Stratz Syndrome

Key Points at a Glance

Key Points of This Disease

• Straatsma syndrome is a rare congenital syndrome characterized by the triad of myelinated retinal nerve fibers (MRNF), axial myopia, and amblyopia.
• First reported in 1979, MRNF is found in approximately 1% of the general population.
• The extent and distribution of MRNF (Types 1–3) correlate with the severity of myopia and amblyopia.
• The effect of amblyopia treatment (refractive correction + occlusion therapy) is limited, and many cases are treatment-resistant.
• The pathogenesis is thought to involve oligodendrocytes invading the retina due to an underdeveloped barrier function of the lamina cribrosa.
• Whole-genome sequencing (WGS) has for the first time shown an association with the transcription factor RUNX2.

1. What is Straatsma syndrome?

Straatsma syndrome is a rare congenital eye disease characterized by the triad of myelinated retinal nerve fibers (MRNF), axial myopia, and amblyopia. It was first reported by Straatsma et al. in 1979¹⁾.

MRNF is a condition in which myelination, which is normally blocked at the lamina cribrosa, extends into the retinal nerve fiber layer. It is found in approximately 1% of the general population^{1, 2)}, and in most cases it is an isolated, asymptomatic finding. However, when extensive, it can be accompanied by axial myopia and amblyopia, forming Straatsma syndrome.

Historically, Virchow first described the presence of myelinated nerve fibers in 1856²⁾, and subsequent research has clarified the relationship between the distribution and extent of MRNF and clinical outcomes.

MRNF

Myelinated retinal nerve fibers: A condition in which myelination, which normally does not extend beyond the optic disc, invades the retina.

Observed in the fundus as white, linear or feathery patches.

Axial myopia

Axial myopia: A refractive error due to elongation of the axial length of the eye.

The greater the extent of MRNF, the stronger the tendency toward myopia.

Amblyopia

Amblyopia: A developmental impairment of visual acuity during the sensitive period of visual development.

It tends to be treatment-resistant, and the prognosis needs to be carefully evaluated.

Q Does MRNF always cause a syndrome?

A

MRNF is present in about 1% of the general population, but most cases are isolated asymptomatic findings ^{1, 2)}. When it is extensive or involves the peripapillary or macular area, it is associated with axial myopia or amblyopia and is diagnosed as Straatsma syndrome.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

• Decreased visual acuity: Mainly due to amblyopia. Corrected visual acuity is reduced, and simple refractive correction does not improve vision.
• Myopia: Develops as axial myopia and may progress from early childhood.
• May be asymptomatic: When MRNF is confined to the periphery, subjective symptoms are absent.

Clinical Findings

Fundus examination reveals characteristic white linear or feathery opacities around the optic disc or in the peripheral retina ¹⁾.

The extent and morphology of MRNF vary by case and are classified into the following three types ¹⁾.

Classification of MRNF (according to Karakosta 2022) is shown.

Classification	Features	Myopia/Amblyopia
Type 1	Isolated/localized	Mild or none
Type 2	Extends around the optic disc	Moderate
Type 3	Extensive, involving the macula	Severe, treatment-resistant

On OCT (optical coherence tomography), marked thickening of the retinal nerve fiber layer (RNFL) is observed at the MRNF site. There is a significant difference in RNFL thickness compared to the healthy eye ²⁾.

Q Is Straatsma syndrome usually unilateral?

A

MRNF is often unilateral, and Straatsma syndrome also frequently presents with prominent findings in one eye ¹⁾. Bilateral cases have been reported, but when evaluating unilateral amblyopia, comparison with the contralateral eye is essential.

3. Causes and Risk Factors

The etiology of Straatsma syndrome lies in the underdevelopment of the myelination barrier at the lamina cribrosa.

Normally, retinal nerve fibers remain unmyelinated as they pass through the lamina cribrosa. If this barrier fails, oligodendrocytes (myelin-producing cells) are thought to invade the retina, causing myelination of nerve fibers ²⁾.

As a genetic background, whole-genome sequencing (WGS) analysis has suggested an association with the transcription factor RUNX2 gene ²⁾. RUNX2 is known to be involved not only in bone and cartilage differentiation but also in the development of the nervous system.

Precautions in daily life

• If diagnosed with Strabismus syndrome, continue regular ophthalmology visits.
• In children undergoing amblyopia treatment, maintaining adherence to occlusion therapy affects visual prognosis.
• Monitor the progression of myopia and obtain appropriate prescription for glasses or contact lenses.

4. Diagnosis and examination methods

The diagnosis of Strabismus syndrome is based on clinical diagnosis by the combination of the characteristic triad.

Fundus examination

Direct observation of white feathery lesions (MRNF) spreading around the optic disc to the retina under dilated fundus examination ¹⁾. The extent and distribution of lesions are evaluated as Type 1 to 3.

OCT examination

Quantitative evaluation of RNFL thickening at MRNF sites ²⁾. It is useful for confirming differences between the affected and healthy eyes and for tracking changes over time. The peripapillary RNFL thickness map allows objective assessment of lesion spread.

Refraction and visual acuity tests

Cycloplegic refraction (e.g., with cyclopentolate eye drops) evaluates the degree of axial myopia. The difference between corrected and uncorrected visual acuity determines the severity of amblyopia. In young children, preferential looking tests (e.g., Teller acuity cards) are used.

Q What are the diagnostic criteria for amblyopia?

A

Amblyopia is diagnosed when corrected visual acuity is below the age norm, or when the interocular visual acuity difference is two lines or more. In Strabismus syndrome, both refractive and anisometropic amblyopia may be involved.

5. Standard Treatment

Refractive Correction

Full correction with glasses or contact lenses for axial myopia is the first step in treatment ^{1, 3)}. To minimize the impact of amblyopia on visual development, early and appropriate refractive correction is recommended.

Occlusion Therapy (Patching the Healthy Eye)

This treatment involves covering the healthy eye to increase visual stimulation to the amblyopic eye ^{1, 3)}. It is a standard method for amblyopia treatment and is also recommended in the AAO Amblyopia PPP (2024) ³⁾.

The choice of occlusion duration and method (full-time vs. partial occlusion) is determined based on the severity of amblyopia and the patient’s age. Optical occlusion with atropine eye drops is also an option ⁴⁾.

Treatment Resistance

Amblyopia in straatsma syndrome tends to be more treatment-resistant than typical amblyopia ¹⁾. When MRNF extensively involves the macula (Type 3), the visual prognosis is particularly poor.

Differences in outcomes among patients are shown below.

Feature	Good Prognosis	Poor Prognosis
Extent of MRNF	Localized (Type 1-2)	Extensive (Type 3)
Start of treatment	Early within the sensitive period	Delayed

Refractive correction

Full correction glasses: Correct axial myopia and promote clear image formation on the retina.

Foundation of amblyopia treatment. Early initiation within the sensitive period is important.

Occlusion therapy

Occlusion of the healthy eye: Forces use of the amblyopic eye to promote visual development.

Full-time occlusion or atropine eye drops are chosen. Adherence determines prognosis.

Follow-up

Regular visual acuity assessment: Continuously monitor treatment effect.

The sensitive period for visual development (until around 8-10 years of age) is particularly important.

Precautions in treatment

• Amblyopia in Strabismus syndrome is often treatment-resistant ¹⁾. Early aggressive treatment is important, but effects may be limited.
• Excessive occlusion therapy (amblyopia of the healthy eye) requires caution.
• After the sensitive period, the effectiveness of amblyopia treatment decreases significantly.

Q How long should amblyopia treatment be continued?

A

The sensitive period for amblyopia treatment is generally considered to be up to around 8–10 years of age ⁴⁾. Early treatment should be continued to achieve visual improvement within this period. In Strabismus syndrome, treatment resistance is common, requiring long-term follow-up and evaluation ¹⁾.

6. Pathophysiology and Detailed Mechanisms

Developmental Background of Myelination

In a normal eye, the axons of retinal ganglion cells remain unmyelinated as they pass through the lamina cribrosa. The lamina cribrosa is a structure composed of glial cells and collagen fibers, and it acts as a barrier that physically and biochemically prevents oligodendrocytes, which are responsible for myelination, from entering the retina.

If this barrier is congenitally nonfunctional, oligodendrocytes can invade the retina and cause myelination of nerve fibers ²⁾. This results in white, feathery MRNF.

Effects on Photoreceptors in the Macula

In extensive MRNF, disruption of the ellipsoid zone (EZ), located between the cone and rod cells in the macula, is observed ¹⁾. The EZ corresponds to the area where mitochondria are densely packed in photoreceptors, and its disruption suggests impairment of photoreceptor function. This is considered the organic basis of severe amblyopia in Type 3 cases with macular involvement.

Genetic Findings

WGS analysis has suggested that mutations in the transcription factor RUNX2 may be involved in the development of MRNF ²⁾. RUNX2 is originally known as a transcription factor involved in skeletal development, but it also plays a role in the differentiation of glial and neuronal cells. It has been hypothesized that functional abnormalities of RUNX2 impair the barrier formation of the lamina cribrosa, promoting the invasion of oligodendrocytes into the retina ²⁾.

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7. Latest Research and Future Perspectives (Research-stage Reports)

For patients: Please read this

The following content 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.

First Application of Whole Genome Sequencing (WGS)

Sills et al. (2024) applied WGS for the first time to MRNF cases and reported an association with the transcription factor RUNX2 ²⁾. WGS detected mutations that could not be identified by conventional candidate gene approaches, opening new avenues for elucidating the genetic background of MRNF.

The RUNX2 mutation identified by WGS is thought to promote oligodendrocyte invasion of the retina through impaired cribriform plate formation ²⁾. This finding is expected to be applied to future genetic counseling and targeted therapy development.

Q Is genetic analysis by WGS currently performed in clinical practice?

A

At present, it is still at the research stage, and its implementation in general clinical practice is limited ²⁾. The diagnosis and treatment of Stargardt syndrome are still based on clinical evaluation (fundus examination, OCT, visual acuity testing). Further elucidation of the pathogenesis is expected with advances in genetic research.

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8. References

1. Karakosta A, et al. Straatsma syndrome: case series, classification, and outcomes. Ophthalmology. 2022.
2. Sills C, et al. Whole genome sequencing in myelinated retinal nerve fibers: first application and RUNX2 association. Invest Ophthalmol Vis Sci. 2024.
3. American Academy of Ophthalmology. Amblyopia Preferred Practice Pattern. 2024.
4. Meier K, Tarczy-Hornoch K. Amblyopia treatment: a review. Ophthalmology. 2024.