POMGNT1

Retinitis Pigmentosa 76

Clinical Characteristics
Ocular Features: 

Onset of night blindness occurs early in the second decade of life.  Vision is in the range of 20/40 to 20/100 in the first decades worsens slowly but there is a wide range.  Some older individuals may have hand motion vision in at least one eye but some retain 20/40.  All patients have peripheral field restrictions and some have pallor of the optic disc.  Retinal vessels are attenuated.  Fundus pigmentation is usually abnormal with some combination of bone spicule and diffuse salt and pepper pigmentation.  The macula is usually involved with a flat fovea, cystoid macular edema, and chorioretinal atrophy.

Retinal thinning is seen on OCT.  The ERG can be flat but in some individuals the rod responses are primarily reduced.

Systemic Features: 

No systemic abnormalities have been associated.

Genetics

Homozygous or compound heterozygous mutations in the POMGNT1 gene (1p34) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treeatment is available.

References
Article Title: 

Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa

Xu M, Yamada T, Sun Z, Eblimit A, Lopez I, Wang F, Manya H, Xu S, Zhao L, Li Y, Kimchi A, Sharon D, Sui R, Endo T, Koenekoop RK, Chen R. Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa. Hum Mol Genet. 2016 Apr 15;25(8):1479-88.

PubMed ID: 
26908613

Walker-Warburg Syndrome

Clinical Characteristics
Ocular Features: 

The eyes are usually small and contain either retinal dysplasia or a congenital retinal detachment.  Colobomas, PHPV, cataracts, glaucoma, buphthalmos, anterior chamber dysgenesis, optic atrophy, and optic nerve hypoplasia have also been reported. 

Systemic Features: 

Hydrocephalus and congenital muscular dystrophy are the most important systemic features of these syndromes.  A Dandy-Walker malformation is often present.  Type II lissencephaly, cerebellar malformations and severe mental retardation are other features.  More variable signs include macro- or microcephaly, ventricular dilatation, cleft lip and/or palate, and congenital contractures.  WWS has a severe phenotype and death often occurs in the first year of life.  Brain histology shows severely disorganized cytoarchitecture and suggests a neuronal migration disorder. Microtia has been reported in several patients.

Most developmental milestones are delayed or never achieved and death may occur in early childhood. 

Genetics

The MDDGs (muscular dystrophy dystroglycanopathies) comprise a genetically and clinically heterogeneous group of disorders (sometimes called muscle-eye-brain disease) of which the A types are more severe than the B types.  The mutant genes responsible are involved in glycosylation of DAG1 (alpha-dystroglycan). 

Types A1 (MDDGA1; 236670), B1 (MDDGB1; 613155) and C1 (MDDGC1; 609308) result from mutations in a gene known as POMT1 (9p34.1).  The muscular dystrophy in type C1 is of the limb-girdle type LGMD2K.

A2 (MDDGA2; 613150) is caused by mutations in POMT2 (14q24.3).  Mutations in POMT2 may also cause the less severe muscle-eye-brain disease (MEB) type B2 (MDDGB2; 613156), and a similar disease (C2) in which the muscle dystrophy is of the limb-girdle type LGMD2N and eye findings may be absent (MDDGC2; 613158).

Mutations in POMGNT1 (1p34-p33) cause type A3 (MDDGA3; 253280) and type B3 (MDDGB3; 613151).  The muscular dystrophy in B3 is of the limb-girdle type.  POMGNT1 mutations may be associated with congenital glaucoma, retinal dysplasia, and high myopia. Type C3 (MDDGC3; 613157), also with a limb-girdle type of muscular dystrophy (LGMD2O), is caused by mutations in POMGNT1 as well.

FKTN mutations cause type A4 MDDG (MDDGA4; 253800) associated with the Fukuyama type of congenital muscular dystrophy but they can also cause type B4 (MDDGB4; 613152) which does not have mental retardation, and type C4 (MDDGC4; 611588) with seizures and a limb-girdle type (LGMD2M) of muscular dystrophy.

Types A5 (MDDG5A; 613153) and B5 (MDDGB5; 606612) are the result of mutations in the FKRP gene (19q13.3).  Of the two the latter is the less severe and the muscular dystrophy is of the limb-girdle type.  The eyes may be microphthalmic and have retinal pigmentary changes and congenital glaucoma.

Type A6 (MDDGA6; 613154) and B6 (MGGDB6; 608840) are caused by mutations in the LARGE gene (22q12.3).  MDDGA7, or type A7 (614643) results from homozygous or compound heterozygous mutations in the ISPD gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available but early indications are that FKRP gene therapy restores functional glycosylation and improves muscle functions.

References
Article Title: 

Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study

Mercuri E, Messina S, Bruno C, Mora M, Pegoraro E, Comi GP, D'Amico A, Aiello C, Biancheri R, Berardinelli A, Boffi P, Cassandrini D, Laverda A, Moggio M, Morandi L, Moroni I, Pane M, Pezzani R, Pichiecchio A, Pini A, Minetti C, Mongini T, Mottarelli E, Ricci E, Ruggieri A, Saredi S, Scuderi C, Tessa A, Toscano A, Tortorella G, Trevisan CP, Uggetti C, Vasco G, Santorelli FM, Bertini E. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology. 2009 May 26;72(21):1802-9.

PubMed ID: 
19299310
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