autism spectrum

Microphthalmia and Anophthalmia, ALDH1A3 Associated

Clinical Characteristics
Ocular Features: 

Patients have a variety of ocular malformations including microphthalmia and clinical anophthalmia.  Some have orbital cysts. Imaging may reveal hypoplastic optic nerves and chiasms.

Systemic Features: 

Both cardiac (pulmonary stenosis and septal defects) and neurological deficits (autism spectrum disorders and 'intellectual disability') have been reported.  Birth weight and head circumference are often low.  However, brain imaging has revealed no consistent malformations.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in the gene ALDH1A3 (15q26.3) which encodes the enzyme retinaldehyde dehydrogenase.  Mutations in ALDH1A3 impair the enzymatic oxidation of retinaldehyde important to the synthesis of retinoic acid, a key signaling molecule in eye development. 

However, mutations in other genes important to ocular development such as GJA3 and SOX2 (a transcription factor) may result in a similar phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the ocular problems is available.

References
Article Title: 

ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia

Fares-Taie L, Gerber S, Chassaing N, Clayton-Smith J, Hanein S, Silva E, Serey M, Serre V, G?(c)rard X, Baumann C, Plessis G, Demeer B, Br?(c)tillon L, Bole C, Nitschke P, Munnich A, Lyonnet S, Calvas P, Kaplan J, Ragge N, Rozet JM. ALDH1A3 Mutations Cause Recessive Anophthalmia and Microphthalmia. Am J Hum Genet. 2013 Feb 7;92(2):265-70.

PubMed ID: 
23312594

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: 

Goldenhar Syndrome Spectrum

Clinical Characteristics
Ocular Features: 

There is considerable clinical heterogeneity in this syndrome.  Upper eyelid colobomas and ocular dermoids or lipdermoids are the primary ocular signs (lower lid colobomas are more common in Treacher Collins-Franceschetti syndrome [154500]).  The caruncles may be dysplastic, displaced or even bilobed.  Iris, optic nerve and chorioretinal colobomas also occur.  Microphthalmia is uncommon.  All ocular features are usually unilateral but are bilateral in a minority of cases.

Systemic Features: 

The facial asymmetry (hemifacial microsomia) can be a striking feature.  The side with microsomia may have a malformed external auricle, preauricular tags, pretragal fistulas, and microtia or even atresia of the external auditory canal.  A wide variety of other anomalies are often found including left lip and palate, mandibular hypoplasia, vertebral anomalies, facial nerve paralysis, congenital heart defects, and conductive hearing loss.  Mental deficits are often present along with features of the autism spectrum in 11%.

Genetics

Most cases are sporadic but other family patterns support autosomal recessive and autosomal dominant inheritance with the latter being the most common.  A locus at 14q32 has been associated with OAVS but so far no mutant gene has been identified.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Some patients benefit from scoliosis and cosmetic surgery.  Assistive hearing devices can be helpful and children especially should be monitored for physical and cognitive development.

References
Article Title: 

Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients

Beleza-Meireles A, Hart R, Clayton-Smith J, Oliveira R, Reis CF, Venancio M, Ramos F, Sa J, Ramos L, Cunha E, Pires LM, Carreira IM, Scholey R, Wright R, Urquhart JE, Briggs TA, Kerr B, Kingston H, Metcalfe K, Donnai D, Newman WG, Saraiva JM, Tassabehji M. Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients. Eur J Med Genet. 2015 Sep;58(9):455-65.

PubMed ID: 
26206081
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