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Leber congenital amaurosis
Leber congenital amaurosis (LCA) is a retinal dystrophy defined by blindness and responses to electrophysiological stimulation (Ganzfeld electroretinogram (ERG)) below threshold, associated with severe visual impairment within the first year of life.
ORPHA:65Classification level: Disorder
- Amaurosis congenita of Leber
- Prevalence: 1-9 / 100 000
- Inheritance: Autosomal dominant or Autosomal recessive
- Age of onset: Infancy, Neonatal
- ICD-10: H35.5
- OMIM: 179900 204000 204100 604232 604393 604537 608553 610612 611755 612712 613341 613826 613829 613835 613837 613843 614186 615360 618513
- UMLS: C0339527
- MeSH: D057130
- GARD: 634
- MedDRA: 10070667
The prevalence of LCA is 1/50,000 - 1/33,000 live births and accounts for 5% of all retinal dystrophies and 20% of blindness in school age children.
LCA is characterized by severely reduced visual acuity (less or equal 20/400) or blindness within in the first year of life. Sluggish pupillary responses, roving eye movement, photophobia, high hyperopia, nystagmus, convergent strabismus, or keratoconus may occur depending on the genetic cause. The Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing is pathognomonic. LCA may be associated with mutations in genes linked to syndromes presenting with neurodevelopmental delay, intellectual disability, oculomotor apraxia-type behavior (difficulty moving the eye) and renal dysfunction.
To date, mutations in genes encoding retina specific proteins have been reported to cause LCA. This includes GUCY2D (17p13.1), CEP290 (12q21.33), RPGRIP1 (14q11.2), RDH12 (14q24.1), SPATA7 (14q31.3), AIPL1 (17p13.1), RD3 (1q32.3), CRB1 (1q31-q32.1), CRX (19q13.3), IMPDH1 (7q31.3-q32), IQCB1 (3q21.1), KCNJ13 (2q37), LCA5 (6q14), NMNAT1 (1p36.22), and TULP1 (6p21.3). These mutations cause severe functional impairment or are mostly related to retinal dystrophies. Mutations in CRX or IMPDH1 genes may cause an early and severe onset disease. Patients with GUCY2D mutations present with very slow progressive morphological degeneration and a mostly functional defect.
Diagnosis relies on clinical observation which shows a pupillary response that may be sluggish or near-absent in early life; on funduscopy findings revealing attenuation of retinal vessels along with variable signs of retinal degeneration (from almost unremarkable to an overall granulated appearance). Diagnosis is confirmed by sedated ERG close to or below threshold. Molecular diagnosis is indispensable and may be performed using an arrayed primer extension (APEX) chip (tests a subset of known mutations in known LCA genes; diagnosis achieved in 50-70% of cases) and next generation sequencing (NGS) (covering the whole sequence of the known reported genes; this is the preferable method covering up to 90% of patients). Confirmation of identified mutations and segregation analysis in the parents by Sanger sequencing is the final step.
Differential diagnosis includes retinitis pigmentosa, Alström syndrome, Joubert syndrome, Stargardt disease, Senior-Loken syndrome, Conorenal syndrome and infantile neuronal ceroid lipofuscinosis. Cortical blindness is a frequent misdiagnosis when there is limited access to functional testing or high resolution morphological examination.
Prenatal diagnosis may be offered by specialized laboratories for at-risk couples with identified disease-causing mutations.
LCA is typically an autosomal recessive inherited disease. Rarely, mutations within CRX or IMPDH1 genes are inherited in an autosomal dominant manner that may overlap with the diagnosis of LCA.
Management and treatment
Currently LCA is an incurable disease. Treatment is mainly supportive and includes correction of refractive error and use of low-vision aids. Repeated poking and pressing on the eyes should be discouraged. Periodic ophthalmic evaluation and assessment of the presence of amblyopia, glaucoma, or cataract should be achieved. Therapies are presently being investigated, including gene therapy (particularly for RPGRIP and CEP290) and optogenetics (genetic targeting of light-sensing molecules to residual cells in a degenerate retina).
Vision commonly declines with age until complete blindness is observed most often latest by the third or fourth decade of life.