autosomal recessive

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

Cataracts, Congenital Nuclear

Clinical Characteristics
Ocular Features: 

Congenital nuclear cataracts are the only ocular abnormalities in these conditions.  There may be some cortical opacifications as well.  The nuclear opacifications may not be sufficiently dense in some patients to require cataract surgery.  Nothing is known of their natural history, however.

Systemic Features: 

No systemic disease is associated with these congenital cataracts.

Genetics

All three of these nuclear cataracts are inherited in autosomal recessive patterns.  They have been reported in rare families in which the parents were consanguineous.

CATCN1 was reported in a 4-generation Pakistani family having an unknown mutation localized to 19q13.

Another congenital nuclear cataract (CATCN2) results from mutations in the CRYBB3 (22q11.23) gene reported in 2 consanguineous Pakistani families.

CATCN 3 results from mutations in CRYBB1 (22q12.1) as reported in two consanguineous Israeli Bedouin families with 14 affected individuals.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Surgical removal may be indicated if the lens opacities are visually significant.  Vision may be sufficiently impaired in some children that surgery is required before 2 years of age.

References
Article Title: 

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 5th 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: 

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

Cataracts, Congenital, Autosomal Recessive 2

Clinical Characteristics
Ocular Features: 

Bilateral nuclear lens opacities are either present at birth or noted during infancy.  The cataracts were sufficiently dense that surgery is necessary within several months of age in most patients.  No other ocular disease is present.

Systemic Features: 

No systemic abnormalities are present.

Genetics

CATC2 is an autosomal recessive condition that has been reported in 12 consanguineous Pakistani families.  Homozygous mutations in FYCO1 (3p21.31) segregated with the lens opacities as expected.  Mutations in FYC01 are among the most common causes of congenital cataracts in Pakistan and may account for about 10% of the total genetic load of cataracts in this country.  Mutations in the same gene have been found segregating in several consanguineous Arab families with congenital cataracts as well.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataract surgery is frequently necessary during infancy.

References
Article Title: 

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

Majewski Syndrome

Clinical Characteristics
Ocular Features: 

No clinical information is available on the ocular features in this disorder.  The fundi have been described as normal in one patient but postmortem histopathology at 8 weeks revealed optic nerve edema with segmental axonal dropout and loss of myelin.  The nerve fiber layer of the retina was prominent with some proliferation of glial tissue.  Early nuclear sclerosis was also present.

Systemic Features: 

This disorder results from a dysgenesis of the cilia and is one of a group of short rib-polydactyly disorders.  Congenital anomalies are found in multiple organs including heart, lungs, skeleton, intestines, genitalia, pancreas, liver, and kidneys.  The diagnostic characteristic of SRPS type II is extreme shortening of the tibia in addition to short ribs in this type of short-limbed dwarfism.

Midline facial clefting, especially cleft lip, is common.  The epiglottis and lungs are often hypoplastic and the kidneys are polycystic.  Polydactyly and polysyndactyly of both pre- and postaxial types are usually present.  Most neonates with SRPS type II do not live beyond infancy.

Genetics

This is an autosomal recessive condition resulting from homozygous mutations in the NEK1 gene (4q33), or, rarely, from digenic biallelic mutations in NEK1 and DYNC2H1 (11q22.3).

Another condition with some of the same features leading to respiratory distress is asphyxiating thoracic dysplasia 1 (208500), or Jeune syndrome.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is available for this condition but surgical treatment could be considered for specific anomalies.

References
Article Title: 

NEK1 mutations cause short-rib polydactyly syndrome type majewski

Thiel C, Kessler K, Giessl A, Dimmler A, Shalev SA, von der Haar S, Zenker M, Zahnleiter D, Stoss H, Beinder E, Abou Jamra R, Ekici AB, Schroder-Kress N, Aigner T, Kirchner T, Reis A, Brandst?SStter JH, Rauch A. NEK1 mutations cause short-rib polydactyly syndrome type majewski. Am J Hum Genet. 2011 Jan 7;88(1):106-14.

PubMed ID: 
21211617

Joubert Syndrome and Related Disorders

Clinical Characteristics
Ocular Features: 

Ocular findings like systemic features are highly variable both within and between families.  Vision can be normal but in other patients it is severely reduced to the range of 20/200.  The pupils may respond sluggishly or even paradoxically to light.  ERG recordings have been reported to be normal in some patients, but absent or reduced in others.  The fundus appearance is often normal but in other individuals the pigmentation is mottled, the retinal arterioles are attenuated, and the macula has a cellophane maculopathy.  Drusen and colobomas are sometimes seen in the optic nerve while occasional patients have typical chorioretinal colobomas.  The eyebrows are often highly arched.

The oculomotor system is frequently involved.  Apraxia to some degree is common with most patients having difficulty with smooth pursuit and saccadic movements.  Compensatory head thrusting is often observed.  A pendular nystagmus may be present while esophoria or esotropia is present in many patients.

Systemic Features: 

There is a great deal of clinical heterogeneity in this group of ciliary dyskinesias.  Developmental delays, cognitive impairment, truncal ataxia, breathing irregularities, and behavioral disorders are among the more common features.  Hyperactivity and aggressiveness combined with dependency require constant vigilance and care.  Postaxial polydactyly is a feature of some cases.  Hypotonia is evident at birth.  Liver failure and renal disease develop in many individuals.  Neuroimaging of the midbrain-hindbrain area reveals agenesis or some degree of dysgenesis of the vermis with the ‘molar tooth sign’ in the isthmus region considered to be a diagnostic sign.  The fourth ventricle is usually enlarged while the cerebellar hemispheres may be hypoplastic.

The facies features are said to be distinctive in older individuals.  The face appears long with frontal prominence due to bitemporal narrowing, the nasal bridge and tip are prominent, the jaw is prominent, the lower lip protrudes, and the corners of the mouth are turned down.

Genetics

This is a clinically and genetically heterogeneous group of disorders with many overlapping features.  Most disorders in this disease category, known as JSRD, are inherited in an autosomal recessive pattern.  Mutations in at least 18 genes have been identified.  One, OFD1 (300804), is located on the X chromosome (Xp22.2).

There are significant clinical similarities with Meckel syndrome (249000) and with Smith-Lemli-Opitz syndrome (270400).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Treatment is mostly for specific symptoms such as respiratory distress, renal disease, speech and physical therapy, low vision, and hepatic failure.

References
Article Title: 

Ophthalmological findings in Joubert syndrome

Sturm V, Leiba H, Menke MN, Valente EM, Poretti A, Landau K, Boltshauser E. Ophthalmological findings in Joubert syndrome. Eye (Lond). 2010 Feb;24(2):222-5.

PubMed ID: 
19461662

Retinitis Pigmentosa 1

Clinical Characteristics
Ocular Features: 

Night blindness, the predominant presenting symptom, is often noted in the first decade of life but may not be a significant complaint until the third decade.  Concentric peripheral field loss likewise follows a similar timeline.  ERG responses progressively decrease in amplitude and may become undetectable in the second decade.  The retinal disease progresses relentlessly, albeit slowly, as the result of photoreceptor degeneration and most patients have severe visual handicaps by midlife but there is considerable clinical variation.  The pigmentary retinopathy is typical for classical retinitis pigmentosa with vascular attenuation, perivascular bone-spicule pigment clumping, optic atrophy, and generalized retinal atrophy with relative sparing of the macula early in the disease.  Lens opacities in late stages of the disease are common.

Systemic Features: 

No systemic disease is associated with the ocular disorder caused by mutations in RP1.

Genetics

Multiple heterozygous, homozygous, and compound heterozygous mutations in the RP1 gene (8q12.1) sometimes called the oxygen-regulated photoreceptor protein 1 or ORP1 gene are responsible for this disorder.  The protein product is active specifically in retinal photoreceptors.  Retinitis pigmentosa 1 is generally considered to be an autosomal dominant disorder and accounts for 5-7% of dominantly inherited RP disease.  However, recent reports suggest that some mutations in RP1 are responsible for familial cases transmitted in an autosomal recessive pattern in which the clinical disease is more severe. 

More than 20 different mutant genes have been associated with autosomal dominant RP but many cases lack a family history suggesting additional genetic heterogeneity remains.  Reduced penetrance and variable expressivity characteristic of genetic disease likely contributes to the clinical heterogeneity as well.  For more about autosomal dominant retinitis pigmentosa, see Retinitis Pigmentosa, AD (180380, 268000).  

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Photoreceptor transplantation has been tried in a number of patients without improvement in central vision or interruption in the rate of vision loss.  Longer term results are needed.  Resensitizing photoreceptors with halorhodopsin using archaebacterial vectors shows promise in mice.  High doses of vitamin A palmitate slow the rate of vision loss but plasma levels and liver function need to be checked at least annually.  Oral acetazolamide can be helpful in reducing macular edema.

Low vision aids and mobility training can be facilitating for many patients.  Cataract surgery may restore several lines of vision at least temporarily.

Several pharmaceuticals should be avoided, including isotretinoin, sildenafil, and vitamin E.

References
Article Title: 

External Ophthalmoplegia with Progressive Scoliosis

Clinical Characteristics
Ocular Features: 

Horizontal ophthalmoplegia is the ocular hallmark of this condition.  It is often present at birth with complete lack of horizontal gaze but in other individuals develops sometime in the first decade of life.  Horizontal smooth pursuit, saccades, optokinetic nystagmus, and vestibuloocular responses are lacking.  Vertical pursuit movements are usually intact except for smooth pursuit which is often saccadic.  Pendular nystagmus (usually horizontal) may be present and head shaking accompanies the nystagmus in some patients.  Many patients are orthophoric but some have a mild esotropia and/or vertical deviation.  The degree of convergence is variable.  Amblyopia does not usually occur and vision has been described as normal or near normal in spite of the presence of nystagmus.  Fusion and some degree of stereoacuity are generally present.  Compensatory head motion can effectively mask the horizontal palsy.

Some individuals are considered to have Duane retraction syndrome or congenital esotropia before the scoliosis becomes apparent.

Systemic Features: 

Progressive thoracolumbar scoliosis begins early in the first decade of life and may be evident by 2 years of life.  MRI reveals hypoplasia of the pons and cerebellar peduncles and electrophysiology studies provides evidence of abnormal (uncrossed) corticospinal and dorsal column-medial lemniscus pathways.  Cranial nerves VI and III seem to be intact.

Genetics

Homozygous mutations in the ROBO3 gene (11q24.2) are responsible for this autosomal recessive disorder.  The ROBO3 protein product is important for normal midline axon crossing in the brainstem. Consanguinity is common among parents.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Scoliosis may require surgical stabilization.  Physical therapy can be beneficial.

References
Article Title: 

Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis

Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, R?ob U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004 Jun 4;304(5676):1509-13.

PubMed ID: 
15105459

Dyskeratosis Congenita

Clinical Characteristics
Ocular Features: 

The conjunctiva and eyelids are prominently involved as part of the generalized mucocutaneous disease.  Keratinization of the lid margins, absent lacrimal puncta, trichiasis, cicatrizing conjunctivitis, entropion, ectropion, blepharitis, sparse eyelashes, and symblephara are important features.  The cornea is also involved with keratinization of the epithelial surface and vascularization.  The nasolacrimal duct is sometimes blocked.

Systemic Features: 

Dyskeratosis congenita consists of a heterogeneous (genetic and clinical) group of inherited bone marrow failure and premature aging syndromes with the common feature of shortened telomeres.  There is considerable variability in the clinical features.  Prominent manifestations include nail dysplasia, oral leukoplakia, abnormal dentition, and reticulated skin pigmentation. Some patients have cognitive impairments.  Liver failure, testicular atrophy, pulmonary fibrosis, aplastic anemia, and osteoporosis along with features of aging such as premature grey hair and loss are typical.  There is an increased risk of malignancies, especially acute myelogenous leukemia.  Bone marrow failure is the major cause of early death.

Genetics

At least three autosomal dominant, three autosomal recessive, and one X-linked form of dyskeratosis congenita are recognized.  Mutations in at least 7 genes have been implicated.

Autosomal dominant disease can result from mutations in the TERC gene (DKCA1; 3q36.2; 127550), the TERT gene (DKCA2; 5p15.33; 613989), and the TINF2 gene (DKCA3; 14q12; 613990).  Mutations in the TINF2 gene are also responsible for R?(c)v?(c)sz syndrome (268130) with many features of DKC in addition to ocular findings of an exudative retinopathy resembling Coats disease.

Autosomal recessive disease is caused by mutations in the NOP10 (NOLA3) gene (DCKB1; 224230; 15q14-q15), the  NHP2 (NOLA2) gene (DKCB2; 5q35; 613987), and the WRAP53 gene (DKCB3; 17p13; 613988).  Mutations in the TERT gene may also cause autosomal recessive disease known as DKCB4 (613989).  

The X-linked disease (DKCX) (Zinsser-Engman-Cole syndrome) results from a mutation in the DKC1 gene (Xq28; 305000).  The same gene is mutated in Hoyeraal-Hreidarsson syndrome (300240) which some consider to be a more severe variant of dyskeratosis congenita with the added features of immunodeficiency, microcephaly, growth and mental retardation, and cerebellar hypoplasia.  At least one patient had an exudative retinopathy.

The majority of mutations occur in genes that provide instructions for making proteins involved in maintainence of telemeres located at the ends of chromosomes.  Shortened telomeres can result from maintainence deficiencies although the molecular mechanism(s) remain elusive.

Pedigree: 
Autosomal dominant
Autosomal recessive
X-linked recessive, carrier mother
X-linked recessive, father affected
Treatment
Treatment Options: 

Treatment for DKC with hematopoietic stem cell transplantation can be curative but its long-term efficacy is poor.  Some advocate androgen therapy first.  Lifelong cancer surveillance and frequent ocular and dental evaluations are important with specific treatment as indicated.

References
Article Title: 

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