CLN3-Associated Retinal Degeneration
Title: CLN3-Associated Retinal Degeneration
Author(s): Sam Wilkinson, MD, Cecinio Ronquillo, MD, PhD
Photographer: Glen Jenkins
Keywords/Main Subjects: CLN3, Juvenile neuronal ceroid lipofuscinosis, Batten Disease, Retinal degeneration, Retinitis pigmentosa
Diagnosis: CLN3 disease (also known as juvenile neuronal ceroid lipofuscinosis, Spielmeyer-Vogt-Sjögren-Batten disease, or CLN3 Batten disease)
Description of Case: A 7-year-old otherwise healthy male presented to ophthalmology clinic with decreased distance and near vision. He does not have a family history of blindness. He did not have any non-ocular symptoms.
The patient’s ophthalmic examination was remarkable for a best corrected visual acuity of OD: 20/200 and OS: 20/200. His pupils, external, motility, and fields by confrontation were within normal limits.
Imaging of the patient was obtained, including color fundus photos remarkable for OU retinal pigmentary changes in a ring around the macula. The photos also showed attenuated vessels. Macula optical coherence tomography was remarkable for OU macular thinning and central loss of ellipsoid zone. The electroretinography (ERG) was poor in all visual fields.
The patient’s examination, imaging findings, and ERG were consistent with a cone-rod dystrophy, which prompted genetic testing. Genetic testing revealed a homozygous 1 kb deletion of the CLN3 gene (Batten’s disease). The patient was counseled on prognosis and referred to the pediatric neurology clinic.
Epidemiology: CLN3 disease is the most common type of neuronal ceroid lipofuscinosis (NCL). The prevalence for NCL ranges between 2 to 4 per 100,000 people in the U.S. and as high as 7 per 100,000 in Scandinavian countries. The prevalence for CLN3 disease is unknown.
Genetics: Batten’s disease can be caused by a variety of mutations, including deficiencies and abnormalities of CLN1, CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, CLN8, and CLN10. The patient is homozygous for a 1 kb deletion of the CLN3 gene, which is located on the short arm of chromosome 16 and encodes a transmembrane protein called battenin. 76% of patients are homozygous for CLN3 mutations and 22% have compound heterozygosity. CLN3 protein can be found in many tissues throughout the body. It participates in numerous cellular processes, but its main role is unclear. The common mutations lead to a shortened protein, less of the protein, or misfunctioning protein. The mutations lead to accumulation of proteins and other substances in lysosomes in cells throughout the body; however, the accumulation most adversely affects neurons, causing cell death. The death of neurons leads to the neurologic effects of CLN3 disease. The relation between CLN3 protein and accumulation of proteins in lysozymes is unknown.
Clinical Exam: Patients typically present with vision loss prior to the onset of neurological or psychiatric manifestations. The most common retinal finding is diffuse retinal pigment epithelium atrophy of the macula (63% of patients). Ocular findings include rotary nystagmus, eccentric viewing/overlooking, and macular mottling or typical Bull’s eye maculopathy (20% of patients). Patients may also have pigmentary retinopathy with peripheral pigmentation. Optic disc pallor and arteriolar attenuation can be seen in about 75% of patients. Cataract and secondary acute glaucoma can be a complication of CLN3 disease.
Diagnosis/Testing: Genetic testing of common disease alleles is used to confirm the diagnosis.
OCT findings include reduced thickness of the retinal layers (central, inner, and outer), hyperreflective granules in the retinal pigment epithelium, and homogeneous reflectivity in the inner retinal layer.
Fundus autofluorescence levels imaging reveals a darkened fovea and diffusely subnormal to normal autofluorescence.
ERG shows a significant loss of amplitude. Typically, greater and earlier-onset loss in b-wave amplitude compared to a-wave amplitude, thus lower b:a wave ratio.
Suspicion of Batten disease should prompt the ophthalmologist to refer to neurology. Genetic testing can confirm the diagnosis; however, pathologic diagnosis can be made with skin, rectal mucosa, or lymphocytes when genetic testing is not available or is inconclusive. Electron microscopy of the tissue is used to observe ultrastructural abnormalities indicative of the diagnosis.
Clinical Course: Vision impairment and other neurological disorders start after 4-6 years of normal development. Vision declines from normal vision to functional blindness within one year. The patient’s initial complaint is typically vision loss, night blindness, photophobia, loss of color vision, and/or decreased peripheral vision. Light-dark perception is typically retained for several years. Vision loss is followed by seizure, ataxia, and cognitive decline. Patients also develop a severe stuttering dysarthria around 10 years old. Mental decline continues until mortality in early 20s.
Management: There is no definitive treatment for CLN3 disease. Current treatment protocols aim to address symptom management. Specifically, atypical antipsychotics are used to treat psychiatric manifestations. Anti-convulsant medications are used to manage seizures. And baclofen or tizanidine is used to treat spasticity. Physical therapy, speech therapy, and supportive care are helpful as well. Prognosis is poor. Patients typically live between 15 and 30 years.
Images or video:
Figure 1. Color fundus photos remarkable for retinal pigmentary changes in a ‘bulls-eye’ pattern and attenuated vessels in both eyes.
Figure 2. Macula optical coherence tomography remarkable for central macular thinning with loss of the outer retina in both eyes.
Summary of the Case:
- CLN3 mutation causing decreased or aberrant transmembrane proteins leading to build-up of byproducts that adversely affects neurons first.
- Rod-cone dystrophy with thin retinal layers on OCT, darkened fovea on fundal autofluorescence, and loss of amplitude seen on ERG (b-wave amplitude decreased more significantly than a-wave).
- Non-ocular findings include seizure and neurologic deficit.
- No definitive treatment.
- Ouseph MM, Kleinman ME, Wang QJ. Vision loss in juvenile neuronal ceroid lipofuscinosis (CLN3 disease). Ann N Y Acad Sci. 2016;1371(1):55-67. doi:10.1111/nyas.12990
- Mole SE, Cotman SL. Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochim Biophys Acta – Mol Basis Dis. 2015;1852(10):2237-2241. doi:10.1016/j.bbadis.2015.05.011
- Mirza M, Vainshtein A, DiRonza A, et al. The CLN3 gene and protein: What we know. Mol Genet Genomic Med. 2019;7(12). doi:10.1002/mgg3.859
Faculty Approval by: Paul S. Bernstein, MD, PhD
Copyright statement: Copyright Sam Wilkinson, MD, Cecinio Ronquillo, MD, PhD, ©2021. For further information regarding the rights to this collection, please visit: http://morancore.utah.edu/terms-of-use/
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