Occult Macular Dystrophy

Key points at a glance

Highlights of this disease

• Occult macular dystrophy (OMD) is a hereditary macular dystrophy in which central vision progressively declines despite normal fundus findings.
• Also called Miyake disease, first reported by Miyake in 1989.
• The main causative gene is RP1L1, and autosomal dominant inheritance is most common.
• Routine fundus examination, fluorescein angiography, and full-field electroretinography are all normal, so it is easily overlooked.
• The key to diagnosis is focal macular electroretinography or multifocal electroretinography (mfERG), which detects reduced macular response.
• No effective treatment currently exists; low vision care is the mainstay.
• Visual loss progresses slowly over 10–15 years and rarely leads to severe visual impairment.

1. What is Occult Macular Dystrophy?

Occult macular dystrophy (OMD) is a hereditary macular dystrophy characterized by progressive central vision loss despite normal fundus findings. It was first reported by Miyake in 1989 and is also called Miyake disease after the discoverer.

The causative gene is RP1L1 (retinitis pigmentosa 1-like 1). The most common inheritance pattern is autosomal dominant, but autosomal recessive and sporadic cases have also been reported. RP1L1 mutations show incomplete penetrance ¹⁾. Detectable genetic causes are identified in only about 50% of patients.

The most common mutation is c.133C>T (p.Arg45Trp). Age of onset ranges widely from 10 to 70 years, with an average of 25–30 years ¹⁾. Previously thought to be more common in East Asian patients, reports in Swiss and German individuals suggest possible underdiagnosis in other ethnic groups ¹⁾.

It is one of the macular dystrophies, alongside vitelliform macular dystrophy (Best disease), Stargardt disease, and central areolar choroidal dystrophy.

Q Are Miyake disease and occult macular dystrophy the same disease?

A

They are the same disease. It is also called Miyake disease after the discoverer. OMD with autosomal dominant inheritance due to RP1L1 mutation is sometimes specifically called RP1L1-associated OMD (Miyake disease).

2. Main Symptoms and Clinical Findings

Subjective Symptoms

The main symptom is slowly progressive bilateral vision loss. The rate of progression varies greatly among individuals.

• Vision loss: At the initial visit, best-corrected visual acuity is often around 0.1 to 0.5 in both eyes. In the largest case series, mean visual acuity was 20/80 (equivalent to 0.25).
• Central scotoma and metamorphopsia: Visual field testing shows decreased sensitivity in the central area. Metamorphopsia may also be present. However, dynamic perimetry may fail to detect abnormalities.
• Photophobia: About 50% of patients experience photophobia during the course of the disease, but only a few report it at the initial visit.
• No night blindness: Peripheral retinal function is preserved, so there is no vision impairment in the dark. This is an important distinguishing feature from retinitis pigmentosa.

Clinical Findings

As the name of this disease suggests, routine fundus examination reveals no abnormalities.

• Fundus examination: Ophthalmoscopically completely normal. However, in certain RP1L1 mutations, mild granular changes of the RPE may be observed in the macula ¹⁾.
• Fluorescein angiography (FA): Usually normal.
• Fundus autofluorescence (FAF): Normal in most cases, but may show mild hyperautofluorescence at the fovea.
• OCT: Plays an important role in diagnosis. Findings include blurring/discontinuity of the ellipsoid zone (EZ) and loss of the interdigitation zone (IZ) at the fovea. Severe cases may show thinning of the outer nuclear layer (ONL), but the retinal pigment epithelium (RPE) is preserved. In some patients, the EZ may appear thickened and dome-shaped.

In a study by Nakamura et al., three clinical stages based on photoreceptor structure on OCT have been proposed.

Zabek et al. (2022) reported a case of OMD in a 34-year-old Swiss man ¹⁾. BCVA was 20/125 in the right eye and 20/160 in the left eye. OCT showed EZ discontinuity and ONL thinning, and FAF was nearly normal with only mild mottling.

The Concept of RP1L1 Maculopathy

When OMD progresses and obvious macular findings (such as vitelliform lesions or geographic atrophy) are observed on fundus examination, it is sometimes called “RP1L1 maculopathy” ²⁾. This term refers to a phenotype that is no longer “occult” (hidden).

3. Causes and Risk Factors

The main cause of OMD is a mutation in the RP1L1 gene.

• Inheritance pattern: Autosomal dominant is most common. Autosomal recessive and sporadic cases have also been reported.
• Major mutation: c.133C>T (p.Arg45Trp) is the most common.
• Incomplete penetrance: Some individuals within the same family carry the mutation but remain asymptomatic ¹⁾.
• Gene detection rate: Only about 50% of OMD patients have a detectable genetic cause identified.

The RP1L1 gene encodes a component of the axoneme (central structure of the cilium) of the photoreceptor outer segment and is thought to be involved in maintaining the structure and function of the outer segment ²⁾. RP1L1 is expressed in both rods and cones.

RP1L1 mutations are known to be associated not only with OMD but also with autosomal recessive retinitis pigmentosa and cone dystrophy ²⁾.

Prevention and Daily Care

Since OMD is a genetic disorder, prevention through lifestyle changes is difficult. If you have unexplained vision loss, see an ophthalmologist early. If there is a family history, consider genetic counseling. Due to autosomal dominant inheritance (with incomplete penetrance), some family members who carry the mutation may not develop the disease. It is recommended to consult a genetic counselor about the genetic risk for future generations.

Q Can genetic testing sometimes fail to find a mutation?

A

Only about 50% of OMD patients have a detectable gene mutation. There may be unidentified causative genes other than RP1L1. It is important to confirm the diagnosis through a combination of clinical findings and electrophysiological tests.

4. Diagnosis and Testing Methods

OMD is difficult to diagnose because routine eye examinations often fail to detect abnormalities. This disease should be considered when there is unexplained bilateral vision loss.

The characteristics of the main testing methods are shown below.

Test method	Findings in OMD	Diagnostic significance
Full-field electroretinogram	Completely normal	Useful for exclusion
Focal electroretinogram/mfERG	Marked reduction in macular response	Key to diagnosis
OCT	EZ blurring, IZ loss	Useful for structural evaluation

• Full-field electroretinogram: Both rod and cone responses are completely normal. Because peripheral retinal cone and rod function is preserved, this disease cannot be detected by full-field ERG alone. This “normal full-field ERG” is the most characteristic feature of this disease and provides a basis for excluding widespread retinal diseases such as retinitis pigmentosa.
• Focal macular electroretinogram / multifocal electroretinogram (mfERG): This is the key test for diagnosing this disease. Only the macular response is markedly reduced. mfERG can classify three functional phenotypes: parafoveal dysfunction, uniform central dysfunction, and widespread dysfunction. The dissociation of normal full-field ERG and abnormal mfERG is essential for a definitive diagnosis.
• OCT: Spectral-domain OCT detects blurring/discontinuity of the EZ and loss of the IZ. In severe cases, thinning of the ONL is observed.
• Visual field testing: May detect decreased sensitivity in the central area, but the degree is mild, and dynamic perimetry may be normal.
• Fundus examination and fluorescein angiography: Completely normal.
• Genetic testing: Detection of RP1L1 mutation is useful for confirming the diagnosis. However, mutations are detected in only about 50% of patients.

Differential Diagnosis

In patients with normal fundus and decreased visual acuity, the following conditions should be differentiated.

• Cone dystrophy: Photophobia and color vision abnormalities are prominent, and it is distinguished by reduced cone responses on full-field electroretinography.
• Early ABCA4-related retinopathy (Stargardt disease): Often shows abnormalities (e.g., dark choroid) on fundus autofluorescence or fluorescein angiography.
• Optic neuropathy: Differentiated by abnormalities in visual evoked potentials (VEP) or the presence of a relative afferent pupillary defect (RAPD).
• Amblyopia: Diagnosed based on history and visual development history.
• Psychogenic visual disturbance: Excluded if objective retinal dysfunction is demonstrated by electrophysiological testing. The combination of normal full-field ERG and abnormal mfERG is key for differentiation.
• Early Best disease (vitelliform macular dystrophy): Abnormal EOG is an indicator for differentiation. In OMD, EOG is normal.
• Central serous chorioretinopathy (CSC): Can be differentiated by fluorescein leakage on fluorescein angiography.

Q Why is no abnormality found on routine fundus examination?

A

In OMD, functional impairment of photoreceptors (especially cones) is localized to the macula and is not accompanied by structural changes visible with an ophthalmoscope in the early stages. OCT can detect subtle abnormalities in the outer retinal layers, and electrophysiological testing objectively demonstrates reduced macular function.

5. Standard Treatment

Currently, there is no effective treatment for OMD.

The mainstay of treatment is low vision care, which includes the following measures:

• Prescription of visual aids: Prescribe low vision aids such as magnifiers and loupes.
• Genetic counseling: Since autosomal dominant inheritance is common, providing information and genetic counseling to families is important.
• Regular follow-up: Monitor functional and structural changes using OCT and mfERG.

Precautions in treatment

• Currently, there is no evidence-based drug therapy or surgical treatment for OMD.
• If misdiagnosed as another macular disease, unnecessary treatment interventions (such as anti-VEGF injections) may be performed. Accurate diagnosis is important.

Q How much does vision decrease?

A

In many patients, vision gradually declines over 10 to 15 years and then tends to stabilize. Severe visual impairment is rare, and many patients maintain visual acuity of 0.1 or better in at least one eye even in old age.

6. Pathophysiology and detailed pathogenesis

The RP1L1 gene encodes a component of the axoneme (central structure of the cilium) of the photoreceptor outer segment ²⁾. Although its exact function is not fully understood, it is suggested to be involved in maintaining the structure and function of the photoreceptor outer segment.

In early or mild cases, cone cells are affected first. In advanced cases, rod function in the macula is also affected. It is unclear why this disease primarily affects the fovea and does not cause more widespread cone dysfunction.

OMD (typical type)

Fundus findings: Normal

OCT findings: Indistinct EZ, absent IZ

Inheritance: Mainly autosomal dominant

Visual acuity: Slowly decreasing

RP1L1 Maculopathy

Fundus findings: Vitelliform lesions or geographic atrophy

OCT findings: EZ/IZ thickening, subretinal deposits

Inheritance: Dominant or recessive

Course: Repeated enlargement and regression

The phenotypic spectrum of RP1L1 mutations is broad. In addition to typical OMD (normal fundus), phenotypes with obvious fundus abnormalities such as vitelliform lesions and geographic atrophy have been reported as RP1L1 maculopathy²⁾.

Amato & Yang (2025) followed an 8-year-old boy with a homozygous RP1L1 mutation (c.831del) for 5 years, observing progression from EZ/IZ thickening to vitelliform lesions and partial absorption²⁾. At age 13, BCVA was good at 20/20, but microperimetry showed mild macular dysfunction.

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7. Latest Research and Future Perspectives (Investigational Reports)

For patients: Please read carefully

The following information is currently at the research stage or under clinical trial and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Potential for Gene Therapy

OMD is attracting attention as a future target for gene therapy. Unlike many other inherited retinal degenerations, OMD patients often develop symptoms in adulthood, do not have amblyopia, and the progression is slow and predictable. Therefore, it is considered to have a wide therapeutic window¹⁾.

However, the rarity of the disease and the insufficient understanding of the function of the RP1L1 gene are major challenges in the development of gene therapy¹⁾.

Expanding the Phenotypic Spectrum

In recent years, it has been reported that the phenotypes caused by RP1L1 mutations are expanding beyond the traditional scope of OMD²⁾. The presence of phenotypes that do not fit the conventional definition of OMD, such as vitelliform lesions and geographic atrophy, further complicates the understanding of RP1L1 function and disease mechanisms.

It has also been suggested that mutational load (the burden of mutations in multiple genes) may be involved in incomplete penetrance and variability in age of onset²⁾. In the future, large-scale genotype-phenotype correlation studies are expected to improve the accuracy of prognosis prediction.

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8. References

1. Zabek O, Lamprakis I, Rickmann A, et al. Rare occult macular dystrophy with a pathogenic variant in the RP1L1 gene in a patient of Swiss descent. Am J Ophthalmol Case Rep. 2022;26:101527.
2. Amato A, Yang P. Evolution of vitelliform maculopathy in a pediatric patient with a homozygous RP1L1 variant. Am J Ophthalmol Case Rep. 2025;38:102305.
3. Toland A. Case Report: Occult Macular Dystrophy. Optom Vis Sci. 2022;99(4):405-412. PMID: 35001063.