Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

Abstract

IMPORTANCE Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported.OBJECTIVE To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. DESIGN, SETTING, AND PARTICIPANTSA multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. MAIN OUTCOMES AND MEASURESLongitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients.RESULTS There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses.CONCLUSIONS AND RELEVANCE This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

Extensive genic and allelic heterogeneity underlying inherited retinal dystrophies in Mexican patients molecularly analyzed by next‐generation sequencing

“…For example, pathogenic changes in CLN3 (MIM *607042) are well known as causative of the severe disease juvenile neuronal ceroid lipofuscinosis or Batten disease, a rare neurodegenerative disorder associating early retinal degeneration and progressive neurologic deterioration (Jalanko & Braulke, ). Nonetheless, CLN3 variants were recently identified in patients with non‐syndromic RDs (Ku et al, ; Wang et al, ). In our study, a novel homozygous p.Arg89Gln CLN3 substitution was identified in an ARRP patient and in her affected sister.…”

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

“…For example, in a rare type of CLN2 disease (autosomal recessive spinocerebellar ataxia type 7), ataxia is the primary phenotype with no accom panying epilepsy or vision loss, 24 and in one type of juvenile CLN2 disease associated with a particular mutation, survival is into the fourth decade of life. 25 Some patients with mutations in CLN3 have only isolated nonsyndromic recessive retinal degeneration, 26 and others experience visual failure, seizures, and cardiac involvement, but no motor deterioration even many decades after disease onset. 27 A pathophysiological link between NCLs and an adult degenerative dementia is assumed given that homo zygous mutations in GRN cause NCLs presenting at around age 20 years with visual failure, seizures, and ataxia, whereas heterozygous mutations in this gene are a common cause of frontotemporal lobar degeneration with TDP43 inclusions.…”

High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses

“…All 33 patients presented with a history of developmental delay or developmental regression leading to NCL molecular genetic test request. There were seven patients with CLN1 ( PPT1 ), five patients with CLN2 ( TPP1 ), seven patients with CLN3 (patients 13 and 15 reported previously []), one patient with CLN5 , four patients with CLN6 , six patients with CLN7 ( MFSD8 ) and three patients with CLN8 disease. Their clinical features and investigation results are summarized in Table .…”

“…In silico analysis and ACMG variant classification of all variants are listed in Table S1. There were 52 different variants in seven genes in 91 patients including 11 novel and 41 known variants: CLN1 (PPT1) variants n = 8 [10][11][12]18,19 ; CLN2 (TPP1) variants n = 11 [12][13][14][20][21][22][23] ; CLN3 variants n = 11 9,12,15,24,25 ; CLN5 variants n = 5 12,21,26 ; CLN6 variants n = 7 12,21,27,28 ; CLN7 (MFSD8) variants n = 8 12 and CLN8 variants n = 2. 17,30 The number of missense and truncating variants for each gene is depicted in Figure S3.…”