optic nerve hypoplasia

Microcephaly 20, Primary, Autosomal Recessive

Clinical Characteristics
Ocular Features: 

Microphthalmia and optic nerve hypoplasia with "blindness" seem to be common.

Systemic Features: 

Short stature and global developmental delay are usually present.  Poor or absent speech is characteristic and intellectual disability may be severe.  Few individuals can walk.  Foot deformities and hypotonia are often present.  Behavior problems are common having features of ADHD, autism, and aggression.  Foot deformities have been noted. 

Imaging of the brain may reveal cerebellar hypoplasia, a simplified gyral pattern, and absence of the corpus callosum. 

Genetics

Homozygous or compound heterozygous mutations in the KIF14 gene (1q32.1) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic variants in KIF14 cause intellectual disability with microcephaly

Makrythanasis P, Maroofian R, Stray-Pedersen A, Musaev D, Zaki MS, Mahmoud IG, Selim L, Elbadawy A, Jhangiani SN, Coban Akdemir ZH, Gambin T, Sorte HS, Heiberg A, McEvoy-Venneri J, James KN, Stanley V, Belandres D, Guipponi M, Santoni FA, Ahangari N, Tara F, Doosti M, Iwaszkiewicz J, Zoete V, Backe PH, Hamamy H, Gleeson JG, Lupski JR, Karimiani EG, Antonarakis SE. Biallelic variants in KIF14 cause intellectual disability with microcephaly. Eur J Hum Genet. 2018 Mar;26(3):330-339.

PubMed ID: 
29343805

Mutations of KIF14 cause primary microcephaly by impairing cytokinesis

Moawia A, Shaheen R, Rasool S, Waseem SS, Ewida N, Budde B, Kawalia A, Motameny S, Khan K, Fatima A, Jameel M, Ullah F, Akram T, Ali Z, Abdullah U, Irshad S, Hohne W, Noegel AA, Al-Owain M, Hortnagel K, Stobe P, Baig SM, Nurnberg P, Alkuraya FS, Hahn A, Hussain MS. Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann Neurol. 2017 Oct;82(4):562-577.

PubMed ID: 
28892560

Epileptic Encephalopathy, Early Infantile 58

Clinical Characteristics
Ocular Features: 

Infants are noted early to have poor fixation and visual following of targets.  Optic nerve hypoplasia is evident on brain MRIs.

Systemic Features: 

Epilepsy and development delay are hallmarks of this condition.  The seizures are of multiple types and have their onset in the first year of life.  The EEG often shows diffuse slowing, multifocal spikes and hypsarrhythmia.  These are often difficult to control.  Severe intellectual disability is usually present.  Feeding difficulties are evident early and slow growth is common.  Hypotonia is common but hyperreflexia and spasticity are also reported.

Brain MRIs show delayed or reduced myelination.  Acquired microcephaly is often seen.

Genetics

De novo heterozygous mutations in the NTRK2 gene (9p21.33) have been found in 4 unrelated individuals.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, Schneider A, Hollingsworth G; Deciphering Developmental Disorders Study, FitzPatrick DR, Donaldson A, Canham N, Blair E, Kerr B, Fry AE, Thomas RH, Shelagh J, Hurst JA, Brittain H, Blyth M, Lebel RR, Gerkes EH, Davis-Keppen L, Stein Q, Chung WK, Dorison SJ, Benke PJ, Fassi E, Corsten-Janssen N, Kamsteeg EJ, Mau-Them FT, Bruel AL, Verloes A, Ounap K, Wojcik MH, Albert DVF, Venkateswaran S, Ware T, Jones D, Liu YC, Mohammad SS, Bizargity P, Bacino CA, Leuzzi V, Martinelli S, Dallapiccola B, Tartaglia M, Blumkin L, Wierenga KJ, Purcarin G, O'Byrne JJ, Stockler S, Lehman A, Keren B, Nougues MC, Mignot C, Auvin S, Nava C, Hiatt SM, Bebin M, Shao Y, Scaglia F, Lalani SR, Frye RE, Jarjour IT, Jacques S, Boucher RM, Riou E, Srour M, Carmant L, Lortie A, Major P, Diadori P, Dubeau F, D'Anjou G, Bourque G, Berkovic SF, Sadleir LG, Campeau PM, Kibar Z, Lafreniere RG, Girard SL, Mercimek-Mahmutoglu S, Boelman C, Rouleau GA, Scheffer IE, Mefford HC, Andrade DM, Rossignol E, Minassian BA, Michaud JL. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Am J Hum Genet. 2017 Nov 2;101(5):664-685.

 

PubMed ID: 
291000083

Neurodevelopmental Disorder With or Without Seizures and Gait Abnormalities

Clinical Characteristics
Ocular Features: 

Nystagmus and strabismus are common ocular features.  Optic nerve hypoplasia is present in some individuals.

Systemic Features: 

Symptoms may begin in early infancy or childhood.  Several neonates with irritability, hypertonia, increased startle reflexes, and stiffness have been reported.  Hypotonia may occur in the neonatal period though.  Intellectual disability and severe developmental delay are common and some patients are unable to follow simple commands.  Seizures of variable severity frequently occur at some point.  Speech may be absent.  Some patients are unable to walk while those that do have a clumsy, spastic gait.  Joint contractures may develop.

The most obvious dysmorphic feature are large ears.  Choreiform and stereotypic hand movements are sometimes present.  Feeding difficulties and sleeping problems may be noted.  Cortical atrophy and thinning of the corpus callosum has been seen on brain imaging.  One mildly affected individual was short in stature.

Genetics

Heterozygous mutations in the GRIA4 gene (11q22.3) have been found in 5 unrelated patients.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Coloboma, Microphthalmia, Albinism, and Deafness

Clinical Characteristics
Ocular Features: 

A 5 year old male has been described with uveal colobomas in microphthalmic eyes plus small corneas with a pannus, dense cataracts, translucent irides, and hypopigmentation of the skin, hair and eyes.  A brain MRI showed hypoplasia of the optic nerves and chiasm.   

A 9 month old female from another family had severe microphthalmia and small optic nerves.  The internal ocular features were not reported.

Systemic Features: 

The complete phenotype is uncertain since it is based on only two reported and unrelated individuals.  The head circumference one one patient was consistent with macrocephaly accompanied by frontal bossing, shallow orbits, preauricular pits and posteriorly rotated ears.  A skeletal survey revealed evidence for osteopetrosis.  He had a sensorineural hearing deficit said to be congenital in onset.

The other patient, a 9 month old female, belonged to another nonconsanguineous family, and had similar skeletal and craniofacial features with the addition of micrognathia and hypotonia.  Congenital neurosensory hearing loss and general lack of pigmentation were noted.

All four parents have congenital sensorineural hearing loss, blue irides and fair skin with premature graying of hair.  Four sibs in the two families have phenotypes similar to that of the parents.  Only one child, a female, had no features of the phenotype.

Genetics

This condition, so far reported only in a male and a female in unrelated families, is the result of doubly heterozygous mutations in the MITF gene (3p13).  One mutation that causes Waardenburg syndrome 2  (WS2A) (193510) is combined with a dominant-negative allele (c.952_954delAGA [p.Arg318del]) to produce the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Optic Atrophy 11

Clinical Characteristics
Ocular Features: 

Optic atrophy is seen as early as 5 years of age but may be congenital in origin as hypoplasia of the optic nerve was present in all patients.  Three of 4 affected children also were myopic.

Systemic Features: 

This is a form of mitochondriopathy with considerable clinical heterogeneity.  A single consanguineous family with 4 affected children of ages 5-16 years of age has been reported.

Common features include short stature, microcephaly (1 had macrocephaly), hearing impairment. Ataxia, dysmetria, and athetotic movements may be present.  Motor and mental development are delayed as is expressive speech.  Intellectual disability is present in all 4 patients.  Leukoencephalopathy was seen in all patients and one had brain atrophy.  Cerebellar hypoplasia was present in 2 of four patients.

Muscle mitochondria in one patient had morphologic changes.  Lactate levels and lactate/pyruvate ratios were elevated in the blood and CSF fluid of three patients.

Genetics

Homozygous mutations in the YME1L1 gene (10p12.1) were responsible for this condition in 4 offspring of a consanguineous Saudi Arabian family.   This is a nuclear encoded mitochondrial gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.Hom

References
Article Title: 

Chorioretinopathy with Microcephaly 3

Clinical Characteristics
Ocular Features: 

The eyes are not notably small although several patients have been reported to have significant hyperopia.  Vision can be impaired and some individuals have early-onset nystagmus.  The ERG responses are attenuated and may be absent.  The retina is dysplastic with multiple atrophic punched-out lesions, attenuated retinal vessels, and sparse pigmentation. Large retinal folds have been described and one patient developed a retinal detachment.  Optic atrophy was noted in one individual.

Systemic Features: 

Microcephaly of 3-4 standard deviations below normal is a constant feature.  Motor and language abilities can be mildly delayed and  several patients have had mild learning difficulties.   Brain imaging has been normal in most individuals but a shortened and thin corpus callosum was present in one patient.

Genetics

Family and genetic evidence suggest autosomal recessive inheritance.  Compound heterozygous mutations in the TUBGCP4 gene (15q15.3) code for part of a protein complex involved in microtubule organization.

For a somewhat similar condition with a different mutation involving the same microtubule complex see Chorioretinopathy with Microcephaly 1 (251270).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Low vision aids may be helpful in selected patients.

References
Article Title: 

Mutations in TUBGCP4 Alter Microtubule Organization via the γ-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy

Scheidecker S, Etard C, Haren L, Stoetzel C, Hull S, Arno G, Plagnol V, Drunat S, Passemard S, Toutain A, Obringer C, Koob M, Geoffroy V, Marion V, Strahle U, Ostergaard P, Verloes A, Merdes A, Moore AT, Dollfus H. Mutations in TUBGCP4 Alter Microtubule Organization via the g-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy. Am J Hum Genet. 2015 Apr 2;96(4):666-74.

PubMed ID: 
25817018

Cerebral Atrophy, Autosomal Recessive

Clinical Characteristics
Ocular Features: 

Severe visual impairment is noted before one year of age when infants cease following objects in their environment.  Cortical visual impairment has been diagnosed although 'atrophic optic fundi' and hypotrophic optic nerves and fovea have also been described.  Nystagmus has been observed as well.

Systemic Features: 

Microcephaly relative to age norms is evident usually by 2 months of age and there is little subsequent growth of the skull.  Regression of developmental milestones is noted by 4 months of age with signs of irritability, akathisia, spasticity, visual impairment, seizures, and increased startle responses.  Sucking responses and eye-to-eye contact are usually lost by 6 months of age.  Repetitive body stiffening and extension of arms in older individuals consistent with seizure activity has been confirmed by EEG in at least one infant.  Imaging consistently reveals cerebral atrophy with ventriculomegaly and general loss of brain volume. Progressive muscle weakness is evident after about 1 year of age and oral feeding is impaired. There is complete lack of responsive interaction beyond irritability and agitation while motor function is limited to involuntary responses.  Two individuals have lived into the second decade of life.

Genetics

This condition has been described in 4 individuals who were products of consanquineous Amish couples.  Homozygous mutations in the TMPRSS4 gene (11q23.3), whose product is a serine transmembrane protease, seems to be responsible.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Microphthalmia, Syndromic 5

Clinical Characteristics
Ocular Features: 

One or both eyes may be small, sometimes resembling clinical anophthalmia. Other ocular anomalies such as coloboma, microcornea, cataracts, and hypoplasia or agenesis of the optic nerve have been reported.

A pigmentary retinopathy has been described.  The retinal vessels are often attenuated and sometimes sparse.  The optic nerves and chiasm are frequently absent or hypoplastic as seen on the MRI.  ERG and VEP responses are inconsistent but are generally abnormal indicating photoreceptor malfunction.  

Systemic Features: 

Patients have a variety of systemic abnormalities including pituitary dysfunction, joint laxity, hypotonia, agenesis of the corpus callosum, and seizures.  Hypothyroidism and deficiencies of growth hormone, gonadotropins, and cortisol are present in some patients.  Developmental delay and cognitive impairment are frequently present but mental functioning is normal in some patients.  The genitalia of males are often underdeveloped.  Patients are often short in stature.

Genetics

This is an autosomal dominant condition secondary to heterozygous mutations in the OTX2 gene (14q22.3).  A variety of point mutations as well as microdeletions involving the OTX2 gene have been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the syndrome but surgical and/or endocrinological treatment may be used to correct individual features.  Special education and low vision aids may be helpful in selected patients.

References
Article Title: 

Heterozygous mutations of OTX2 cause severe ocular malformations

Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA, Clarke MP, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera JP, Ruddle P, Hurst J, Collin JR, Salt A, Cooper ST, Thompson PJ, Sisodiya SM, Williamson KA, Fitzpatrick DR, van Heyningen V, Hanson IM. Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet. 2005 Jun;76(6):1008-22. Apr 21. Erratum in: Am J Hum Genet. 2005 Aug;77(2):334..

PubMed ID: 
15846561

Meckel Syndrome

Clinical Characteristics
Ocular Features: 

The ocular phenotype is highly variable.  The globe is often malformed or may be clinically absent.  Cryptophthalmos, clinical anophthalmia, and microphthalmos with sclerocornea and microcornea have been reported.  Posterior staphylomas, retinal dysplasia, partial aniridia, cataracts, and hypoplasia or absence of the optic nerve are sometimes seen.  Some patients have incompletely formed eyes with shallow anterior chambers, angle anomalies, and a persistent tunica vasculosa with lens opacification.  Histopathology may reveal thinning of the nerve fiber layer and a paucity of retinal ganglion cells.  The retina has been described as dysplastic with foci of rosette-like structures and abundant glial cells.

Systemic Features: 

Meckel or Meckel-Gruber syndrome is a clinically and genetically heterogeneous group of disorders with severe multisystem manifestations.  The triad of cystic renal disease, polydactyly (and sometimes syndactyly), and a skull malformation (usually an encephalocele) is considered characteristic of MKS.  However, these signs are variable and only about 60% of patients have all three features.  Many patients have additional signs such as malformations of the biliary tree, cleft palate (and/or lip), sloping forehead, low-set ears, short neck, low-set ears, ambiguous genitalia, and short, bowed limb bones.  Pulmonary hypoplasia is common which, together with kidney and liver disease, is responsible for the poor prognosis of most infants. 

Many clinical abnormalities resemble those present in the Smith-Lemli-Opitz syndrome (270400) and in Joubert syndrome (213300).

Genetics

Most conditions in this group are inherited in an autosomal recessive pattern.  Mutations in 9 genes have been identified as responsible for some variant of MKS in which there is a considerable range of clinical expression.  There is significant clinical overlap with Joubert syndrome and it is not surprising that at least 5 of these mutations have been identified in both conditions.  Further nosological confusion is generated by those who consider patients with the severe, lethal phenotype to have Meckel syndrome while those with milder disease are labeled Joubert syndrome, regardless of genotype.

Rare heterozygotes have been reported with isolated features such as polydactyly.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this syndrome.  The prognosis for life beyond infancy is poor due to the advanced dysfunction of numerous organs such as the kidney, lungs, liver and the central nervous system.

References
Article Title: 

Clinical and genetic heterogeneity in Meckel syndrome

Paavola P, Salonen R, Baumer A, Schinzel A, Boyd PA, Gould S, Meusburger H, Tenconi R, Barnicoat A, Winter R, Peltonen L. Clinical and genetic heterogeneity in Meckel syndrome. Hum Genet. 1997 Nov;101(1):88-92.

PubMed ID: 
9385376

Blue Diaper Syndrome

Clinical Characteristics
Ocular Features: 

A single patient has been reported with microcornea, optic nerve hypoplasia, and 'abnormal' eye movements.  The full ocular phenotype is unknown but 'visual problems' are sometimes mentioned in other reports.

Systemic Features: 

Nephrocalcinosis and blue urine are the major systemic manifestations of blue diaper syndrome.  Symptoms of fever, constipation, poor weight gain, failure to thrive, and irritability can also be part of the syndrome.

Genetics

This is considered an autosomal recessive disorder although an X-linked defect cannot be ruled out since reported patients have been male.  Parental consanguinity is present in some families.  Nothing is known about the mutation or its locus.  Intestinal transport of tryptophan is defective and bacterial degradation results in excessive indole production.  Oxidation in the urine to indigo blue results in the characteristic discoloration.        

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Restriction of dietary tryptophan has been suggested.

References
Article Title: 

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