Severe Early Childhood Onset Retinal Dystrophy

Severe Early Childhood Onset Retinal Dystrophy (SECORD) is a rare, inherited eye disorder that causes severe vision problems starting in infancy or early childhood. Children with SECORD are typically born with severe night blindness and significantly reduced overall vision. They may also have nystagmus, which is involuntary, rapid eye movements. While their vision is poor from a very young age, it is usually better than that of children with a similar but more severe condition called Leber congenital amaurosis (LCA). SECORD is a progressive disease, meaning vision gets worse over time. The condition affects the retina, the light-sensitive tissue at the back of the eye, causing its cells to slowly break down. Children with SECORD often have enough vision to attend regular schools during their early years, especially in bright light. However, as they grow older, their side (peripheral) vision narrows, and their central vision continues to decline. Most people with SECORD become legally blind by the time they reach their 20s or 30s. Because SECORD is a genetic condition, it is passed down through families. It can be caused by changes (mutations) in many different genes. Knowing the specific gene involved is very important because it can help predict how the disease might progress and determine if the patient is eligible for certain new treatments, such as gene therapy. Families affected by SECORD should work closely with an eye specialist and a genetic counselor to understand the condition and explore available support and treatment options.

Condition category: Retinal Dystrophy

Prevalence: Unknown (Rare disease, exact prevalence hard to predict due to overlap with LCA)

Inheritance patterns: Autosomal Recessive (most common), Autosomal Dominant, X-Linked

Age of onset: Childhood, Infancy (typically first year of life to early childhood)

Clinical overview: Severe early childhood onset retinal dystrophy (SECORD) is a severe, progressive inherited retinal dystrophy that falls on the phenotypic spectrum between Leber congenital amaurosis (LCA) and early-onset retinitis pigmentosa. It is characterized by severe congenital night blindness, nystagmus, significantly reduced visual acuity (typically ≤ 0.3), and a progressive panretinal dystrophy that includes macular involvement. The onset of symptoms typically occurs during infancy or early childhood, distinguishing it from the congenital or early infantile onset of LCA. Clinically, SECORD overlaps significantly with LCA, particularly regarding the genetic etiology, as mutations in many of the same genes can cause either phenotype. However, SECORD is differentiated by better residual visual function in the early stages of the disease and the presence of small but detectable electroretinogram (ERG) signals, particularly for the lesser-affected photoreceptor system, whereas LCA typically presents with an undetectable or severely abnormal ERG from birth. The fundus may appear normal at birth but progressively develops signs of panretinal dystrophy, including pigmentary changes, vascular attenuation, and macular alterations. The specific clinical features and the rate of progression can vary widely depending on the underlying genetic mutation. Despite the relatively better initial visual function compared to LCA, SECORD is a progressive condition that ultimately leads to severe visual impairment or complete blindness, typically by the second or third decade of life.

Patient and family guide: Severe Early Childhood Onset Retinal Dystrophy (SECORD) is a rare, inherited eye disorder that causes severe vision problems starting in infancy or early childhood. Children with SECORD are typically born with severe night blindness and significantly reduced overall vision. They may also have nystagmus, which is involuntary, rapid eye movements. While their vision is poor from a very young age, it is usually better than that of children with a similar but more severe condition called Leber congenital amaurosis (LCA). SECORD is a progressive disease, meaning vision gets worse over time. The condition affects the retina, the light-sensitive tissue at the back of the eye, causing its cells to slowly break down. Children with SECORD often have enough vision to attend regular schools during their early years, especially in bright light. However, as they grow older, their side (peripheral) vision narrows, and their central vision continues to decline. Most people with SECORD become legally blind by the time they reach their 20s or 30s. Because SECORD is a genetic condition, it is passed down through families. It can be caused by changes (mutations) in many different genes. Knowing the specific gene involved is very important because it can help predict how the disease might progress and determine if the patient is eligible for certain new treatments, such as gene therapy. Families affected by SECORD should work closely with an eye specialist and a genetic counselor to understand the condition and explore available support and treatment options.

Symptoms and clinical features: The hallmark symptoms of SECORD include severe congenital night blindness (nyctalopia) and significantly reduced visual acuity (typically ≤ 0.3) that is noticeable in the first year of life or early childhood. Nystagmus (involuntary, rapid eye movements) is also a common early sign. Color vision is typically impaired. Unlike Leber congenital amaurosis, infants with SECORD may have better initial visual function, allowing them to navigate and function in bright light environments during their early years. However, the condition is progressive. Patients experience a gradual loss of peripheral vision, leading to severe visual field constriction (tunnel vision), and a progressive decline in central visual acuity. The rate of progression varies, but it typically leads to complete blindness by the second or third decade of life.

Molecular pathology: SECORD is genetically highly heterogeneous, caused by mutations in numerous genes that are also associated with Leber congenital amaurosis (LCA) and other inherited retinal dystrophies. The most frequently implicated genes include RPE65 (accounting for 2-10% of SECORD patients) and LRAT. Other associated genes include ABCA4, ADAMTS18, AIPL1, BEST1, CRB1, CRX, GUCY2D, IMPDH1, IMPG1, IMPG2, IQCB1, KCNJ13, LCA5, MERTK, NMNAT1, RDH12, RPGR, RPGRIP1, SPATA7, and TULP1. These genes encode proteins with diverse and critical functions in the retina and retinal pigment epithelium (RPE). For example, RPE65 and LRAT are essential enzymes in the visual cycle, responsible for regenerating the visual pigment chromophore (11-cis-retinal) after light exposure. Mutations in these genes lead to a severe deficiency of 11-cis-retinal, causing profound dysfunction of rod and cone photoreceptors and eventual retinal degeneration. Other genes are involved in phototransduction (e.g., GUCY2D), photoreceptor structure and development (e.g., CRX, CRB1), or ciliary function. The molecular mechanism of disease depends on the specific gene mutated. In cases involving visual cycle defects (like RPE65), the primary issue is a biochemical block preventing photoreceptors from responding to light, which secondarily leads to structural degeneration over time. In contrast, mutations in structural or developmental genes may cause primary photoreceptor death or abnormal retinal formation. This genetic diversity explains the phenotypic variability observed in SECORD patients.

Genetics: SECORD is usually inherited in an autosomal recessive manner, meaning an individual must inherit two mutated copies of the responsible gene (one from each parent) to develop the condition. However, autosomal dominant inheritance (where only one mutated copy is needed) has been observed for mutations in specific genes such as CRX, GUCY2D, IMPDH1, IMPG1, and IMPG2. X-linked inheritance has also been reported in some cases. Because of the genetic heterogeneity, genetic counseling is highly recommended for affected individuals and their families. The specific inheritance pattern, recurrence risk for future pregnancies, and implications for other family members depend entirely on the specific gene involved. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known. Penetrance is generally complete, but expressivity can vary even among family members with the same mutation.

Diagnostic evaluation: Diagnosis of SECORD includes rod and cone responses below or near threshold in electroretinography (ERG). Psychophysical testing predicts cone-rod and rod-cone dystrophies. Patients may show a normal appearing fundus at birth but develop a panretinal dystrophy including the macula later in infancy and early childhood. Corresponding alterations of retinal layers are seen with spectral domain optical coherence tomography (OCT). A lack of fundus autofluorescence is observed from early childhood in a subset of patients with RPE65 or LRAT mutations. Goldmann perimetry reveals severe visual field constriction and central scotomata depending on the type of progression. Bone spicules are usually not detected but pigment accumulations develop with the progress of the disease. Molecular diagnosis is performed by using next generation sequencing panel covering the whole sequence of the known reported genes (90% cases). Identified mutations and segregation analysis in the parents is confirmed by Sanger sequencing.

Differential diagnosis: Leber congenital amaurosis (LCA), Alström syndrome, autosomal recessive bestrophinopathy, Bardet-Biedl syndrome, achromatopsia, Stargardt disease, Usher syndrome, Senior-Loken syndrome, Saldino-Mainzer syndrome, Joubert syndrome, abetalipoproteinemia, infantile Refsum disease, neonatal adrenoleukodystrophy, Zellweger syndrome, juvenile neuronal ceroid lipofuscinosis

Natural history: SECORD presents in early childhood, typically after infancy but before age 5. Patients initially experience severe congenital night blindness and significantly reduced visual acuity (usually ≤ 0.3). Unlike Leber congenital amaurosis (LCA), visual function in SECORD is better preserved early on, allowing attendance at regular schools during elementary years. However, the condition is characterized by a progressive panretinal dystrophy. Visual acuity gradually declines, and visual fields become severely constricted. While useful visual function is frequently preserved beyond the second decade of life, and some patients retain residual islands of peripheral vision into their third decade, blindness is often complete by the age of 30 years. The rate of progression varies depending on the underlying genetic mutation.

Management and treatment research: ### Current management and supportive care There is currently no cure for most genetic causes of severe early childhood onset retinal dystrophy (SECORD). Care focuses on preserving and maximizing remaining vision, supporting development and education, and identifying the genetic cause. Management may include: - **Regular care with a pediatric ophthalmologist or inherited retinal disease specialist** to monitor vision, retinal health, and complications that may occur with specific genetic subtypes. - **Glasses or contact lenses** to correct refractive errors, such as farsightedness or astigmatism, when needed. - **Low-vision rehabilitation**, including magnifiers, electronic reading devices, high-contrast materials, and orientation and mobility training. - **Early-intervention and school supports**, such as individualized education plans, braille or large-print materials, audio resources, and assistive technology. - **Genetic testing and genetic counseling.** SECORD can be caused by variants in many different genes. A genetic diagnosis can clarify the condition, help inform prognosis and family planning, and identify whether gene-specific treatment or research may be relevant. ### Approved therapy for *RPE65*-associated disease For individuals with confirmed **biallelic *RPE65*-related retinal dystrophy**—meaning disease-causing variants are present in both copies of the *RPE65* gene—an approved gene therapy is available: **voretigene neparvovec-rzyl (Luxturna)**. Luxturna uses a modified adeno-associated virus vector to deliver a functional copy of the *RPE65* gene to retinal cells. It is administered by **subretinal injection**, a surgical procedure that places the treatment beneath the retina. Eligibility includes confirmation of biallelic *RPE65* variants and sufficient remaining viable retinal cells. The treatment can improve light sensitivity and functional vision for some people with *RPE65*-associated disease, but it does not replace retinal cells that have already been lost. Continued ophthalmic follow-up is needed after treatment. ### Investigational therapies The current treatment pipeline does not list active condition-specific investigational therapies for SECORD. SECORD is genetically diverse, and research in inherited retinal diseases more broadly includes approaches such as gene replacement, gene editing, RNA-based therapies, and treatments intended to protect or support retinal cells. Whether an investigational approach may be relevant depends on the specific gene involved and the amount of remaining retinal function. ### Clinical trial participation A recruiting rare-disease registry and natural-history study is available: - **NCT01793168** — Rare Disease Patient Registry & Natural History Study – Coordination of Rare Diseases at Sanford; recruiting; Sanford Health. Registry and natural-history studies do not test a treatment. They collect information about genetic diagnoses, symptoms, and changes in vision over time. This information can help researchers better understand rare diseases and plan future clinical trials. Genetic testing may help families and retinal specialists identify research opportunities that are relevant to a specific form of SECORD.

Outlook: The visual prognosis for SECORD is poor, as it is a progressive blinding disorder. While visual performance in bright light often permits attendance at regular schools during elementary years, visual acuity and visual fields progressively decline. Useful visual function is frequently preserved beyond the second decade of life, and some patients retain residual islands of peripheral vision into the third decade. However, blindness is often complete by the age of 30 years. The specific rate of progression and ultimate visual outcome can vary depending on the underlying genetic mutation. Quality of life is significantly impacted by the progressive loss of independence and the need for low-vision aids and specialized educational support.

Epidemiology: The exact prevalence of SECORD is unknown and hard to predict, as many SECORD patients have been previously diagnosed as Leber congenital amaurosis (LCA) patients. It is considered a rare disease. It occurs globally without a specific known ethnic predilection, though certain mutations may be more prevalent in specific populations.

Selected references: 1. Orphanet. Severe early-childhood-onset retinal dystrophy. ORPHA:364055. Last update: December 2017. 2. Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br J Ophthalmol. 2017;101(9):1147-1154. 3. De Zaeytijd J, Van Dongen V, Leroy BP. A multidisciplinary approach to inherited retinal dystrophies from diagnosis to initial care: a narrative review with focus on retinitis pigmentosa and Leber congenital amaurosis. Orphanet J Rare Dis. 2023;18(1):221. 4. Henderson RH, Mackay DS, Li Z, et al. The Phenotype of Severe Early Childhood Onset Retinal Dystrophy (SECORD) from Mutation of RPE65 and Differentiation from Leber Congenital Amaurosis. Invest Ophthalmol Vis Sci. 2011;52(1):276-285.