Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview

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Retrieved

2021-01-18

Source

Gene_reviews

Trials

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Genes

GUCY2D, CRB1, RPGRIP1, TULP1, RPE65, CEP290, AIPL1, PROM1, NMNAT1, IQCB1, PTPRC, RDH12, CRX, CLTA, LCA5, SPATA7, LRAT, KCNJ13, CRB2, RPE, CXCL8, RHO, MERTK, RD3, CCT2, IMPDH1, OLFM4, NR2E3, IFT140, SH2D3A, TUBB4B, PCYT1B, BCL6, NUB1, KRT20, AHI1, CNTLN, CABP4, SLC7A14, NYX, MPP5, SLC25A22, POC1B, CYP4V2, SLC16A12, SQSTM1, SORD, LOH19CR1, FUT4, HTC2, GUCA2A, GUCA1A, GRB10, GNAT2, GFAP, ERBB2, BEST1, DIO3, CYP3A4, CTNNA1, CNGA3, TNFRSF8, MS4A1, IL6, IRF1, MEF2C, MITF, MYCN, MYO7A, NRL, OTX2, PDE6B, RBP3, PRPH2, RHEB, GRK1, RPS19, CACNA1F, TNF, TUB, LCA10

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Summary

The purpose of this overview is to increase the clinician's awareness of Leber congenital amaurosis (LCA) / early-onset severe retinal dystrophy (EOSRD) and its clinical phenotypes, genetic causes, and management.

The following are the goals of this overview.

Goal 1.

Describe the clinical characteristics of LCA/EOSRD.

Goal 2.

Review the genetic causes of LCA/EOSRD.

Goal 3.

Provide an evaluation strategy to identify the genetic cause of LCA/EOSRD in a proband (when possible).

Goal 4.

Inform (when possible) medical management of LCA/EOSRD based on genetic cause.

Goal 5.

Inform genetic counseling for LCA/EOSRD.

Diagnosis

Clinical Characteristics

Differential Diagnosis

Table 1.

Retinal Disorders to be Considered in the Differential Diagnosis of LCA/EOSRD

Disorder		Gene(s)	MOI	Distinguishing Clinical Features / Assessments
Nonsyndromic	Achromatopsia	CNGB3 CNGA3 GNAT2 PDE6C ATF6 PDE6H	AR	In achromatopsia: Absent / markedly reduced cone responses w/normal rod ERG responses Stationary natural history In LCA/EOSRD: Non-recordable / markedly reduced full-field ERGs Progressive disease
	Congenital stationary night blindness (See X-Linked Congenital Stationary Night Blindness.)	>10 genes ¹	XL AR AD	Can be differentiated by ERG phenotype & natural history
	Ocular (see Ocular Albinism, X-Linked) & oculocutaneous (see OCA Type 4; OMIM PS203100) albinism	>10 genes ²	XL AR	Clinical exam (hypopigmentation of skin, hair, eyebrows/eyelashes, iris, retina) Retinal imaging (OCT & FAF); OCT can highlight foveal hypoplasia Normal ERG & chiasmal misrouting on VEP
Syndromic	Neuronal ceroid-lipofuscinoses (NCL)	13 genes ³	AR AD ⁴	Infantile NCL presents w/congenital or early-onset (age <6 mos) blindness. Late-infantile & juvenile-onset NCL present at ages 2-4 & ≥6 yrs, respectively. ERG can show a negative waveform. NCL is assoc w/neurocognitive decline & epilepsy.
	Joubert syndrome	>30 genes ⁵	AR XL ⁶	Presents w/severe visual impairment, ocular motor abnormalities Characteristic MRI appearance incl "molar tooth sign" Nephronophthisis in later childhood
	Zellweger spectrum disorder	13 genes ⁷	AR	Assoc features: Sensorineural deafness Dysmorphic features Developmental delay Hepatomegaly Early death
	Alström syndrome	ALMS1	AR	Presenting features: Infantile-onset nystagmus Photophobia Cone-rod dystrophy Other systemic features: Childhood obesity Hyperinsulinemia Type 2 diabetes mellitus Hepatic dysfunction Heart failure Sensorineural hearing loss Renal failure
	Cobalamin C deficiency (See Disorders of Intracellular Cobalamin Metabolism.)	MMACHC	AR	Variable phenotype. Severely affected individuals have progressive, infantile-onset, metabolic, neurologic, & ophthalmic manifestations: Infantile nystagmus Bull's-eye maculopathy ↓ responses on ERG

: Adapted from Kumaran et al [2017] (Table 2)
: AD = autosomal dominant; AR = autosomal recessive; EOSRD = early-onset severe retinal dystrophy; ERG = electroretinography; FAF = fundus autofluorescence; LCA = Leber congenital amaurosis; MOI = mode of inheritance; OCA = oculocutaneous albinism; OCT = optical coherence tomography; VEP = visual evoked potentials; XL = X-linked
1.: See Night Blindness, Congenital Stationary: OMIM Phenotypic Series for a list of genes associated with this phenotype.
2.: X-linked ocular albinism is caused by pathogenic variants in GPR143. See Oculocutaneous Albinism: OMIM Phenotypic Series for a list of genes associated with oculocutaneous albinism.
3.: Pathogenic variants in PPT1, TPP1, CLN3, CLN5, CLN6, MFSD8, CLN8, CTSD, DNAJC5, CTSF, ATP13A2, GRN, and KCTD7 are known to cause NCL.
4.: The NCLs are inherited in an autosomal recessive manner; adult-onset NCL can also be inherited in an autosomal dominant manner.
5.: Pathogenic variants in ARL13B, B9D1, B9D2, C2CD3, C5orf42, CC2D2A, CEP41, CEP104, CEP120, CEP290, CSPP1, IFT172, INPP5E, KATNIP (KIAA0556), KIAA0586, KIF7, MKS1, NPHP1, OFD1, PDE6D, POC1B, RPGRIP1L, TCTN1, TCTN2, TCTN3, TMEM67, TMEM107, TMEM138, TMEM216, TMEM231, TMEM237, TTC21B, and ZNF423 are known to cause Joubert syndrome.
6.: Joubert syndrome is predominantly inherited in an autosomal recessive manner. Joubert syndrome caused by pathogenic variants in OFD1 is inherited in an X-linked manner. Digenic inheritance has been reported.
7.: Pathogenic variants in PEX1, PEX6, PEX12, PEX26, PEX10, PEX2, PEX5, PEX13, PEX16, PEX3, PEX19, PEX14, and PEX11β are known to cause Zellweger spectrum disorder.