optic atrophy

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: 

Duane-Radial Ray Syndrome

Clinical Characteristics
Ocular Features: 

Most individuals have features of Duane’s anomaly, sometimes unilaterally.  Optic pallor with poor vision has been described in well-studied patients who also had thinning of the retinal nerve fiber layer.  The optic disk may appear hypoplastic.  Visual evoked potentials and pattern ERG amplitudes are decreased.

Other less common ocular features are microcornea, microphthalmia, ophthalmoplegia, hypertelorism, cataracts, epicanthal folds, colobomas, and chorioretinal scars.

Systemic Features: 

The systemic features are inconsistent (variable expressivity) with most patients having some variation of hypodactyly, polydactyly, syndactyly, and malformation of the hands.  The thumb is the most common digit involved and this is often associated with thenar hypoplasia.  Other skeletal features of the radial ray syndrome including absence of the radial and ulnar bones are variably present.  Hearing loss is described as sensorineural in etiology but malformations of the pinnae and external meatus are sometimes present.

Kidney anomalies include horseshoe malformations, abnormal rotation, ectopia, small size, vesicoureteric reflux, and pelvicalyceal dilatation.

Genetics

This is an autosomal dominant disorder due to heterozygous mutations in the SALL4 gene (20q13.2).

This syndrome is sometimes confused with the Holt-Oram syndrome but the latter is the result of mutations in a different gene and lacks ocular and renal abnormalities.  Duane syndrome 1 and 2 may also occur as isolated conditions.

The considerable clinical heterogeneity has led to alternate titles for this syndrome. For example, what is sometimes called the IVIC syndrome (147750) with similar features is also caused by mutations in this gene.  Duane-radial ray syndrome has also been called Okihiro syndrome. 

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Treatment is symptomatic in most cases although reconstructive surgery may be helpful for severe hand deformities.  Low vision aids may be beneficial.  

References
Article Title: 

Peroxisome Biogenesis Disorder 3B (Infantile Refsum Disease)

Clinical Characteristics
Ocular Features: 

This peroxisomal disorder presents in the first year of life with both systemic and ocular features.  Night blindness is the major ocular feature and at least some have optic atrophy similar to the adult form.  Nystagmus may be present.  Reduction or absence of rod responses on ERG can be used in young children to document the retinopathy. Blindness and deafness commonly occur in childhood.

Systemic Features: 

This disorder is classified as a peroxisomal biogenesis disorder (PBD) associated with the breakdown of phytanic acid.  Ataxia and features of motor neuron disease are evident early.  Hepatomegaly and jaundice may also be an early diagnostic feature as bile acid metabolism is defective.  Infant hypotonia is often seen.  Nonspecific facial dysmorphism has been reported as a feature. The teeth are abnormally large and often have yellowish discoloration.  Postural unsteadiness is evident when patients begin walking.  Diagnosis can be suspected from elevated serum phytanic and pipecolic acid (in 20% of patients) or by demonstration of decreased phytanic acid oxidation in cultured fibroblasts.  Other biochemical abnormalities such as hypocholesterolemia and elevated very long chain fatty acids and trihydroxycholestanoic acid are usually present.  Anosmia and mental retardation are nearly universal features.  Early mortality in infancy or childhood is common although some survive into the 2nd and 3rd decades.

Genetics

This is an autosomal recessive peroxisomal biogenesis disorder (PBD) resulting from mutations in a number of PEX genes (PEX1, PEX2, PEX3, PEX12, PEX26).  It shares many features with other PBDs including those formerly called Zellweger syndrome (214100), rhizomelic chondrodysplasia punctata (215100), and neonatal adrenoleukodystrophy (601539).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

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

Spastic Paraplegia 7

Clinical Characteristics
Ocular Features: 

Many but not all individuals have significant visual loss due to optic atrophy.  Other ocular signs include supranuclear palsy, ptosis, and nystagmus.  Older individuals with advanced disease may have progressive external ophthalmoplegia.

Systemic Features: 

There is a great deal of clinical heterogeneity between families and not all individuals have severe neurological disease.  Progressive neurological signs (primarily abnormal gait) are often present in late childhood or early adolescence but may occur late in life.  Clinical features include muscle atrophy and weakness with spasticity (more pronounced in the lower limbs), ataxia, pyramidal signs, dysphagia, and cerebellar dysarthria.  Hyperreflexia and extensor plantar responses are often present.  Cognitive deficits are manifest as deficits in attention and higher levels of reasoning.  Some patients have a mild peripheral neuropathy with decreased vibratory sense.  Many patients have significant dysfunction of the bladder sphincter.  Adults may lose their mobility and are confined to a wheelchair.

Some patients develop scoliosis and pes cavus.  The MRI often shows cerebellar and mild frontal cortical atrophy.

Genetics

This type of spastic paraplegia results from mutations in the paraplegin gene, SPG7 (16q24.3).  It is usually transmitted in an autosomal recessive pattern although heterozygous patients with symptoms have been reported. Evidence suggests that the symptoms arise from a defect in mitochondrial respiration.

Patients with spastic paraplegia 15 (270700) have a similar neurological phenotype plus a flecked retina.  Congenital cataracts are part of the phenotype of spastic paraplegia 46 (614409).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is symptomatic.  Physical, speech, and occupational therapy may be helpful in selected patients.  Low vision aids may be of benefit in some individuals, at least early in the disease.

References
Article Title: 

Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance

Pfeffer G, Gorman GS, Griffin H, Kurzawa-Akanbi M, Blakely EL, Wilson I, Sitarz K, Moore D, Murphy JL, Alston CL, Pyle A, Coxhead J, Payne B, Gorrie GH, Longman C, Hadjivassiliou M, McConville J, Dick D, Imam I, Hilton D, Norwood F, Baker MR, Jaiser SR, Yu-Wai-Man P, Farrell M, McCarthy A, Lynch T, McFarland R, Schaefer AM, Turnbull DM, Horvath R, Taylor RW, Chinnery PF. Mutations in the SPG7 gene cause chronic progressive external ophthalmoplegia through disordered mitochondrial DNA maintenance. Brain. 2014 Apr 10. [Epub ahead of print].

PubMed ID: 
24727571

A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia

Arnoldi A, Tonelli A, Crippa F, Villani G, Pacelli C, Sironi M, Pozzoli U, D'Angelo MG, Meola G, Martinuzzi A, Crimella C, Redaelli F, Panzeri C, Renieri A, Comi GP, Turconi AC, Bresolin N, Bassi MT. A clinical, genetic, and biochemical characterization of SPG7 mutations in a large cohort of patients with hereditary spastic paraplegia. Hum Mutat. 2008 Apr;29(4):522-31.

PubMed ID: 
18200586

Majewski Syndrome

Clinical Characteristics
Ocular Features: 

No clinical information is available on the ocular features in this disorder.  The fundi have been described as normal in one patient but postmortem histopathology at 8 weeks revealed optic nerve edema with segmental axonal dropout and loss of myelin.  The nerve fiber layer of the retina was prominent with some proliferation of glial tissue.  Early nuclear sclerosis was also present.

Systemic Features: 

This disorder results from a dysgenesis of the cilia and is one of a group of short rib-polydactyly disorders.  Congenital anomalies are found in multiple organs including heart, lungs, skeleton, intestines, genitalia, pancreas, liver, and kidneys.  The diagnostic characteristic of SRPS type II is extreme shortening of the tibia in addition to short ribs in this type of short-limbed dwarfism.

Midline facial clefting, especially cleft lip, is common.  The epiglottis and lungs are often hypoplastic and the kidneys are polycystic.  Polydactyly and polysyndactyly of both pre- and postaxial types are usually present.  Most neonates with SRPS type II do not live beyond infancy.

Genetics

This is an autosomal recessive condition resulting from homozygous mutations in the NEK1 gene (4q33), or, rarely, from digenic biallelic mutations in NEK1 and DYNC2H1 (11q22.3).

Another condition with some of the same features leading to respiratory distress is asphyxiating thoracic dysplasia 1 (208500), or Jeune syndrome.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for this condition but surgical treatment could be considered for specific anomalies.

References
Article Title: 

NEK1 mutations cause short-rib polydactyly syndrome type majewski

Thiel C, Kessler K, Giessl A, Dimmler A, Shalev SA, von der Haar S, Zenker M, Zahnleiter D, Stoss H, Beinder E, Abou Jamra R, Ekici AB, Schroder-Kress N, Aigner T, Kirchner T, Reis A, Brandst?SStter JH, Rauch A. NEK1 mutations cause short-rib polydactyly syndrome type majewski. Am J Hum Genet. 2011 Jan 7;88(1):106-14.

PubMed ID: 
21211617

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: 

Sengers Syndrome

Clinical Characteristics
Ocular Features: 

This is a mitochondrial DNA depletion syndrome in which congenital cataracts are the hallmark ocular feature.  The bilateral lens opacification is usually total at birth or within the first few weeks of life as manifested by leucocoria. Lens extraction is necessary within the first 6 months of life but visual rehabilitation is nearly always compromised postoperatively by nystagmus and strabismus.  In one series only one eye recovered to 20/40 but the average postoperative acuity was in the range of 20/200 and virtually all students require special education in schools for the visually impaired.  Axial myopia is common with most patients having myopic fundus changes and requiring less than +10 diopters of aphakic correction.  Pale optic disks and a pigmentary retinopathy were noted among 8 of 18 eyes in one series.  Mild and inconsistent dyschromatopsia has been reported in a few patients.  The ERG sometimes shows diminished rod and cone function.

Systemic Features: 

Hypertrophic cardiomyopathy is often diagnosed within a fews days after birth but 40% may escape detection until the second or third decade of life.  It is usually progressive and often fatal in the neonatal period.  Myopathy involves both cardiac and skeletal muscles.  Generalized hypotonia, exercise intolerance, and delayed motor development are important features in the majority of patients.  Metabolic lactic acidosis occurs with relatively minimal excercise.  Skeletal muscle biopsies show ragged-red fibers with combined deficiencies of mitochondrial complexes I, III, and IV along with severe depletion of mtDNA.  Increased urine levels of 3-methylglutaconic have been reported.

The central nervous system is usually not involved and mental development is normal if lactic acidosis is controlled.  However, several children with mental retardation have been reported.

Genetics

Homozygous or compound heterozygous mutations in AGK (7p34), a lipid metabolism gene, are responsible for this condition.  There is considerable variation in the severeity of the phenotypic features but no ocular or cardiac disease has been found in heterozygotes. 

The same gene was found to be mutated in an autosomal recessive congenital cataract (614691) in a single reported sibship. Thorough systemic evaluation found no evidence of cardiac and skeletal muscle disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical removal of cataracts may be indicated.

References
Article Title: 

Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome

Mayr JA, Haack TB, Graf E, Zimmermann FA, Wieland T, Haberberger B, Superti-Furga A, Kirschner J, Steinmann B, Baumgartner MR, Moroni I, Lamantea E, Zeviani M, Rodenburg RJ, Smeitink J, Strom TM, Meitinger T, Sperl W, Prokisch H. Lack of the mitochondrial protein acylglycerol kinase causes Sengers syndrome. Am J Hum Genet. 2012 Feb 10;90(2):314-20.

PubMed ID: 
22284826

Retinitis Punctata Albescens

Clinical Characteristics
Ocular Features: 

Uniform white dots are symmetrically distributed in the midportion and periphery of the retina but the central portion of the macula is usually relatively spared in early stages of the disease.  These flecks are present in the first decade of life increasing in density and covering larger areas of the retina in older individuals.  Difficulties with night vision are also noted early and visual acuity may be compromised, in the range of 20/40.  By the fifth and sixth decades there may be retinal pigment atrophy in the midperiphery and this eventually progresses to geographic atrophy of the macular RPE as the visual field becomes more constricted.  The fundus in older individuals resembles that seen in retinitis pigmentosa with retinal vascular attenuation, frank bone spicule pigmentation, macular disease, and pallor of the optic nerves with significant loss of vision.  The ERG shows reduction in scotopic responses and mild reductions in photopic amplitudes.

This form of flecked retina is sometimes considered to be a variant of fundus albipunctatus (136880).  In favor of this argument are the observations in families in which some young members have the fundus picture of fundus albipunctatus (136880) while older ones with more advanced disease have all of the features of retinitis punctata albescens.  Also supportive is the fact that mutations in RLBP1 have been identified in both conditions.  

However, many individuals with fundus albipunctatus (136880) are described as having a stable disease with night blindness as the major symptom while many patients reported with retinitis albescens clearly have a more progressive and more serious disease with a fundus picture in late stages resembling retinitis pigmentosa.  The relationship of these two conditions should become clearer once we learn more about the natural history of these rare disorders.

Systemic Features: 

No systemic abnormalities have been reported.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in RLBP1 (15q26.1).  Parental consanguinity is frequently present.  Mutations in the same gene are also responsible for Bothnia type retinal dystrophy (607475), fundus albipunctatus (136880), and occasional patients with classical retinitis pigmentosa. 

Some authors consider retinitis punctata albescens to have an autosomal dominant pattern of transmission, perhaps based on the presence of white spots in the retina of parents.  However, heterozygotes are always asymptomatic.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes

Fishman GA, Roberts MF, Derlacki DJ, Grimsby JL, Yamamoto H, Sharon D, Nishiguchi KM, Dryja TP. Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes. Arch Ophthalmol. 2004 Jan;122(1):70-5.

PubMed ID: 
14718298

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