cataracts

External Ophthalmoplegia, C10ORF2 and mtDNA Mutations

Clinical Characteristics
Ocular Features: 

Ptosis and external ophthalmoplegia are found in almost all patients.  These have a variable onset with some patients not symptomatic until midlife or later.  External ophthalmoplegia may be the only symptom.  Onset in late adolescence has also been reported.  Cataracts often occur.

Systemic Features: 

About half (52%) of patients have fatigue and weakness.  Ataxia and peripheral neuropathy with paresthesias are sometimes present. Some patients report bulbar symptoms of dysphagia, dysarthria and dysphonia.  Skeletal muscle biopsies show typical ragged red fibers and evidence of mitochondrial dysfunction with cytochrome c oxidase (COX) deficiency.  Late onset of typical features of parkinsonism including a resting tremor, rigidity, and bradykinesia is seen in some patients.  Several individuals have reported major depression and/or bipolar disorder. Myopathy (33%) with muscle wasting and respiratory difficulties can occur.   As many as 24% of patients have cardiac abnormalities consisting primarily of conduction defects.

Genetics

This an autosomal dominant disorder secondary to mutations in the C10ORF2 (Twinkle) gene (10q24) in association with mitochondrial DNA depletion.  It accounts for approximately 35% of autosomal dominant cases of external ophthalmoplegia.

At least two additional mutations cause similar external ophthalmoplegia syndromes: PEOA1 (157640, 258450), and PEOA2 (609283).

The same gene may have mutations that are responsible for spinocerebellar ataxia, infantile-onset (271245), a more generalized and progressive neurodegenerative disease transmitted in an autosomal recessive pattern.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

The clinical, histochemical, and molecular spectrum of PEO1(Twinkle)-linked adPEO

Fratter C, Gorman GS, Stewart JD, Buddles M, Smith C, Evans J, Seller A, Poulton J, Roberts M, Hanna MG, Rahman S, Omer SE, Klopstock T, Schoser B, Kornblum C, Czermin B, Lecky B, Blakely EL, Craig K, Chinnery PF, Turnbull DM, Horvath R, Taylor RW. The clinical, histochemical, and molecular spectrum of PEO1(Twinkle)-linked adPEO. Neurology. 2010 May 18;74(20):1619-26.

PubMed ID: 
20479361

External Ophthalmoplegia, POLG and mtDNA Mutations

Clinical Characteristics
Ocular Features: 

Progressive external ophthalmoplegia of these types is often associated with widespread neurological and muscle manifestations.  The ophthalmoplegia is adult in onset and frequently combined with exercise intolerance.  Significant lens opacities may be seen in early childhood but may not cause vision problems until early adulthood. Progressive ptosis is often an early and disabling sign.

Systemic Features: 

Facial muscles can be weak, generally in older individuals.  Some patients complain of dysphagia.  Sensoirneural hearing loss, dysarthria, and dysphonia are often associated.  Neurological symptoms include ataxia, sensory neuropathy, tremors, depression and symptoms of parkinsonism but these are variable.   Some patients experience rhabdomyolysis following alcohol consumption.  Dilated cardiomyopathy can be a part of the autosomal recessive form of this disease.

A possible subcategory of this disease is associated with hypogonadism evidenced by delayed sexual maturation, primary amenorrhea, early menopause and testicular atrophy.  Other features as described above may be associated.  Muscle biopsy shows ragged-red fibers with multiple mitochondrial deletions.

Genetics

Progressive external ophthalmoplegia of the type described here is the result of mutations in the autosomal gene POLG combined with deletions in mitochondrial DNA.  POLG mutations account for 13-45% of patients with progressive external ophthalmoplegia who also have mitochondrial deletions.  The inheritance pattern in some families resembles the classical autosomal dominant pattern (PEOA1, 157640) whereas in others the pattern suggests autosomal recessive transmission (PEOB, 258450).  The autosomal defect is in the POLG gene at locus 15q25 which codes for the nuclear-encoded DNA polymerase-gamma gene.  The phenotype in the recessive disease tends to be more severe than in autosomal dominant cases. 

Other autosomal mutations with a less complex clinical picture associated with ophthalmoplegia are located in genes ANT1 (SLC25A4) (609283) at 4q35, and C10ORF2 (606075) at 10q24.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for the general disorder but consideration should be given to ptosis repair.

References
Article Title: 

Kniest Dysplasia

Clinical Characteristics
Ocular Features: 

High myopia and vitreoretinal degeneration are characteristic ocular features in this disorder.   The myopia is in the range of -7.5 to -15.25 with most patients having about -11 diopters.  Acuity may be normal but inoperable retinal detachments can lead to blindness.  The vitreous demonstrates liquefaction and syneresis and often detaches posteriorly forming a retrolental curtain.  About half of affected eyes have perivascular lattice degeneration and the same proportion of patients at some point develop a retinal detachment.  Giant tears and retinal dialysis are commonly the cause.  The lens is often dislocated and cataracts are common.

Systemic Features: 

Short stature, cleft palate, stiff joints, and conductive hearing loss are characteristic extraocular features of Kniest dysplasia.  Some patients develop frank joint contractures and many are unable to make a tight fist due to inflexibility of the interphalangeal joints.  Lumber kyphoscoliosis is common.  Epiphyseal cartilage has a 'Swiss cheese appearance' with prominent lacunae.  The facies are round and the midface is underdeveloped with a flat nasal bridge.  Mild psychomotor retardation is sometimes seen.  

High levels of keratin sulfate are found in the urine.

Genetics

Mutations in the COL2A1 gene (12q13.11-q13.2) coding for type II collagen is responsible for this autosomal dominant disorder. This is one of a number of disorders known as type II collagenopathies (see Stickler syndrome I [609508]).  The clinical features arise from a defect in type II procollagen.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the dysplasia.  Displaced lenses can be removed but the myopia and degenerated vitreous require a cautious approach.  Rhegmatogenous detachments demand prompt attention.

References
Article Title: 

Ophthalmic and molecular genetic findings in Kniest dysplasia

Sergouniotis PI, Fincham GS, McNinch AM, Spickett C, Poulson AV, Richards AJ, Snead MP. Ophthalmic and molecular genetic findings in Kniest dysplasia. Eye (Lond). 2015 Jan 16. doi: 10.1038/eye.2014.334. [Epub ahead of print].

PubMed ID: 
25592122

The Kniest syndrome

Siggers CD, Rimoin DL, Dorst JP, Doty SB, Williams BR, Hollister DW, Silberberg R, Cranley RE, Kaufman RL, McKusick VA. The Kniest syndrome. Birth Defects Orig Artic Ser. 1974;10(9):193-208.

PubMed ID: 
4214536

Stickler Syndrome, Type I

Clinical Characteristics
Ocular Features: 

High myopia and vitreous degeneration dominate the ocular manifestations of Stickler syndrome, type I.  The vitreous often appears optically empty as it liquefies and the fibrils degenerate.  The vitreous is sometimes seen to form 'veils', especially in the retrolenticular region but they may also float throughout the posterior chamber.  They are often attached to areas of lattice degeneration in the retina as well as other areas.  Posterior vitreous detachments are common.  Vitreoretinal degeneration is progressive and by the second decade rhegmatogenous detachments occur in half of affected patients.  As many as three quarters of adult patients have retinal breaks.  The retina has pigmentary changes with deposition circumferentially near the equator and more peripherally.  Hypopigmentation is more common early creating a tessellated appearance.  Lenticular opacities occur also early with cortical flecks and wedge-shaped changes.

The ERG may be normal early but evidence of rod and cone dysfunction soon appears and is progressive.  Dark adaptation is defective later in the course of the disease.  The EOG is virtually always depressed.  The visual field is constricted and may show a ring scotoma coincident with the equatorial chorioretinal atrophy.

Glaucoma is not uncommon and may be infantile in onset and difficult to control.  

Phthisis is a significant risk especially for individuals who have multiple surgical procedures for retinal detachments. 

Systemic Features: 

It has been suggested that there is a nonsyndromic or ocular type of Stickler syndrome lacking many of the extraocular features characteristic of the complete syndrome.  However, the evidence for the ocular type described here as a distinct entity remains slim and the clinical picture may simply reflect variable expressivity of mutations in the same gene.  Type I Stickler syndrome has multiple systemic features such as cleft palate, hearing impairment, premature arthritis, micrognathia, kyphoscoliosis, and some signs such as arachnodactyly that are found in the Marfan syndrome.

Genetics

This is an autosomal dominant disease of collagen formation as a result of mutations in the COL2A1 gene (12q13.11-q13.2). The mutations causing both syndromal and the suggested nonsyndromal ocular type of Stickler disease are in the same gene.  Mutations in the same gene are known to cause autosomal dominant rhegmatogenous retinal detachments in patients who have none of the systemic clinical signs (609508).  These patients may lack the signs of vitreous degeneration seen in Kniest dysplasia (156550)  and in the disorder described here.

There is better evidence for a second type of Stickler syndrome, STL2 or type II (604841) based on phenotypic differences and the fact that a second locus (1p21) containing mutations in COL11A1 has been linked to it. 

Type III is caused by mutations in COL11A2 and has systemic features similar to types I and II but lacks the eye findings since this gene is not expressed in the eye.

Type IV also has important ocular features but is an autosomal recessive disorder caused by mutations in COL9A2.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

The combination of progressive vitreoretinal degeneration, frequency of posterior vitreous detachments, and axial myopia creates a lifelong threat of retinal tears and detachments.   Half to three quarters of all patients develop retinal tears and detachments.  Certainly all patients with Stickler syndrome deserve repeated and thorough retinal exams throughout their lives.  In addition to prompt treatment of tears and detachments, some have advocated prophylactic scleral banding to reduce vitreous traction, or applying 360 degree cryotherapy.

References
Article Title: 

Stickler syndrome in children: a radiological review

McArthur N, Rehm A, Shenker N, Richards AJ, McNinch AM, Poulson AV, Tanner J, Snead MP, Bearcroft PWP. Stickler syndrome in children: a radiological review. Clin Radiol. 2018 Apr 13. pii: S0009-9260(18)30118-1. doi: 10.1016/j.crad.2018.03.004. [Epub ahead of print].

PubMed ID: 
29661559

High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1

Richards AJ, Laidlaw M, Whittaker J, Treacy B, Rai H, Bearcroft P, Baguley DM, Poulson A, Ang A, Scott JD, Snead MP. High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1. Hum Mutat. 2006 Jul;27(7):696-704. Erratum in: Hum Mutat. 2006 Nov;27(11):1156.

PubMed ID: 
16752401

Marfan Syndrome

Clinical Characteristics
Ocular Features: 

Marfan syndrome typically has skeletal, ocular and cardiovascular abnormalities.  The globe is elongated creating an axial myopia and increasing the risk of rhegmatogenous retinal detachments.  Ectopia lentis is, of course, the classical ocular feature and is often if not always congenital with some progression.  The lenses most frequently dislocate superiorly and temporally and dilating the pupils often reveals broken and retracted lens zonules.  Phacodenesis and iridodenesis are commonly present even in the absence of evident lens dislocations. Cataracts develop several decades earlier than in unaffected individuals. The cornea is generally several diopters flatter than normal and there is an increased risk of open angle glaucoma.  There is considerable clinical variation among patients.

Systemic Features: 

Patients with the Marfan phenotype are usually tall with disproportionately long limbs (dolichostenomelia) and digits (arachnodactyly).   Patients frequently have scoliosis or kyphoscoliosis.  The joints are lax and hyperflexible although contractures can also occur.  The sternum is often deformed, either as a pectus excavatum, or sometimes pectus carinatum.  The hard palate is high and narrow resulting in crowding of the teeth and maloccclusion.  The defect in fibrillin is responsible for the weakness in connective tissue that leads to frequent cardiac valve malfunction, especially insufficiency of the aortic valve resulting from aortic dilatation, tear, and rupture.  The latter is often life-threatening as aortic dissection can be fatal.  Mitral valve prolapse is seen as well.  Cardiovascular disease is primarily responsible for the shortened life expectancy in this disease, more pronounced among males.

Genetics

As many as 25% of cases are caused by new mutations, but familial cases usually follow an autosomal dominant pattern of inheritance.  Autosomal recessive inheritance is claimed for several individuals in a consanguineous Turkish family.  Mutations in the fibrillin-1 gene (FBN1) on chromosome 15 (15q21.1) are considered responsible for the typical phenotype.  The exact nature of the fibrillin defect is unknown but the result is a generalized weakness in connective tissue.

The same gene is mutant in the autosomal dominant form of the Weill-Marchesani syndrome (608328) which is allelic to the Marfan syndrome.

Mutations in FBN1 have also been found in cases with isolated autosomal dominant ectopia lentis (129600).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Isometric exercises such as weight lifting should be avoided as should contact sports in which blunt trauma to the chest may occur because of the weakened aortic wall due to cystic changes that predispose the athlete to aortic dissection.  A dislocated and/or cataractous lens may need to be removed from the visual axis, and, of course, periodic retinal examinations for retinal holes and retinal detachments should be made.   Beta-adrenergic blockade reduces the risk of aortic dilatation and improves survival.

Pravastatin has been reported to reduce aortic dilation in marfan mice.

References
Article Title: 

Pravastatin reduces marfan aortic dilation

McLoughlin D, McGuinness J, Byrne J, Terzo E, Huuskonen V, McAllister H, Black A, Kearney S, Kay E, Hill AD, Dietz HC, Redmond JM. Pravastatin reduces marfan aortic dilation. Circulation. 2011 Sep 13;124(11 Suppl):S168-73.

PubMed ID: 
21911808

Cataracts, Anterior Polar with Guttata

Clinical Characteristics
Ocular Features: 

The combination of corneal guttata and anterior polar cataracts has been reported in at least 4 multigenerational families.  Cataracts have their onset in the first decade of life, sometimes as early as 6 months but often are not noted until 3 to 4 years of age.  The polar opacities range in size from that of a small dot to 3 mm in diameter.  These progress slowly and become nearly stationary in early adulthood but can progress sufficiently to interfere with acuity and sometimes require removal by the 3rd or 4th decades of life.  The guttata also appear sometime after birth and are more pronounced centrally.  Histologically the stroma is normal but the epithelium shows some edematous changes and the Descemet membrane progressively thickens with age along with the corneal clouding.  Visual impairment early is generally caused by the lens opacity while later in life corneal edema is more likely the cause.

Vision across a variety of ages ranges from 20/20 to 20/40 in patients with more stationary disease.

Systemic Features: 

No associated systemic disease has been reported.

Genetics

This is a presumed autosomal dominant disorder resulting from heterozygous mutations in the TMCO3 gene (13q34).

Another type of autosomal dominant anterior polar cataract, CTAA2 (601202), but without corneal disease has been mapped to 17p13 and yet another (CTAA1) (115650) is associated with chromosomal aberrations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract extraction and corneal transplantation can improve vision but are seldom necessary.

References
Article Title: 

Corneal Dystrophy, Gelatinous Drop-like

Clinical Characteristics
Ocular Features: 

White, gelatinous deposits of amyloid are seen in the subepithelial region giving the surface of the cornea a multilobulated appearance resembling a mulberry.  These usually appear in the first decade of life and cause photophobia as well as tearing from irritation caused by a severe foreign body sensation.  The corneal changes are variable and some patients have only a mild amount of anterior stromal opacification while others have subepithelial vascularization.  Vision loss can be severe when the deposits coalesce to opacify the cornea.  These deposits are found in the subepithelial region but in some families it may also be found in the Bowman layer.   The appearance of fusiform deposits in the stroma in some patients has led some to categorize gelatinous drop-like corneal dystrophy as a lattice dystrophy and have designated it as type III.  GDLD seems to occur more commonly in Japan but often has a much later onset and the lattice appearance is more striking suggesting that it may be a unique form of corneal amyloidosis.  True GDLD, however, occurs in diverse ethnic groups throughout the US, Europe, Latin America, and the Asian subcontinent.  Cataracts have been reported in several young individuals with corneal amyloidosis.

Systemic Features: 

No systemic abnormalities occur as part of this syndrome.

Genetics

Autosomal recessive corneal amyloidosis results from multiple mutations in the M1S1 (TACSTD2) gene located on chromosome 1 (1p32).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No satisfactory permanent treatment has been found.  Ablative treatments may give temporary relief from symptoms and improve vision but the deposits recur within a few years.

References
Article Title: 

Basal Cell Nevus Syndrome

Clinical Characteristics
Ocular Features: 

Eyelid basal-cell carcinomas are the most common ocular finding of this syndrome.  These malignancies may be multiple and may occur on the neck, chest, back, arms and elsewhere on the face.   Those on the eyelids generally have their onset in the postpubertal period, usually by age 35 years, and are often multiple.  Their indolent nature can result in considerably delay in diagnosis, however, and local recurrences are common.  Deformities of the skull often result in the appearance of hypertelorism and proptosis.  Epidermal cysts are found in one-fourth of patients, especially on the palms, but may occur in the tarsal conjunctiva as well.  Intratarsal keratinous eyelid cysts occur in 40% of patients.  Less common reported ocular findings are colobomas, glaucoma, nystagmus, strabismus, and cataracts but these may simply be associations.

Systemic Features: 

This disorder is one of a few in which a disposition to neoplasia is associated with skeletal deformities.  These include bifid ribs, scoliosis, skull deformities such as frontal bossing, increased occipitofrontal circumference, broad nasal root with hypertelorism, mandibular prognathia, and bony cysts.  Medulloblastoma is an infrequent but important sign.  Palmar and/or plantar pits are often present.  Basal cell carcinomas and jaw cysts occur in over 90% of patients by the age of 40 years.  Invasive oral tumors are found in 78% of individuals.

Genetics

This is an autosomal dominant disorder, caused by heterozygous mutations in the PTCH1 gene located on chromosome 9 (9q22.3).  Interestingly, somatic mutations in the PTCH1 gene have also been found in isolated cases with only basal cell carcinoma or medulloblastoma.  Perhaps 40% of cases arise de novo, i.e., without a family history, and older paternal age at conception increases the risk of new mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is directed at the location of clinical disease with excision of basal cell carcinomas having the highest priority.  Patients must be monitored throughout life for new lesions as well as recurrence at treated sites. Radiotherapy and non-essential diagnostic X-rays should probably be avoided due to sensitivity to ionizing radiation.

Oral administration of an experimental small molecule signaling inhibitor (GDC-0449 or Vismodegib; Genetech) of the Hedgehog signaling pathway has shown promise in reduction of the number of new lesions as well as shrinkage of existing skin lesions.  BCC lesions have been successfully treated with ingenol mebutate in a single patient.

References
Article Title: 

Eyelid Cysts in Gorlin Syndrome: A Review and Reappraisal

Wolkow N, Jakobiec FA, Yoon MK. Intratarsal Keratinous Eyelid Cysts in Gorlin Syndrome: A Review and Reappraisal. Surv Ophthalmol. 2017 Dec 26. pii: S0039-6257(17)30236-9. doi: 10.1016/j.survophthal.2017.12.007.

PubMed ID: 
29287708

Basal cell nevus syndrome: a brave new world

Goldberg LH, Firoz BF, Weiss GJ, Blaydorn L, Jameson G, Von Hoff DD. Basal cell nevus syndrome: a brave new world. Arch Dermatol. 2010 Jan;146(1):17-9. PubMed PMID: 20083687.

PubMed ID: 
20083687

Goldmann-Favre Syndrome/ESCS

Clinical Characteristics
Ocular Features: 

Enhanced S-cone syndrome, sometimes called Goldman-Favre syndrome, is a retinal disorder characterized by increased sensitivity to blue light, night blindness from an early age, and decreased vision.  Additional features include an optically empty liquefied vitreous, progressive foveal or peripheral retinoschisis, macular cysts, chorioretinal atrophy and pigmentary retinopathy as well as posterior subcapsular cataract formation.  Hyperopia is a feature, at least in childhood.   Enhanced S-cone syndrome is the only retinal disorder that has a gain of a subtype of photoreceptors, in this case the S-cones (short wave length) that detect blue light. Rod photoreceptors and red and green cone receptors are degenerated to a variable degree. Electroretinography shows an extinct rod photoreceptor response and hypersensitivity to shorter wavelengths.

There is considerable variation in the clinical features of NR2E3 mutations which has led to some confusion in the nosology.  Some cases are called juvenile retinoschisis, others are called retinitis pigmentosa, or clumped pigment retinopathy.  Central acuity ranges from near normal (20/40) in young people to 20/200 or worse especially in older adults.  Visual field constriction likewise varies from patient to patient.  Retinal pigmentary changes and the amount of cystic changes in the macula are somewhat age dependent.

Systemic Features: 

No general systemic manifestations are associated with enhanced S-cone syndrome and Goldman-Favre syndrome.

Genetics

This is an autosomal recessive retinal disorder caused by mutations in NR2E3, also known as PNR, located on chromosome 15q23.  It is a part of a transcription factor complex necessary for the development of photoreceptors.  Mutations in NR2E3 cause degeneration of rod photoreceptors and an increased number of S-cone photoreceptors resulting in an increased ratio of blue to red-green cone photoreceptors. Mutations in the NR2E3 gene can also cause a clinical picture resembling simple autosomal recessive retinitis pigmentosa.

Two brothers with an enhanced S-cone phenotype and normal rod function have been reported.  Scotopic b-wave ERG amplitudes were normal but OCT showed flattening of the macular area and thinning of the photoreceptor layer.  This may be the result of a different mutation in this family but no molecular defect was found.

Several Moroccan families have been reported with homozygous or compound heterozygous mutations in the NRL gene (162080).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is presently no effective treatment for the disorder, but visual function can be improved with low vision aids. Cataract surgery may be beneficial.

Improvement in vision has been reported with the use of topical carbonic anhydrase inhibitors.

References
Article Title: 

Expanded Clinical Spectrum of Enhanced S-Cone Syndrome

Yzer S, Barbazetto I, Allikmets R, van Schooneveld MJ, Bergen A, Tsang SH, Jacobson SG, Yannuzzi LA. Expanded Clinical Spectrum of Enhanced S-Cone Syndrome. JAMA Ophthalmol. 2013 Aug 29.  [Epub ahead of print] PubMed PMID: 23989059.

PubMed ID: 
23989059

Phenotypic variation in enhanced S-cone syndrome

Audo I, Michaelides M, Robson AG, Hawlina M, Vaclavik V, Sandbach JM, Neveu MM, Hogg CR, Hunt DM, Moore AT, Bird AC, Webster AR, Holder GE. Phenotypic variation in enhanced S-cone syndrome. Invest Ophthalmol Vis Sci. 2008 May;49(5):2082-93.

PubMed ID: 
18436841

Alport Syndrome (Collagen IV-Related Nephropathies)

Clinical Characteristics
Ocular Features: 

X-linked Alport syndrome is a basement membrane disease with important ocular manifestations.  The lens is usually normal at birth but lens opacities eventually occur in a significant number of individuals with the most characteristic type being anterior polar in location.  Involvement of the anterior lens capsule often results in bilateral anterior lenticonus (25%) and may be progressive.  It is claimed that the severity of the lenticonus is a valuable marker in judging the overall disease severity.  In early stages it may be difficult to detect but its presence is suggested by an 'oil droplet' reflex during retinoscopy or slit lamp examination.  All males with anterior lenticonus should be evaluated for Alport syndrome. 

Posterior polymorphous corneal dystrophy and posterior subcapsular opacities have also been noted.  The defect in basement membranes may lead to recurrent corneal erosions, even in children, which can be incapacitating and difficult to treat.  Involvement of Bruch's membrane has been considered the source of retinal pigment epithelial changes described as a flecked retina, or 'fundus albipunctatus', found in 85% of patients.  More recent evidence using OCT suggests that the dot-and-fleck retinopathy results primarily from abnormalities in the internal limiting membrane and the nerve fiber layer.  The yellowish and/or whitish flecks are most commonly located in the posterior pole and particularly in the macula.  There is no night blindness or visual impairment from the retinal involvement.  Fluorescein angiography shows patchy areas of hyperfluorescence.  The amount of visual impairment depends primarily on the extent of lens involvement.

Termporal macular thinning occurs to some extent in all types of Alport syndrome based on OCT findings.   In one series all patients with X-linked disease had temporal thinning suggesting that this might be a useful diagnostic sign.  However, similar thinning is also seen in Leber hereditary optic neuropathy (535000), and dominant optic atrophy (165500).

Systemic Features: 

Nephritis with hematuria secondary to basement membrane disease of the glomeruli is the most life threatening aspect of this disorder.  It occurs in both sexes but more commonly in males in which it has an earlier onset.  Progressive sensorineural hearing loss beginning with high frequencies occurs in many patients, often with subtle onset in childhood, but many adults retain some hearing capacity.  In males, the onset of hearing loss often occurs before kidney disease is evident.  Hearing loss is less frequent and less severe in females.  However, there is considerable clinical and genetic heterogeneity and not all patients have the complete syndrome of nephritis, deafness and ocular disease.  In fact, it has been suggested that Alport syndrome can be subtyped into at least six categories based on the extent of organ involvement.

Genetics

Alport syndrome is a member of a group of disorders known as collagen IV-related nephropathies.  It is a genetically heterogeneous disease with 85% inherited in an X-linked pattern and most of the remainder occurring in an autosomal recessive pattern and only a few seemingly autosomal dominant.  All result from a defect in type IV collagen found in basement membranes.  About 80% of cases have a mutation in the COL4A5 gene which is located at Xq22.3.  Males seem to be more severely affected than females in the X-linked form of the disease but clearly this disorder affects both sexes reflecting the genetic heterogeneity, much of which remains to be delineated.  The autosomal disease generally results from mutations in the COL4A3 or COL4A4 genes and has been seen in both recessive and dominant patterns of transmission.

Pedigree: 
Autosomal dominant
Autosomal recessive
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Renal transplantation can be lifesaving but a minority of individuals develop a specific antiglomerular basement membrane antibody (anti-GBM) that may lead to graft rejection.  Allograft survival rates are generally excellent though.  Lens extraction is beneficial where the media is compromised.

References
Article Title: 

Alport syndrome: a genetic study of 31 families

M'Rad R, Sanak M, Deschenes G, Zhou J, Bonaiti-Pellie C, Holvoet-Vermaut L,
Heuertz S, Gubler MC, Broyer M, Grunfeld JP, et al. Alport syndrome: a genetic
study of 31 families.
Hum Genet. 1992 Dec;90(4):420-6.

PubMed ID: 
1483700

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