Genetic identification of variants in PHYH and PHYN contributes to understanding the genetic landscape of IRDs.
- Early diagnosis of Refsum disease allows for dietary modification to improve prognosis, though visual recovery may be limited.
Purpose:
Two patients with a suspected inherited retinal dystrophy (IRD) were referred to a specialist ophthalmology clinic for genetic testing to determine the cause of their disease.
Case Report:
A 50-year-old female patient (P1) presented with retinitis pigmentosa and poor vision since childhood. Molecular genetic testing in P1 revealed two novel pathogenic variants in PHYH (NM_006214.4): p.(Val93*) and p.(Asn71Ilefs*23). A 57-year-old male patient (P2) presented with pigmentary changes at the macula. Molecular genetic testing in P2 revealed two novel variants in PHYN: p.(Phe183Ser) and c.2461G>C (splice acceptor). Both patients were referred to the metabolic disease clinic and phytanic acid levels were found to be 256 µg/mL in P1 (normal is < 3 µg/mL) and 48.2 µmol/L in P2 (normal is < 2.2 µmol/L) confirming the diagnosis of Refsum disease. Both patients shared systemic features of the disease including bilaterally abnormal metatarsals and dry skin, while P1 also had characteristic anosmia, kidney disease, peripheral neuropathy and mild hearing impairment.
Conclusion:
We document for the first time an association between macular dystrophy and Refsum disease. Early diagnosis is important so that diet can be modified to improve prognosis for the complications associated with Refsum disease, although improvements in vision, slowing the retinal degeneration and overcoming refractory miosis, are less achievable.
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