cataracts

Spastic Paraplegia 46

Clinical Characteristics
Ocular Features: 

Congenital cataracts (not further described) have been reported in several individuals with this type of complicated spastic paraplegia.  Optic atrophy and nystagmus have not been reported.

Systemic Features: 

Stiffness and weakness of the lower limbs begins between 2 and 20 years of age.  This is slowly progressive although most individuals are still mobile with mild to moderate handicaps into the 4th decade.  The gait is spastic with weakness, hyperreflexia, and extensor plantar responses in the lower limbs.  The upper limbs are variably involved and movements are dysmetric.  Dysarthria and bladder dysfunction are often present.  Cerebellar ataxia is common and some patients first present with this as a prominent sign in the first and second decades.  Early cognitive development is normal but mild cognitive decline appears eventually.  Pes cavus and scoliosis may occur.

Brain imaging can show thinning of the corpus callosum, with mild cerebellar and cerebral atrophy.

Genetics

Linkage analysis identified a locus at 9p13.3 and sequencing confirmed homozygous or compound heterozygous mutations in GBA2.  The presence of parental consanguinity in some families supports autosomal recessive inheritance.

This database contains two other types of autosomal spastic paraplegia with ocular signs: spastic paraplegia 15 (270700) with a "flecked retina", and spastic paraplegia 7 (607259) with optic atrophy and nystagmus.  Cataracts have not been reported in these two conditions.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known for the neurological deficits but cataract surgery may be beneficial for visually significant cataracts.

References
Article Title: 

Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity

Hammer MB, Eleuch-Fayache G, Schottlaender LV, Nehdi H, Gibbs JR, Arepalli SK, Chong SB, Hernandez DG, Sailer A, Liu G, Mistry PK, Cai H, Shrader G, Sassi C, Bouhlal Y, Houlden H, Hentati F, Amouri R, Singleton AB. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet. 2013 Feb 7;92(2):245-51. PubMed PMID: 23332917.

PubMed ID: 
23332917

Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia

Martin E, Sch?ole R, Smets K, Rastetter A, Boukhris A, Loureiro JL, Gonzalez MA, Mundwiller E, Deconinck T, Wessner M, Jornea L, Oteyza AC, Durr A, Martin JJ, Schols L, Mhiri C, Lamari F, Z?ochner S, De Jonghe P, Kabashi E, Brice A, Stevanin G. Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet. 2013 Feb 7;92(2):238-44. PubMed PMID: 23332916.

PubMed ID: 
23332916

A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum

Boukhris A, Feki I, Elleuch N, Miladi MI, Boland-Aug?(c) A, Truchetto J, Mundwiller E, Jezequel N, Zelenika D, Mhiri C, Brice A, Stevanin G. A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum. Neurogenetics. 2010 Oct;11(4):441-8.

PubMed ID: 
20593214

Retinitis Pigmentosa 25

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity with a wide range in age of onset and progression.  Night blindness, sometimes with photophobia, has its onset in the second or third decade of life and central acuity can be impacted by age 30 years.  Other patients have no symptoms until the fifth decade.  Some patients lose the ability to perceive light by the sixth decade.  The visual fields are usually constricted although one patient had a central scotoma.  The ERG is usually nonrecordable but other patients may have a variable rod-cone pattern of attenuation.  The retinal vessels are also attenuated and some patients have mild optic atrophy.  The pigmentary retinopathy is also variable with sometimes central lesions and in other patients more peripheral.  One patient had posterior subcapsular cataracts.

Systemic Features: 

No systemic disease has been reported.

Genetics

This is an autosomal recessive form of retinitis pigmentosa resulting from homozygosity or compound heterozygosity in the EYS gene (6q12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Knobloch Syndrome 3

Clinical Characteristics
Ocular Features: 

High myopia and marked nystagmus are cardinal ocular findings.  Night blindness leads to symptoms between 2 and 4 years of age.  Vision loss leads to complete blindness by age 15 to 18.  Visual acuity in young adults is often 20/400 to NLP.  Cataracts with subluxated lenses, glaucoma, and chorioretinal atrophy are often present.  Scattered pigment clumping, attenuation of the retinal vasculature, and prominent choroidal vessels can often be seen.  Marked optic atrophy is usually present.  Phthisis and band keratopathy may be seen in older individuals although no retinal detachments have been reported.  The vitreous is described as degenerated in several patients and a vitreal hemorrhage was seen in one patient.

Systemic Features: 

This variant was identified in a four-generation consanguineous Pakistani family in which detailed information was obtained in 5 members. A hairless, purplish-red patch is usually present in the occipital-parietal region during infancy but becomes smaller as children grow.  No encephalocele is present.  Hearing loss and heart defects have not been reported.  Intelligence is normal.

Genetics

This is an autosomal recessive condition resulting from a presumed homozygous mutation on chromosome 17 (17q11.2).

Other variants of Knobloch syndrome are Knobloch 1 (267750) caused by homozygous mutations in COL18A1 (21q22.3) and Knobloch 2 (608454) secondary to homozygous mutations in ADAMTS18 at 16q23.1.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts and dislocated lenses may be removed.

References
Article Title: 

Knobloch Syndrome 2

Clinical Characteristics
Ocular Features: 

In an 18 month infant, ectopia lentis, cataract, and myopia with poor vision were noted.  This individual subsequently developed retinal degeneration and a serous retinal detachment.

Systemic Features: 

Only one patient has been reported.  While the clinical signs resemble Knobloch 1 syndrome, brain imaging does not reveal malformations in this syndrome.  The only systemic sign, in addition to an occipital encephalocele, is a minor delay in fine motor skills.

Genetics

This autosomal recessive disorder results from homozygous loss of function mutations in the ADAMTS18 gene (16q23.1).  The gene product has been found in the lens and retina in the murine eye.

Mutations in ADAMTS18 have also been found in the syndrome of Micorcornea, Myopia, Chorioretinal atrophy, and Telecanthus.  It may also be responsible for a retinal dystrophy.

Knobloch 2 syndrome was identified in a single female born to consanguineous parents.

This disorder is separate to Knobloch 1 syndrome (267750) based on the causative mutations.  A third type, KNO3, has been proposed since the Knobloch clinical features were found in a 4-generation consanguineous Pakistani family but the phenotype mapped to 17q11.2.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The skull defect can be closed and the lenses can be removed if indicated.

References
Article Title: 

Hereditary Mucoepithelial Dysplasia

Clinical Characteristics
Ocular Features: 

Impaired epithelial cohesion is the fundamental defect in this disorder.  Photophobia may be present in infants and this is soon evident as secondary to keratitis with eventual formation of a pannus and corneal neovascularization.  Vision is impaired early and as the disease progresses, many patients by early adulthood are severely impaired.  Cataracts are present in the majority of individuals, often present as early as the second decade of life.  Eyelashes and eyebrows may be sparse.  Nystagmus has been reported in some patients.

Systemic Features: 

This is a panepithelial disease of impaired cohesion due, at least in part, to a reduced number of desmosomes and defective gap junctions.  Oral, nasal, vaginal, cervical, perineal, urethral, and bladder mucosa, in addition to external ocular surfaces, are involved.  With exception of the ocular involvement, the lesions are usually not painful, but may be during acute flare-ups.  Demarcated erythematous patches are often seen in the oral mucosa.  Non-scarring alopecia, keratosis pilaris, and perineal intertrigo are usually present.  Histological examination of oral mucosa and skin shows dyskeratotic features, decreased number of desmosomes, and intracytoplasmic vacuoles.

Genetics

Pedigrees suggest autosomal dominant inheritance but few families have been reported.  The location of the responsible mutation, if any, has not been found. 

Somewhat similar genodermatoses are KID syndrome (148210), an autosomal dominant disorder with neurosensory hearing loss and sometimes mental and physical delays secondary to mutations in GJB2, and IFAP (308205), an X-linked condition with mental and physical delays and severe organ deformities.  Cataracts are not features of KID or IFAP syndromes.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been found.

References
Article Title: 

Cataracts, CRYAA Mutations

Clinical Characteristics
Ocular Features: 

This seems to be a clinically heterogeneous group of lens opacities all due to mutations in the crystallin gene CRYAA.  Some patients also have colobomas and may have microcornea and corneal opacities.  The lens opacities are usually bilateral but there is considerable asymmetry in their morphology.  Opacities may be nuclear, polar, cortical, sutural, embryonal, and anterior subcapsular in location.  The cataracts are often present at birth.

Systemic Features: 

Systemic disease is absent.

Genetics

A variety of mutations in the CRYAA (21q22.3) have been reported in a several ethnic groups.  Most pedigrees are consistent with autosomal dominant inheritance but autosomal recessive inheritance has been suggested in other families.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Lens extraction may be necessary.

References
Article Title: 

Williams Syndrome

Clinical Characteristics
Ocular Features: 

Blue irides (77%) and a lacey or stellate pattern (74%) of the iris are characteristic.  The stroma appears coarse with radial or cartwheel striations.  The iris collarette is usually absent or anomalous.  Features of the Peters' anomaly may be present.  The periorbital tissues are described as 'full' and prominent.  Strabismus (usually esotropia) occurs in more than half of patients.  Retinal vessel tortuosity is present in 22% of patients.  Cataracts may be found in younger individuals but are uncommon. Hyperopia is the most common refractive error.  Keratoconus has been described in at least 3 patients.

Systemic Features: 

The phenotype is variable, likely depending upon the size of the deletion.  Cardiovascular disease, primarily hypertension and large vessel stenosis, are among the most important features.  The elastin arteriopathy lead to thickened arterial walls with peripheral pulmonary stenosis and supravalvular aortic stenosis.  The facies is considered unique with bitemporal narrowing, a wide mouth, full lips, malocclusion, small jaw, and prominent earlobes.  The teeth are small and widely spaced.  Connective tissue abnormalities include joint hyperextensibility, hernias, lax skin, hypotonia, and bowel/bladder diverticulae.  Small birth size is common and infants often fail to thrive but at puberty patients can experience a growth spurt.  Ultimate height in adults is usually in the third centile.

Vocal cord anomalies and paralysis can result in a hoarse voice.  A sensorineural hearing loss is common among adults but hyperacusis is often present in young children.

Hypercalcemia and hypercalciuria are common and some (10%) have hypothyroidism.

Most individuals have some cognition difficulties and delays but normal intelligence has also been reported.  Patient personalities consist of anxiety, attention deficit disorder, marked friendliness and a high level of empathy.  Visiospatial construction is often impaired.  Most adults are unable to live independently.

Genetics

This is a deletion syndrome but included in this database because the major features are due to the loss of a single gene (ELN).  The deletion segment consists of 1.4-1.8 Mb at 7q11.23 containing as many as 28 genes.   Most cases occur sporadically but parent-child transmission and affected siblings have been reported.  The recurrence risk is low.

Increased tortuosity of the retinal arterioles is also a feature of Fabry disease (301500) and of a condition known as isolated retinal arteriolar tortuosity (611773, 180000).

Treatment
Treatment Options: 

Feeding issues should be addressed early in infants who fail to thrive.  Early intervention with speech and physical therapy plus special education can be helpful.  Psychological evaluations may help in managing behavioral issues.

Hypertension can often be managed medically but surgery may be required for vascular stenoses.   Hypercalcemia and hypothyroidism often respond to medical therapy. Strabismus, vessel narrowing, and valvular malfunctions can be treated surgically.

References
Article Title: 

The iris in Williams syndrome

Holmstrom G, Almond G, Temple K, Taylor D, Baraitser M. The iris in Williams syndrome. Arch Dis Child. 1990 Sep;65(9):987-9.

PubMed ID: 
2221973

Ocular findings of Williams' syndrome

Hotta Y, Kishishita H, Wakita M, Inagaki Y, Momose T, Kato K. Ocular findings of Williams' syndrome. Acta Paediatr Scand. 1990 Aug-Sep;79(8-9):869-70.

PubMed ID: 
2239289

Knobloch Syndrome 1

Clinical Characteristics
Ocular Features: 

The ocular findings include high myopia, vitreoretinal degeneration, dislocated lenses, cataracts, and retinal detachment.  Some patients have early onset (2-4 years old) night blindness and progress to total blindness before 20 years of age.  Nystagmus, strabismus, small optic discs, glaucoma, and cataracts have been reported.  Poor vision and progressive loss of acuity are common.  The vitreous appears to be condensed into sheets and there may be distortion of the vitreoretinal interface with irregular white dots and lines.  Pigmentary changes are common in the retina which some have described as consistent with choroidal sclerosis and chorioretinal atrophy.  Atrophic changes are often seen in the macula.

Systemic Features: 

The degree of skull and brain defects is variable.  Some patients have only occipital scalp defects while others have occipital encephaloceles.  The scalp defect may contain heterotopic neuronal tissue suggesting neuronal migratory defects.  Brain imaging has revealed a variety of defects and some patients have cognitive deficits and personality changes.  Cerebellar atrophy with ataxia is found in some patients.

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in the COL18A1 gene (21q22.3).  Mutated COL18A1 leads to defects in type XVIII collagen which is a component of basement membranes throughout the body, especially in the eye.

In spite of some clinical similarities, this disorder is genetically distinct from Knobloch 2 syndrome (608454).  A third type, KNO3, has been proposed since the Knobloch clinical features were found in a 4-generation consanguineous Pakistani family but the phenotype mapped to 17q11.2.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is largely supportive.  Attempts at repair of retinal detachments often fail and phthisis bulbi is not uncommon.

References
Article Title: 

Mannosidosis, Alpha B

Clinical Characteristics
Ocular Features: 

Many (probably most) patients have lens opacities and some have corneal opacities as well.  Nystagmus and strabismus have been described.  Pigmentary changes of a mottled nature can be present in the posterior pole and may be associated with retinal vessel attenuation and diminished ERG responses.  Retinal thinning can be demonstrated.  A mixture of hypo- and hyperautofluorescence is often visible.  Mild optic atrophy has been seen.  There is evidence for progressive visual loss, even late in life.  Eyebrows appear thick.    

Systemic Features: 

Mannosidosis is a highly variable multisystem disorder.  Onset may be in infancy but in other patients symptoms appear later in the first decade.  Progression of disease is more rapid in individuals with early onset (type 3) with rapid mental, motor deterioration and early death.  The characteristic coarse facial features usually are evident later in milder cases (types 1 and 2) that have mild or moderate intellectual disabilities.  Regardless, mannosidosis is relentlessly progressive with mental deterioration and motor disabilities.  Ataxia is a common feature.  Dental anomalies (diastema), large ears, macroglossia, joint stiffness,, hepatosplenomegaly, enlarged head circumference, hearing loss (sensorineural), increased susceptibility to infections, dysarthria, and spondylolysis may be present.

Genetics

Alpha-mannosidoosis is an autosomal recessive lysosomal storage disorder resulting from mutations in the MAN2B1 gene (19p13.2).  There is another form of mannosidosis known as beta A  (248510) caused by mutations in MANBA but ocular features have not been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Prompt treatment for infections is required and prophylactic vaccinations are indicated.  All individuals should be seen annually and assistive devices such as wheel chairs and hearing aids prescribed when needed.

References
Article Title: 

Retinal and optic nerve degeneration in α-mannosidosis

Matlach J, Zindel T, Amraoui Y, Arash-Kaps L, Hennermann JB, Pitz S. Retinal and optic nerve degeneration in a-mannosidosis. Orphanet J Rare Dis. 2018 Jun 1;13(1):88. doi: 10.1186/s13023-018-0829-z.

PubMed ID: 
29859105

Ocular findings in mannosidosis

Arbisser AI, Murphree AL, Garcia CA, Howell RR. Ocular findings in mannosidosis. Am J Ophthalmol. 1976 Sep;82(3):465-71. PubMed PMID: 961797.

PubMed ID: 
961797

Fructose Intolerance

Clinical Characteristics
Ocular Features: 

Dense cataracts have been reported in the first decade of life in several patients.

Systemic Features: 

Abdominal pain, vomiting and hypoglycemia usually appears in infancy upon the introduction of fructose or sucrose to the diet.  Some infants have a more severe reaction to such sugars with lethargy, seizures and coma.  Older children and adults develop a protective aversion to fruits and sweets.  Chronic ingestion leads to liver cirrhosis, renal tubule damage, growth retardation, and even malnutrition.  Adults may also have hypoglycemia and metabolic acidosis when challenged with sucrose and fructose.

Genetics

This is an autosomal recessive disorder resulting from mutations in the ALDOB gene (9q31.1).  However, several heterozygous patients with symptoms have been reported and such individuals may be predisposed to hyperuricemia.  Multiple mutations have been identified in the ALDOB gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment with a fructose restricted diet is highly effective but must be strictly enforced to allow normal growth.

References
Article Title: 

Hereditary fructose intolerance

Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet. 1998 May;35(5):353-65. Review.

PubMed ID: 
9610797

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