Peroxisomal diseases are a group of inherited metabolic disorders caused by abnormalities in the formation of peroxisomes, which are intracellular organelles responsible for fatty acid metabolism and amino acid synthesis, leading to systemic symptoms primarily affecting the nervous system.
They are classified into 15 diseases, including the most common adrenoleukodystrophy and the most severe Zellweger syndrome. All follow an autosomal recessive inheritance pattern and are designated as intractable diseases.
Zellweger syndrome (cerebrohepatorenal syndrome) was first reported by Bowen et al. in 1964. The incidence varies greatly by region: 1 in 50,000 in the United States, 1 in 12,000 in Quebec, and 1 in 500,000 in Japan.
The following four disease types are representative of those with ocular symptoms.
Zellweger syndrome: Most severe, with onset early after birth
Neonatal adrenoleukodystrophy: Milder than Zellweger syndrome
Refsum disease: caused by deficiency of phytanic acid metabolism enzyme
Rhizomelic chondrodysplasia punctata: characterized by limb shortening and punctate calcification of joints
QWhat types of peroxisomal diseases are there?
A
There are 15 classified diseases, but the representative types with ocular symptoms are Zellweger syndrome, neonatal adrenoleukodystrophy, Refsum disease, and rhizomelic chondrodysplasia punctata. The most common is adrenoleukodystrophy, and the most severe is Zellweger syndrome.
Ocular symptoms of peroxisomal diseases vary greatly depending on the disease type.
Night blindness: This is the most common initial symptom in Refsum disease. Patients notice decreased vision in dark places due to retinitis pigmentosa. It may go unnoticed in childhood.
Vision loss: Occurs with progression of retinitis pigmentosa or onset of cataracts. In Zellweger syndrome, severe visual impairment is present from infancy.
Visual field constriction: As retinitis pigmentosa progresses, the peripheral visual field is affected first.
In Zellweger syndrome, ophthalmological findings common to all peroxisomal diseases include pigmentary retinopathy, retinal arteriolar narrowing, optic atrophy, and extinguished electroretinogram. Zellweger syndrome is additionally characterized by corneal opacity, glaucoma, and cataracts.
Zou et al. (2024) reported a case of a 4-year-old girl with a homozygous mutation (c.2528G>A, p.Gly843Asp) in the PEX1 gene 1). Visual acuity was 5/80 in both eyes, with esotropia, sensory cyclotorsional vertical nystagmus, and hyperopic astigmatism. Ultra-widefield fundus photography revealed pale optic disc halos, arteriolar narrowing, diminished foveal reflex, and coarse pigment clumps in the periphery. OCT showed thickening and splitting/edema of the outer retinal layers.
QWhat are the ocular symptoms of Refsum disease?
A
In Refsum disease, retinitis pigmentosa is invariably present, and many cases present with night blindness. Fluorescein angiography shows a characteristic patchy block of background fluorescence. Electroretinography reveals early amplitude reduction. Adult-onset Refsum disease typically begins around age 20 and is accompanied by cerebellar ataxia and polyneuropathy in addition to retinitis pigmentosa2).
Peroxisomal diseases are caused by mutations in genes involved in peroxisome formation and function. Peroxisomes are abundant in the liver, kidneys, and oligodendrocytes, and they break down hydrogen peroxide, uric acid, amino acids, and fatty acids through oxidation reactions.
PEX gene mutations: Mutations in any of the 14 PEX genes cause peroxisome biogenesis disorders. PEX1 mutations account for 70% of all cases1)
Refsum disease: Deficiency of phytanic-CoA hydroxylase (phyH) leads to increased blood phytanic acid. Age of onset ranges from 7 months to 50 years, and the timing and severity of onset do not necessarily correlate.
Peroxisomal dysfunction leads to the following metabolic abnormalities.
Accumulation of very long-chain fatty acids (VLCFA): due to impaired β-oxidation
Decreased plasmalogen: Reduction of lipids important for myelin synthesis
Accumulation of phytanic acid and pipecolic acid: Due to impaired degradation pathways
Accumulation of bile acid intermediates: Due to abnormalities in bile acid synthesis pathway
The effect on the retina is due to impaired endogenous synthesis of docosahexaenoic acid (DHA). DHA is essential for brain and retinal development and function, and its deficiency causes retinal dystrophy 1).
Symptoms such as facial abnormalities, hypotonia, and hepatomegaly are present from birth, but general biochemical tests often do not detect abnormalities.
Differential diagnoses of retinitis pigmentosa include adult-onset Refsum disease, which is caused by a deficiency of phytanoyl-CoA oxidase localized in peroxisomes and typically presents around age 202). Infantile Refsum disease is a peroxisomal biogenesis disorder that manifests in infancy, is accompanied by nystagmus, and often leads to death in early childhood2).
Cataract surgery: Performed to maintain visual acuity
Refractive correction: Prescription of glasses for refractive errors
Treatment for macular edema: Dorzolamide eye drops and intravitreal dexamethasone injection (Ozurdex 0.7mg) have been attempted1)
In the case reported by Zou et al. (2024), for severe macular edema, dorzolamide eye drops twice daily were initially started, but as edema progressed, it was switched to bilateral intravitreal dexamethasone 0.7mg implant (Ozurdex) injections1). Improvement in macular edema and visual acuity was achieved, with final best-corrected visual acuity reaching 20/125 in both eyes. Thereafter, repeated injections every 6 months are continued.
Refsum disease: Dietary therapy with a phytanic acid-restricted diet (avoidance of whole-fat dairy products, high-fat meat products from ruminants, and fatty fish)
Liver dysfunction: Supplementation of vitamin K and other fat-soluble vitamins. Cholic acid (Cholbam) replacement therapy to reduce C27 bile acid intermediates
Seizures: Antiepileptic drug treatment by an experienced neurologist
Peroxisomes are intracellular organelles present in almost all cells. They are most abundant in the liver, kidneys, and oligodendrocytes. Their main functions are as follows:
Beta-oxidation of fatty acids: Degradation of very long-chain fatty acids
Synthesis of plasmalogens: Major components of myelin sheaths
Bile acid and cholesterol synthesis
Decomposition of hydrogen peroxide: detoxification by catalase
Peroxisome biogenesis disorders (PBD) are a group of diseases in which peroxisome formation and maintenance are impaired due to mutations in any of the 14 PEX genes. PEX1 mutations are the most common, accounting for 70% of all cases1).
The main cause of retinal damage is impaired endogenous synthesis of DHA (docosahexaenoic acid)1). DHA is essential as a structural lipid in the outer segments of retinal photoreceptors, and its deficiency leads to structural and functional abnormalities of photoreceptors.
Histologically, the following changes have been confirmed1).
Loss of photoreceptors: Progressive degeneration of rods and cones
Pigment dispersion: Migration of pigment within the retina
Optic disc pallor and hypoplasia
Narrowing of retinal arterioles
Mutations in the PRPH2 gene (peripherin 2) may also be involved 1). Peripherin 2 is a photoreceptor-specific glycoprotein essential for the normal formation of rod and cone outer segments. Its mutations are associated with macular degeneration, neuroretinal degeneration, RPE atrophy, and choroidal defects.
7. Latest Research and Future Prospects (Investigational Reports)
The possibility of gene augmentation therapy using adeno-associated virus 9 (AAV9) for patients with PBD-ZSS has been reported 1). Research is underway aiming to restore peroxisome function by introducing a normal copy of the PEX1 gene.
Cell-type transplantation is also being considered as a future treatment option for patients with PBD-ZSS 1). Studies are ongoing to replace degenerated retinal cells and nerve cells.
These treatments are all at the basic research or preclinical stage, and further verification of safety and efficacy is needed for clinical application.
Zou H, Sutherland L, Geddie B. Pigmentary retinal dystrophy associated with peroxisome biogenesis disorder-Zellweger syndrome spectrum. Oxf Med Case Reports. 2024;2024(6):263-265.
日本眼科学会. 網膜色素変性診療ガイドライン.
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