SRD5A3

Congenital Disorder of Glycosylation, Type Iq

Clinical Characteristics

Ocular Features:

Colobomas (iris, choroid, and sometimes optic nerve), optic nerve hypoplasia and nystagmus have been reported. Visual acuity is variable depending upon the degree of nerve hypoplasia. The eyebrows may be highly arched, while downward slanting lid fissures, and hypertelorism may also be present.

Congenital cataracts, glaucoma and microphthalmia have been reported in several individuals.

Systemic Features:

Onset of symptoms commonly begins in infancy with severe hypotonia while developmental delays soon become evident as most children do not achieve normal milestones. The amount of cognitive impairment is variable. Congenital cardiac defects, ichthyosis, and hypertrichosis may be present. The skin over the dorsum of the hands and feet often appears dark. Ataxia is sometimes present and MRIs may reveal vermal and cerebellar hypoplasia.

Facial dysmorphism is common. Low-set malformed ears, low hairline, depressed nasal bridge, redundant facial skin, decreased subcutaneous tissue, large mouth, thin lips, and long face have been noted.

There is considerable variation in clinical manifestations and longevity varies from infancy to adulthood.

Genetics

This glycosylation disorder is one of a number of rare hepatic/intestinal disorders caused by a deficiency in N-oligosaccharide synthesis. It is inherited in an autosomal recessive pattern as a result of mutations in SRD5A3 (4q12). Both homozygous and compound heterozygous genotypes have been reported. It is allelic to Kahrizi syndrome (612713) with a number of overlapping features including ocular colobomas and cognitive deficiencies.

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

The administration of caloric supplements through tube feeding may be required to maintain adequate nutrition.Orthopedic deformities can sometimes be corrected surgically.

References

Article Title:

A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism

Morava E, Wevers RA, Cantagrel V, Hoefsloot LH, Al-Gazali L, Schoots J, van Rooij A, Huijben K, van Ravenswaaij-Arts CM, Jongmans MC, Sykut-Cegielska J, Hoffmann GF, Bluemel P, Adamowicz M, van Reeuwijk J, Ng BG, Bergman JE, van Bokhoven H, Korner C, Babovic-Vuksanovic D, Willemsen MA, Gleeson JG, Lehle L, de Brouwer AP, Lefeber DJ. A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. Brain. 2010 Nov;133(11):3210-20.

PubMed ID:

20852264

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder

Cantagrel V, Lefeber DJ, Ng BG, Guan Z, Silhavy JL, Bielas SL, Lehle L, Hombauer H, Adamowicz M, Swiezewska E, De Brouwer AP, Bl?omel P, Sykut-Cegielska J, Houliston S, Swistun D, Ali BR, Dobyns WB, Babovic-Vuksanovic D, van Bokhoven H, Wevers RA, Raetz CR, Freeze HH, Morava E, Al-Gazali L, Gleeson JG. SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder. Cell. 2010 Jul 23;142(2):203-17.

PubMed ID:

20637498

A new autosomal recessive syndrome of ocular colobomas, ichthyosis, brain malformations and endocrine abnormalities in an inbred Emirati family

Al-Gazali L, Hertecant J, Algawi K, El Teraifi H, Dattani M. A new autosomal recessive syndrome of ocular colobomas, ichthyosis, brain malformations and endocrine abnormalities in an inbred Emirati family. Am J Med Genet A. 2008 Apr 1;146(7):813-9.

PubMed ID:

18271001

Kahrizi Syndrome

Clinical Characteristics

Ocular Features:

In an Iranian family with 3 affected sibs, cataracts (not further characterized) were noted in late adolescence. Iris colobomas, unilateral in one sib and bilateral in another, were present.

Systemic Features:

Children have severe psychomotor delays from birth and have severe mental retardation. Speech and normal motor function never develop fully. Thoracic kyphosis begins in late childhood and contractures develop in the elbows and knees. A CAT scan in one patient revealed only normal findings. Facial features have been described as ‘coarse’ with prominent lips, broad nasal bridge, and a bulbous nose. Some individuals with this condition have lived into the 5^th decade. Ataxia is usually present although the cerebellum may be normal on MRI.

Genetics

This is an autosomal recessive condition resulting from homozygous mutations in the SRD5A3 gene (4q12).

Kahrizi syndrome is allelic to CDG1Q, or congenital disorder of glycosylation type Iq (612379), an autosomal recessive disorder with mutations in the same gene and a partially overlapping ocular phenotype.

At least 10 families have been reported with mutations in this gene considered important to glycosylation.

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

No specific treatment is available for this condition although physical therapy and cataract surgery might be considered in specific individuals.

References

Article Title:

Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3

Kahrizi K, Hu CH, Garshasbi M, Abedini SS, Ghadami S, Kariminejad R, Ullmann R, Chen W, Ropers HH, Kuss AW, Najmabadi H, Tzschach A. Next generation sequencing in a family with autosomal recessive Kahrizi syndrome (OMIM 612713) reveals a homozygous frameshift mutation in SRD5A3. Eur J Hum Genet. 2011 Jan;19(1):115-7.

PubMed ID:

20700148

SRD5A3 is required for converting polyprenol to dolichol and is mutated in a congenital glycosylation disorder

PubMed ID:

20637498

An autosomal recessive syndrome of severe mental retardation, cataract, coloboma and kyphosis maps to the pericentromeric region of chromosome 4

Kahrizi K, Najmabadi H, Kariminejad R, Jamali P, Malekpour M, Garshasbi M, Ropers HH, Kuss AW, Tzschach A. An autosomal recessive syndrome of severe mental retardation, cataract, coloboma and kyphosis maps to the pericentromeric region of chromosome 4. Eur J Hum Genet. 2009 Jan;17(1):125-8.

PubMed ID:

18781183

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