optic atrophy

Leber Optic Atrophy

Clinical Characteristics
Ocular Features: 

The hereditary optic atrophy of Leber usually begins during early midlife (approximately 30 years of age) and affects 4 times as many males as females.  The first symptom is usually a sudden onset of unilateral painless blurry vision, followed within two months by the same symptoms in the other eye.  In a minority of patients, vision deteriorates more slowly over several years.  Vision loss can be severe, often in the count fingers range, sometimes to no light perception.  However, not all patients have such extreme vision loss.  It is not uncommon, moreover, for some recovery of vision to occur, even months to years later. Visual field testing reveals a central or cecocentral scotoma and color vision defects.  In the acute phase the disc can be swollen and hyperemic.  The peripapillary nerve fiber layer becomes edematous while vessels on the nerve head and nearby retina appear tortuous and increased in number.  Shortly thereafter the optic disc becomes pale and visual evoked potentials confirm dysfunction of the optic nerve.

A small number of patients have an onset in childhood.

Systemic Features: 

A large number of associated neurologic abnormalities have been reported including ataxia, hyperreflexia, nonspecific myopathy, tremors, movement disorders, dystonia, and a peripheral neuropathy.  Cardiac conduction defects are present in some patients.  Some females have a multiple sclerosis-like neurologic illness.

Genetics

This disorder results from mutations in mitochondrial genes.  Mitochondrial DNA has 16,500 basepairs and codes for 37 genes, many of which are involved in oxidative phosphorylation.  For example, mutations in those that encode subunits of NADH dehydrogenase, MT-ND1, MT-ND2, MT-ND4, MT-ND5, and MT-ND6, are known to be responsible for LHON but at least 18 allelic variants are suspected to be causative. 

Changes in basepairs located at base pairs 3460, 11778, and 14484 account for more than 90% of cases.  In general, there is little clinical difference in the disease resulting from these mutations.  The vision loss seems to be least among patients with mutations at bp 14484 and over 50% of patients recover some vision up to a year later.  Those with mutations m.3460G>A and m.14484T>C are more likely to have some vision recovery.  Mutations at bp 11778 tends to cause the most severe loss, especially in females.

The disorder is always inherited from the maternal side (males do not contribute mitochondria via their sperm).  Many cases seem to arise de novo but in a majority of families there is a history of a similar disease among maternal relatives.

Treatment
Treatment Options: 

No effective therapy is available at this time.

References
Article Title: 

Hereditary optic neuropathies share a common mitochondrial coupling defect

Chevrollier A, Guillet V, Loiseau D, Gueguen N, de Crescenzo MA, Verny C, Ferre M, Dollfus H, Odent S, Milea D, Goizet C, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P. Hereditary optic neuropathies share a common mitochondrial coupling defect. Ann Neurol. 2008 Jun;63(6):794-8.

PubMed ID: 
18496845

Peroxisome Biogenesis Disorder 1A (Zellweger)

Clinical Characteristics
Ocular Features: 

Ocular signs resemble those of other peroxisomal disorders with cataracts and retinopathy.  The lethal consequences of ZWS have hampered delineation of the full spectrum of ocular manifestations but many infants have these features plus optic atrophy and horizontal nystagmus.  Most infants do not follow light.  Pupillary responses may be normal in early stages but disappear later. Hypertelorism has been described but metrics are often normal.

Systemic Features: 

Many infants have hepatomegaly at birth and may develop splenomegaly as well.  Jaundice often occurs with intrahepatic biliary dysgenesis.   Severe hypotonia is present at birth but improves in those patients who survive for several years.  Psychomotor retardation can be profound and seizures may occur but sensory examinations are normal.  Most infants have a peculiar craniofacial dysmorphology with frontal bossing, large fontanels, and wide set eyes.  Pipecolic acid levels are low in serum and absent in the CSF.  Most infants do not survive beyond 6 months of age.

 

Genetics

This is a peroxisome biogenesis disorder with a complex biochemical profile resulting from a large number of mutations in at least 13 PEX genes.  It is inherited in an autosomal recessive pattern.

What was formerly called Zellweger Syndrome is now more properly called Zellweger Spectrum Disorder, or sometimes a peroxisomal biogenesis disorder in the Zellweger spectrum of disorders.  The spectrum also includes neonatal adrenoleukodystrophy (601539) and Infantile Refsum disease (601539). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

Peroxisome Biogenesis Disorder 1B (neonatal adrenoleukodystrophy)

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.  Central acuity is reduced secondary to macular degeneration.  A pigmentary retinopathy is frequently present and often follows the appearance of whitish retinal flecks in the midperipheray.  Nystagmus and cataracts are common features.  Reduction or absence of ERG responses 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 leukodystrophy, or disease of white matter of the brain, associated with the breakdown of phytanic acid.  Ataxia and features of motor neuron disease are evident early.  Hepatomegaly and jaundice may also be early diagnostic features as bile acid metabolism is defective.  Infant hypotonia is often seen.  Nonspecific facial dysmorphism has been reported.  The ears are low-set and epicanthal folds are present.  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, developmental delays, and mental retardation are nearly universal features.  Early mortality in infancy or childhood is common.

Genetics

This is a genetically heterogeneous disorder of peroxisome biogenesis caused by mutations in at least three genes, PEX1 (7q21-q22), PEX2 (8q21.1), and PEX6 (22q11-21).  Each is inherited in an autosomal recessive pattern.  The mechanism of disease is different from the classic or adult Refsum disorder (266500) and some have debated whether the term ‘infantile Refsum disease’ is appropriate.

This disorder shares some clinical features with other peroxisomal disorders such as Zellweger syndrome (214100) and rhizomelic chondrodysplasia punctata (215100).  Zellweger syndrome (214100), neonatal adrenoleukodystrophy and infantile Refsum disease (601539) are now considered to be peroxisomal biogenesis or Zellweger spectrum disorders.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Spastic Ataxia 7, with Miosis

Clinical Characteristics
Ocular Features: 

Several large pedigrees have been reported in which both males and females had congenital miosis and decreased pupillary light responses.  The pupils are about 2 mm in size and have been described as 'fixed' since they do not dilate in low light or constrict in bright light.  They also do not respond well to mydriatics.  Several individuals also had nystagmus and dysconjugate eye movements.

Optic atrophy is not a consistent feature although several in the original reported family were reported to have this feature which is often found in other spastic ataxia disorders, such as Friedreich's ataxia (229300).

Systemic Features: 

Ataxia in gait and limb motion with pyramidal signs is part of this disorder.  Deep tendon reflexes are increased and plantar responses are often extensor in direction.  Both pyramidal signs and the ataxia progress little.  Affected individuals begin walking late and often have slurred speech.  The IQ's in one family were measured to be less than 90.  CT scans have not revealed cerebellar atrophy.

Genetics

This condition is likely inherited in an autosomal dominant pattern based on one pedigree with 21 members in 4 generations and another with an affected mother and 3 of 5 affected children.  Nothing is known about the locus responsible.

Optic atrophy is also found in autosomal recessive SPAX4 (613672) and in an ill-defined autosomal recessive form of spastic ataxia with mental retardation (270500).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for this disorder.

References
Article Title: 

Incontinentia Pigmenti

Clinical Characteristics
Ocular Features: 

This is primarily a disorder of skin, teeth, hair, and the central nervous system but 35% of patients have important ocular features.  The iris is variably atrophic and has pigmentary anomalies often with posterior synechiae.  Nystagmus, strabismus, and limited vision are often present.  The majority (up to 90%) of individuals have significant retinal disease.  The retinal vascular pattern is anomalous with tortuosity in some areas and absence of vessels in others.  Preretinal fibrosis and retinal detachments may suggest the presence of a retinoblastoma.  Cataracts are common in patients who have a retinal detachment and some patients have microphthalmia. The retinal pigment epithelium is often abnormal with various-sized patches of sharply demarcated depigmentation.  Cases with uveitis, papillitis and chorioretinitis have been observed and it has been suggested that the observed retinal and choroidal changes result from prior inflammatory disease, perhaps even occurring in utero. There is a great deal of asymmetry in the clinical findings in the two eyes.

Systemic Features: 

Skin changes consisting of erythematous eruptions in a linear pattern are often present at birth and this may be followed by a verrucous stage.  The acute, early findings of inflammatory disease eventually subside, ultimately resulting in pigmentary changes that appear in a 'marbled pattern' in young adults.  Hypodontia and anodontia may be present.  Alopecia and CNS abnormalities are found in nearly half of patients.  Skeletal and structural deformities are common in patients with severe neurological deficits.  The only sign of this disorder in adult women may be a whorled pattern of scarring alopecia.

As many as 30% of patients have neurological features which may be present in the neonatal period.  Seizures of various types occur in 30% of patients.  MRI findings include periventricular and subcortical white matter changes, as well as corpus callosum hypoplasia, cerebral atrophy, and cerebellar hypoplasia.

 

Genetics

The majority of evidence suggests that this is an X-linked dominant disorder with lethality in males although sporadic cases occur.  The mutation occurs as a genomic rearrangement of the IKK-gamma gene, also known as NEMO (IKBKG) located at Xq28.  There is evidence from skin cultures that cells with the mutant X chromosome inactivated are preferentially viable.  It has been proposed that cells with the mutant bearing X chromosome as the active one are gradually replaced by those in which the normal X chromosome is active accounting for the post-natal course of the skin disease.

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

No treatment for the generalized disorder is available although ocular surgery might be beneficial in rare cases with cataracts and detachments.

References
Article Title: 

Carpenter Syndrome

Clinical Characteristics
Ocular Features: 

A variety of ocular anomalies have been reported in Carpenter syndrome with none being constant or characteristic.  The inner canthi are often spaced widely apart and many have epicanthal folds and a flat nasal bridge.  Other reported abnormalities are nystagmus, foveal hypoplasia, corneal malformations including microcornea, corneal opacity, and mild optic atrophy and features of pseudopapilledema.

Systemic Features: 

Premature synostosis involves numerous cranial sutures with the sagittal suture commonly involved causing acrocephaly (tower skull).  Asymmetry of the skull and a 'cloverleaf' deformity are often present.  The polydactyly is preaxial and some degree of syndactyly is common especially in the toes.  The digits are often short and may be missing phalanges.  Some patients are short in stature.  Structural brain defects may be widespread including atrophy of the cortex and cerebellar vermis.  Septal defects in the heart are found in about one-third of patients.  The ears can be low-set and preauricular pits may be seen.  Some but not all patients have obesity and a degree of mental retardation.

Genetics

This is an autosomal recessive syndrome caused by a mutation in the RAB23 gene (6p12.1-q12).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment of the ocular defects is necessary in most cases. Craniectomy may be required in cases with severe synostosis.

References
Article Title: 

Carpenter syndrome

Hidestrand P, Vasconez H, Cottrill C. Carpenter syndrome. J Craniofac Surg. 2009 Jan;20(1):254-6.

PubMed ID: 
19165041

RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity

Jenkins D, Seelow D, Jehee FS, Perlyn CA, Alonso LG, Bueno DF, Donnai D, Josifova D, Mathijssen IM, Morton JE, Orstavik KH, Sweeney E, Wall SA, Marsh JL, Nurnberg P, Passos-Bueno MR, Wilkie AO. RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity. Am J Hum Genet. 2007 Jun;80(6):1162-70. Erratum in: Am J Hum Genet. 2007 Nov;81(5):1114. Josifiova, Dragana [corrected to Josifova, Dragana].

PubMed ID: 
17503333

Crouzon Syndrome

Clinical Characteristics
Ocular Features: 

The primary ocular features result from pattern-specific, premature synostoses of cranial sutures.  The orbits are often shallow resulting in proptosis, sometimes to such an extent that exposure keratitis or even spontaneous subluxation of the globe results.  This is exacerbated by the midface hypoplasia that is often present.  As many as 22% of patients have optic atrophy, most likely secondary to chronic papilledema from elevated intracranial pressure.  Strabismus is common, often with a V-pattern exotropia.  Overaction of the inferior obliques and underaction of the superior obliques have been described.  One patient with narrow angle glaucoma has been reported.

Systemic Features: 

The coronal sutures are the most commonly affected by the premature synostosis and hence the skull is often brachycephalic and the forehead is prominent.  Increased intracranial pressure is a risk.  The nose is parrot-beaked and the upper lip is short.  Maxillary hypoplasia from the midface underdevelopment can cause crowding and displacement of the upper teeth.

Genetics

This type of craniosynostosis is caused by mutations in the fibroblast growth factor receptor-2 gene, FGFR2, located at 10q26.  It is generally considered an autosomal dominant disorder based on familial cases but most occur sporadically.  A paternal age effect on mutations has been found. 

The same gene is mutant in other craniosynostosis disorders sometimes clinically separated such as Pfeiffer Syndrome (101600), Jackson-Weiss syndrome (123150), Beare-Stevenson Syndrome (123790), Apert Syndrome (101200), and Saethre-Chotzen Syndrome (101400).  However, this entire group has many overlapping features making classification on clinical grounds alone difficult.  Only Apert syndrome (101200) is caused by a unique mutation whereas other syndromes seem to owe their existence to multiple mutations.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Exposure keratitis must be treated.  Cranial surgery has been necessary for some patients to relieve the papilledema but the post operative outcome can be complicated by hydrocephalus.

References
Article Title: 

Glaucoma with Crouzon Syndrome

Alshamrani AA, Al-Shahwan S. Glaucoma with Crouzon Syndrome. J Glaucoma. 2018
Mar 19. doi: 10.1097/IJG.0000000000000946. [Epub ahead of print].

PubMed ID: 
29557836

Apert Syndrome

Clinical Characteristics
Ocular Features: 

In 10% of patients, keratitis and corneal scarring occur from the sometimes marked proptosis and corneal exposure.  Optic atrophy is present in over 20% of patients.  Strabismus, primarily exotropia, is found in more than 70% and various extraocular muscle anomalies may be detectable.  Usually the exotropia has a V-pattern with overaction of the inferior oblique muscles while the superior oblique is weak.  Amblyopia occurs in nearly 20%.  The lid fissures often slant downward and the eyebrows may be interrupted.

Systemic Features: 

This brachysphenocephalic type of acrocephaly is associated with syndactyly in the hands and feet.  Pre- and postaxial polydactyly may be present.  There is considerable variation in expression with some patients so mildly affected that they appear virtually normal, whereas others have extreme degrees of brachycephaly with high foreheads, midface hypoplasia, and proptosis secondary to shallow orbits.  Imaging often reveals one or more CNS anomalies such as defects of the corpus callosum, partial absence of the septum pellucidum, ventriculomegaly, and sometimes hydrocephalus.  A small but significant proportion of patients have some developmental delay and cognitive impairment.  Over 39% of patients have a normal IQ.

Genetics

This type of craniosynostosis is caused by mutations in the fibroblast growth factor receptor-2 gene, FGFR2, located at 10q26.13.  It is generally considered an autosomal dominant disorder based on familial cases but most occur sporadically.  A paternal age effect on mutations has been found.  The same gene is mutant in allelic disorders sometimes clinically separated and labeled Crouzon (123500) and Pfeiffer (some cases) (101600) syndromes.  Jackson-Weiss syndrome (123150) maps to the same locus.  However, this entire group has many overlapping features making classification on clinical grounds alone difficult.  Only Apert syndrome is caused by mutations in a single gene whereas other syndromes seem to result from mutations in multiple genes.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No specific treatment is available for this disorder but exposure keratitis may require surveillance and therapy.

References
Article Title: 

Cerebrotendinous Xanthomatosis

Clinical Characteristics
Ocular Features: 

Juvenile cataracts are the primary ocular feature of this disorder and are found in virtually all patients.  These often cause the first symptoms and become evident in the first decade and almost always by the third decade of life.  Lens opacification may require extraction at that time and aspirated lens material may contain lipid-containing vacuoles.  However, some cataracts may not be diagnosed until the 5th or 6th decades after the onset of neurological symptoms, usually because the opacities are located in the peripheral cortex and do not cause visual symptoms. 

Optic atrophy occurs in nearly half of affected individuals.  Yellowish flakes resembling cholesterol crystals can sometimes be seen in the vitreous. The fundus may have scattered hard exudates and cholesterol-like deposits along the vascular arcades and arterioles show evidence of atherosclerosis.  RPE window defects are common.

Systemic Features: 

CTX has serious systemic neurologic signs and symptoms resulting from a deficiency of a mitochondrial enzyme, sterol 27-hydroxylase.  The result is reduced bile acid synthesis and increased levels of cholestanol in plasma, tissues, and CSF.  This results in a characteristic phenotype of tendon xanthomas, and neurological dysfunction including mental regression or illness, cerebellar ataxia, peripheral neuropathy, seizures, and pyramidal signs to various degrees.  Neonatal jaundice and diarrhea are common.

Genetics

This autosomal recessive disorder results from a mutation in the CYP27A1 gene (2q33-qter) encoding sterol 27-hydroxylase.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

This is a treatable disorder in which administration of chenodeoxycholic acid (CDCA) is beneficial.  This compound is virtually absent from bile in people with CTX.  Exogenous administration reduces high levels of cholesterol and cholestanol in the CSF, tissues, and plasma with improvement in mental function and signs of peripheral neuropathy and cerebellar dysfunction.  It is frequently given in combination with other HMG-CoA inhibitors such as pravastatin.  Early diagnosis and treatment are important.

References
Article Title: 

Cohen Syndrome

Clinical Characteristics
Ocular Features: 

Patients have early onset night blindness with defective dark adaptation and corresponding ERG abnormalities.  Visual fields are constricted peripherally and central visual acuity is variably reduced.  A pigmentary retinopathy is often associated with a bull’s eye maculopathy. The retinopathy is progressive as is high myopia.  The eyebrows and eyelashes are long and thick and the eyelids are highly arched and often ‘wave-shaped’.  Congenital ptosis, optic atrophy, and ectopia lentis have also been reported.

Systemic Features: 

Affected individuals have a characteristic facial dysmorphism in which ocular features play a role.  They have a low hairline, a prominent nasal root, and a short philtrum.  The tip of the nose appears bulbous. The head circumference is usually normal at birth but lags behind in growth so that older individuals appear microcephalic.  Delays in developmental milestones are noticeable in the first year of life.  Mild to moderate mental retardation is characteristic but does not progress.  Hypotonia is common early, and many individuals are short in stature.  Low white counts and frank neutropenia are often seen and some patients have frequent infections, especially of the oral mucosa and the respiratory tract.  A cheerful disposition is said to be characteristic.

Genetics

This is an autosomal recessive disorder caused by a mutation in the COH1 (VPS13B) gene on chromosome 8 (8q22-q23).  However, a variety of mutations have been reported including deletions and missense substitutions and, since these are scattered throughout the gene, complete sequencing is necessary before a negative result can be confirmed.

There is evidence of significant clinical heterogeneity between cohorts descended from different founder mutations.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Corrective lenses for myopia can be helpful.  For patients with sufficient vision, low vision aids can be helpful.  Selected individuals may benefit from vocational and speech therapy.  Infections should be treated promptly.

References
Article Title: 

Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport

Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Traskelin AL, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, Fryns JP, de la Chapelle A, Lehesjoki AE. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet. 2003 Jun;72(6):1359-69.

PubMed ID: 
12730828

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