cataracts

Spastic Paraplegia 5A

Clinical Characteristics
Ocular Features: 

Gaze-evoked nystagmus and saccadic pursuit movements are present in about 10% of patients.  Optic atrophy was reported in one individual.  Rare patients have been reported to have cataracts.  

Systemic Features: 

This is a progressive disorder of neurological deterioration.  Age of onset (mean 16.4 years) and rate of neurological dysfunction are highly variable.  Gait difficulties are the most common presenting signs.  Some gait ataxia is usually present.  The lower limbs are more severely affected by spasticity and weakness and walking is often delayed with difficulty running and clumsiness in childhood.  Some patients (38%) are wheelchair-bound after disease duration of more than 33 years.  Dysphagia and dysarthria are uncommon. 

Some sensory impairments such as impaired vibratory sense, decreased proprioception, and absent touch sensation in the lower extremities are frequently present.  Urge incontinence of bladder and rectum is sometimes a feature.

Genetics

Bialllelic mutations in the CYP7B1 gene (8q12.3) have been identified in this disorder resulting in a marked accumulation of neurotoxic oxysterols in plasma and CSF.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment for the general disorder has been reported.

References
Article Title: 

Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial

Schols L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, Jagle C, Fraidakis MJ, Martinuzzi A, Saute JA, Scarlato M, Antenora A, Stendel C, Hoflinger P, Lourenco CM, Abreu L, Smets K, Paucar M, Deconinck T, Bis DM, Wiethoff S, Bauer P, Arnoldi A, Marques W, Jardim LB, Hauser S, Criscuolo C, Filla A, Zuchner S, Bassi MT, Klopstock T, De Jonghe P, Bjorkhem I, Schule R. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain. 2017 Dec 1;140(12):3112-3127.

PubMed ID: 
29126212

CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5

Goizet C, Boukhris A, Durr A, Beetz C, Truchetto J, Tesson C, Tsaousidou M, Forlani S, Guyant-Marechal L, Fontaine B, Guimaraes J, Isidor B, Chazouilleres O, Wendum D, Grid D, Chevy F, Chinnery PF, Coutinho P, Azulay JP, Feki I, Mochel F, Wolf C, Mhiri C, Crosby A, Brice A, Stevanin G. CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5. Brain. 2009 Jun;132(Pt 6):1589-600.

PubMed ID: 
19439420

Cataracts and Ichthyosis

Clinical Characteristics
Ocular Features: 

Cortical cataracts have been reported.

Systemic Features: 

Icthyosis is associated with cataracts in some family members.

Genetics

Three families have been reported in which cataracts and ichthyosis were associated.  Two male offspring of normal Japanese parents had cortical cataracts and ichthyosis.  In another family of unknown ethnicity, three sisters had cataracts but only two had ichthyosis.  In a third in which the mother had cataracts and ichthyosis, two of her female children had cataracts.

Treatment
Treatment Options: 

Treatment is unknown.

References
Article Title: 

Muscular Dystrophy, Congenital, with Cataracts and Intellectual Disability

Clinical Characteristics
Ocular Features: 

Cataracts have been diagnosed by 6 months of age and may be congenital in origin. Several patients have had strabismus.

Systemic Features: 

Progressive muscle weakness begins in early childhood.  Hypotonia is usually present at birth followed by atrophy of the proximal muscles (especially in the lower limbs).  Muscle weakness progresses for several years and may stabilize but not before severe gait difficulties occur.  Most adult patients are confined to a wheelchair.  No cardiac involvement occurs although respiratory weakness is often present.  Serum creatine kinase is usually elevated and biopsied muscle fibers show dystrophic changes and increased variability in fiber size with vacuolization.

Other signs in some individuals are contractures, scoliosis, seizures, short stature, cognitive deficits (usually mild), and spinal rigidity.  Paradoxically, some patients have limb spasticity and hyperreflexia with pyramidal signs.  No cerebellar signs are present.

Genetics

This condition results from homozygous or compound heterozygous mutations in the INPP5K gene (17p13).  

See Marinesco-Sjogren Syndrome for a disorder with a somewhat similar clinical presentation plus cerebellar signs.  It is caused by a different mutation, however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts have been surgically removed in several patients by the age of two years.  Physical therapy may be beneficial.  Selected individuals could benefit from release of contractures.

References
Article Title: 

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment

Wiessner M, Roos A, Munn CJ, Viswanathan R, Whyte T, Cox D, Schoser B, Sewry C, Roper H, Phadke R, Marini Bettolo C, Barresi R, Charlton R, Bonnemann CG, Abath Neto O, Reed UC, Zanoteli E, Araujo Martins Moreno C, Ertl-Wagner B, Stucka R, De Goede C, Borges da Silva T, Hathazi D, Dell'Aica M, Zahedi RP, Thiele S, Muller J, Kingston H, Muller S, Curtis E, Walter MC, Strom TM, Straub V, Bushby K, Muntoni F, Swan LE, Lochmuller H, Senderek J. Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment. Am J Hum Genet. 2017 Mar 2;100(3):523-536.

PubMed ID: 
28190456

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

Osborn DP, Pond HL, Mazaheri N, Dejardin J, Munn CJ, Mushref K, Cauley ES, Moroni I, Pasanisi MB, Sellars EA, Hill RS, Partlow JN, Willaert RK, Bharj J, Malamiri RA, Galehdari H, Shariati G, Maroofian R, Mora M, Swan LE, Voit T, Conti FJ, Jamshidi Y, Manzini MC. Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjogren Syndrome and Dystroglycanopathy. Am J Hum Genet. 2017 Mar 2;100(3):537-545.

PubMed ID: 
28190459

Coloboma, Microphthalmia, Albinism, and Deafness

Clinical Characteristics
Ocular Features: 

A 5 year old male has been described with uveal colobomas in microphthalmic eyes plus small corneas with a pannus, dense cataracts, translucent irides, and hypopigmentation of the skin, hair and eyes.  A brain MRI showed hypoplasia of the optic nerves and chiasm.   

A 9 month old female from another family had severe microphthalmia and small optic nerves.  The internal ocular features were not reported.

Systemic Features: 

The complete phenotype is uncertain since it is based on only two reported and unrelated individuals.  The head circumference one one patient was consistent with macrocephaly accompanied by frontal bossing, shallow orbits, preauricular pits and posteriorly rotated ears.  A skeletal survey revealed evidence for osteopetrosis.  He had a sensorineural hearing deficit said to be congenital in onset.

The other patient, a 9 month old female, belonged to another nonconsanguineous family, and had similar skeletal and craniofacial features with the addition of micrognathia and hypotonia.  Congenital neurosensory hearing loss and general lack of pigmentation were noted.

All four parents have congenital sensorineural hearing loss, blue irides and fair skin with premature graying of hair.  Four sibs in the two families have phenotypes similar to that of the parents.  Only one child, a female, had no features of the phenotype.

Genetics

This condition, so far reported only in a male and a female in unrelated families, is the result of doubly heterozygous mutations in the MITF gene (3p13).  One mutation that causes Waardenburg syndrome 2  (WS2A) (193510) is combined with a dominant-negative allele (c.952_954delAGA [p.Arg318del]) to produce the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Retinitis Pigmentosa 77

Clinical Characteristics
Ocular Features: 

The onset of nyctalopia apparently varies from early childhood to 20 years of age and is usually the presenting symptom.  The loss of acuity is progressive (20/30 to 20/400) with older patients generally having more severe loss but there is little direct correlation with age.  Peripheral fields are progressively constricted, ranging from 10 to 30 degrees.  Some patients develop posterior subcapsular cataracts.  Retinal pigmentation is often mottled but 'bone spicules' are seen in about half of individuals.  Retinal vessels are narrowed.  The ERG shows generalized rod-cone dystrophy.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Homozygous or compound heterozygous mutations in the REEP6 gene (19p13.3) are responsible for this disorder.  Five unrelated families have been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported although cataract removal may be visually beneficial.  

References
Article Title: 

Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa

Arno G, Agrawal SA, Eblimit A, Bellingham J, Xu M, Wang F, Chakarova C, Parfitt DA, Lane A, Burgoyne T, Hull S, Carss KJ, Fiorentino A, Hayes MJ, Munro PM, Nicols R, Pontikos N, Holder GE; UKIRDC., Asomugha C, Raymond FL, Moore AT, Plagnol V, Michaelides M, Hardcastle AJ, Li Y, Cukras C, Webster AR, Cheetham ME, Chen R. Mutations in REEP6 Cause Autosomal-Recessive Retinitis Pigmentosa. Am J Hum Genet. 2016 Dec 1;99(6):1305-1315.

PubMed ID: 
27889258

Anterior Segment Dysgenesis 8

Clinical Characteristics
Ocular Features: 

This is a congenital anterior segment dysplasia syndrome with considerable clinical heterogeneity.  Iris hypoplasia with transillumination, corectopia, iridodenesis, and iridocorneal adhesions are often seen.  Intraocular pressure may be elevated in older individuals.  Ectopia lentis is often present.  Lenticular opacities consisting primarily of posterior cortical opacification are common.  Visual acuity varies from 6/6 to 6/24.

No foveal hypoplasia is present but one of four reported patients was described with bilateral optic nerve dysplasia.     

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

Three families with 4 affected individuals with similar clinical features have been reported with homozygous or compound heterozygous mutations in the CPAMD8 gene (19p13.11).

A single male patient of native American/French Canadian background with somewhat similar clinical features has been reported with compound heterozygous mutations in the CYP1B1 gene (2p22.2) but this is likely a unique condition (Anterior Segment Dysgenesis 6).

The genes FOXE3 and PAX6 are characterized as transcription factors and play important roles in ocular development.  However, while mutations in these are frequently found in patients with dysgenesis of the anterior chamber they often cause more widespread ocular and systemic anomalies (e.g., Gillespie syndrome [206700]).  Therefore in this database the anterior chamber constellations of anomalies associated with mutations in these genes are not considered to be simplex conditions. 

See also related disorders iridogoniodysgenesis type 1 (601631) and type 2 (137600), and anterior segment mesenchymal dysgenesis (107250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Several patients have had cataract surgery.  Monitoring intraocular pressure throughout life is necessary and prompt treatment for glaucoma is important.

References
Article Title: 

Aniridia 3

Clinical Characteristics
Ocular Features: 

One 4-generation Chinese family with 8 affected members has been reported. Complete bilateral iris defects were seen all patients who by 10 years of age also had cataracts.  No corneal opacities were seen.  Two patients were diagnosed with glaucoma.  No fundus abnormalities were reported.

Systemic Features: 

No systemic abnormalities have been reported. 

Genetics

Hereditary aniridia results from a dysfunction of the regulatory gene PAX6.  In aniridia 1 (106210) the PAX6 gene (a transcription regulator) gene itself contains mutations.  In anirdia 2 (617141) the mutation occurs in the ELP4 gene, whose product is a cis-regulatory enhancer of PAX6. 

Aniridia 3 results from heterozygous mutations in the TRIM44 gene (11p13).  The TRIM44 gene is a negative regulator which normally suppresses the expression of PAX6 and the reported missense mutation (p.G155R) enhances its activity.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Surgical removal of cataracts and glaucoma treatment may be of benefit.

Aniridia 2

Clinical Characteristics
Ocular Features: 

A 17-year-old male with this condition was diagnosed at the age of two years with bilateral iris hypoplasia.  Cataracts were seen at the age of 17 years.  There was no foveal depression.

In a 5 generation Chinese family there were additional signs including optic atrophy, ectopia lentis, pigmentary retinopathy, and 'dysplasia' of the trabecular meshwork in 5 members.

Systemic Features: 

No systemic abnormalities have been reported.  A single extensively studied patient, who had no developmental problems, was normal by renal ultrasound, audiometric studies, and neurologic evaluations.

Genetics

Autosomal dominant aniridia is the result of PAX6 (a transcription regulator gene) dysfunction.  In the majority of cases there are mutations in the PAX6 gene itself as in AN1.  There are reports, however, of familial aniridia in which direct PAX6 mutations have been excluded.  Two additional forms of aniridia in which there are alterations in genes that modulate the expression of PAX6 have been reported.  AN2 described here with mutations in ELP4, a nucleotide variant within an intron of the ELP4 gene (11p13) located distal to the 3-prime end of the PAX6 gene, plus AN3 (617142) with mutations in TRIM44.  Both ELP4 and TRIM44 are regulators of the PAX6 transcription gene.

Aniridia 2 has been reported in one patient with a nucleotide variant within an intron of the ELP4 gene (11p13) located distal to the 3-prime end of the PAX6 gene.  The gene product is a cis-regulatory enhancer.  

Other evidence for aniridia resulting from regulatory modification of PAX6 gene function comes from families in which there are structural alterations such as deletions in chromosome 11, downstream of the PAX6 gene location.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment has not been reported.

References
Article Title: 

A deletion 3' to the PAX6 gene in familial aniridia cases

D'Elia AV, Pellizzari L, Fabbro D, Pianta A, Divizia MT, Rinaldi R, Grammatico B, Grammatico P, Arduino C, Damante G. A deletion 3' to the PAX6 gene in familial aniridia cases. Mol Vis. 2007 Jul 23;13:1245-50.
 

PubMed ID: 
17679951

Cataracts, Congenital, Intellectual Disability, Abnormal Striatum, and ADHD

Clinical Characteristics
Ocular Features: 

Cataracts (not further described) were described as congenital although the diagnosis was usually made early in the first decade of life.  One patient was diagnosed at the age of 8 years with glaucoma and a cloudy cornea of the left eye.  Another patient had cataract surgery.  Visual acuities have not been reported.

Systemic Features: 

Four members of a consanguineous Saudi family have been reported with growth and mental retardation, microcephaly, dystonia, and spasticity.  IQs in the range of 77-89 were reported.  Linguistic delay is common.  Dysarthria and decreased cognitive function are present.  MRIs revealed thinning of the lentiform nucleus and swelling of the caudate heads.  

Genetics

Homozygous mutations in the KCNA4 (11p14.1) (176266) gene are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the general condition.  Cataract surgery may be considered.

References
Article Title: 

KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability

Kaya N, Alsagob M, D'Adamo MC, Al-Bakheet A, Hasan S, Muccioli M, Almutairi FB, Almass R, Aldosary M, Monies D, Mustafa OM, Alyounes B, Kenana R, Al-Zahrani J, Naim E, Binhumaid FS, Qari A, Almutairi F, Meyer B, Plageman TF, Pessia M, Colak D, Al-Owain M. KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability. J Med Genet. 2016 Aug 31. pii: jmedgenet-2015-103637. doi: 10.1136/jmedgenet-2015-103637. [Epub ahead of print].

PubMed ID: 
27582084

Mental Retardation, X-Linked 99, Syndromic, Female-Restricted

Clinical Characteristics
Ocular Features: 

Palpebral fissures are generally shortened and may slant up or down.  Cataracts of unknown morphology have been reported and strabismus is common.

Systemic Features: 

The systemic phenotype is highly variable.  Skull and facial anomalies are common with brachycephaly, bitemporal narrowing, and a broad low nasal bridge. There is general developmental delay in both motor and cognitive abilities.  Patients are short in stature while scoliosis, hip dysplasia, and post-axial polydactyly may be present.  The teeth may be malformed and numerous (29%) of individuals have hypertrichosis.  Nearly a third of individuals have a cleft palate/bifid uvula.   Heart malformations, primarily atrial septal defects, are found in about half of affected individuals and urogenital anomalies such as renal dysplasia are relatively common.  Feeding difficulties have been reported while anal atresia is present in about half of patients.   

Brain imaging reveals hypoplasia of the corpus callosum, enlarged ventricles, Dandy-Walker malformations, cerebellar hypoplasia, and abnormal gyration patterns in the frontal lobe.  Generalized hypotonia has been diagnosed in half of reported patients and seizures occur in 24%.

Genetics

This female-restricted syndrome is caused by heterozygous mutations in the USP9X gene (Xp11.4).  X-chromosome inactivation is skewed greater than 90% in the majority of females but the degree of skewing in one study was independent of clinical severity.  The majority of cases occur de novo.

In males, hemizygous mutations in the USP9X gene (300919) cause a somewhat similar disorder (MRX99) without the majority of the congenital malformations having mainly the intellectual disabilities, hypotonia, and behavioral problems.

Pedigree: 
X-linked dominant, mother affected
Treatment
Treatment Options: 

There is no known treatment for the general disorder but individual anomalies or defects such as atrial septal defects, cleft palate, and anal atresia might be surgically corrected.

References
Article Title: 

De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Reijnders MR, Zachariadis V, Latour B, Jolly L, Mancini GM, Pfundt R, Wu KM, van Ravenswaaij-Arts CM, Veenstra-Knol HE, Anderlid BM, Wood SA, Cheung SW, Barnicoat A, Probst F, Magoulas P, Brooks AS, Malmgren H, Harila-Saari A, Marcelis CM, Vreeburg M, Hobson E, Sutton VR, Stark Z, Vogt J, Cooper N, Lim JY, Price S, Lai AH, Domingo D, Reversade B; DDD Study, Gecz J, Gilissen C, Brunner HG, Kini U, Roepman R, Nordgren A, Kleefstra T. De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations. Am J Hum Genet. 2016 Feb 4;98(2):373-81.

PubMed ID: 
26833328

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