Sorsby Fundus Dystrophy

Autosomal dominant macular dystrophy with complete penetrance caused by heterozygous variants in TIMP3, with deposits in Bruch's membrane, night blindness, choroidal neovascularisation in adulthood and progressive chorioretinal atrophy.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and names

In 1949, Arnold Sorsby, M. E. Joll Mason and N. Gardener described, in the British Journal of Ophthalmology, five English families with a dominantly transmitted, late-onset fundus dystrophy, which they entitled “a fundus dystrophy with unusual features”, subtitled as a central retinal lesion with oedema, haemorrhage and exudates progressing to generalised choroidal atrophy with massive pigment proliferation [9, 32]. The disease presented at around 40 years of age with an exudative and haemorrhagic macular lesion; over the years, atrophy and pigmentation appeared with peripheral extension, the choroidal vessels became exposed and sclerotic in appearance and, about 35 years after onset, the whole fundus was involved, with extensive choroidal atrophy as the end stage [2]. In these families, night blindness was not recorded at any stage, and the authors interpreted the process as primarily choroidal [2]. There followed the description of new cases by Burn in 1950 and the histological study by Ashton and Sorsby in 1951 [33, 34]. In 1976, Kalmus and Seedburgh established a genealogical link between one of the original English families and an Australian family published in 1971, the first indication of a founder effect [2].

The term “pseudoinflammatory” originates from a debate about the nature of the disease: Sorsby and other authors accepted an inflammatory basis, whereas Duke-Elder, sceptical of that route, introduced the term “Sorsby's pseudo-inflammatory fundus dystrophy” [35]. The term remains clinically relevant, because the sudden onset of a unilateral exudative maculopathy in a young adult continues to be mistaken for infectious or inflammatory choroiditis [35]. Orphanet uses “Sorsby fundus dystrophy” as its preferred term and lists Sorsby macular dystrophy and Sorsby pseudoinflammatory fundus dystrophy as synonyms; OMIM adds “haemorrhagic macular dystrophy” [1, 2].

1.2. Variability of the original families and nosological controversy

Follow-up of Sorsby's families revealed marked differences between them. In the Kempster family, affected individuals reported difficulty with night vision up to 25 years before loss of acuity, and two patients had atrophic macular disease without CNV; in the Carver family, difficulty adapting to abrupt changes in light and slow progression with chorioretinal atrophy predominated; in the Ewbanks family, patients were asymptomatic until sudden central loss due to macular subretinal neovascularisation [2]. This variability raised the hypothesis that Sorsby dystrophy encompassed more than one entity, and the 1993 study of colour vision in at-risk carriers went so far as to support that interpretation [10, 36]. In parallel, an autosomal recessive form was proposed on the basis of a consanguineous Finnish family from the parish of Lavia, in which an affected couple had eight affected children with macular haemorrhage at 20–25 years and, in the most severe case, at 13 years [2, 6].

1.3. Molecular discovery and reclassifications

In 1994, Weber and colleagues mapped the locus to 22q13-qter in a large family and identified, in two families, point mutations in the TIMP3 gene, which encodes tissue inhibitor of metalloproteinases 3; the dystrophy has since been presented as a Mendelian model of age-related macular degeneration (AMD) [2, 37]. In 1997, Felbor and colleagues re-examined the Finnish family and found the same heterozygous variant in all affected individuals (Gly166Cys in the historical numbering, now p.Gly189Cys), with an affected mother–daughter pair in another branch of the pedigree; they concluded that the recessive form was doubtful and that the disease is genetically homogeneous and autosomal dominant [6, 10]. In the same year they showed that the Ser181Cys mutation (now p.Ser204Cys) of the British Isles is a founder mutation and that carriers living in Canada, the United States and South Africa descend from the same British ancestor [12]. Variants were initially numbered from the mature protein, without the 23-amino-acid signal peptide; current Human Genome Variation Society (HGVS) nomenclature includes the signal peptide, so historical numbers differ from current ones by 23 residues [15].

Two later reclassifications broadened the spectrum. In 2016, Meunier and colleagues described two French families with ocular disease and late-onset obstructive lung disease, proposing a syndromic form [7]. In 2022, Guan and colleagues showed that signal peptide variants (p.Leu10His and p.Gly12Arg) cause an early-onset diffuse maculopathy without CNV, with a mechanism and phenotype distinct from the classic form [38]. Families with a retinitis pigmentosa-like phenotype have also been described [39].

1.4. Definition of the entities in this article

Sorsby fundus dystrophy is defined as an autosomal dominant retinal dystrophy with complete penetrance, caused by a heterozygous pathogenic variant in TIMP3, characterised by drusen-like deposits in Bruch's membrane, scotopic dysfunction and a high risk of CNV and macular atrophy in adulthood [2, 9, 14]. Retinopathies due to signal peptide variants and retinitis pigmentosa-like forms are treated as phenotypic variants of the same gene, because they share the molecular cause but differ in age at onset, distribution of lesions and absence of CNV [38, 39]. Families with a similar phenotype and no TIMP3 variant fall outside the definition and are discussed in the differential diagnosis [2, 40]. Sorsby syndrome, described by the same author in 1935, is a different entity: bilateral congenital pigmented macular coloboma with brachydactyly type B [4, 41]. Late-onset retinal degeneration (L-ORD) is defined as the autosomal dominant retinal dystrophy caused by a heterozygous pathogenic variant in C1QTNF5, with deposits between the RPE and Bruch's membrane, delayed dark adaptation, long anterior zonules and progressive chorioretinal atrophy from the 6th decade; it is grouped in this article as a separate entity, covered in section 6.4 [25, 28].

2. Molecular Genetics and Pathophysiology

2.1. The TIMP3 gene and the TIMP-3 protein

TIMP3 is located at 22q12.3, has five exons and shares an overlapping gene architecture with SYN3, lying within one of its introns [6, 7]. The MANE Select reference transcript is NM_000362.5, which encodes the protein NP_000353.1 [8]. TIMP-3 is one of the four tissue inhibitors of metalloproteinases; the tertiary structure of these proteins is based on six disulphide bonds between twelve conserved cysteines, and the N-terminal domain is responsible for inhibition of the matrix metalloproteinases (MMP) [7, 9]. TIMPs form complexes with MMP-1, -2, -3, -7, -9, -13, -14 and -15, whereas the C-terminal domain mediates additional functions, such as binding to the extracellular matrix (ECM) [6, 7]. Unlike TIMP-1, TIMP-2 and TIMP-4, which are soluble, TIMP-3 is insoluble and resides entirely in the ECM, in glycosylated (27 kD) and unglycosylated (24 kD) forms [6, 9].

In addition to MMPs, TIMP-3 inhibits the α-secretases ADAM10 and ADAM17, enzymes that release from the cell surface the LRP1 receptor (low-density lipoprotein receptor-related protein 1) and tumour necrosis factor (TNF) [3, 15]. In the Timp3-/- mouse, increased activity of TNF-α converting enzyme (ADAM17) causes constitutive TNF release, lymphocytic infiltration and hepatic necrosis, which identifies TIMP-3 as a negative regulator of TNF [6]. TIMP-3 also binds directly to vascular endothelial growth factor receptor 2 (VEGFR2) and prevents binding of VEGF-A, an antiangiogenic function independent of metalloproteinase inhibition [3, 9]. In the retina, it is expressed mainly by the retinal pigment epithelium (RPE) and the choroidal endothelium and is part of Bruch's membrane, where it interacts with fibulin-3 (EFEMP1), the protein implicated in Doyne honeycomb dystrophy [7, 9]. TIMP-3 levels are regulated post-translationally by the balance between LRP1-mediated endocytosis and binding to sulphated glycosaminoglycans of the ECM [15].

2.2. Disease mechanism

The characteristic histological lesion is a confluent amorphous deposit between the inner collagenous layer of Bruch's membrane and the RPE basement membrane, present throughout the retina and not only in the macula [2, 7, 11]. TIMP-3 is present in these deposits and accumulates through increased deposition rather than gene overexpression; studies point to the RPE as the source of the accumulated protein [9, 14]. Most pathogenic variants introduce a new cysteine or remove a paired cysteine, leaving a free thiol group that favours intermolecular disulphide bonds and dimer formation [14, 15]. The mutants studied in RPE cells (Ser181Cys, Ser156Cys and Glu139Ter in the historical numbering, corresponding to NM_000362.5:c.610A>T p.(Ser204Cys), c.536C>G p.(Ser179Cys) and c.484G>T p.(Glu162*)) were all resistant to turnover, but their ability to inhibit MMP2 activation ranged from complete to none; hence the conclusion that the likely initial event is the deposition of active TIMP-3 rather than loss of metalloproteinase inhibition [2, 6]. The resulting thickening of Bruch's membrane compromises RPE function and the RPE-retina barrier, creating conditions for macular atrophy or CNV [7, 9].

Studies in patient-derived models reinforce the toxic gain-of-function hypothesis. In RPE derived from induced pluripotent stem cells (iPSC) from three p.(Ser204Cys) patients, mutant TIMP-3 accumulated on the basolateral side without altered gene expression, retained MMP inhibitory activity and was associated with increased ECM proteins, monocyte chemoattractant protein 1, PDGF and angiogenin, without altered VEGF secretion; dimers appeared in both patients and controls [42]. In another iPSC-RPE model, S204C cells formed more sub-RPE deposits (6–90 µm), accumulated about 18 times more TIMP-3 in the ECM, had less reduced glutathione and greater vulnerability to oxidative stress, and correction of the variant by CRISPR-Cas9 reduced the deposits [43]. The dimerisation hypothesis is not universal: p.(Ser38Cys) does not dimerise in patient fibroblasts and disrupts the Cys36–Cys143 bond, forming a new intramolecular Cys36–Cys38 bond [13]. Conversely, a 2025 study in ARPE-19 cells showed that p.(Tyr191Cys) reduces binding to MMP2 and MMP9 and inhibition of these enzymes and promotes apoptosis under inflammatory stress [44]. Whether the mutant proteins retain MMP inhibition and VEGFR2 blockade remains an open question [9, 15].

Night blindness has its own pathophysiological explanation. The barrier formed by the deposit in Bruch's membrane is thought to hinder the passage of vitamin A from the choroid to the photoreceptors, creating a local rather than systemic deficiency; in 1995, oral administration of 50,000 international units (IU)/day of vitamin A abolished night blindness within a week in patients in the early stage [2, 45]. The improvement in rod-mediated dark adaptation in a patient on high-dose vitamin A, observed in 2022, is consistent with this hypothesis [18]. CNV is related to loss of the barrier and of local regulation of angiogenesis, but patients do not have an abnormal underlying choroidal structure, so the variants may retain part of their capacity to restrain VEGF signalling [9]. On optical coherence tomography angiography (OCTA), patients in the early stage have more choriocapillaris flow deficits than controls (+20.0 percentage points; 95% CI 13.3–26.7), even outside the areas of deposit, suggesting early choriocapillaris involvement [46].

2.3. Variant spectrum and nomenclature

The 2024 review by Vergaro and colleagues aligned all published variants with NM_000362.5 and classified them according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria, with gene-adapted criteria: 23 heterozygous variants, of which 11 pathogenic, 11 likely pathogenic and one of uncertain significance [11]. The 2024 review of mechanisms counted 21 disease-associated variants and recorded the typical age at onset of each [15]. The table brings the two sources together, with ClinVar classifications consulted in October 2026 and historical names confirmed in ClinVar.

Table sources: [11, 15, 47]. The historical names Ser181Cys, Tyr168Cys, Ser156Cys, Gly166Cys and Glu139Ter correspond to the OMIM alleles and are confirmed in ClinVar; the correspondences Glu139Lys, His158Arg and Tyr159Cys result from the normalisation in the 2024 reviews [6, 11, 47]. VariantValidator confirmed the c./p. descriptions of the main variants on the MANE transcript, for example NM_000362.5:c.610A>T, NP_000353.1:p.(Ser204Cys), NC_000022.11:g.32859351A>T [8]. Some publications use inconsistent forms, such as “p.Arg204Cys” or “c.530A>G (p.Tyr200Cys)”, which should be read as p.(Ser204Cys) and p.(Tyr177Cys), respectively [11, 19, 48].

Most variants lie in exon 5, in the C-terminal domain, and replace a residue with cysteine; the exceptions are the signal peptide variants, those in the N-terminal domain (p.Cys24Arg and p.Ser38Cys) and those that do not generate a free cysteine (p.Leu10His, p.Gly12Arg, p.Glu162Lys and p.His181Arg) [11, 15]. p.His181Arg was the first coding variant described without an unpaired cysteine, in a North American family with onset in the 5th–7th decades [49]. p.Glu162Lys, identified in a Welsh family and absent from 534 control chromosomes, dimerises and retains MMP inhibition without changing the number of cysteines [50]. For interpretation, Vergaro proposed specific ACMG/AMP criteria: PM1 at moderate strength when the variant introduces or removes a cysteine, PM2 at supporting strength (late-onset disease, compatible with carriers in gnomAD), PP4 strong in the presence of a clinical diagnosis of SFD with a consistent phenotype and PS4 graded by the number of observations; the PP5 criterion was not used [11].

2.4. Founder variants

The p.(Ser204Cys) variant accounts for most cases in the United Kingdom [9]. In 1996, analysis of 15 unrelated British families showed the same 3 cM haplotype in 11 of them and a haplotype extending up to 7 cM in five, evidence of a single mutational event responsible for most of the disease in the British Isles [6]. The Canadian, North American and South African carriers studied descend from the same ancestor [12]. The p.(Ser38Cys) variant, in exon 1, is a founder variant in Belgian and northern French families: eight patients from three families shared a haplotype of about 6.4 Mb (maximum 6.47 Mb) around the gene, a sign of an ancient common ancestor in Western Europe [13].

2.5. Genotype–phenotype correlations, penetrance and modifiers

Penetrance is complete, but age at onset, rate of progression and morphology vary between and within families [9, 13]. Some variants are associated with early onset, such as p.(Ser179Cys), with a mean age of 25 years and involvement of the second eye within a few months in the original German-Czech family, and p.(Tyr174Cys), with symptoms around the 3rd decade [6, 17]. Others are associated with late onset mimicking AMD, such as p.(Ser38Cys), p.(Tyr177Cys), p.(Tyr182Cys) and p.(His181Arg) [17, 49, 51]. Severity cannot be reliably predicted from the residue affected; the hypothesis that substitution by a larger amino acid would worsen the phenotype has not been confirmed [7, 9]. Smoking and the genetic background of susceptibility to AMD have been proposed as modifiers, without quantification [9].

2.6. Allelic forms and syndromic extension

The signal peptide variants p.Leu10His and p.Gly12Arg, studied in 11 individuals from two families at the National Eye Institute between 2009 and 2021, cause an early-onset diffuse maculopathy without CNV; biochemical studies showed defective cleavage and maturation and reduced extracellular deposition, in contrast to the typical accumulation [38]. The variants p.Tyr137Cys and p.Ser193Cys have been described in patients with a retinitis pigmentosa-like phenotype and drusen, a reason to include TIMP3 in the investigation of atypical retinitis pigmentosa [11, 39].

Pulmonary extension has been described in two French families: p.(Tyr191Cys) in a family with severe emphysema without smoking in affected individuals over 50 years of age and p.(Ser38Cys) in another with bronchial wall thickening and mild bronchiectasis [7]. Biological plausibility rests on the high expression of TIMP-3 in the lung and on the phenotype of the Timp3-/- mouse, with enlarged airspaces and abnormal bronchiolar branching [7, 15]. The finding has not been replicated in other series: Czech carriers reported no bronchopulmonary disease and two British sisters had normal pulmonary function tests and bone densitometry [9, 11]. Dilated cardiomyopathy and osteoarthritis have also been described in the null mouse, with no demonstrated counterpart in patients [15].

2.7. Relationship with age-related macular degeneration

TIMP-3 also accumulates in Bruch's membrane in AMD and retinitis pigmentosa, and the deposits of Sorsby dystrophy resemble the drusen of AMD [9, 14]. The structural difference is extent: in Sorsby dystrophy, thickening of Bruch's membrane is diffuse and not confined to the macula [13]. Because of these similarities, the disease is used as a monogenic model to study AMD mechanisms, although the pathogenic pathways are not identical [15, 37].

3. Clinical Spectrum and Manifestations by System

3.1. Overview and age at onset

Sorsby fundus dystrophy affects men and women equally, has complete penetrance and becomes symptomatic, on average, in the 4th–5th decade, although some patients have symptoms in the 2nd decade [9, 19]. Orphanet places onset between the 3rd and 6th decades and describes the sequence of central loss, then peripheral, leading to blindness [1]. Before anti-VEGF treatment, the natural course led to severe bilateral visual loss and blindness [9, 19]. Age at onset depends partly on the variant, as summarised in section 2.5, and varies within the same family [13, 15].

3.2. Presymptomatic phase and initial symptoms

The first symptoms are night blindness, difficulty with dark adaptation, metamorphopsia and altered colour vision [9, 19]. Night blindness may precede central loss by many years, as in the Kempster family, in which it preceded the fall in acuity by up to 25 years, but it is not universal: in the Belgian families with p.(Ser38Cys), only a third of patients reported it in the 5th decade [2, 13]. In a prospective study of 16 patients and 20 controls in Bonn, photopic best-corrected visual acuity (BCVA) was normal, whereas low-luminance acuity was reduced (0.30 logMAR, interquartile range 0.20–0.45, versus 0.20 logMAR, 0.03–0.28; p<0.05), the rod intercept time on dark adaptation was markedly prolonged (21 minutes versus 4.05 minutes; p<0.001) and dark-adapted sensitivity to a cyan stimulus was reduced by a mean of 11.80 dB; dark adaptation could be slowed without any change on multimodal imaging, and vision-related quality of life was reduced [18]. In a 1993 study of 34 asymptomatic people at 50% risk, 16 had raised colour contrast thresholds, mainly on the tritan axis; in one of the three families the defect appeared without ophthalmoscopic change [36].

In young carriers, imaging may already be abnormal. In the 2015 German series, three asymptomatic carriers with normal fundus and imaging showed characteristic hypofluorescence in the late phase of indocyanine green angiography (ICGA), more marked and extensive in advanced stages [17]. In two asymptomatic French boys under 20 years of age, Bruch's membrane was thickened on spectral-domain optical coherence tomography (SD-OCT) [7]. Conversely, a Czech carrier followed annually with OCT and OCTA from age 30 to 33 years had no measurable change [11].

3.3. Fundus findings

The initial changes are yellowish drusen-like deposits at the posterior pole and, frequently, throughout the fundus [9, 11]. Reticular pseudodrusen are frequent: in a study of 16 patients from four families (mean age 56.8 years; 23–78), they were found in 5 of 7 patients in the 6th decade (71%), were absent in the 3 youngest patients and could not be assessed in the 6 patients aged 70 years or older because of extensive atrophy or fibrosis; they predominated in the superior quadrant, spared the fovea, were hyporeflective on infrared reflectance, hypoautofluorescent and lay above the RPE on SD-OCT [2, 52]. Peripheral pseudodrusen and soft drusen were less frequent [52]. The Dutch family without a TIMP3 variant, with a similar picture, had mid-peripheral pisciform flecks [40].

3.4. Choroidal neovascularisation

CNV is the main cause of central loss and the treatable event of the disease [9, 16]. It has a sudden onset, with metamorphopsia and fall in acuity, subretinal haemorrhage, exudation, macular oedema and RPE detachment; it is typically a classic, type 2 CNV, above the RPE [11, 19]. In the historical Moorfields Eye Hospital cohort of 42 p.(Ser204Cys) patients, the median age at CNV was 46.1 years in the first eye and 50.3 years in the second, with a mean interval of 4.5 years between eyes; acuity fell to 20/200 or worse at a median age of 48 years in the first eye and 54 years in the second [16]. In the 2021 systematic review, the mean age at CNV onset in the case reports was 40 years and a third of patients (10 of 31; 32.3%) had both eyes affected [19]. In the French p.(Tyr191Cys) family, CNV appeared between 23 and 40 years [7]; in the families with p.(Ser38Cys), between 56 and 64 years, with the second eye affected 4–6 years later [51]. Macular and peripheral polypoidal choroidal vasculopathy have been described [17, 53, 54]. The French PNDS for genetic maculopathies places Sorsby dystrophy at the extreme of greatest neovascular risk among the inherited maculopathies: it describes CNV as very frequent and practically constant around the age of 50 years, compared with about 15% of cases in Best disease and exceptional occurrence in Stargardt disease [23]. This statement is an expert synthesis and not a cohort figure; series with a denominator show median ages of 46–50 years and a fraction of patients with only one eye involved at the time of publication, so “constant” should be read as a very high lifetime risk in carriers, and not as occurrence in all eyes by that age [16, 19].

3.5. Geographic atrophy and chorioretinal atrophy

Geographic atrophy may progress rapidly and replace CNV as the cause of central loss, as in the family with p.(Glu162*), in which 5 of 6 eyes had macular atrophy rather than CNV, with peripheral pigmentary changes and abnormal scotopic electroretinogram (ERG) in all three patients [17, 55]. Severe late-stage visual loss without CNV has been described [56] and, in 2026, a multilobulated pattern of RPE atrophy termed “archipelago” [57]. Late manifestations are uniform across families: extensive chorioretinal atrophy, subretinal fibrosis, disciform scar and choroidal thinning [17, 19]. The peripheral retina is involved later, with possible loss of navigational vision in the 7th decade [9]. In the German-Czech family with p.(Ser179Cys), the disease progressed within a few years to tapetoretinal dystrophy with bone-spicule pigment proliferation, arterial attenuation, choriocapillaris atrophy, peripheral field loss and subnormal scotopic and photopic ERG [6]. Anti-VEGF treatment does not prevent progression of atrophy or of the macular scar [9, 19].

3.6. Allelic forms

Signal peptide variants cause a diffuse maculopathy with onset in the 2nd decade without CNV, and the variants p.Tyr137Cys and p.Ser193Cys a retinitis pigmentosa-like picture with drusen [11, 38, 39]. These forms have a prognosis and surveillance needs different from the classic form, because the risk of CNV has not been described [38].

3.7. Extraocular manifestations

In the French p.(Tyr191Cys) family, all affected members of generation III (70, 67, 59 and 53 years), without smoking or asthma, had expiratory flow limitation with forced expiratory volume in one second (FEV1) reduced to between 28% and 73%, air trapping, bronchial wall thickening and mild basal bronchiectasis; two required oxygen therapy for chronic respiratory failure and the mother had died of severe emphysema [7]. A 44-year-old patient had air trapping with normal function tests and a 16-year-old adolescent had air trapping, resting hypoxaemia (79 mmHg) and complex congenital heart disease [7]. In the p.(Ser38Cys) family, lung disease was milder (bronchial thickening, one cylindrical bronchiectasis, no emphysema) and the mother developed atypical asthma after the age of 70 years [7]. Lung disease began one to three decades after visual loss and all patients over 55 years of age had pulmonary involvement [7]. The Czech carriers and two British sisters studied had no respiratory disease, so the true frequency of pulmonary involvement is unknown [9, 11].

3.8. Natural history and treated disease

The natural history documented before anti-VEGF is that of a disease leading to bilateral legal blindness; in the British cohort, acuity in the second eye fell to 20/200 or worse at a median age of 54 years, and in the French p.(Tyr191Cys) family all patients over 30 years were legally blind, except the only one treated with bevacizumab, who maintained 20/20 in one eye [7, 16]. In four relatives from a North American family with p.(Ser204Cys), legal blindness occurred before the age of 50 years, despite laser photocoagulation [6]. Since the introduction of anti-VEGF, the systematic review of 31 cases shows preservation of functional vision in most eyes treated early, with slow decline associated with scarring and atrophy (sections 7 and 11) [19].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Sorsby dystrophy should be considered in macular CNV in an adult in the 3rd to 5th decade without predisposing factors, such as high myopia, or in irregular thickening of Bruch's membrane on SD-OCT [7]. CNV in a person in the 4th or 5th decade, or a family history of early macular disease, should lead to genetic testing instead of a diagnosis of AMD by exclusion [3, 58]. A family history of “wet AMD” over several generations or of blindness before 60 years is a warning sign, because late-onset variants mimic neovascular AMD [13, 51, 58]. Night blindness in an adult with diffuse drusen, hypoautofluorescent pseudodrusen outside the usual age range and bilateral disease point in the same direction [18, 52]. Absence of a family history does not exclude the disease: the variant may be de novo, as in one of the Czech families [11].

The French PNDS for genetic maculopathies defines the general picture that leads to suspicion of an inherited maculopathy: reduced central acuity not improved by optical correction, usually bilateral and symmetrical, central scotoma and dyschromatopsia proportional to the loss of acuity; it considers, in contrast, that presenting photophobia points to a cone dystrophy and that night blindness or constriction of the peripheral field point to a mixed cone-rod dystrophy [23]. Sorsby dystrophy is an exception to this general rule, because scotopic dysfunction is part of the initial picture and may precede central loss by several years (section 3.2); night blindness in an adult with maculopathy should therefore add Sorsby dystrophy and L-ORD to the list of hypotheses, not rule them out [2, 18, 28]. The initial history includes a pedigree, medicines and supplements, and a search for extraocular signs (obesity, polydactyly, hearing loss, diabetes, epilepsy, developmental regression, cerebellar signs), which point to syndromic forms [23].

4.2. Emergency signs

Recent-onset metamorphopsia, a central spot or a sudden fall in acuity in a known carrier or patient indicate CNV until proven otherwise and require urgent examination, because the delay between symptoms and the start of anti-VEGF determines scar formation and functional prognosis [9, 19]. The French PNDS stresses that, in genetic maculopathies, metamorphopsia is rare in the absence of atrophy or neovascular complication, so its onset points to CNV [23]. A unilateral exudative and haemorrhagic lesion in a young adult may be mistaken for infectious or inflammatory choroiditis; the presence of drusen in the fellow eye and the family history guide the diagnosis [35].

4.3. Screening

There is no newborn or population screening. Carriers are identified by cascade testing within families (section 8).

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

No formal clinical criteria have been published. Diagnosis rests on a compatible phenotype (drusen-like deposits or pseudodrusen, scotopic dysfunction, CNV or macular atrophy in an adult, dominant pattern) confirmed by identification of a heterozygous pathogenic or likely pathogenic variant in TIMP3; no biochemical or functional test confirms the diagnosis [3, 11]. When the picture is fully manifest, the signs are specific enough to justify targeted sequencing of the gene [11]. The French PNDS for genetic maculopathies also does not set its own criteria for Sorsby dystrophy; it characterises it, in its table of rare non-syndromic maculopathies, by onset in childhood or adulthood, autosomal dominant inheritance, thickening of Bruch's membrane on SD-OCT, a heterogeneous hypo- and hyperautofluorescent zone on FAF and very frequent CNV, and insists that the list of these rare maculopathies is not exhaustive, which makes genetic testing indispensable [23].

5.2. Ophthalmological assessment

The 2022 AAO clinical statement includes the inherited macular dystrophies among the four classes of inherited retinal degeneration and recommends, at initial assessment, ocular, medical and family history with a pedigree, BCVA with an ETDRS (Early Treatment Diabetic Retinopathy Study) chart, optional colour vision, biomicroscopy, intraocular pressure and ophthalmoscopy, SD-OCT, fundus autofluorescence (FAF) with reduced illumination, infrared imaging, kinetic visual fields, microperimetry when available and full-field ERG when appropriate [20]. In young patients with disease apparently confined to the macula, full-field ERG allows diffuse disease to be excluded; multifocal ERG is useful in maculopathies, with limited accuracy when fixation is unstable [20]. The Oxford Desk Reference recommends electrophysiology according to International Society for Clinical Electrophysiology of Vision (ISCEV) standards, visual fields and retinal imaging, and notes that full-field ERG is generally normal in macular dystrophies [59, 60].

The French PNDS for genetic maculopathies is more prescriptive. It considers full-field ERG according to ISCEV standards indispensable in any maculopathy, at any age, to measure severity, estimate progression and separate maculopathies from cone dystrophies and mixed dystrophies, with the sole exception of typical Best disease [23]. In adults and children it recommends distance and near acuity, visual fields focused on detecting scotoma with peripheral preservation, colour fundus photographs, SD-OCT with macular scans, temporal scans and ganglion cell layer analysis, macular and wide-field FAF and, if the ERG is normal in a deposit disease or a toxic cause is suspected, electro-oculogram; in young children it favours rapid macular and temporal OCT scans, to recognise a mixed dystrophy early [23]. The same document considers FAF indispensable and states that it has completely replaced fluorescein angiography, which is no longer indicated in the diagnosis of inherited dystrophies [23]. In Sorsby dystrophy, this rule applies to characterisation of the dystrophy, not to CNV: the PNDS does not address angiographic confirmation of suspected neovascularisation, which the sources on CNV continue to perform by fluorescein angiography when OCT and OCTA are insufficient (divergence in section 7.10) [11, 22, 23].

In Sorsby dystrophy, the highest-yield investigations are the following. SD-OCT shows sub-RPE deposits, thickening of Bruch's membrane, subretinal pseudodrusen and, in CNV, intra- or subretinal fluid and hyperreflective material [7, 48, 52]. FAF and infrared reflectance document pseudodrusen and atrophy [52]. OCTA detects CNV non-invasively and repeatably, has been used to diagnose CNV and follow its regression and, in a Czech patient, made it possible to identify a 0.16 mm² CNV when fundoscopy showed only subtle pigmentary changes [11, 48]. Fluorescein angiography remains the reference investigation for confirming and characterising active CNV, but it is invasive and unsuitable for repetition in asymptomatic people [11, 22]. Late-phase ICGA shows hypofluorescence even in presymptomatic carriers and characterises polypoidal vasculopathy [17]. Scotopic tests (rod-mediated dark adaptation and dark-adapted fundus-controlled perimetry) are the sensitive measures of early dysfunction; BCVA is insensitive at this stage [18]. Choriocapillaris flow deficits on OCTA have been proposed as an early outcome for trials [46].

5.3. Genetic testing

Genetic testing is appropriate for most patients with suspected inherited retinal degeneration, may be done by single-gene analysis, a retinal dystrophy panel or exome, and should be interpreted and communicated with genetic counselling [20, 61]. The strategy depends on the phenotype: in a Czech patient with no family history and at an early stage, the variant was found on a panel of 548 ocular genes, whereas in the patient with a typical phenotype and family history only TIMP3 was sequenced by Sanger [11]. Sequencing must include all coding exons and junctions: in a Belgian family, the exon 1 p.(Ser38Cys) variant was not detected while analysis was limited to exon 5 [13]. In series of inherited retinal degenerations in general, the causal variant is identified in 56–76% of patients; with a good phenotype and family history, the Oxford Desk Reference estimates about 55% genetic diagnosis on panels in the United Kingdom [20, 59]. These rates refer to retinal dystrophies as a whole and not to test sensitivity in Sorsby dystrophy.

In France, the PNDS for genetic maculopathies requires written consent for genetic testing and provides two pathways: a rapid panel of about 208 retinal dystrophy genes, with exonic copy number analysis to detect deletions and duplications, or genome sequencing under the France Genomic Medicine Plan 2025 (PFMG2025), in which maculopathies are a pre-indication, with the genome acceptable as first line and, preferably, as a trio with the parents [23]. Interpretation follows the ACMG/AMP recommendations in an accredited laboratory. The document counts 21 inherited maculopathy genes, excluding cone dystrophies, and states that, across maculopathies, more than half of patients obtain an explanatory result, compared with about 30% in recessive maculopathies other than Stargardt; these yields, presented by the PNDS without a denominator or period, concern maculopathies as a whole and not sensitivity in Sorsby dystrophy [23]. The PNDS justifies testing even in isolated cases, because isolated forms due to dominant genes are frequent and carry a risk of transmission, and because molecular diagnosis is a prerequisite for future gene, pharmacological or cell therapies [23].

5.4. Limitations of testing

A negative result does not exclude the disease, because absence of a variant may depend on the method [20]. In Sorsby dystrophy, the documented limitation is incomplete coverage of the gene, as in the exon 1 example; the ability of each laboratory to detect intronic variants and copy number variation in TIMP3 should be checked in the report, because the sources consulted do not describe these mechanisms in the disease [13, 20]. There are families with a similar picture and linkage to 22q without an identified TIMP3 variant (exons, promoter and 3' untranslated region), which shows that a negative result may correspond to a genocopy or an undetected variant [2, 40]. Negative or inconclusive tests should be re-evaluated as new genes, better technology and better variant interpretation emerge [20]. The French PNDS adds that a negative panel does not exclude the clinical diagnosis, because the variant may lie in unexplored regions of the panel genes, in genes absent from the panel or in genes not yet described, and proposes exome or genome in that case; a variant in an unexpected gene should prompt review of the clinical diagnosis, and novel variants may require functional studies before they are classified [23].

5.5. Report and variant interpretation

The report should state the gene, the transcript with version (NM_000362.5), the HGVS c. and p. description, zygosity (heterozygous), the ACMG/AMP class and the evidence used [8, 11]. Variants of uncertain significance are frequent in a gene with few described variants: the c.455A>G p.(Tyr152Cys) variant was first classified as of uncertain significance and was only reclassified as pathogenic after the development of CNV, identification in a second family and demonstration of de novo occurrence with confirmed paternity and maternity [11]. Family segregation and the specific phenotype (PP4 criterion) weigh in the classification; p.(Asp167Asn) remains of uncertain significance and p.(Glu162*), p.(Tyr137Cys) and p.(Leu10His) have divergent classifications in ClinVar [11, 47]. The 2024 review warned that the gene-adapted criteria were agreed only by the authors and may be altered by an expert panel [11].

5.6. Practical algorithm

5.7. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible when the familial variant has been identified [59, 60]. The options and the counselling context are described in section 8.

6. Differential Diagnosis

6.1. Principles

In the young adult, the differential includes other inherited macular dystrophies with AMD-like morphology and secondary CNV of other causes, which is rarely bilateral; a positive family history often simplifies the decision [19]. The Oxford Desk Reference lists as macular dystrophies to consider Stargardt disease (ABCA4), dominant drusen (EFEMP1), Sorsby dystrophy, Best disease and the pattern dystrophies, the latter two vitelliform and RPE-centred [59]. The next step is to distinguish isolated dystrophies from syndromic forms and from treatable metabolic disorders with night blindness [59].

6.2. Comparative table

6.3. Main differentials

Neovascular AMD is the most frequent differential in late-onset forms. Three patients with p.(Ser38Cys) were first diagnosed with neovascular AMD and had bilateral CNV with onset between 56 and 64 years, and two had a family history of AMD [51]. What distinguishes Sorsby dystrophy is bilaterality, night blindness, diffuse thickening of Bruch's membrane and mid-peripheral changes that are earlier and progress faster than in AMD [7, 13]. Age is the decisive criterion for requesting genetic testing [3].

C1QTNF5-associated late-onset retinal degeneration shares night blindness, the diffuse sub-RPE deposit, CNV and atrophy, but begins later, in the 5th–6th decade; the deposits of both diseases resemble those of AMD histologically [25]. The distinction requires genetic testing and is developed in section 6.4. Dominant drusen due to EFEMP1 (Doyne honeycomb dystrophy and malattia leventinese) involve fibulin-3, a partner of TIMP-3 in Bruch's membrane [7, 25, 59].

Secondary CNV in young adults, such as that associated with angioid streaks (including pseudoxanthoma elasticum), inflammatory choroidopathy, central serous chorioretinopathy and idiopathic CNV, constitutes the group of “uncommon causes” in which ranibizumab was studied in the MINERVA trial [21, 66]. Besides pseudoxanthoma elasticum, angioid streaks are part of other genetic disorders with systemic features, such as osteoectasia with hyperphosphatasia (juvenile Paget disease, TNFRSF11B, AR), in which macular atrophy and optic atrophy are also described, and familial LCAT (lecithin-cholesterol acyltransferase) deficiency, with retinal haemorrhages and corneal opacities; the skeletal, lipid or renal context distinguishes them from Sorsby dystrophy [69, 70]. TIMP3 retinitis pigmentosa-like forms and signal peptide maculopathies should be borne in mind when a panel identifies a TIMP3 variant in a patient without CNV [38, 39].

The French PNDS for genetic maculopathies requires that, in an isolated case, acquired causes be systematically excluded before concluding that a maculopathy is inherited: medicines (synthetic antimalarials, antiretrovirals), drugs such as inhaled nitrites, laser injuries, diabetes, vascular occlusions and inflammatory or infectious diseases (toxoplasmosis, multifocal choroiditis, placoid epitheliopathy, cat-scratch disease) [23]. It adds to the differential the dome-shaped macula of adults, which macular OCT identifies, occult macular dystrophy, unmasked by OCT and multifocal ERG with a normal full-field ERG, AMD after the age of 50 years, with more asymmetric and sequential involvement of the two eyes, and EMAP, whose extensive vertically oriented atrophy and progression to legal blindness within 5–10 years separate it from Sorsby dystrophy, in which acute central loss depends mainly on CNV [23]. The syndromic forms in the table in section 6.2 justify a search for extraocular signs and a full-field ERG, which is abnormal in Bardet-Biedl syndrome and electronegative or undetectable in neuronal ceroid lipofuscinosis type 3 [23].

The eponym causes confusion with Sorsby syndrome, described in 1935 in a mother and five children with bilateral pigmented macular coloboma and brachydactyly, in whom one patient had unilateral renal agenesis; a new generation of the original family included bifid thumbs, nail aplasia, syndactyly, 70–80 dB sensorineural hearing loss and a single kidney, and ROR2 was excluded [4, 41]. It is a congenital malformation and not a progressive adult dystrophy.

6.4. Late-onset retinal degeneration (L-ORD, C1QTNF5)

Late-onset retinal degeneration (L-ORD; OMIM 605670; ORPHA:67042) is the closest monogenic differential of Sorsby dystrophy: both are autosomal dominant with complete penetrance, accumulate material between the RPE and Bruch's membrane, cause night blindness before central loss and progress to CNV and chorioretinal atrophy [25, 26, 28]. It is grouped in this article because of its pathophysiological and clinical proximity.

6.4.1. Names and historical milestones

In 1986, Duvall and colleagues described two brothers aged 62 and 74 years, diagnosed with dominant retinitis pigmentosa, with night blindness from the 5th decade and extensive deposits of amorphous material beneath the RPE; they were later recognised as the first published cases of the disease [28]. The name “late-onset dominant retinal degeneration” appeared in 1996, when Kuntz and colleagues studied the eye of an 80-year-old donor with a thick deposit between the RPE and Bruch's membrane, from the optic disc to the ora serrata, without coding variants in RHO, PRPH2 and TIMP3 and with exclusion of RHO and TIMP3 by linkage [25, 28]. In 2000, Milam and colleagues showed that the ultrastructure and staining of the deposits, rich in esterified and unesterified cholesterol, resemble those of AMD and Sorsby dystrophy, and suggested an extracellular matrix protein as the cause [25]. In 2003, Hayward and colleagues mapped the locus to 11q23.3 in an extended family and identified the founder variant p.(Ser163Arg) in CTRP5, now C1QTNF5, in 7 of 14 families; two families not linked to the locus and two affected siblings without the variant in a carrier family demonstrated genetic heterogeneity and phenocopies [25, 71]. In 2005, Ayyagari and colleagues linked macular degeneration and long anterior lens zonules to the same gene in a 55-member family, each segregating independently with maximum LOD scores of 3.31 and 5.41 [72]. The old synonyms, “autosomal dominant haemorrhagic macular dystrophy” and “late-onset macular degeneration”, have fallen into disuse; the term “late onset” refers to the relatively advanced age for a Mendelian dystrophy, although the macula is affected earlier than in AMD [28].

6.4.2. Molecular genetics and mechanism

C1QTNF5 (OMIM 608752; 11q23.3) encodes CTRP5, a secreted 243-amino-acid protein with a signal peptide (residues 1–15), a collagenous domain with 23 Gly-X-Y repeats (30–98) and a C1q globular domain (99–243); the gene is contained within the 3′ untranslated region of MFRP, with which it shares a bicistronic transcript, and is expressed mainly in the RPE and ciliary epithelium [72–74]. The MANE Select transcript is NM_001278431.2 (NP_001265360.1); the coding numbering of the described variants coincides with that of transcript NM_015645.5, used in several series [8, 75]. The protein forms trimers and a bouquet-like octadecamer, similar to that of adiponectin and C1q; residue Ser163 participates in a hydrogen-bond network that holds the globular heads together [73]. Pathogenic variants destabilise folding and assembly, divert secretion from the apical to the basolateral pole and, when coexpressed with the normal protein in RPE cells, reduce the high-molecular-weight form from 15% to 1.5% of the total, which supports a dominant-negative mechanism [73]. In RPE derived from patient induced pluripotent stem cells, mutant CTRP5 is less secreted, binds less well to adiponectin receptor 1 and keeps AMP-activated kinase (AMPK) activated in a manner insensitive to the AMP/ATP ratio, with abnormal lipid metabolism, reduced mitochondrial respiration and sub-RPE deposits [76]. In p.Ser163Arg knock-in mouse models, CTRP5 binds to the protease HTRA1, whose locus is the main genetic risk factor for AMD; the mutant protein resists cleavage and the two proteins accumulate in Bruch's membrane [77]. The exact physiological function of CTRP5 remains to be established [73, 74].

The correspondences between nucleotide and protein were confirmed in VariantValidator. The 2013 series by Soumplis and colleagues describes the founder variant as c.686C>G, a numbering that does not correspond to the current reference transcripts; the protein, p.(Ser163Arg), is the same [8, 83]. All L-ORD variants lie in the globular domain, so testing should cover at least the whole region encoding it; the variant p.(Asn22Lys), in the N-terminal region between the signal peptide and the collagenous domain, is the exception, and its pathogenicity remains uncertain [28, 73, 82]. The variant p.(Gln180Glu), identical by descent in two German families, causes a different phenotype, autosomal dominant choroidal dystrophy resembling gyrate atrophy, with confluent atrophy from the 2nd decade, foveal involvement at around 60 years and absence of subretinal deposits, pigmentation and CNV; a sporadic case at 70 years confirmed the association in 2025 [62, 63]. The recessive diseases of MFRP (nanophthalmos and retinopathy) should not be attributed to C1QTNF5, despite the shared transcript [74].

6.4.3. Clinical Manifestations and Natural History

The disease is bilateral and symmetrical; no unilateral cases have been described [28]. The first functional sign is delayed dark adaptation, which may precede symptoms and fundus changes by at least a decade: in three families, 6 of 12 at-risk relatives in one of them had abnormal adaptation kinetics, the youngest at 35 years [29]. Night blindness usually sets in in the 5th decade, with normal acuity; central loss appears when atrophy reaches the fovea, usually in the 6th–7th decade, and may progress to complete loss of vision over one to two decades [28, 83]. The anterior segment distinguishes L-ORD from other dystrophies: long anterior zonules, inserted less than 3 mm from the centre of the lens and best seen by retroillumination before dilation, which may appear before the age of 40 (the youngest case was 24 years), and atrophy of the iris stroma and the pupillary collarette, with photophobia and poor dilation [28, 72]. In a series of 6 patients with p.(Ser163Arg), the median count was 160 long zonules per eye, symmetrical between eyes and inversely related to age [84]. In the Belgian founder variant p.(Pro188Thr), long zonules were absent in 24 of 26 patients, and iris transillumination and sphincter atrophy were the dominant anterior findings [80]. The fundus first shows yellowish subretinal deposits in a reticular pattern, similar to pseudodrusen, predominating in the temporal macula and the inferior mid-periphery; this is followed by confluence of the deposits, disorganisation of the ellipsoid zone and areas of scalloped atrophy extending to all quadrants [28, 83]. Cataract is part of the phenotype; the glaucoma described in some families appears to correspond to primary open-angle glaucoma not caused by the gene [28, 72]. No extraocular manifestations are attributed to the gene [28, 74].

Neovascular complications take two forms. Exudative type 1 CNV, in the transition zones between atrophic and preserved retina, causes sudden treatable loss and warrants urgent examination in the presence of metamorphopsia, as in Sorsby dystrophy [28]. In four patients with p.(Ser163Arg), non-exudative type 1 membranes, extensive and progressive in the mid-periphery, grew over years without fluid and without atrophy in the areas involved [86]. Spontaneous regression of CNV has been described in isolated cases [28, 78].

6.4.4. Diagnosis

There are no formal criteria. The diagnosis rests on a dominant family history, night blindness in the 5th decade, long anterior zonules and reticular subretinal deposits, and is confirmed by identification of a heterozygous pathogenic variant in C1QTNF5 [26, 28]. Two-colour dark adaptometry at 30° eccentricity is the most sensitive functional test in presymptomatic carriers; the full-field ERG shows scotopic reduction with b-wave predominance and normal photopic responses early on, and prolonged dark adaptation (16 hours) improved the a- and b-waves in 4 of 8 patients, which indicates dysfunctional but still present rods [28, 29]. A normal ERG does not exclude the disease [28]. SD-OCT shows reticular pseudodrusen, separation between the RPE and Bruch's membrane and choroidal thinning; autofluorescence delineates the deposits (hyperautofluorescent) and the atrophy (hypoautofluorescent), and indocyanine green angiography helps to find peripheral CNV [28, 86]. Measurement of serum vitamin A excludes acquired deficiency, which produces a similar scotopic picture [28]. Molecular testing is done with a retinal dystrophy panel or exome sequencing covering the whole globular domain; a negative result does not exclude an L-ORD phenotype, because there are families not linked to the locus [28, 71]. The report should state transcript NM_001278431.2 with its version, the HGVS notation, the zygosity and the ACMG/AMP class; for rare variants such as p.(Asn22Lys), family segregation is necessary before the result is used for predictive testing [8, 82].

In AMD, night blindness is usually absent, onset is after 55–60 years, progression is slower and the deposits and atrophy are mainly macular, without anterior segment changes [28]. Dominant drusen due to EFEMP1 do not affect the anterior segment and have honeycomb deposits peripapillary and nasally [28]. In the terminal stage, L-ORD may be confused with retinitis pigmentosa or choroideraemia, which begin in childhood and progress more slowly [28]. Late-onset night blindness with peripheral flecks due to defects of the retinoid cycle is neither dominant nor associated with C1QTNF5 [28]. The yellow-white dots of the early forms may mimic fundus albipunctatus, and repeating the ERG over the years helps to correct the diagnosis [81].

6.4.5. Treatment

There is no targeted treatment and no specific guideline; management addresses the complications and quality of life, and the visual outcome depends on the structural state of the fovea [28, 74]. Exudative CNV is treated with intravitreal anti-VEGF, off-label in the USA and, in the EU, within the general indication of ranibizumab for CNV. The evidence is limited to isolated cases: three monthly ranibizumab injections after failure of argon laser, ranibizumab in one eye and bevacizumab in the other, a single aflibercept injection in a 72-year-old woman with advanced atrophy, and 14 injections over 4 years in a man with bilateral CNV [28, 82, 87–89]. In the absence of doses published for L-ORD, the doses of section 7.3.3 are used by extrapolation. For ranibizumab, the SmPC indicates 0.5 mg (0.05 ml) per injection in adults, which is also the maximum dose per administration, with a minimum interval of 4 weeks in the same eye. For aflibercept, 2 mg (0.05 ml), with a minimum interval of 1 month in myopic CNV. For bevacizumab, 1.25 mg (0.05 ml), according to the AAO summary for AMD and the SmPC of Lytenava® [21, 22, 90, 91]. The 2026 case illustrates an individualised schedule: bevacizumab every 4–5 weeks, change to aflibercept because of partial response, progressive extension of the intervals to 3 months and then treatment as needed, with retreatment for fluid, membrane growth, haemorrhage or a fall in acuity [82]. The extensive non-exudative membranes were not treated in the series that described them and did not develop atrophy in the areas involved, so injection is justified only in the presence of exudation [86]. Laser and photodynamic therapy, used in the past, have a questionable risk-benefit ratio [28].

Phacoemulsification is safe despite the long zonules. In a British series of 11 eyes from 7 patients, capsulorhexis was more difficult but was always completed, without intraocular lens stability problems over 6–84 months. Acuity improved when the foveal photoreceptors and RPE were preserved, and most patients reported subjective benefit, even with advanced disease [31]. Oral vitamin A has been tried by analogy with vitamin A deficiency. At a dose of 50,000 IU/day for 1 month, in 3 patients, it accelerated dark adaptation kinetics without normalising them. At a dose of 15,000 IU/day for 6 months, in one patient, it shortened adaptation only while it was being taken; in another case, it improved subjective colour and contrast without objective change [28, 29, 72]. These doses exceed the tolerable upper level for adults (3000 µg of retinol activity equivalents per day, about 10,000 IU), and vitamin A does not form part of the current recommendations (section 7.7) [28, 92, 93]. Metformin corrected the metabolic changes and the deposits in patient-derived RPE, but has not been tested in patients and is not recommended [28, 76].

The gene therapies under study are genome editing approaches, still at the preclinical stage. The dominant-negative mechanism makes the benefit of simply adding a normal gene with an adeno-associated virus (AAV) vector uncertain, although the addition of normal CTRP5 attenuated the phenotype in patient-derived RPE [28, 76]. The preferred strategy targets the mutant allele, by inactivation followed by replacement or by correction. The variant c.489C>G creates a new protospacer adjacent motif (PAM), which allows the Cas9 nuclease or a prime editor to target the mutant allele only. Cas9 cuts both strands and repair occurs mainly by non-homologous end joining, which is useful for inactivating the allele. The prime editor, a Cas9 nickase fused to a reverse transcriptase and guided by a pegRNA, can reverse the substitution with little off-target editing, but its size makes packaging into AAV difficult and prolonged expression of the machinery raises safety concerns. None of the known variants is a target for cytidine editors, and only p.(Pro188Leu) would be a target for an adenine editor [30]. The RPE is transfected by viral vectors more easily than photoreceptors, and the accessibility of the retina to imaging and functional testing favours trial design [30]. The 2023 natural history study was designed to prepare for an editing trial: it identified retinal regions with a therapeutic window at all stages, such as the region 6° above the fovea, where, 14 years before the local critical age of 49 years, the only expected change is the sub-RPE deposit [30]. In October 2026 no clinical trial of gene therapy or editing in L-ORD was identified in the sources consulted.

6.4.6. Genetic Counselling and Surveillance

Transmission is autosomal dominant with complete penetrance: each child of a carrier has a 50% risk and, if the variant is inherited, will develop the disease, with intrafamilial variability in age at onset and rate of progression, particularly with p.(Pro188Thr) [28, 80]. Identification of the variant allows cascade testing. Carriers can be recognised clinically by adaptometry or by the long zonules a decade or more before symptoms, but the absence of these signs does not exclude carrier status [28, 29]. As the disease begins in adulthood and has no preventive treatment, predictive testing in minors follows the principles of section 8.3. Prenatal diagnosis and preimplantation genetic testing are possible when the familial variant is known (section 8.4) [28, 94]. Correcting a diagnosis of AMD to L-ORD changes the prognosis and the family implications [28].

6.4.7. Epidemiology and published case

Prevalence is unknown; the 2022 review estimated more than a hundred confirmed patients worldwide, in families from the USA, the United Kingdom, Canada, France and Belgium, with probable underdiagnosis due to confusion with AMD and possible double counting of relatives seen at different centres [26, 28]. Most patients are of Western European descent; the p.(Ser163Arg) founder variant goes back to a probable ancestor from south-east Scotland and p.(Pro188Thr) is a founder variant in Belgium [28, 80]. The independent recurrence of c.489C>A and the description, in 2026, of a Chinese family from Singapore with c.489C>G without European ancestry indicate that codon 163 is also a mutational hotspot [73, 78]. The sources consulted do not include patients from Portugal or Brazil; an image of long anterior zonules in a carrier of a C1QTNF5 variant was published in 2024 by ophthalmologists from Coimbra [95]. The European reference network is ERN-EYE [24].

In family 2 described by Stanton and colleagues, the index case noticed difficulty with dark adaptation after light exposure in the mid-5th decade. Night blindness worsened over the following decade, until a torch was needed in dimly lit settings. At 60 years, acuity had fallen from 6/6 in both eyes to 6/12 in the right and 6/9 in the left, with peripapillary chorioretinal atrophy extending close to the fovea and sub-RPE deposits on OCT [73]. Sequencing showed absence of p.(Ser163Arg) and the heterozygous variant c.562C>A p.(Pro188Thr), present in two other affected relatives with onset in the mid-7th decade and at the end of the 6th [73]. The case illustrates intrafamilial variability in age at onset and the need to sequence the entire globular domain, rather than testing only for the founder variant.

7. Treatment and Risk Management Strategies

7.1. Objectives and evidence base

There is no treatment that corrects the TIMP-3 defect and no gene therapy available; the aim is to detect and treat CNV before scar formation, preserve central vision and support adaptation to visual loss [9, 19]. There is no randomised trial or specific guideline for Sorsby dystrophy; the evidence comes from case reports and retrospective series with few eyes, brought together in a systematic review, and practical recommendations are extrapolated from guidelines on inherited retinal degenerations and on CNV in AMD, as well as from the European ranibizumab label for CNV of any cause [19–22].

7.2. Education, self-monitoring and general measures

Patients should be explicitly informed of the risk of CNV and trained in daily self-testing with the Amsler grid, to detect metamorphopsia and seek emergency eye care immediately [3, 9, 11]. The summary of the AAO recommendations for AMD calls for monitoring of monocular near vision (reading and Amsler grid), surveillance of the fellow eye in patients with unilateral disease, immediate reporting of new symptoms and smoking cessation [22]. The 2022 review advises avoiding tobacco and maintaining a diet rich in fruit and vegetables, on the grounds that these habits may delay degeneration [9]. The authors who described the form with pulmonary involvement recommend smoking avoidance and physical exercise for all patients, and investigation for lung disease from the age of 55 years [7]. The French PNDS for genetic maculopathies sets out the same lifestyle rules for all inherited maculopathies, in greater detail: abstinence from smoking, a varied diet rich in fruit, vegetables and antioxidants, fish three times a week, regular physical activity, even moderate, of about one hour a day, and protection from bright light with filter lenses and a peaked cap; these measures are preventive and do not modify the genetic defect [23].

The AAO statement recommends low vision rehabilitation at baseline and then every 1–2 years as needed, attention to signs of depression, support with mobility, employment and school, and information about registries and clinical trials [20]. The Oxford Desk Reference stresses the need for regular reviews, because copathologies such as macular oedema or cataract may arise, and for psychological support and a multidisciplinary team [59].

The French PNDS describes visual rehabilitation in detail. It begins with the best possible optical correction and an assessment by a low vision orthoptist, who schedules rehabilitation sessions in liaison with the ophthalmologist and the specialised optician, close to home or in a multidisciplinary centre [23]. Therapeutic education focuses on training eccentric fixation, that is, the use of preserved retina outside the fovea, and on handling optical aids (magnifying lenses, loupes, telescopes), non-optical aids (large-print books, talking clocks, enlarged keyboards) and electronic aids (reading systems, mini-cameras attached to spectacles that read the text pointed at, character and voice recognition software) [23]. Filter lenses with wraparound frames and wide arms improve outdoor comfort when there is photophobia; Braille and institutional care are rarely necessary, but a mobility instructor, occupational therapy and, in severe loss, a guide dog may be useful; physiotherapy treats musculoskeletal pain caused by compensatory postures [23]. The risk of depression should be reassessed periodically and a psychology consultation offered to the patient and family, especially in the phase of loss of acuity that precedes stabilisation and learning of eccentric fixation [23]. Referral to patient organisations is offered systematically, with the decision left to the patient [23].

7.3. Treatment of choroidal neovascularisation with anti-VEGF

7.3.1. Evidence

The introduction of intravitreal anti-VEGF, about five years after photodynamic therapy (early 2000s), changed the prognosis of the disease [9, 19]. The systematic review by Baston and colleagues (search in February 2021; 907 records; 14 publications and one own case) gathered 31 cases with a mean follow-up of 54 months: of the 27 eyes in the case reports, 67% maintained decimal Snellen acuity ≥0.2 (functional vision with reading aids) and 51% maintained ≥0.5 (reading and driving vision) at the end of follow-up [19]. Of the 20 eyes with acuity before and after treatment, 7 remained stable, 6 gained more than one line and 5 lost more than one line [19]. Immediate treatment (13 eyes) was associated with a mean acuity gain of 0.16 and delayed treatment (5 eyes) with a loss of 0.38, although baseline acuity was better in the delayed group (1.12 versus 0.46) [19]. A mean of 12.78 injections was administered [19].

Two cohorts presented at congresses, cited in the review, point in the same direction. In a group of 8 patients (9 eyes) with p.(Ser204Cys), 22.2% of treated eyes had significant visual loss at 24 months, compared with 100% in a historical control group, which the authors translated into a 96% risk reduction [19]. The review gives discordant denominators for these two series between the text and the table (five patients, eight eyes or nine eyes), so the absolute numbers should be read with caution [19]. In another series of 5 patients treated with bevacizumab and followed for at least 60 months, acuity stabilised, but there was a linear decline of about 0.1 logMAR per year until scar formation [9, 19]. In the 2015 German series, patients with CNV or polypoidal vasculopathy responded favourably to bevacizumab [17]. Individual reports describe regression of CNV on OCTA with two monthly bevacizumab injections, partial recovery from 1/10 to 4/10 with eight injections, and maintenance of 20/20 after 15 years with ranibizumab [19, 35, 48].

When a disciform scar is already present, the benefit of anti-VEGF is limited, and the disease may progress despite effective control of CNV, through geographic atrophy or macular scarring [9, 19]. The French PNDS for genetic maculopathies takes the same position: intravitreal anti-VEGF injections are discussed in the active phase of CNV and are not indicated, being ineffective, in the fibrotic phase; the document recognises no other validated pharmacological treatment for inherited maculopathies [23]. Cases of patients who lost vision despite several years of injections, such as the Czech patient with final acuities of 0.2 and 0.08 at 44 years after photodynamic therapy, 18 bevacizumab injections and 13 ranibizumab injections, illustrate this limitation [11].

7.3.2. Treatment regimens and divergence between authors

There is no consensus on the regimen. Tsokolas and colleagues treated two sisters for 12 years with bevacizumab, first on a pro re nata (PRN, as needed) regimen and, from April 2015, on a treat-and-extend (T&E) regimen, and concluded that T&E appeared to minimise recurrences; Kaye's series also advocated T&E [9, 96]. Baston and colleagues do not recommend it generically, because long periods without activity are frequent in this young population; in their patient, 24 PRN ranibizumab injections over ten years maintained 20/20 [19]. The European ranibizumab label for CNV defines treatment individually, according to activity, and accepts that some patients may need only one injection in the first 12 months and others monthly injections [21]. The AAO, for CNV in AMD, recommends reassessment about 4 weeks after each treatment and subsequent decisions according to clinical findings [22].

7.3.3. Medicines, doses and dosage

The table summarises the medicines used. As there is no published Sorsby dystrophy-specific dose in a guideline, the reference dose is that of the label for CNV (ranibizumab in the EU) or that of the AAO guideline for CNV in AMD, applied by extrapolation and stated as such [21, 22]. The French PNDS for genetic maculopathies also does not specify an anti-VEGF medicine, dose or regimen, so it does not change the values in the table [23].

Ranibizumab should be administered by an ophthalmologist experienced in intravitreal injections, using aseptic technique; patients are monitored during the following week and instructed to report symptoms of endophthalmitis immediately, and IOP and optic disc perfusion should be monitored [21]. Very common adverse effects include vitritis, vitreous detachment, retinal and conjunctival haemorrhage, eye pain, floaters and hyperaemia; raised IOP, cataract, uveitis and RPE detachment or tear are common; endophthalmitis and blindness are uncommon [21]. Limited data on bilateral treatment, including on the same day, do not suggest an increase in systemic effects, and the medicine should not be combined with other anti-VEGF agents [21]. The AAO asks that the patient be instructed to report eye pain, increasing redness, blurred vision, photophobia or increased floaters after each injection [22].

7.4. Comparative regulatory status

Sources: [21, 90, 91, 98, 100–103]. Authorisation is not equivalent to marketing or reimbursement; Infomed records a public funding assessment report for Lucentis® [102]. ANVISA open data record the products and registration dates, but not the indications approved in the Brazilian package insert [103].

7.5. Studies supporting treatment

The MINERVA trial is the only randomised trial in CNV of uncommon causes and was the basis for the European indication; the list of diagnoses in the “miscellaneous” category appears in supplementary material, and the text of the article does not state whether patients with Sorsby dystrophy were included [21, 66]. The Sorsby dystrophy data come from retrospective studies, with heterogeneous reporting, eyes pre-treated with photodynamic therapy or corticosteroids, variable follow-up and probable publication bias; they do not allow comparison of medicines or regimens, and the 96% relative reduction rests on a historical control of few eyes [9, 19]. No negative, suspended or withdrawn trials were identified for this disease on ClinicalTrials.gov [104].

7.6. Abandoned treatments

Thermal laser photocoagulation did not improve acuity and was associated with aggressive recurrences of CNV; in the Moorfields cohort, argon laser and photodynamic therapy were ineffective [9, 16]. In a North American family with p.(Ser204Cys), the patient treated with several laser sessions reached bilateral 20/400 through foveal recurrence and disciform scarring [6, 105]. Photodynamic therapy with verteporfin, alone or combined with an intravitreal corticosteroid, had limited and unpredictable benefit and was abandoned; functional success was associated with subretinal fibrovascular scarring with long-term visual loss [9, 19]. These treatments should not be offered as an alternative to anti-VEGF [9].

7.7. Investigational treatments and isolated reports

Oral vitamin A (off-label). In 1995, 50,000 IU/day of oral vitamin A abolished night blindness within a week in patients from a family at an early stage [45]. In a 2022 study, a patient on high-dose vitamin A, without an approved indication, had marked improvement in dark adaptation and dark-adapted thresholds [18]. Low doses were ineffective and high doses caused hepatotoxicity, so vitamin A has not been adopted in practice; it has no effect on CNV [9, 19]. OMIM stresses that the minimum effective dose, long-term toxicity and effect on natural history remain to be determined [2]. For comparison, the European Food Safety Authority (EFSA) maintains at 3000 µg of retinol equivalents (RE) per day (about 10,000 IU) the tolerable upper intake level (UL) of preformed vitamin A in adults, including women of childbearing age, pregnant and breastfeeding women and postmenopausal women, with teratogenicity as the critical effect and hepatotoxicity among the effects assessed; the value rests on a no observed adverse effect level (NOAEL) of 3000 µg/day for congenital malformations, without an uncertainty factor, and the lowest dose associated with hepatotoxicity in human reports is 2.5 times that NOAEL [93]. In the United States, the Food and Nutrition Board of the Institute of Medicine (IOM, now the National Academies) set in 2001 the same UL of 3000 µg/day of preformed vitamin A for adults from 19 years, including pregnancy and lactation, by two distinct routes: in women of childbearing age, a NOAEL of 4500 µg/day for cranial neural crest-derived malformations, divided by an uncertainty factor of 1.5; in other adults, hepatotoxicity, with a lowest observed adverse effect level (LOAEL) of 14,000 µg/day (Ito cell hypertrophy after 10 years of intake), divided by a factor of 5 [92]. For preformed vitamin A (retinol and retinyl esters), 1 µg RE corresponds to 1 µg of retinol activity equivalents (RAE), the unit used in the USA, and 1 IU of retinol corresponds to 0.3 µg RAE; the adult UL is thus equivalent to 10,000 IU/day [93, 106]. The dose used in 1995 corresponds to about 15,000 µg/day, five times that limit and above the IOM hepatic LOAEL; chronic toxicity is described mainly with intakes of 30,000 µg/day or more over months or years, and acute toxicity with single or short-term doses of 150,000 µg or more in adults, so the teratogenic and hepatic risks must be weighed before any use [9, 92, 93].

The two assessments diverge on four points. In children and adolescents, both extrapolate the adult value, but the IOM adjusts it by relative body weight and EFSA by allometric scaling (body weight raised to 0.75), with different age groups: the EFSA values are higher from 1 to 8 years, from 11 to 13 years and at 18 years, and lower at 9–10 years (1500 versus 1700 µg/day), at 14 years (2000 versus 2800 µg/day) and from 15 to 17 years (2600 versus 2800 µg/day) [92, 93]. In infants, the IOM derives 600 µg/day from a LOAEL of about 6000 µg/day (bulging fontanelle after 1–3 months of 5500–6750 µg/day) with an uncertainty factor of 10 and applies it from birth, whereas EFSA sets 600 µg RE/day from 4 months [92, 93]. On bone, the IOM considered the data on bone mineral density and hip fracture contradictory and did not use them, and EFSA concluded that causality between intakes of 1000–3000 µg RE/day and fracture risk cannot be established, applying the UL of 3000 µg RE/day also to postmenopausal women, instead of the level of 1500 µg RE/day advised in 2002 by the European Commission's Scientific Committee on Food (SCF) [92, 93]. On scope, the IOM states that the UL is not intended for people receiving vitamin A under medical supervision or for patients treated with vitamin A for diseases such as retinitis pigmentosa, and accepts higher doses in controlled clinical trials, with informed consent about toxicity and safety monitoring; EFSA applies its values to the European general population and provides for an exception for therapeutic use under medical supervision only in the case of supplemental β-carotene, not preformed vitamin A [92, 93].

The warnings from the three sources apply to an adult with Sorsby dystrophy considering high-dose vitamin A. The teratogenic risk is concentrated in the first trimester, with craniofacial, central nervous system (excluding neural tube defects), thymic and cardiac malformations; the National Institutes of Health (NIH) advises against supplements above 3000 µg RAE (10,000 IU) per day for women who are pregnant, who may become pregnant or who are breastfeeding [92, 106]. Alcohol potentiates the hepatotoxicity of vitamin A, whose spectrum ranges from a reversible rise in liver enzymes to fibrosis, cirrhosis and, at times, death [92]. Chronic toxicity presents with dry skin, muscle and joint pain, fatigue, depression and abnormal liver function tests, and acute toxicity with severe headache, blurred vision, nausea, dizziness, incoordination and intracranial hypertension [92, 106]. Oral retinoids, such as acitretin and bexarotene, add to the risk of hypervitaminosis A, and orlistat reduces vitamin A absorption [106]. β-carotene is not teratogenic and does not cause hypervitaminosis A, but supplemental β-carotene increased the risk of lung cancer in smokers, and neither the IOM nor EFSA set a UL for it; EFSA advises smokers to avoid supplements containing β-carotene [92, 93, 106]. Its use is justified only in a research setting or with specialist monitoring, with off-label use declared.

Intravitreal triamcinolone (off-label). A 35-year-old woman with aggressive bilateral CNV, treated from 2003 with photodynamic therapy and intravitreal triamcinolone 4 mg, subsequently maintained on 4 mg every 3–4 months in the right eye, retained 20/20 after 15.5 years; the left eye, with extensive scarring, was not treated [107]. During the periods of switching to bevacizumab and then to ranibizumab, the patient again had exudation and haemorrhage about one month after each injection, which prompted a return to triamcinolone; corticosteroid therapy necessitated extraction of a steroid-induced cataract and filtration surgery for uncontrolled glaucoma [108]. This is a single eye, with risks of cataract and of ocular hypertension or steroid-induced glaucoma, and without benefit once a scar is present [9, 108].

Subcutaneous adalimumab (off-label). In the same patient, the switch to bevacizumab was accompanied by activity, which regressed with further triamcinolone; because of the risk of endophthalmitis associated with intraocular corticosteroid injections in an eye with a filtering bleb, she was switched to subcutaneous adalimumab (Humira® and biosimilars), with two initial doses of 40 mg followed by 40 mg twice a month, and had 18 months without activity, with no need for rescue corticosteroid or anti-VEGF and no known adverse effects, with 20/20 [108]. This regimen is close to the European label regimen for non-infectious uveitis in adults (initial dose of 80 mg and then 40 mg on alternate weeks from the following week), the indication from which the dose is extrapolated; the label contraindicates the medicine in active tuberculosis, severe infections and New York Heart Association class III–IV heart failure [109]. The rationale is local regulation of TNF-α by TIMP-3, but data from a single patient do not support use outside studies, and the medicine entails immunosuppression and a lengthy funding process [9, 108].

Corticosteroid combined with anti-VEGF. In a patient with intraocular inflammation attributed to bevacizumab, the combination of bevacizumab with intravitreal dexamethasone controlled the CNV without inflammation, and the switch to ranibizumab was well tolerated [99].

Preclinical approaches. Base editing was analysed in silico for c.610A>T: a glycosylase base editor could revert the amino acid to the original, and an adenine base editor with SpCas9 could introduce p.(Ser204Arg), predicted to be tolerated, with a bystander edit p.Ile205Thr [58]. Correction of the variant by CRISPR-Cas9 in iPSC-derived RPE reduced the sub-RPE deposits [43]. Patient iPSC lines exist, including one with c.484G>A [42, 110]. The 2024 review raised the possibility of testing pegcetacoplan in Sorsby dystrophy, a C3 inhibitor approved by the FDA in February 2023 for geographic atrophy in AMD, with the caveat that the mechanisms of the two diseases differ; there are no data in Sorsby dystrophy [15].

7.8. Developments in the last 12 months

Between November 2025 and October 2026 no interventional clinical trial, regulatory application or authorisation was identified for Sorsby dystrophy; ClinicalTrials.gov lists only a Foundation Fighting Blindness registry of inherited retinal degenerations, recruiting [104]. The level of evidence of the developments is preclinical: a functional study published in December 2025 showed that p.(Tyr191Cys) reduces binding to and inhibition of MMP2 and MMP9 in ARPE-19 cells [44]; the US National Institutes of Health are funding until 2027 a project on metabolic dysfunction of the RPE through ECM remodelling in Sorsby dystrophy [111]; and a 2026 imaging description characterised a multilobulated pattern of RPE atrophy [57]. The absence of trials in the databases consulted does not prove the non-existence of unregistered programmes. In the L-ORD grouped in this article, the developments of the period are observational: the first family without European ancestry, Chinese from Singapore, with c.489C>G and spontaneous regression of CNV, and a case of bilateral CNV with the p.(Asn22Lys) variant controlled with anti-VEGF for 4 years; gene editing remains preclinical (section 6.4.5) [30, 78, 82].

7.9. Special populations and situations

Pregnancy and breastfeeding. There are no clinical data on exposure to ranibizumab in pregnancy; from its mechanism of action, the label considers it potentially teratogenic and embryofetotoxic, recommends effective contraception in women of childbearing potential, use in pregnancy only if the benefit justifies the risk and an interval of at least three months between the last dose and conception; breastfeeding is not recommended during treatment [21]. As CNV often appears in the 4th decade, this should be discussed before a planned pregnancy. High-dose vitamin A should not be used in pregnancy, when planning pregnancy or while breastfeeding: the NIH advises against supplements above 3000 µg RAE (10,000 IU) per day in these situations, teratogenicity is the critical effect underlying the IOM and EFSA limits, and EFSA advises women planning pregnancy or pregnant to avoid liver and offal [92, 93, 106].

Children and adolescents. The classic disease rarely manifests before adulthood, but signal peptide variants cause maculopathy in the 2nd decade and CNV at 13 years was described in a Finnish family [2, 38]. The European label does not establish the safety and efficacy of ranibizumab below 18 years outside retinopathy of prematurity; in MINERVA, five adolescents aged 12–17 years treated with 0.5 mg improved by between 5 and 38 letters, without a dosage recommendation [21].

Lung disease. Respiratory investigation from the age of 55 years and smoking avoidance are recommendations of the authors of the report, without a guideline; the same authors suggest testing for TIMP3 variants in patients with familial bronchiectasis or emphysema and a history of visual loss or CNV [7].

Transition and working life. The disease appears during working age and has implications for driving, which depends on acuity (the decimal threshold of 0.5 is used in the systematic review as “driving vision”), and for employment; the AAO recommends vocational support, assistive technology and rehabilitation [19, 20]. The French PNDS sets an operational criterion: in adults with acuity below 5/10 or with a central scotoma, driving is no longer permitted, and fitness to drive (acuity and binocular visual field) and for the workplace is reassessed at follow-up visits [23]. When the occupation is incompatible with the visual loss, the occupational physician and the social worker take part in adapting the workstation and hours or in occupational retraining, and rehabilitation in a specialised institute is offered to adults with visual impairment [23]. In families with early-onset variants, the school measures described in the same document for maculopathies in children apply by analogy: a seat facing the board with adequate lighting, a computer or tablet with magnification, digital materials, a school support assistant when needed, extra time in examinations and an individualised support plan; at the end of adolescence, transition to adult services should be organised so as not to interrupt follow-up [23, 38].

7.10. Summary of recommendations and divergences

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

The disease is transmitted in an autosomal dominant manner with complete penetrance: each child of a carrier has a 50% probability of inheriting the variant and, if they inherit it, will develop the disease, although age at onset and severity cannot be predicted exactly [9, 13]. The recessive form proposed in the Finnish family from Lavia was explained by heterozygosity in a couple in which both spouses were affected; the sources do not describe the phenotype of any homozygotes [6, 10]. De novo occurrence is documented, with confirmed paternity and maternity, so the absence of a family history neither excludes the disease nor guarantees zero risk for siblings [11]. Germline mosaicism has not been described in the sources consulted, which does not allow this mechanism to be excluded; therefore, even with clinically and genetically negative parents, zero risk for the siblings of the index case cannot be asserted. In the absence of gene-specific empirical data, the Oxford Desk Reference considers a recurrence risk of 1–2% for siblings reasonable after an apparently sporadic dominant variant [113]. When the variant is transmitted, severity in the child may be similar to, greater or lesser than that of the parent, and apparently unaffected parents should be examined carefully before concluding that they are not carriers [13, 113].

8.2. Cascade and predictive testing

Identification of the familial variant allows testing to be offered to at-risk relatives, with genetic counselling; the AAO notes that the implications of testing asymptomatic people, in the absence of therapies that alter the underlying defect, must be discussed, and that counselling should help with psychosocial risks and the implications for the family [20]. In Sorsby dystrophy, predictive testing has a concrete clinical utility: it identifies who should learn self-monitoring and be followed up so that CNV can be treated early, whereas non-carriers can forgo surveillance [11, 13]. The Oxford Desk Reference places this scenario within predictive testing for diseases in which the result changes clinical management: testing is offered at a consultation that covers natural history, the implications of a high-risk result, the surveillance and treatment available and the evidence of their benefit (surveillance remaining accessible to those who decline testing), the implications for other relatives and the possible consequences for insurance and credit; consent is documented and the way the result will be given is agreed beforehand [112]. In people at 25% risk, whose result may reveal a parent's status, testing is performed only after attempts to counsel the parent at 50% risk have been exhausted [112]. As family testing may reveal undisclosed paternity, this possibility should be discussed in pre-test counselling, especially when parents are studied to demonstrate a de novo occurrence [11, 112]. The Oxford Desk Reference recommends taking the age at onset in the family into account when interpreting a normal examination, because a normal fundus at 20 years is of little reassurance in an adult-onset disease [60]. Ophthalmological examination of relatives may detect early signs, such as hypofluorescence on late ICGA, thickening of Bruch's membrane or altered colour contrast, but their absence does not exclude carrier status [7, 11, 17, 36].

8.3. Minors

In one of the Czech families, testing of the patient's 13-year-old daughter was recommended only after consultation with a clinical geneticist and had not yet been carried out; in another family, an asymptomatic sister declined testing [11]. As the classic form does not manifest in childhood and relevant surveillance begins in adulthood, predictive testing in asymptomatic minors should be considered case by case, with counselling, the exception being families with very early-onset variants [2, 11, 38]. This position coincides with the British guidance summarised in the Oxford Desk Reference: in adult-onset diseases without effective preventive or therapeutic measures in childhood, testing should generally be deferred until the child can decide for themselves, informing the family of the existence of the test and the reasons for deferral; when effective measures exist in childhood, testing should be offered [112]. The French PNDS for genetic maculopathies is more restrictive: a minor is tested only with the agreement of the parents or guardian and if they have clinical signs, so that, in a dominant disease, the unaffected minor child cannot be tested to learn their status; it also recommends discussing with parents the psychological impact of systematic clinical examination of the siblings of young patients [23]. In families with early-onset variants, the exception accepted above applies only where the legal and ethical framework permits it.

8.4. Prenatal and preimplantation genetic testing

Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing are possible [59, 60]. Prenatal diagnosis is performed by chorionic villus sampling or amniocentesis, and sequencing of cell-free DNA in maternal plasma to infer the fetal genotype is available in some centres when the variant is known [94]. Preimplantation testing requires ovarian stimulation, in vitro fertilisation and embryo biopsy, with pregnancy rates of 21% per oocyte retrieval and 25% per embryo transfer in monogenic diseases, high costs and limited safety data [94]. Gamete donation (sperm if the carrier is the father, oocytes if the mother) is another way of avoiding transmission of a dominant disease [94]. The decision should weigh onset in adulthood, complete penetrance, the existence of effective treatment for CNV and the variability of severity [9, 19]. In France, the PNDS for genetic maculopathies treats preimplantation and prenatal diagnosis as tightly regulated possibilities, to be discussed case by case with a genetic counsellor or geneticist, with numerous restrictions and with the limits of distinguishing rare benign from pathogenic variants; for dominant maculopathies it gives a 50% risk in each pregnancy when one parent carries the causal variant, noting that variability of expression prevents prediction of severity in the child [23].

8.5. Content of counselling

Counselling should explain dominant inheritance and complete penetrance, intrafamilial variability, the significance of CNV and the importance of self-monitoring and rapid access to treatment, pregnancy on anti-VEGF (section 7.9), the possibility of pulmonary involvement described in two families and the current absence of gene therapy [7, 9, 19, 21]. The AAO recommends repeating counselling at later stages of life [20]. The French PNDS asks that the diagnosis be disclosed at a dedicated consultation, which may bring together ophthalmologist, geneticist, psychologist, orthoptist and social worker, with explanation of the disease, its course and the possible or non-existent therapies, the plan for follow-up and detection of complications, the risks of recurrence and transmission and with presentation of patient organisations; the genetics clinic consultation should take place as early as possible and support continues at each difficult phase of the disease [23]. In L-ORD, recurrence risks are those of dominant inheritance with complete penetrance, and carriers may be recognised by adaptometry or long anterior zonules before symptoms (section 6.4.6) [28, 29].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The only published prevalence estimate is 1/220,000, presented in a 2017 review and repeated in subsequent reviews [9, 14, 15]. It does not come from a population study and should be read as an order of magnitude (≈0.45 per 100,000); Orphanet records the prevalence as unknown and not validated [1, 3, 9]. The disease affects both sexes [9]. As context, the French PNDS estimates that genetic maculopathies account for about 15% of retinal dystrophies followed at a retina referral centre, a hospital case-mix proportion that does not measure population prevalence and within which Sorsby dystrophy is among the rare forms [23]. For L-ORD there is also no prevalence estimate: Orphanet records it as unknown and the 2022 review counted more than a hundred confirmed patients, mainly of Western European descent (section 6.4.7) [26, 28].

9.2. Geography and founder effect

Most published cases are European. In the British Isles, where the disease was described, fifteen unrelated families share the p.(Ser204Cys) variant and a common haplotype, and descendants of that ancestor have been found in Canada, the United States, South Africa and Australia [2, 6, 12]. The p.(Ser38Cys) variant is a founder variant in Belgian and northern French families [13]. Families have been described in Germany (p.Tyr174Cys, p.Tyr177Cys, p.Tyr182Cys), Finland (p.Gly189Cys), the Czech Republic (p.Tyr152Cys, the first report in the country), France, Wales (p.Glu162Lys), North America (p.His181Arg), China (p.Tyr191Cys and p.Glu162Lys) and Morocco [7, 10, 11, 17, 35, 44, 49, 50, 110]. The sources consulted do not include data from Portugal or Brazil, which does not mean that the disease is absent from these populations.

9.3. Special populations

Women of childbearing age on anti-VEGF and adolescents with early-onset variants require the precautions described in section 7.9 [21]. Patients with late-onset variants are often followed as AMD, which delays diagnosis and family counselling [51, 58].

9.4. Reference networks and patient organisations

In Europe, the relevant reference network is ERN-EYE; the 2024 Czech series was carried out within this network [11, 24]. The AAO lists as resources Retina International and the Foundation Fighting Blindness, which maintains a registry of patients with inherited retinal degenerations [20, 104, 114, 115]. In the United Kingdom, the Oxford Desk Reference lists the Macular Society, the Royal National Institute of Blind People (RNIB), RP Fighting Blindness, Fight for Sight and SENSE [59, 116]. In Brazil there is Retina Brasil [117].

In France, the PNDS for genetic maculopathies organises the care pathway around the rare disease reference centres of the SENSGENE network: MAOLYA (genetic sensory disorders, Montpellier, coordinator of the protocol), REFERET (retinal and macular disorders of genetic origin, Quinze-Vingts National Ophthalmology Hospital, Paris), CARGO (Strasbourg) and OPHTARA (Necker Hospital, Paris), supported by competence centres in Clermont-Ferrand, Grenoble, Brest, Lille, Nantes, Marseille, Nice, Bordeaux, Poitiers, Toulouse and Saint-Denis de La Réunion [23]. Follow-up is led by an expert from one of these centres, who organises the care network close to the patient's home; the general practitioner and ophthalmologist suspect the diagnosis and refer, ensure regular follow-up and coordinate medico-social matters, such as 100% coverage as a long-term condition outside the list (exemption from co-payment), the application to the Maison Départementale des Personnes Handicapées (MDPH) and liaison with the school and occupational health [23]. The French organisations listed include Retina France, the Fédération des Aveugles de France, the Association Valentin Haüy, SOS Rétinite, RETGEN, Information Recherche Rétinite Pigmentaire and Histoire de voir un peu [23].

10. Illustrative Clinical Case

A 54-year-old Czech woman was referred to an ophthalmology department in Prague after a next-generation sequencing panel of 548 ocular genes identified the heterozygous variant NM_000362.5:c.455A>G p.(Tyr152Cys) in TIMP3, then classified as of uncertain significance [11]. She had had night blindness since the age of 40 years and there was no family history of eye disease; her elderly parents denied significant visual problems and did not carry the variant, which, with paternity and maternity confirmed by 16 markers, demonstrated de novo occurrence (pedigree and chromatogram in Figure 1 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC11011298/figure/ijms-25-03744-f001/) [11]. BCVA was 0.8 in both eyes; the fundus showed drusen-like deposits and diffuse chorioretinal thinning, SD-OCT revealed focal disruption of the RPE and photoreceptor layer and FAF showed hyper- and hypoautofluorescent dots in the macula [11].

Six months later, the patient noticed loss of vision in the right eye over three weeks, with BCVA of 0.1 and an Amsler test positive for metamorphopsia; fundoscopy showed only subtle pigmentary changes, but SD-OCT suggested type 2 CNV with serous detachment of the neurosensory retina and OCTA located a subfoveal CNV of about 0.16 mm² in the avascular complex (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC11011298/figure/ijms-25-03744-f002/) [11]. She was treated with intravitreal anti-VEGF at another institution; the article does not describe the medicine, the number of injections or the course of acuity [11]. Her eldest son, a carrier, examined at 30 years and followed annually with OCT and OCTA, remained unchanged at 33 years [11]. Identification of the same variant in a second Czech family, with CNV at 37 and 39 years and an affected father, and the de novo occurrence allowed the variant to be reclassified as pathogenic according to gene-adapted ACMG/AMP criteria [11].

The case illustrates the absence of a family history in a dominant disease, night blindness as the initial symptom several years before CNV, the usefulness of OCTA for detecting a small CNV when the fundus is uninformative and the pathway of reclassification of a variant of uncertain significance. Annual surveillance with OCTA of an asymptomatic carrier was a decision of the authors and not a guideline recommendation [11].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Without treatment, CNV leads to rapid and irreversible central loss: in the Moorfields cohort with p.(Ser204Cys), acuity fell to 20/200 or worse at a median age of 48 years in the first eye and 54 years in the second, and fundus involvement progresses to extensive choroidal atrophy about 35 years after onset, with possible loss of navigational vision in the 7th decade [2, 9, 16]. With anti-VEGF started early, the systematic review shows 51% of eyes with acuity ≥0.5 and 67% with ≥0.2 after a mean of 54 months, and there are patients with 20/20 more than 15 years after the start of treatment [19, 107]. Prognosis depends mainly on the delay between symptoms and treatment, the presence of a scar at the outset and the progression of geographic atrophy, which anti-VEGF does not halt; a decline of about 0.1 logMAR per year until scarring was described in one treated series [19]. Night blindness and scotopic loss progress independently of CNV and reduce vision-related quality of life [18, 19]. In families with pulmonary involvement, respiratory disease may reach chronic respiratory failure decades after visual loss [7].

11.2. Surveillance

There is no validated surveillance protocol for Sorsby dystrophy. The table combines the AAO statement on inherited retinal degenerations, the French PNDS for genetic maculopathies, the summary of the AAO recommendations for CNV, the ranibizumab label and authors' recommendations, identifying the source of each item.

12. Summary and Final Considerations

Sorsby fundus dystrophy is an autosomal dominant macular dystrophy, with complete penetrance, caused by heterozygous variants in TIMP3, with an estimated prevalence of the order of 1/220,000 [9, 14]. Most variants, concentrated in exon 5, create or remove a cysteine; mutant TIMP-3 resists turnover and accumulates in Bruch's membrane, which thickens throughout the retina, disturbing RPE function, the passage of vitamin A to the photoreceptors and local control of angiogenesis [2, 11, 45]. The clinical picture combines drusen-like deposits and reticular pseudodrusen, early scotopic dysfunction, typically bilateral CNV in the 4th–5th decade and progressive geographic and chorioretinal atrophy, with variability depending on the variant and the family [16–18].

The diagnosis should be considered in CNV or diffuse drusen in an adult before the usual age of AMD, especially with night blindness, bilateral disease or a family history of early blindness, and is confirmed by complete sequencing of TIMP3; OCTA and scotopic tests add sensitivity at the early stage [7, 11, 13]. The treatment that changes prognosis is intravitreal anti-VEGF started without delay, which allows useful vision to be maintained in most eyes treated early, without halting atrophy; in the EU and Portugal, ranibizumab is indicated for CNV of any cause, whereas bevacizumab and aflibercept are used off-label [19, 21, 102]. Thermal laser and photodynamic therapy have been abandoned, and vitamin A, intravitreal corticosteroids and adalimumab remain experimental [9, 45, 108].

The organisation of care rests on three pillars: genetic confirmation and cascade testing, education for self-monitoring with rapid access to treatment, and lifelong ophthalmological and low vision follow-up [9, 20]; in France, the PNDS for genetic maculopathies adds annual follow-up by the ophthalmologist and periodic review at a reference or competence centre of the SENSGENE network [23]. The true frequency of pulmonary involvement, the epidemiology outside the United Kingdom and Western Europe, the ideal anti-VEGF regimen and the exact mechanism of TIMP-3 toxicity remain to be clarified, questions that patient-derived models and gene-editing approaches, still preclinical, seek to answer [7, 15, 43, 58]. Late-onset retinal degeneration due to C1QTNF5, grouped in this article, shares with Sorsby dystrophy the deposits beneath the RPE, night blindness and CNV, but is distinguished by later onset, long anterior zonules and scalloped atrophy; genetic testing separates the two diseases, and the founder variant p.(Ser163Arg) is a candidate for gene editing directed at the mutant allele [28, 30].

13. References

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2. Online Mendelian Inheritance in Man (OMIM). #136900 Sorsby fundus dystrophy; SFD. Baltimore: Johns Hopkins University. Available from: https://omim.org/entry/136900
3. GeneGuidance. TIMP3 — Sorsby fundus dystrophy (OMIM 136900). Extraction from the GeneGuidance database of 2026-09-26.
4. Online Mendelian Inheritance in Man (OMIM). 120400 Macular coloboma with brachydactyly type B (Sorsby syndrome). Baltimore: Johns Hopkins University. Available from: https://omim.org/entry/120400
5. Orphanet. Sorsby syndrome (ORPHA:1471). Paris: INSERM; updated 2026-07-02. Available from: https://www.orpha.net/en/disease/detail/1471
6. Online Mendelian Inheritance in Man (OMIM). *188826 TIMP metallopeptidase inhibitor 3; TIMP3. Baltimore: Johns Hopkins University. Available from: https://omim.org/entry/188826
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