optic atrophy

Hunter Syndrome (MPS II)

Clinical Characteristics
Ocular Features: 

Corneal clouding may be noted as early as 6 months of age but is usually absent. When present it is milder than in some other forms of mucopolysaccharidosis.  A pigmentary retinopathy with variable severity is often present.  The disc may be elevated and appears swollen.  Secondary optic atrophy may be seen in long standing cases.

Systemic Features: 

Mild to severe developmental delays are common and mental retardation has been reported in some cases.  There is often 'pebbling' of the skin over the neck and chest.  Joint stiffness, short stature, and skeletal deformities are common.   Many have short necks, a protuberant abdomen, a broad chest, and facial coarseness.  Hepatosplenomegaly, hearing loss, hernias, and carpal tunnel syndrome are often present.  The skull is large with a J-shaped sella, the vertebral bodies are hypoplastic anteriorly, the pelvis and femoral heads are hypoplastic and the diaphyses are expanded.

A severe form, type A, has its onset in the first two to four years of life, with more rapid progression and death commonly by adolescence.  Many patients have obstructive pulmonary disease and heart failure.  The IDS deficiency is similar to that of type B which is less severe and compatible with life into the 7th decade.  Intelligence is often normal in type B.

Genetics

Hunter syndrome, or MPS II, is one of seven lysosomal enzyme deficiencies responsible for the degradation of mucopolysaccharides, and the only one known to be X-linked (Xq28).  The mutation in IDS leads to a deficiency of iduronate sulfatase resulting in accumulation of dermatan and heparin sulfate.  Rare affected females may have chromosomal deletions instead of a simple mutation in IDS.

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

Various therapies are under development including enzyme replacement, gene transfers, and bone marrow transplantation.  Human iduronate-2-sulfatase (Idursulfase) has been used with encouraging signs but it is too early to determine the long term effectiveness.

References
Article Title: 

Tuberous Sclerosis 2

Clinical Characteristics
Ocular Features: 

The primary clinical characteristic of tuberous sclerosis of both types 1 and 2 are the occurrence of hamartomas at multiple anatomic sites.  Ocular lesions include those of the eyelids which often appear in early childhood along with other facial angiofibromas (formerly called adenoma sebaceum).  Of greater clinical significance are lesions of the optic nerve and retina reported in about 75% of patients.  The latter (astrocytic hamartomas) may appear as mulberry-like growths typically located in the peripapillary area or as flat translucent lesions located more peripherally.  These are usually static but aggressive growth with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients.  Calcification of these lesions may occur in utero or early in life.  They are seldom of clinical significance although optic atrophy has been reported.  The ocular phenotype is similar in types 1 and 2.

Systemic Features: 

Hamartomas develop throughout the body in many organs such as the skin, brain, eye, kidney, and heart.  Ninety per cent of patients have skin lesions, including hypomelanotic patches called 'ashleaf' spots that can best be visualized under a Woods lamp.  Symptoms vary widely depending upon the location and size of the growths.  These appear as rhabdomyomas in the heart, angiomyolipomas in the kidneys, bone cysts, and oral fibromas.  Other intracranial growths such as subependymal astrocytomas and cortical tubers are evidence of CNS involvement that can interfere with brain function leading to seizures (in 80% of patients) and subnormal intellectual abilities (60-70% patients) as manifested by learning difficulties, subnormal IQs, as well as social and communication difficulties.   Hypoplasia of dental enamel with pitting in permanent teeth is seen in the majority of patients.  Some progression of tumor size and symptoms may occur.  Most hamartomas are benign but renal carcinoma has been reported in some patients.

There is some evidence that the clinical disease is more severe in this type (TSC2) than in type 1 (191100).  TSC2 has more hypomelanotic patches and brain tubers.  Cognitive defects are more severe.  Those with TSC2 mutations also have an earlier onset of seizures and a higher incidence of infantile spasms.

Genetics

This is the more severe and more common of the two tuberous sclerosis complex phenotypes.  It is caused by mutations in the TSC2 gene encoding tuberin on chromosome 16p13.3.  Genotyping is necessary to determine which mutation is responsible for the TS complex in each case as the phenotypic differences are inadequate to distinguish between types 1 and 2.

Many cases (two-thirds) occur sporadically but numerous reported pedigrees are consistent with autosomal dominant inheritance.  Type 1 TSC (191100) is caused by mutations in the TSC1 gene (9p34) encoding hamartin and is responsible for the disorder in about 25% of patients.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective preventative treatment exists but individual lesions can be surgically removed when indicated.

References
Article Title: 

Tuberous Sclerosis 1

Clinical Characteristics
Ocular Features: 

The primary clinical characteristic of tuberous sclerosis of both types 1 and 2 are the occurrence of hamartomas at multiple anatomic sites.  Ocular lesions include those of the eyelids which often appear in early childhood along with other facial angiofibromas (formerly called adenoma sebaceum).  Of greater clinical significance are lesions of the optic nerve and retina reported in about 75% of patients.  The latter (astrocytic hamartomas) may appear as mulberry-like growths typically located in the peripapillary area or as flat translucent lesions located more peripherally.  These are usually static but aggressive growth with retinal detachment and neovascular glaucoma requiring enucleation has been reported in several patients.  Calcification of these lesions may occur in utero or early in life.  These are seldom of clinical significance although optic atrophy has been reported. The iris may have hypopigmented areas.

Systemic Features: 

Hamartomas develop throughout the body in many organs such as the skin, brain, eye, kidney, and heart.  Ninety per cent of patients have skin lesions, including hypomelanotic patches called 'ashleaf' spots that can best be visualized under a Woods lamp.  Symptoms vary widely depending upon the location and size of the growths.  These appear as rhabdomyomas in the heart, angiomyolipomas in the kidneys, bone cysts, and oral fibromas.  Other intracranial growths such as subependymal astrocytomas and cortical tubers are evidence of CNS involvement that can interfere with brain function leading to seizures (in 80% of patients) and subnormal intellectual abilities (60-70% patients) as manifested by learning difficulties, subnormal IQs, as well as social and communication difficulties.   Hypoplasia of dental enamel with pitting in permanent teeth is seen in the majority of patients.  Some progression of tumor size and symptoms may occur.  Most hamartomas are benign but renal carcinoma has been reported in some patients.

Genetics

Many cases (two-thirds) occur sporadically but numerous reported pedigrees are consistent with autosomal dominant inheritance.  Type 1 TSC is caused by mutations in the TSC1 gene (9p34) encoding hamartin and is responsible for the disorder in about 25% of patients.

A more severe phenotype, tuberous sclerosis 2 (613254), is caused by mutations in the TSC2 gene on chromosome 16p13.3 and accounts for the majority of cases of tuberous sclerosis complex.  Genotyping is necessary to determine which mutation is responsible for the TS complex in each case as the phenotypic differences are inadequate to distinguish clinically between types 1 and 2.

New mutations are responsible for 50-70% of cases.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective preventative treatment exists but individual lesions can be surgically removed when indicated.

References
Article Title: 

Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34

van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997 Aug 8;277(5327):805-8.

PubMed ID: 
9242607

Tuberous sclerosis

Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008 Aug 23;372(9639):657-68. Review.

PubMed ID: 
18722871

Optic Atrophy 7

Clinical Characteristics
Ocular Features: 

This is an early onset (4 to 6 years of age) optic atrophy in which acuity even at that age may be only 20/200.  Peripheral field constriction occurs late in contrast to its preservation in another autosomal recessive form of early onset optic atrophy, OPA6 (258500).  Atrophy of the optic nerve and loss of vision also occurs more slowly in the latter.

Systemic Features: 

Several individuals have had systemic disease consisting of hypertrophic cardiomyopathy, MRI changes in the brain, and mild hearing loss but these may have been coincidental.

Genetics

This is an autosomal recessive disorder resulting from a mutation in the TMEM126A gene (11q14.1-q21) encoding a mitochondrial protein.

A less severe form of autosomal recessive optic atrophy (OPA6; 258500) has been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available but low vision aids can be helpful in activities of daily living.

References
Article Title: 

Optic Atrophy 5

Clinical Characteristics
Ocular Features: 

The phenotype in OPA5 has some similarities to that of OPA1 (125250, 165500).  Onset occurs as early as the first decade of life in some families but may not be evident until the third decade in other families.  Visual acuity decreases slowly and color vision is impaired, more so in older patients.  Temporal pallor of the optic nerve is usually present and central scotomas with narrowing of the visual fields can be plotted.  The nerve fiber layer is reduced in thickness.  VEP defects likewise are variable and generally more severe in later stages.  No ERG abnormalities have been reported.  This is a bilateral disease with nearly 100% penetrance.

Systemic Features: 

No systemic abnormalities are present.

Genetics

Heterozygous mutations in the DNM1L gene (12p11.21) are found in patients with OPA5.  Morphologic changes found in mitochondria have been interpreted as consistent with an impairment in fission.  Two families who had been previously reported to have mutations at the 22q12.1 locus were found to have the DNM1L mutation.

Like several other forms of heritable optic atrophy, OPA1 (125250, 165500) and OPA4 (605293), this is an autosomal dominant disorder.  

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment of the optic atrophy is available but low vision aids can be helpful to utilize remaining vision.

References
Article Title: 

Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission

Gerber S, Charif M, Chevrollier A, Chaumette T, Angebault C, Kane MS, Paris A, Alban J, Quiles M, Delettre C, Bonneau D, Procaccio V, Amati-Bonneau P, Reynier P, Leruez S, Calmon R, Boddaert N, Funalot B, Rio M, Bouccara D, Meunier I, Sesaki H, Kaplan J, Hamel CP, Rozet JM, Lenaers G. Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission. Brain. 2017 Oct 1;140(10):2586-2596.

PubMed ID: 
28969390

Smith-Lemli-Opitz Syndrome

Clinical Characteristics
Ocular Features: 

A large number of ocular anomalies have been found in SLO syndrome but the most common is blepharoptosis of some degree.  No consistent pattern of ocular abnormalities has been reported.  Atrophy and hypoplasia of the optic nerve, strabismus, nystagmus, and cataracts may be present.   Abnormally low concentrations of cholesterol and cholesterol precursors have been found in all ocular tissues studied.

Systemic Features: 

This is a syndrome of multiple congenital anomalies.  Among these are dwarfism, micrognathia, hard palate anomalies, hypotonia, anomalies of the external genitalia, polysyndactyly, microcephaly, and mental retardation.  It has been suggested that many individuals have a characteristic behavioral profile consisting of cognitive delays, hyperreactivity, irritability, language deficiency, and autism spectrum behaviors.  Some individuals exhibit aspects of self destructive behavior.  Tissue levels of cholesterol are low.

Genetics

SLO syndrome is an autosomal recessive disorder resulting from mutations in the sterol delta-7-reductase  (DHCR7) gene mapped to 11q12-q13. The result is a defect in cholesterol synthesis.

The clinical features significantly overlap those seen in Meckel (249000) and Joubert (213300) syndromes.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

A high cholesterol diet has been reported to have a beneficial effect on behavior and general well-being.

References
Article Title: 

Optic Atrophy 6

Clinical Characteristics
Ocular Features: 

Visual impairment is often noted under the age of 6 years.  The disease is bilateral and loss of vision procedes slowly, eventually reaching 20/100 to 20/200.  Moderate photophobia and dyschromatopsia are present but nystagmus is absent.  The impact on the visual field seems to be minimal and limited to decreased sensitivity in the central areas.

Systemic Features: 

No systemic abnormalities are associated.

Genetics

Evidence for this presumed autosomal recessive type of optic atrophy is based on a single large, consanguineous French Canadian family.  A locus in the 8q21-q22 region presumably containing the mutant gene, designated OPA6, was found.  Linkage analysis excluded genes linked to autosomal dominant optic atrophy.

Another autosomal recessive optic atrophy disorder (OPA7; 612989) has also been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond low vision aids is helpful.

References
Article Title: 

Optic Atrophy 4

Clinical Characteristics
Ocular Features: 

This form of optic atrophy is clinically heterogeneous similar to others.  It is less common than OPA1 (165500).  Visual acuity ranges from normal to 6/200.  Individuals that carry the mutation usually have some degree of bilateral optic disc pallor and dyschromatopsia even in the presence of 20/20 acuity.  This profile is present in the first decade of life in some patients with most experiencing acute or subacute loss of vision between the ages of 18 and 35 years.  Vision loss is progressive in the majority of patients but unpredictable with some experiencing rapid decline whereas others have only a slow decline.  Age and visual acuity are not strongly correlated but in general older individuals have worse acuity.

Systemic Features: 

There are no systemic findings in OPA4.

Genetics

This is an autosomal dominant disorder secondary to mutations in the OPA4 gene at 18q12.2-q12.3.

Other autosomal dominant optic atrophy disorders include OPA1 (125250, 165500) and OPA5 (610708).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for hereditary optic atrophy but low vision aids can be helpful for visual assistance.

References
Article Title: 

Optic Atrophy 1

Clinical Characteristics
Ocular Features: 

This form of bilateral optic atrophy may have its onset in early childhood with optic disc pallor, loss of acuity, loss of color vision, and centrocecal scotomas.  However, it is often not manifest until the second decade of life.  Moderate to severe temporal or diffuse pallor can be seen.  The optic disc has been described as normal in 29% of documented carriers and 20% have no visual field defect.  Pallor of the complete disc is found in only 10%.  Consequently, the phenotype is variable, with some individuals having minimal symptoms while others have severe vision loss.  The disease is progressive in some but not all families.  The median visual acutity is 20/70 but ranges from normal to hand motions.  

Histologic studies show atrophy of ganglion cells in the retina and loss of myelin sheaths in the optic nerve.   VEPs are absent or subnormal.  Optical coherence tomography reveals a significant reduction in retinal nerve fiber layer and ganglion cell layer thickness, most marked in the temporal quadrants.

Systemic Features: 

OPA1 is generally not associated with systemic disease.  However, some have sensorineural deafness, ataxia, ptosis, and ophthalmoplegia.  Families with both early and late onset have been reported.  Some (~20%) individuals have a myopathy as well.

Genetics

This is an autosomal dominant disorder resulting from mutations in a nuclear gene, OPA1 (3q28-q29).  The gene product is attached to the mitochondrial cristae of the inner membrane and metabolic studies have implicated the oxidative phosphorylation pathway which seems to be defective with reduced efficiency of ATP synthesis.  Penetrance approaches 90% but this is, of course, age dependent to some extent.

An allelic disorder (125250) is associated with sensorineural deafness, ataxia, and ophthalmoplegia but its uniqueness remains to be established since the same mutations in OPA1 have been found in both conditions.

Other autosomal dominant optic atrophy disorders include OPA5 (610708) and OPA4 (605293).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment is available.

References
Article Title: 

OPA1 in multiple mitochondrial DNA deletion disorders

Stewart JD, Hudson G, Yu-Wai-Man P, Blakeley EL, He L, Horvath R, Maddison P, Wright A, Griffiths PG, Turnbull DM, Taylor RW, Chinnery PF. OPA1 in multiple mitochondrial DNA deletion disorders. Neurology. 2008 Nov 25;71(22):1829-31.

PubMed ID: 
19029523

Homocystinuria, Beta-Synthase Deficiency

Clinical Characteristics
Ocular Features: 

More than half of patients have ectopia lentis by the age of 10 years and the dislocation is progressive.  Ectopia lentis occurs in 90% of patients and 94% of these are noted by the age of 20 years.  The lenses seem to be more mobile than those in Marfan syndrome with a significantly increased risk of lens migration into the anterior chamber (19%) or complete dislocation into the posterior chamber (14%).   Lens surgery is required in homocystinuria about 7 years earlier than in Marfan syndrome with 62% of procedures necessitated by pupillary block glaucoma or displacement into the anterior chamber.  Whereas nearly 70% of lenses dislocate superiorly in Marfan syndrome, only 9% of homocystinuria lenses do so.

Other ocular features include optic atrophy (23%), iris atrophy (21%), anterior staphylomas (13%) and corneal opacities (9%).  Retinal detachments occur in 5-10%.  The majority of patients both pre- and postoperatively have vision of 20/50 or worse.

Systemic Features: 

Arachnodactyly and tall stature in some patients may suggest Marfan syndrome.  Mental deficiencies or behavioral problems are present in a majority of patients (50-60%) with mental functioning higher in the subset of patients who are B6-responsive.  Thromboembolic events (strokes, myocardial infarctions) are a significant risk at any age, especially so after age 20 years, and this is responsible for considerable morbidity and mortality.  The risk is especially high following general anesthesia unless hydration is strictly controlled.  Osteoporosis and seizures are common.  Hypopigmentation is often present but darkening of hair has been noted following pyridoxine treatment.  Serum homocysteine is generally elevated and the urine contains elevated levels of methionine.

Genetics

Classic homocystinuria is an autosomal recessive disorder that results from mutations in the CBS (21q22.3) gene encoding cystathionine beta-synthase.  It is the second most common error of amino acid metabolism.  Numerous mutations have been identified but among the most common ones are I278T which causes a pyridoxine-responsive disorder, and the G3307S mutation which leads to a variant that is not responsive to pyridoxine treatment.

For another more aggressive form of homocystinuria caused by mutations in MTHFR (1p36.3) see Homosystinuria, MTHER Deficiency (236250).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Patients with this disorder form two groups: those who respond to pyridoxine (vitamin B6) and those who do not.  Those who do not respond to B6 tend to have more severe disease.  Methionine restriction administered neonatally has been reported to prevent mental retardation and reduce the rate of lens dislocation.  Neonates should be treated with B6 therapy, protein and methionine restriction, betaine, and folate with vitamin B12 supplementation.  Surgical removal of lenses may be required but the rate of vitreous loss is high.

References
Article Title: 

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