cataracts

Retinitis Pigmentosa, Hearing Loss, Ataxia, Cataract, and Polyneuropathy

Clinical Characteristics
Ocular Features: 

Cataracts and a pigmentary retinopathy occur in this condition but only in some, primarily older, patients.  The lens opacities progress and may become visually significant by the third decade.  Bone-spicule-shaped pigment clumping may be present in the midperiphery while the optic disk is often pale and the retinal vessels are attenuated. The ERG responses are consistent with a rod-cone dystrophy.

Systemic Features: 

This is a progressive neurological disorder with onset of signs and symptoms in childhood although full expression may not occur until adulthood.  Young children can have hyporeflexia, pes cavus, spasticity, and gait ataxia.  A sensorineural hearing loss may also be present in childhood but sometimes not until later.  Hyperreflexia with extensor plantar responses and Achilles tendon contractures are often present later.  The peripheral polyneuropathy is predominantly demyelinating with both sensory and motor components and is present in all adults.  Cerebellar atrophy, primarily in the vermis, can be demonstrated on MRI examination.  Mental function is usually not impaired. Some patients have dysarthria. 

This disorder has some clinical similarities to Refsum disease (266500).

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the ABHD12 gene (20p11.21).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is directed at symptoms.  Visually significant cataracts may require removal.  Low vision aids and physical therapy can be helpful.

References
Article Title: 

Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism

Fiskerstrand T, H'mida-Ben Brahim D, Johansson S, M'zahem A, Haukanes BI, Drouot N, Zimmermann J, Cole AJ, Vedeler C, Bredrup C, Assoum M, Tazir M, Klockgether T, Hamri A, Steen VM, Boman H, Bindoff LA, Koenig M, Knappskog PM. Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism. Am J Hum Genet. 2010 Sep 10;87(3):410-7.

PubMed ID: 
20797687

Nystagmus-Split Hand Syndrome

Clinical Characteristics
Ocular Features: 

The only consistent ocular finding is pendular nystagmus beginning at birth.  There is some evidence that the eye movements decrease with age.  Acuity in a 46 year old female was recorded to be 20/40 in each eye whereas one of her children had 20/70.  Two patients (father and daughter) have been described as having cataracts and “fundus changes”, not further defined.  Other patients have been described with normal fundi.  The ERG has been normal in several patients.  Some authors have noted hypertelorism.

The ocular phenotype requires further definition.  For example, in a single published photograph of a young child the medial portion of the eye brows is sparsely populated and all eyelashes in the medial one-third of the upper lid appear to be absent.  This has not been commented on in publications, however.

Systemic Features: 

The hand and foot malformation is severe, described as split-hand/split foot deformity.  It may involve all four extremities or just the upper extremity with monodactyly.  When the hand is involved, it may be called a lobster-claw deformity, or ectrodactyly.  The middle digit is characteristicly missing but other fingers and toes are sometimes absent.

The teeth erupt late, some may be missing and others are often poorly formed. Frontal bossing, sunken cheeks, and thick and everted lips may be part of the facial phenotype.

Genetics

The genetics of Karsch-Neugebauer is obscure although the majority of evidence is consistent with autosomal dominant inheritance.  Parent-child transmission and male-to-male transmission have been observed.  In other families the parents are normal but reduced penetrance has not been ruled out.  Further, there are several types of split-hand deformities but this is the only one associated with nystagmus.  No locus or mutation has been found for this condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical reconstruction can sometimes improve hand function.

References
Article Title: 

Cataracts, Congenital Nuclear

Clinical Characteristics
Ocular Features: 

Congenital nuclear cataracts are the only ocular abnormalities in these conditions.  There may be some cortical opacifications as well.  The nuclear opacifications may not be sufficiently dense in some patients to require cataract surgery.  Nothing is known of their natural history, however.

Systemic Features: 

No systemic disease is associated with these congenital cataracts.

Genetics

All three of these nuclear cataracts are inherited in autosomal recessive patterns.  They have been reported in rare families in which the parents were consanguineous.

CATCN1 was reported in a 4-generation Pakistani family having an unknown mutation localized to 19q13.

Another congenital nuclear cataract (CATCN2) results from mutations in the CRYBB3 (22q11.23) gene reported in 2 consanguineous Pakistani families.

CATCN3 results from mutations in CRYBB1 (22q12.1) as reported in two consanguineous Israeli Bedouin families with 14 affected individuals.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical removal may be indicated if the lens opacities are visually significant.  Vision may be sufficiently impaired in some children that surgery is required before 2 years of age.

References
Article Title: 

Kahrizi Syndrome

Clinical Characteristics
Ocular Features: 

In an Iranian family with 3 affected sibs, cataracts (not further characterized) were noted in late adolescence.  Iris colobomas, unilateral in one sib and bilateral in another, were present.

Systemic Features: 

Children have severe psychomotor delays from birth and have severe mental retardation.  Speech and normal motor function never develop fully.  Thoracic kyphosis begins in late childhood and contractures develop in the elbows and knees.  A CAT scan in one patient revealed only normal findings.  Facial features have been described as ‘coarse’ with prominent lips, broad nasal bridge, and a bulbous nose.  Some individuals with this condition have lived into the 5th decade.  Ataxia is usually present although the cerebellum may be normal on MRI.

Genetics

This is an autosomal recessive condition resulting from homozygous mutations in the SRD5A3 gene (4q12).

Kahrizi syndrome is allelic to CDG1Q, or congenital disorder of glycosylation type Iq (612379), an autosomal recessive disorder with mutations in the same gene and a partially overlapping ocular phenotype.

At least 10 families have been reported with mutations in this gene considered important to glycosylation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No specific treatment is available for this condition although physical therapy and cataract surgery might be considered in specific individuals.

References
Article Title: 

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Bl?omel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 2010 Jul 23;142(2):203-17.

PubMed ID: 
20637498

Cataracts, Congenital, Autosomal Recessive 2

Clinical Characteristics
Ocular Features: 

Bilateral nuclear lens opacities are either present at birth or noted during infancy.  The cataracts were sufficiently dense that surgery is necessary within several months of age in most patients.  No other ocular disease is present.

Systemic Features: 

No systemic abnormalities are present.

Genetics

CATC2 is an autosomal recessive condition that has been reported in 12 consanguineous Pakistani families.  Homozygous mutations in FYCO1 (3p21.31) segregated with the lens opacities as expected.  Mutations in FYC01 are among the most common causes of congenital cataracts in Pakistan and may account for about 10% of the total genetic load of cataracts in this country.  Mutations in the same gene have been found segregating in several consanguineous Arab families with congenital cataracts as well.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataract surgery is frequently necessary during infancy.

References
Article Title: 

Meckel Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype is highly variable.  The globe is often malformed or may be clinically absent.  Cryptophthalmos, clinical anophthalmia, and microphthalmos with sclerocornea and microcornea have been reported.  Posterior staphylomas, retinal dysplasia, partial aniridia, cataracts, and hypoplasia or absence of the optic nerve are sometimes seen.  Some patients have incompletely formed eyes with shallow anterior chambers, angle anomalies, and a persistent tunica vasculosa with lens opacification.  Histopathology may reveal thinning of the nerve fiber layer and a paucity of retinal ganglion cells.  The retina has been described as dysplastic with foci of rosette-like structures and abundant glial cells.

Systemic Features: 

Meckel or Meckel-Gruber syndrome is a clinically and genetically heterogeneous group of disorders with severe multisystem manifestations.  The triad of cystic renal disease, polydactyly (and sometimes syndactyly), and a skull malformation (usually an encephalocele) is considered characteristic of MKS.  However, these signs are variable and only about 60% of patients have all three features.  Many patients have additional signs such as malformations of the biliary tree, cleft palate (and/or lip), sloping forehead, low-set ears, short neck, low-set ears, ambiguous genitalia, and short, bowed limb bones.  Pulmonary hypoplasia is common which, together with kidney and liver disease, is responsible for the poor prognosis of most infants. 

Many clinical abnormalities resemble those present in the Smith-Lemli-Opitz syndrome (270400) and in Joubert syndrome (213300).

Genetics

Most conditions in this group are inherited in an autosomal recessive pattern.  Mutations in 9 genes have been identified as responsible for some variant of MKS in which there is a considerable range of clinical expression.  There is significant clinical overlap with Joubert syndrome and it is not surprising that at least 5 of these mutations have been identified in both conditions.  Further nosological confusion is generated by those who consider patients with the severe, lethal phenotype to have Meckel syndrome while those with milder disease are labeled Joubert syndrome, regardless of genotype.

Rare heterozygotes have been reported with isolated features such as polydactyly.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this syndrome.  The prognosis for life beyond infancy is poor due to the advanced dysfunction of numerous organs such as the kidney, lungs, liver and the central nervous system.

References
Article Title: 

Clinical and genetic heterogeneity in Meckel syndrome

Paavola P, Salonen R, Baumer A, Schinzel A, Boyd PA, Gould S, Meusburger H, Tenconi R, Barnicoat A, Winter R, Peltonen L. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. 1997 Nov;101(1):88-92.

PubMed ID: 
9385376

Retinitis Pigmentosa, Deafness, Mental Retardation and Hypogonadism

Clinical Characteristics
Ocular Features: 

Only two families with this presumed disorder have been reported.  The retinal picture resembles retinitis pigmentosa with ‘bone spicule’ pigment clumps, vascular attenuation, and pale optic nerve heads.  Cataracts and nystagmus have been observed.  Vision is usually limited to light perception by the middle of the first decade of life.

Systemic Features: 

Small testes and gynecomastia are found in males while females have oligo- or amenorrhea.  The hands and feet appear broad and the face has a coarse appearance with a depressed nasal bridge and a broad nose.  Insulin-resistant diabetes and hyperinsulinemia are present.  Acanthosis nigricans, keloids, obesity, and hearing loss are also features.  All patients have significant developmental delays and evident mental retardation.

Genetics

No locus has been identified although autosomal recessive inheritance seems likely: the parents in one family were first cousins and there was no parent to child transmission.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no effective treatment although cataract surgery might be considered if lens opacities are visually significant.

References
Article Title: 

Retinitis Pigmentosa 1

Clinical Characteristics
Ocular Features: 

Night blindness, the predominant presenting symptom, is often noted in the first decade of life but may not be a significant complaint until the third decade.  Concentric peripheral field loss likewise follows a similar timeline.  ERG responses progressively decrease in amplitude and may become undetectable in the second decade.  The retinal disease progresses relentlessly, albeit slowly, as the result of photoreceptor degeneration and most patients have severe visual handicaps by midlife but there is considerable clinical variation.  The pigmentary retinopathy is typical for classical retinitis pigmentosa with vascular attenuation, perivascular bone-spicule pigment clumping, optic atrophy, and generalized retinal atrophy with relative sparing of the macula early in the disease.  Lens opacities are common in late stages of the disease.

Systemic Features: 

No systemic disease is associated with the ocular disorder caused by mutations in RP1.

Genetics

Multiple heterozygous, homozygous, and compound heterozygous mutations in the RP1 gene (8q12.1), sometimes called the oxygen-regulated photoreceptor protein 1 or ORP1 gene, are responsible for this disorder.  The protein product is active specifically in retinal photoreceptors.  Retinitis pigmentosa 1 is generally considered to be an autosomal dominant disorder and accounts for 5-7% of dominantly inherited RP disease.  However, recent reports suggest that some mutations in RP1 are responsible for familial cases transmitted in an autosomal recessive pattern in which the clinical disease is more severe. 

More than 20 different mutant genes have been associated with autosomal dominant RP but many cases lack a family history suggesting additional genetic heterogeneity remains.  Reduced penetrance and variable expressivity characteristic of genetic disease likely contributes to the clinical heterogeneity as well.  For more about autosomal dominant retinitis pigmentosa, see Retinitis Pigmentosa, AD (180380, 268000).  

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Photoreceptor transplantation has been tried in a number of patients without improvement in central vision or interruption in the rate of vision loss.  Longer term results are needed.  Resensitizing photoreceptors with halorhodopsin using archaebacterial vectors shows promise in mice.  High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually.  Oral acetazolamide can be helpful in reducing macular edema.

Low vision aids and mobility training can be facilitating for many patients.  Cataract surgery may restore several lines of vision at least temporarily.

Several pharmaceuticals should be avoided, including isotretinoin, sildenafil, and vitamin E.

References
Article Title: 

Cataracts, Congenital, Autosomal Recessive 4

Clinical Characteristics
Ocular Features: 

This type of cataract has been reported in a single consanguineous family in which 4 sibs (2 males and 2 females) were diagnosed with cataracts shortly after birth.  Open angle glaucoma developed in two individuals at the age of 7 and 8 years.  The lens opacification involves primarily the posterior subcapsular area.  No genital abnormalities were found in this family.

Another unrelated individual developed progressive cataracts from the age of 2 years.  At cataract surgery it was noted that the posterior capsules were abnormal with thinning of one and a frank lenticonus in the other.

Systemic Features: 

Hypospadias was present in an unrelated male with an inversion of chromosome 9 involving at least two genes.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the TDRD7 gene (9p22.33).  Normal function of the gene in vertebrates is required for posttranscriptional control of mRNAs critical to normal lens development.

The single unrelated individual with cataracts and hypospadias had an inversion (inv(9)(q22.33q34.11). One of the two breakpoints (9q34.11) involved the gene NR5A1 which is essential for sexual differentiation.  The ocular and genital phenotypes therefore are likely independent. 

The Tdrd7 gene is expressed in lens fibers and its malfunction causes cataracts in mice.  The evolution of lens opacification in mice closely resembles that observed in the reported patient with cataracts and hypospadias.  Some mutant mice develop open angle glaucoma complete with optic atrophy and nerve cupping.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataract surgery may be indicated and patients should be monitored and treated for glaucoma.

References
Article Title: 

Mutations in the RNA granule component TDRD7 cause cataract and glaucoma

Lachke SA, Alkuraya FS, Kneeland SC, Ohn T, Aboukhalil A, Howell GR, Saadi I, Cavallesco R, Yue Y, Tsai AC, Nair KS, Cosma MI, Smith RS, Hodges E, Alfadhli SM, Al-Hajeri A, Shamseldin HE, Behbehani A, Hannon GJ, Bulyk ML, Drack AV, Anderson PJ, John SW, Maas RL. Mutations in the RNA granule component TDRD7 cause cataract and glaucoma. Science. 2011 Mar 25;331(6024):1571-6.

PubMed ID: 
21436445

Myopia, AR, with Cataracts and Vitreoretinal Degeneration

Clinical Characteristics
Ocular Features: 

Axial myopia and poor vision are noted during childhood.  Most individuals have refractive errors in the range of-5 to -18 diopters with a mean spherical equivalent of -11.3 diopters.  The axial length ranges from 25.1 and 30.5 mm.  Peripheral vitreoretinal degeneration and cataracts are usually present after the onset of myopia.  Lenticular opacities may necessitate cataract surgery in 11 of the 13 myopic patients in one kindred, usually by the second decade of life.  Lens instability or frank subluxation was noted in 8 patients.  At least five eyes suffered retinal detachments secondary to retinal dialyses and blindness of at least one eye occurred in 23% of patients.

Systemic Features: 

Deafness was reported in a single patient.

Genetics

This condition results from homozygous mutations in the gene LEPREL1 (3q28) encoding prolyl 3-hydroxylase.  It was identified in a large consanguineous Israeli Bedouin kindred containing seven affected males and 6 affected females.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataract and retinal surgery may be indicated. However, the instability of the lens can lead to complications. The nature and location of retinal tears likewise make repairs difficult and blindness is a relatively frequent complication.

References
Article Title: 

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