optic atrophy

Optic Atrophy 10

Clinical Characteristics
Ocular Features: 

Low vision is noted in early childhood without systemic symptoms.  The optic nerves appear pale (age of onset uncertain).  The retinal nerve fiber layer may be reduced in thickness in all quadrants but only segmentally in some individuals.  No VEP can be recorded.  On brain MRI examination the optic tracts are thin.  The appearance of the optic nerve is consistent with mild hypoplasia in some patients.

Systemic Features: 

Some patients have ataxia, cognitive deficits, and seizures.  A brother and sister from a consanguineous Moroccan family and two unrelated individuals have been reported.  

Genetics

This autosomal recessive condition is caused by homozygous or compound heterozygous mutations in the RTN4IP1 gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

Angebault C, Guichet PO, Talmat-Amar Y, Charif M, Gerber S, Fares-Taie L, Gueguen N, Halloy F, Moore D, Amati-Bonneau P, Manes G, Hebrard M, Bocquet B, Quiles M, Piro-Megy C, Teigell M, Delettre C, Rossel M, Meunier I, Preising M, Lorenz B, Carelli V, Chinnery PF, Yu-Wai-Man P, Kaplan J, Roubertie A, Barakat A, Bonneau D, Reynier P, Rozet JM, Bomont P, Hamel CP, Lenaers G. Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies. Am J Hum Genet. 2015 Nov 5;97(5):754-60. 

PubMed ID: 
26593267

Infantile Cerebellar-Retinal Degeneration

Clinical Characteristics
Ocular Features: 

Visual tracking can be normal during the newborn period but lack of visual fixation and attention soon become evident.  Strabismus, nystagmus, and abnormal pursuit movements are often present.  Optic atrophy has been reported as early as 3 years of age.  VEP and ERG responses are extinguished in the first two years. The nystagmus may be multidirectional.  Acuity loss seems to be progressive.  A progressive retinal degeneration (not further characterized) has been reported.

Systemic Features: 

Infants generally appear normal at birth.  Within the first 6 months they show signs of developmental delay and neurological signs such as truncal hypotonia, seizures, athetosis and head bobbing.  Milestones of sitting, rolling over, and reactions to others are seldom achieved.  Cerebellar brain imaging shows progressive atrophy in all patients and some have cortical atrophy as well.  Some patients have evidence of hearing loss.   Severe failure to thrive and psychomotor delays are usually present.  Death may occur within several months of birth although some live for several decades.

Genetics

This condition results from homozygous or compound heterozygous mutations in the ACO2 gene (22q13.2).  The mutation has also been associated with optic atrophy 9 (616289).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment beyond supportive care is known.

References
Article Title: 

Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy

Metodiev MD, Gerber S, Hubert L, Delahodde A, Chretien D, Gerard X, Amati-Bonneau P, Giacomotto MC, Boddaert N, Kaminska A, Desguerre I, Amiel J, Rio M, Kaplan J, Munnich A, Rotig A, Rozet JM, Besmond C. Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet. 2014 Dec;51(12):834-8.

PubMed ID: 
25351951

Optic Atrophy 9

Clinical Characteristics
Ocular Features: 

Two brothers have been reported with optic atrophy discovered as early as 3 and 5 years of age.  Visual acuity in the 3rd decade of life was in the 20/200 range which was stable into the 4th and 5th decades. They also had red-green dyschromatopsia and thinning of the nerve fiber layer most pronounced in the temporal areas of the retina corresponding to the location of most marked pallor seen in the optic nerve.  The nasal nerve fiber layer seemed to be preserved.  Paracentral scotomas could be demonstrated. 

Systemic Features: 

There were no systemic abnormalities reported in the brothers. 

Genetics

OPA9 is caused by homozygous or compound heterozygous mutations in the ACO2 gene (22q13.2).   

Mutations in ACO2 also cause infantile cerebellar retinal degeneration (ICRD) (614559) in which optic atrophy is a prominent feature associated with retinal degeneration, extensive neurodegenerative disease, and mitral valve dysfunction.  The mode of inheritance is autosomal recessive.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been described.

References
Article Title: 

Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy

Metodiev MD, Gerber S, Hubert L, Delahodde A, Chretien D, Gerard X, Amati-Bonneau P, Giacomotto MC, Boddaert N, Kaminska A, Desguerre I, Amiel J, Rio M, Kaplan J, Munnich A, Rotig A, Rozet JM, Besmond C. Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. J Med Genet. 2014 Dec;51(12):834-8.

PubMed ID: 
25351951

Retinitis Pigmentosa 71

Clinical Characteristics
Ocular Features: 

Night blindness is noted in the first or second decades of life.  The fundus picture in this condition resembles classic retinitis pigmentosa with attenuated vessels, RPE anomalies with bone spicule clumping and areas of atrophy, and optic disc pallor.  Several patients had optic nerve drusen.  The retina appears to have microcysts, especially in the macula, and the outer retina is thinned.  

Systemic Features: 

Only a few patients have been reported with this form of RP and the full phenotype is unknown.  Some individuals are obese and one patient in addition had postaxial polydactyly and hypercholesterolemia suggestive of a Bardet-Biedl-like phenotype.  No reported patients have had rib dysplasia.

Genetics

Homozygous or compound heterozygous mutations in the IFT172 gene (2p23.3) have been identified in this condition.

The same gene is mutated in the recessive short-rib thoracic dysplasia 10 syndrome with or without polydactyly (615630).  Individuals with the short-rib syndrome may have night blindness and fundus changes resembling retinitis pigmentosa.

Because of the phenotypic overlap with other conditions such as Bardet-Biedl syndrome, the short-rib thoracic 10 syndrome (615630), Majewski syndrome (263520), Jeune syndrome (208520), short-rib thoracic dysplasia 9 (266920), and certain types of polycystic diseases of the kidney with abnormalities of the cilia, it has been suggested that RP71 should be classified as a syndromic ciliopathy.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome

Bujakowska KM, Zhang Q, Siemiatkowska AM, Liu Q, Place E, Falk MJ, Consugar M, Lancelot ME, Antonio A, Lonjou C, Carpentier W, Mohand-Said S, den Hollander AI, Cremers FP, Leroy BP, Gai X, Sahel JA, van den Born LI, Collin RW, Zeitz C, Audo I, Pierce EA. Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome. Hum Mol Genet. 2015 Jan 1;24(1):230-42.

PubMed ID: 
25168386

CHOPS Syndrome

Clinical Characteristics
Ocular Features: 

There is usually some degree of proptosis and apparent hypertelorism.  The eyebrows are bushy and the eyelashes are luxurious.  One of three patients had cataracts and another had mild optic atrophy.

Systemic Features: 

The overall facial appearance may resemble Cornelia de Lange syndrome with hypertrichosis and a coarse, round facies.  Head circumference is low normal.  Septal defects and a patent ductus arteriosus are often present.  Laryngeal and tracheal malacia predispose to recurrent pulmonary infections and chronic lung disease.  Skeletal dysplasia includes brachydactyly and anomalous vertebral bodies resulting in short stature (3rd percentile).  Genitourinary abnormalities include cryptorchidism, horseshoe kidney, and vesiculoureteral reflux.  Delayed gastric emptying and reflux have been reported.

Genetics

Heterozygous mutations in the AFF4 gene (5q31.1) have been identified in 3 unrelated individuals with this condition.  No familial cases have been identified.  The gene is a core component of the super elongation complex that is critical to transcriptional elongation during embryogenesis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the general disorder.  Tracheostomy was required in 2 of three reported patients. 

References
Article Title: 

Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin

Izumi K, Nakato R, Zhang Z, Edmondson AC, Noon S, Dulik MC, Rajagopalan R, Venditti CP, Gripp K, Samanich J, Zackai EH, Deardorff MA, Clark D, Allen JL, Dorsett D, Misulovin Z, Komata M, Bando M, Kaur M, Katou Y, Shirahige K, Krantz ID. Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet. 2015 Apr;47(4):338-44.

PubMed ID: 
25730767

Multiple Mitochondrial Dysfunctions Syndrome 4

Clinical Characteristics
Ocular Features: 

Optic atrophy is the sole ocular sign reported.

Systemic Features: 

Patients have the onset of severe, unrelenting neuroregression by 6 months of age.  They never achieve normal milestones and eventually regress to a vegetative state.  No dysmorphic features are present.  Muscle spasticity has been reported.  Brain imaging shows multiple nonspecific signal anomalies throughout.  Biopsy of skeletal muscle shows atrophic and angulated fibers.

Mitochondrial DNA copy numbers are decreased as is the activity of respiratory complex I. 

Genetics

Homozygous mutations in the ISCA2 gene (14q24.3) segregates with the disease in the 5 reported families.  This gene codes for an essential component of mitochondrial assembly and function.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known and death often occurs before the age of 5 years.

References
Article Title: 

ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder

Al-Hassnan ZN, Al-Dosary M, Alfadhel M, Faqeih EA, Alsagob M, Kenana R, Almass R, Al-Harazi OS, Al-Hindi H, Malibari OI, Almutari FB, Tulbah S, Alhadeq F, Al-Sheddi T, Alamro R, AlAsmari A, Almuntashri M, Alshaalan H, Al-Mohanna FA, Colak D, Kaya N. ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder. J Med Genet. 2015 Mar;52(3):186-94.

PubMed ID: 
25539947

Spastic Paraplegia 74

Clinical Characteristics
Ocular Features: 

Onset of visual impairment occurs at ages of 10-14 years with optic pallor evident on fundoscopy. MRI imaging reveals physical atrophy of the optic nerve.  Visual acuity ranges from 0.5 to finger counting.  Visual field defects include central scotomas and peripheral concentric constriction.

Systemic Features: 

Symptoms consisting of a spastic gait and distal sensory impairment usually appear in the first decade and are slowly progressive.  Increased deep tendon reflexes and extensor plantar responses may be present at that time but later distal leg muscle atrophy and pes cavus appear.  The ankle reflexes later disappear.  Cognitive function is normal and adults are able to lead an independent life.

Nerve conduction studies in 4 individuals showed reduced muscle action potentials and velocity while sensory conduction was normal.  Cerebellar atrophy along with an attenuated corpus callosum and cervical spinal cord atrophy was noted on MRI imaging in one of 3 studied patients.

Genetics

A homozygous splice site mutation in IBA57 (1q42) has been found to segregate with this condition in a large consanquineous Arab family.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for the basic disease but physical therapy and low vision aids are likely beneficial.

References
Article Title: 

Fe S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia

Lossos A, Stumpfig C, Stevanin G, Gaussen M, Zimmerman BE, Mundwiller E, Asulin M, Chamma L, Sheffer R, Misk A, Dotan S, Gomori JM, Ponger P, Brice A, Lerer I, Meiner V, Lill R. Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia. Neurology. 2015 Feb 17;84(7):659-67.

PubMed ID: 
25609768

Retinitis Pigmentosa 72

Clinical Characteristics
Ocular Features: 

The history and fundus findings are typical for classic retinitis pigmentosa with onset of symptoms in the 4th and 5th decades or earlier. Salt and pepper pigmentation may also be present. These consist of night blindness, decreased visual acuity, and constriction of visual fields.  The fields are constricted to 10-30 degrees, and vision ranges from 20/25 to 20/40.  Optic pallor is often present, the retinal vessels are narrowed and bone-spicule pigmentation has been described.  Vitreous 'condensation' sufficient to obscure fundus details may be present.  ERG responses are absent or substantially reduced.  Heterozygotes have no symptoms or fundus abnormalities.

Systemic Features: 

No systemic features have been described.

Genetics

Homozygous mutations in the ZNF408 gene (11p11.2) are responsible for this condition.  The product of this gene is a transcription factor highly expressed in fetal and adult retina and plays a role in vasculogenesis.

Heterozygous mutations in the same gene cause familial exudative vitreoretinopathy (FEVR6) (616468) described in one family with significant vitreal and retinal vascular disease.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the basic disease.  Tinted lenses may provide some benefit.

References
Article Title: 

Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations

Avila-Fernandez A, Perez-Carro R, Corton M, Lopez-Molina MI, Campello L, Garanto A, Fernandez-Sanchez L, Duijkers L, Lopez-Martinez MA, Riveiro-Alvarez R, Da Silva LR, Sanchez-Alcudia R, Martin-Garrido E, Reyes N, Garcia-Garcia F, Dopazo J, Garcia-Sandoval B, Collin RW, Cuenca N, Ayuso C. Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations. Hum Mol Genet. 2015 Jul 15;24(14):4037-48.

PubMed ID: 
25882705

Anterior Segment, Brain, and Facial Anomalies

Clinical Characteristics
Ocular Features: 

The interpupillary distance appears abnormally wide.  VEP and ERG responses suggest abnormal retinal bipolar cells.  Specular microscopy reveals variable sizes and shapes of corneal endothelial cells with scattered vesicles and large 'holes' in the usual hexagonal array.  The iris may be malformed (no collarette, stromal hypoplasia) and there may be peripheral iridocorneal adhesions.  Elevated IOP, band keratopathy, corneal clouding, and keratoconus have been reported.  Visual acuity is impaired to some extent, from near normal (20/25) to NLP.  Progressive optic atrophy was observed in one patient.

Systemic Features: 

Four members of a 3 generation family had malformed pinnae (posterior placement and rotation).  Other features variably present were an empty sella turcica, posterior fossa cyst, and hydrocephalus. The propositus also was found to have abnormal auditory bipolar cells based on the audiogram and audio-evoked brainstem responses.

Genetics

Based on direct sequencing in one family (3 adults and 1 child), this condition seems to be caused by heterozygous variations or mutations in the VSX1 gene (20p11.21). 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Monitoring for glaucoma and appropriate treatment are indicated.  Hearing tests should be performed early.  The usual treatments for keratoconus should be considered.  Excess brain fluid may need surgical drainage.

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References
Article Title: 

PEHO Syndrome

Clinical Characteristics
Ocular Features: 

Optic atrophy is a common feature.  There may be lack of visual fixation from birth or sometimes several months later, attributed to cortical inattention.  Flash visual evoked potentials may be unrecordable. Pupillary responses to light are 'weak' and sluggish. Epicanthal folds may be seen.

Systemic Features: 

Infants are usually born with a normal head circumference but fall behind (2 SD or more) in the first year.  They have neonatal and infantile central hypotonia with brisk peripheral tendon reflexes during early childhood.  They are sometimes described as drowsy or lethargic.  Facial and limb edema can be extensive but transient sometimes and can disappear later in childhood.  The fingers are tapered.  The cheeks are full, the mouth is usually open and the upper lip appears 'tented'.  Global developmental delay is common and normal milestones are seldom attained.  Some patients have been described as severely retarded mentally.  Infantile spasms and myoclonic jerkingcan be seen within the first months of life while frank seizures with hypsarrhythmia are common in the first year of life.  Status epilepticus is a common occurrence.  General drowsiness and poor feeding are often features.  Death usually occurs in infancy or early childhood.  Midface hypoplasia and micrognathia are often present.

Brain imaging (MRI) and histology show severe alterations in myelination and cellular organization.  Neuronal loss is seen in the inner granular layer of the cerebellum but there is relative preservation of Purkinje cells.  General and progressive atrophy of the cerebellum and brain stem have been described.

Genetics

Homozygous frameshift mutations in ZNHIT3 (17q12) have been identified in affected members of several consanguineous families.  The presumed mutation seems to be most prevalent in Finland.

A somewhat similar disorder known as PEHO-like syndrome (617507) is the result of homozygous mutations in the CCDC88A gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Physical therapy to prevent contractures and general supportive care can be helpful.  Supplemental feeding may be required. 

References
Article Title: 

The PEHO syndrome

Riikonen R. The PEHO syndrome. Brain Dev. 2001 Nov;23(7):765-9. Review.

PubMed ID: 
11701291

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