optic atrophy

Pontocerebellar Hypoplasia 3

Clinical Characteristics
Ocular Features: 

Optic atrophy is an inconsistent feature (sometimes even unilateral) of patients with PCH.  Cortical blindness has also been described.  There may be dysmorphic facial features such as wide palpebral fissures, epicanthal folds, and prominent eyes. 

Systemic Features: 

Infants are generally small and hypotonic at birth.  The skull is small and often brachycephalic.  The ears are large and low-set and  facial dysmorphism (full cheeks, long philtrum) is present.  Infants have poor head control and truncal ataxia.  Later, hyperreflexia and spasticity become evident.  Seizures are common.  Developmental delays, both somatic and mental, are nearly universal and large joint contractures are often seen. Many of these signs are progressive.  

Brain imaging generally reveals cerebral and cerebellar atrophy, a hypoplastic corpus callosum, a small cerebellar vermis, and a hypoplastic brainstem.  Short stature is a feature and early death often occurs.

Genetics

PCH3 is one of at least 10 syndromes belonging to a clinically and genetically heterogeneous group of conditions known as pontocerebellar hypoplasias.  Members of this group, while individually rare, nevertheless collectively account for a significant proportion of what was once labeled cerebral palsy.

PCH3 results from homozygous mutations in the PCLO gene (7q21). 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the general disorder.

References
Article Title: 

Loss of PCLO function underlies pontocerebellar hypoplasia type III.

Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A, Al-Turki S, Baple EL, Patton MA, Al-Memar AY, Hurles ME, Partlow JN, Hill RS, Evrony GD, Servattalab S, Markianos K, Walsh CA, Crosby AH, Mochida GH. Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology. 2015 Apr 28;84(17):1745-50.

PubMed ID: 
25832664

Alström Syndrome

Clinical Characteristics
Ocular Features: 

Progressive failure of rods and cones begins in the first year of life and inevitably leads to blindness.  Central vision is lost first and nystagmus in early childhood results.   Photophobia can be evident in the first year of life.  Early ERGs show severe impairment of cone responses with little or no rod dysfunction.  In the second and third decades all rod and cone responses are extinguished.  Vision can be less than 20/400 by the age of 10 years and usually all light perception is lost by the beginning of the third decade.  Pale optic nerves with retinal arteriorlar narrowing and posterior subcapsular cataracts have been seen.

Systemic Features: 

This is a multisystem disease with onset in the first year of life.  Infants may have a normal birth weight but develop truncal obesity in the first year.  Hearing loss is evident in the first decade.  Insulin resistant type 2 diabetes mellitus with hyperinsulinemia often occurs in childhood and may be accompanied by hypothyroidism and hypogonadotropic hypogonadism.  Acanthosis nigricans and some degree of pulmonary dysfunction are common.  The majority of individuals (70%) develop restrictive or dilated cardiomyopathy, many in the first months of life, resulting in cardiac failure.  The liver may become cirrhotic and renal failure occurs late.  Intelligence is usually normal but many patients (25-30%) have early delays in their developmental milestones perhaps secondary to growth hormone deficiency which has been reported (98% are short in stature).  Lifespan is short and many die in childhood.  Few live beyond the age of 40 years.

Alstrom syndrome has some similarities to Bardet-Biedl syndrome (209900) but differs in the absence of mental deficiency and polydactyly.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the ALMS1 gene on chromosome 2 (2p13).  The ALMS1 protein product is found in many cells throughout the body and is located in centrosomes and the base of cilia.  Its function is unknown.

More than 320 mutations have been reported. However, many cases remain in which no mutation has been found suggesting additional genetic heterogeneity remains.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the basic disease.

References
Article Title: 

Alström Syndrome: Mutation Spectrum of ALMS1

Marshall JD, Muller J, Collin GB, Milan G, Kingsmore SF, Dinwiddie D, Farrow EG, Miller NA, Favaretto F, Maffei P, Dollfus H, Vettor R, Naggert JK. Alstrom Syndrome: Mutation Spectrum of ALMS1. Hum Mutat. 2015 Apr 2. doi: 10.1002/humu.22796. [Epub ahead of print].

PubMed ID: 
25846608

Alström syndrome

Marshall JD, Beck S, Maffei P, Naggert JK. Alstrom syndrome. Eur J Hum Genet. 2007 Dec;15(12):1193-202.

PubMed ID: 
17940554

Kaufman Oculocerebrofacial Syndrome

Clinical Characteristics
Ocular Features: 

Alterations in the morphology of periocular structures is the most consistent ocular feature.  These include epicanthal folds, upward-slanting lid fissures, ptosis, blepharophimosis, sparse eyebrows, and telecanthus.  However, pale optic discs, iris colobomas, microcornea, strabismus, nystagmus, and hypertelorism are variably present. 

Systemic Features: 

There is both intrauterine and postnatal growth retardation.  Hypotonia is often noted along with general psychomotor delays.  Neonatal respiratory distress and laryngeal stridor may be present.  The intellectual disability can be severe.  Corpus callosum aplasia and hypoplasia have been reported.  Microcephaly and brachycephaly with delayed suture closure are features.  The face is long and narrow and the mouth is disproportionally large.  A high arched palate can be present and the pinnae are often deformed, posteriorly rotated and may be accompanied by preauricular skin tags. The teeth appear widely spaced (diastema) and the lower jaw is underdeveloped.

Genetics

Kaufman BPIDS syndrome results from homozygous or compound heterozygous mutations in the UBE3B gene (12q23).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No general treatment is available although repair of some specific malformations is possible.

References
Article Title: 

Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome

Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, Arends MJ, Miro X, White JK, Desir J, Abramowicz M, Dentici ML, Lepri F, Hofmann K, Har-Zahav A, Ryder E, Karp NA, Estabel J, Gerdin AK, Podrini C, Ingham NJ, Altmuller J, Nurnberg G, Frommolt P, Abdelhak S, Pasmanik-Chor M, Konen O, Kelley RI, Shohat M, Nurnberg P, Flint J, Steel KP, Hoppe T, Kubisch C, Adams DJ, Borck G. Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome. Am J Hum Genet. 2012 Dec 7;91(6):998-1010.

PubMed ID: 
23200864

An oculocerebrofacial syndrome

Kaufman RL, Rimoin DL, Prensky AL, Sly WS. An oculocerebrofacial syndrome. Birth Defects Orig Artic Ser. 1971 Feb;7(1):135-8.

PubMed ID: 
5006210

Filippi Syndrome

Clinical Characteristics
Ocular Features: 

The ocular features have not been fully described.  The most consistent features are long eyelashes, thick (bushy) eyebrows, and 'visual disturbance'.  Most individuals have a facial dysmorphism which includes a broad nasal base suggestive of hypertelorism.  Optic atrophy and proptosis have been noted. 

Systemic Features: 

Intrauterine growth retardation is sometimes seen.  Microcephaly, short stature, syndactyly, intellectual disability (often labeled mental retardation), and a dysmorphic face are characteristic.  Some individuals have cryptorchidism, seizures, and ectodermal abnormalities including nail hypoplasia, hirsutism, and microdontia.  Mental and physical delays are common.  The syndactyly usually involves only soft tissue between toes 2, 3, and 4 and fingers 3 and 4 accompanied by clinodactyly of the 5th finger.  Polydactyly is sometimes present while radiologically the radial head may show evidence of hypoplasia. 

Genetics

Homozygosity or compound heterozygosity in the CKAP2L gene (2q13) segregates with this phenotype. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome

Hussain MS, Battaglia A, Szczepanski S, Kaygusuz E, Toliat MR, Sakakibara S, Altmuller J, Thiele H, Nurnberg G, Moosa S, Yigit G, Beleggia F, Tinschert S, Clayton-Smith J, Vasudevan P, Urquhart JE, Donnai D, Fryer A, Percin F, Brancati F, Dobbie A, Smigiel R, Gillessen-Kaesbach G, Wollnik B, Noegel AA, Newman WG, Nurnberg P. Mutations in CKAP2L, the human homolog of the mouse Radmis gene, cause Filippi syndrome. Am J Hum Genet. 2014 Nov 6;95(5):622-32.

PubMed ID: 
25439729

Perrault Syndrome

Clinical Characteristics
Ocular Features: 

Nystagmus and limited extraocular movements are usually present in PRLTS1.  Optic atrophy and poor visual acuity have been reported. Ptosis may be present.  The clinical manifestations are variable among and within the types.  Rod dysfunction and ‘retinal atrophy’ were reported in one patient.  The majority of patients have had only limited ocular evaluations.

Systemic Features: 

This is a sex-influenced condition in which both sexes have a sensorineural hearing deficit and neurodegenerative disease (both central and peripheral) but only the females have gonadal dysgenesis.  Motor development is often delayed and ataxia along with a peripheral sensory neuropathy and a variable degree of limb weakness can be present.  Learning difficulties, cognitive decline, and frank mental retardation are frequently described.  The cerebellum may be atrophic.

There is considerable variability in the clinical signs.

Genetics

The combination of hearing loss in males and females, ovarian dysgenesis in females, and variable neurologic signs including external ophthalmoplegia and sometimes optic atrophy is known as Perrault syndrome.  The ocular movement abnormalities are seen primarily in PRLTS1. 

At least 5 unique mutations have been found accounting for types PRLTS1-5.  PRLTS1 (233400) results from mutations in HSD17B4 (5q23.1), type PRLTS2 (614926) is caused by mutations in the HARS2 gene, PPRLTS3 (614129) by mutations in the CLPP gene, PRLTS4 (615300) by mutations in the LARS2 gene, and PRLTS5 (616138) by mutations in C10orf2 (listed in this database as External Ophthalmoplegia, C10orf2, and mtDNA mutations,.

The inheritance pattern among different types may be autosomal recessive or autosomal dominant.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Perrault syndrome: further evidence for genetic heterogeneity

Jenkinson EM, Clayton-Smith J, Mehta S, Bennett C, Reardon W, Green A, Pearce SH, De Michele G, Conway GS, Cilliers D, Moreton N, Davis JR, Trump D, Newman WG. Perrault syndrome: further evidence for genetic heterogeneity. J Neurol. 2012 May;259(5):974-6.

PubMed ID: 
22037954

Perrault syndrome in sisters

McCarthy DJ, Opitz JM. Perrault syndrome in sisters. Am J Med Genet. 1985 Nov;22(3):629-31.

PubMed ID: 
4061497

Epileptic Encephalopathy, Early Infantile 28

Clinical Characteristics
Ocular Features: 

Infants with this lethal neuropathy often have minimal or absent eye contact from birth.  Responses to visual stimuli are often but not always absent.  Optic atrophy may be present and the ERG is abnormal in some individuals. The retinas may have "abnormal" pigmentation while scotopic and photopic flash ERG responses are reduced as are visual evoked potentials indicating delayed visual maturation with severe macular and optic nerve dysfunction. 

Systemic Features: 

Seizures begin within weeks after birth and are resistant to pharmacological treatment.  There is no spontaneous motility and little or no psychomotor development.  Normal developmental milestones are usually not achieved.  Spasticity and hyperreflexia are often present but some newborn infants are hypotonic.  MRI imaging reveals cortical atrophy with hippocampal hypoplasia and a hypoplastic corpus callosum. Progressive microcephaly has been described.

Infants generally do not live beyond two years of age and may die within weeks or a few months. Pulmonary dysfunction can be a significant cause of morbidity. 

Genetics

The transmission pattern is consistent with autosomal recessive inheritance.  Homozygous and compound heterozygous mutations in the WWOX gene (16q23) have been found in several families.

Among the limited number of patients reported, at least two with compound heterozygous mutations had normal brain imaging, appropriate visual responses, and some ability to interact with their environment.  Profound psychomotor delays, however, remained.  Hypotonia replaced spasticity as a neurological feature in some infants.

The same gene is mutated in autosomal recessive spinocerebellar ataxia 12 (614322), a less severe condition in which gaze-evoked nystagmus occurs.

Other forms of epileptic encephalopathy have been reported (see 617105, 617106, and 617113) including Early Onset Epileptic Encephalopathy 48 (617276).  For an autosomal dominant form of epileptic encephalopathy in this database, see Epileptic Encephalopathy, Early Onset 47 (617166).

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for this condition.

References
Article Title: 

WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

Mignot C, Lambert L, Pasquier L, Bienvenu T, Delahaye-Duriez A, Keren B, Lefranc J, Saunier A, Allou L, Roth V, Valduga M, Moustaine A, Auvin S, Barrey C, Chantot-Bastaraud S, Lebrun N, Moutard ML, Nougues MC, Vermersch AI, Heron B, Pipiras E, Heron D, Olivier-Faivre L, Gueant JL, Jonveaux P, Philippe C. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation. J Med Genet. 2015 Jan;52(1):61-70..

PubMed ID: 
25411445

Chorioretinopathy with Microcephaly 2

Clinical Characteristics
Ocular Features: 

Microphthalmia and microcornea are seen in most individuals and one patient had unilateral clinical anophthalmia. Hyperopia and cataracts may be present. Nystagmus is common.  One patient had a corneal opacity.  The chorioretinopathy has not been described beyond evidence of the maculopathy, attenuated retinal vessels, and occasionally hyperpigmented zones.  The ERG is either not recordable or consistent with a severe rod-cone dystrophy.  Vitreous inclusions and a 'vitreoretinal dystrophy' with falciform retinal folds were noted in several patients.  A traction detachment was present in one and bilateral serous detachments were noted in another.

Systemic Features: 

Patients have mild to severe microcephaly (up to -15 SD) with psychomotor delays.  Profound intellectual disability is a consistent feature.  Physical growth is retarded and patients have shortness of stature.  Most patients are unable to sit, stand, or walk unassisted.  One patient died at 5.5 years of age while another was alive at 20 years of age.  Rare patients may have hearing loss and seizures.

Scoliosis, kyphosis, and lordosis may be seen while  other skeletal malformations seem to occur sporadically e.g., triphalangeal thumbs, brachydactyly, postaxial polydactyly, and restricted large joint motion.  

The forehead slopes markedly.  Neuroimaging shows a consistent reduction in cortex size with simple gyral folding while the cerebellum and the brain stem are also small.  Subarachnoid cysts have been noted in several patients and the corpus callosum may be short or otherwise malformed.

Genetics

Homozygous mutations in the PLK4 gene (4q28.2) segregate with this condition.  Its product localizes to centrioles and plays a central role in centriole duplication.

For a somewhat similar condition but without the sloping forhead see Chorioretinoapathy with Microcephaly 1 (251270) but resulting from homozygous mutations in TUBGCP6.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is know.

References
Article Title: 

Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy

Martin CA, Ahmad I, Klingseisen A, Hussain MS, Bicknell LS, Leitch A, Nurnberg G, Toliat MR, Murray JE, Hunt D, Khan F, Ali Z, Tinschert S, Ding J, Keith C, Harley ME, Heyn P, Muller R, Hoffmann I, Daire VC, Dollfus H, Dupuis L, Bashamboo A, McElreavey K, Kariminejad A, Mendoza-Londono R, Moore AT, Saggar A, Schlechter C, Weleber R, Thiele H, Altmuller J, Hohne W, Hurles ME, Noegel AA, Baig SM, Nurnberg P, Jackson AP. Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nat Genet. 2014 Dec;46(12):1283-92.

PubMed ID: 
25344692

Spinocerebellar Ataxia 18

Clinical Characteristics
Ocular Features: 

Ocular signs in SCAR18 include nystagmus, oculomotor apraxia, and optic atrophy.  The nystagmus may be rotatory or horizontal and can be gaze-evoked.  Some patients have intermittent and tonic upgaze.  Visual acuity has not been reported.

Systemic Features: 

Patients are developmentally delayed and have intellectual disability.  These features do not seem to be progressive.  Ataxia, both truncal and cerebellar, is present.  Mobility is impaired from early childhood and eventually requires assistance.   Joint contractures sometimes develop and patients can be wheelchair-bound by the second decade.  Dysarthric speech is common.  No dysmorphic facial features are present.

Brain imaging shows progressive cerebellar and sometimes cerebral atrophy.

Genetics

This autosomal recessive disorder results from homozygous deletions in the GRID2 gene (4q22).  This gene codes for a subunit of the glutamate receptor channel and is thought to be selectively expressed in the Purkinje cells of the cerebellum.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.  However, physical therapy, assistive devices for mobility, and low vision aids may be helpful.

References
Article Title: 

Galloway-Mowat Syndrome

Clinical Characteristics
Ocular Features: 

Microphthalmia, hypertelorism, epicanthal folds and ptosis are prominent ocular features.  Other manifestations include corneal opacities, cataracts, and optic atrophy.  Nystagmus of a roving nature is seen in all individuals and is usually present at birth.  There is evidence of visual impairment in more than 90% of individuals.  Features of an anterior chamber dysgenesis such as a hypoplastic iris are sometimes present.

The ocular features of this syndrome have not been fully described.

Systemic Features: 

Infants are born with low birth weight due to intrauterine growth retardation and there is often a history of oligohydramnios.  Newborns are often floppy and hypotonic although spasticity may develop later.  A small midface and microcephaly (80%) with a sloping forehead and a flat occiput are frequently evident.  The ears are large, floppy, and low-set while the hard palate is highly arched and the degree of micrognathia can be severe.  The fists are often clenched and the digits can appear narrow and arachnodactylous.  Hiatal hernias may be present.

Many patients develop features of the nephrotic syndrome in the first year of life with proteinuria and hypoalbuminemia due to glomerular kidney disease and renal system malformations.  Renal biopsies show focal segmental glomerulosclerosis in the majority of glomeruli.

Evidence of abnormal neuronal migration with brain deformities such as cystic changes, porencephaly, encephalomalacia, and spinal canal anomalies have been reported.  MRI imaging shows diffuse cortical and cerebellar atrophy atrophic optic nerves, and thinning of the corpus callosum.  The normal striated layers of the lateral geniculate nuclei are obliterated.  The cerebellum shows severe cellular disorganization with profound depletion of granule cells and excessive Bergmann gliosis.  The vermis is shortened. 

Multifocal seizures are sometimes (40%) seen in infancy and early childhood and the EEG generally shows slowed and disorganized backgound and sometimes a high-voltage hypsarrhythmia.  The degree of psychomotor delay and intellectual disability is often severe.   Most patients are unable to sit independently (90%), ambulate (90%), or make purposeful hand movements (77%).  The majority (87%) of children have extrapyramidal movements and a combination of axial dystonia and limb chorea.  Mean age of death is about 11 years (2.7 to 28 years in one series) and most die from renal failure.

Genetics

Gallaway-Mowat syndrome is likely a spectrum of disease.  Homozygous mutations in the WDR73 gene (15q25) are responsible for one form of this syndrome.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for GAMOS.

References
Article Title: 

Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73

Jinks RN, Puffenberger EG, Baple E, Harding B, Crino P, Fogo AB, Wenger O, Xin B, Koehler AE, McGlincy MH, Provencher MM, Smith JD, Tran L, Al Turki S, Chioza BA, Cross H, Harlalka GV, Hurles ME, Maroofian R, Heaps AD, Morton MC, Stempak L, Hildebrandt F, Sadowski CE, Zaritsky J, Campellone K, Morton DH, Wang H, Crosby A, Strauss KA. Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73. Brain. 2015 Aug;138(Pt 8):2173-90.  PubMed PMID: 26070982.

PubMed ID: 
26070982

Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome

Colin E, Huynh Cong E, Mollet G, Guichet A, Gribouval O, Arrondel C, Boyer O, Daniel L, Gubler MC, Ekinci Z, Tsimaratos M, Chabrol B, Boddaert N, Verloes A, Chevrollier A, Gueguen N, Desquiret-Dumas V, Ferre M, Procaccio V, Richard L, Funalot B, Moncla A, Bonneau D, Antignac C. Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome. Am J Hum Genet. 2014 Dec 4;95(6):637-48..

PubMed ID: 
25466283

Retinal Dystrophy with Inner Retinal Abnormalities

Clinical Characteristics
Ocular Features: 

Otherwise healthy individuals note onset of light sensitivity between 25 and 40 years of age.  Central vision is progressively lost with average vision levels of 20/50.  In some patients vision is 20/400 but peripheral vision remains normal on visual field testing.  Small central and centrocecal scotomas can be demonstrated.  There is general hyper-reflectivity of the ganglion cell and nerve fiber layers with the latter decreased in thickness especially in the foveal area of all patients.  The optic nerve is often pale.  The ERG recordings are consistent with inner retinal dysfunction with an absent b-wave and a normal a-wave response.  Older patients have additional photopic response abnormalities and delayed implicit times.  Color vision in younger individuals was reported to be normal but older persons had mild deuteranopia.

Systemic Features: 

No systemic disease was noted in the single reported family.  Specifically, no dementia was present in affected individuals (vida infra).

Genetics

This condition has been identified in a single large 3-generation family.  A missense heterozygous mutation in the ITM2B gene (13q14.2) is responsible.  The gene product localizes to the inner nuclear and ganglion cell layers in the eye and co-localizes with the amyloid beta precursor protein of Alzheimer disease in cerebral tissue.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the retinal disease is available but photosensitive individuals may benefit from tinted lenses.  Low vision aid can be useful for near vision.

References
Article Title: 

The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family

Audo I, Bujakowska K, Orhan E, El Shamieh S, Sennlaub F, Guillonneau X, Antonio A, Michiels C, Lancelot ME, Letexier M, Saraiva JP, Nguyen H, Luu TD, Leveillard T, Poch O, Dollfus H, Paques M, Goureau O, Mohand-Said S, Bhattacharya SS, Sahel JA, Zeitz C. The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family. Hum Mol Genet. 2014 Jan 15;23(2):491-501..

PubMed ID: 
24026677

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