autosomal recessive

Congenital Disorder of Glycosylation, Type Ij

Clinical Characteristics

Ocular Features

Bilateral cataracts are present at birth.  Nystagmus, strabismus, and long eyelashes have been reported.

Systemic Features

This is a disorder of glycosylation important to the formation of glycoproteins and glycolipids.  Neurological signs such as tremor, clonus, and muscle fasiculations may be seen soon after birth.  Other neurological abnormalities eventually include psychomotor retardation, seizures, mental retardation, hyperexcitabilty, and ataxia.  Failure to thrive and feeding difficulties are evident early.  Progressive microcephaly is a feature.  Liver dysfunction can lead to coagulopathy and hypoproteinemia with hepatomegaly is sometimes present.  Some patients have facial anomalies, inverted nipples, and subcutaneous fat pads.  The MRI may show areas of brain atrophy, ischemia, and focal necrosis.

Longevity is limited with 2 of 3 reported patients dying within 2 years of life.

Genetics

This is a rare autosomal recessive disorder resulting from mutations in DPAGT1 (11q23.3) resulting in defective N-glycosylation.  There are numerous other types of glycosylation defects with variations in the clinical manifestations.

Treatment Options

Treatment consists of fluid and caloric intake management.  Hypoproteinemia and coagulation defects may respond to oral mannose administration.

References

W?orde AE, Reunert J, Rust S, Hertzberg C, Haverk?SSmper S, N?ornberg G, N?ornberg P, Lehle L, Rossi R, Marquardt T. Congenital disorder of glycosylation type Ij(CDG-Ij, DPAGT1-CDG): Extending the clinical and molecular spectrum of a rare disease. Mol Genet Metab. 2012 Jan 9. [Epub ahead of print]

PubMed ID: 
22304930

Wu X, Rush JS, Karaoglu D, Krasnewich D, Lubinsky MS, Waechter CJ, Gilmore R, Freeze HH. Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1 Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation Type Ij. Hum Mutat. 2003 Aug;22(2):144-50.

PubMed ID: 
12872255

Night Blindness, Congenital Stationary

Clinical Characteristics

Ocular Features

Night blindness is a feature of many pigmentary and other retinal disorders, most of which are progressive.  However, there is also a group of genetically heterogeneous disorders, with generally stable scotopic defects and without RPE changes, known as congenital stationary night blindness (CSNB).  At least 9 mutant genes are responsible with phenotypes so similar that genotyping is usually necessary to distinguish them.  All are caused by defective photoreceptor-to-bipolar cell signaling with common ERG findings of reduced or absent b-waves and generally normal a-waves.  The photopic ERG is usually abnormal to some degree as well and visual acuity may be subnormal.  In the pregenomic era, subtleties of ERG responses were frequently used in an attempt to distinguish different forms of CSNB.  Genotyping now enables classification with unprecedented precision.

The night blindness is usually nonprogressive as the name implies.

Systemic Features

No systemic disease is associated with congenital stationary night blindness.

Genetics

This recently reported type of congenital stationary night blindness has not yet been further classified.  It is inherited in an autosomal recessive pattern resulting from homozygous mutations in GRP179.  The gene encodes an orphan G protein receptor whose function is as yet unknown.

Other autosomal recessive CSNB disorders are: CSNB2B (610427), CSNB1B (257270), and CSNB1C (613216).

Treatment Options

No treatment beyond correction of the refractive error is available but tinted lenses are sometimes used to enhance vision.

References

Audo I, Bujakowska K, Orhan E, Poloschek CM, Defoort-Dhellemmes S, Drumare I, Kohl S, Luu TD, Lecompte O, Zrenner E, Lancelot ME, Antonio A, Germain A, Michiels C, Audier C, Letexier M, Saraiva JP, Leroy BP, Munier FL, Mohand-Sa?Od S, Lorenz B, Friedburg C, Preising M, Kellner U, Renner AB, Moskova-Doumanova V, Berger W, Wissinger B, Hamel CP, Schorderet DF, De Baere E, Sharon D, Banin E, Jacobson SG, Bonneau D, Zanlonghi X, Le Meur G, Casteels I, Koenekoop R, Long VW, Meire F, Prescott K, de Ravel T, Simmons I, Nguyen H, Dollfus H, Poch O, L?(c)veillard T, Nguyen-Ba-Charvet K, Sahel JA, Bhattacharya SS, Zeitz C. Whole-Exome Sequencing Identifies Mutations in GPR179 Leading to Autosomal-Recessive Complete Congenital Stationary Night Blindness. Am J Hum Genet. 2012 Feb 10;90(2):321-30.

PubMed ID: 
22325361

Peachey NS, Ray TA, Florijn R, Rowe LB, Sjoerdsma T, Contreras-Alcantara S, Baba K, Tosini G, Pozdeyev N, Iuvone PM, Bojang P Jr, Pearring JN, Simonsz HJ, van Genderen M, Birch DG, Traboulsi EI, Dorfman A, Lopez I, Ren H, Goldberg AF, Nishina PM, Lachapelle P, McCall MA, Koenekoop RK, Bergen AA, Kamermans M, Gregg RG. GPR179 Is Required for Depolarizing Bipolar Cell Function and Is Mutated in Autosomal-Recessive Complete Congenital Stationary Night Blindness. Am J Hum Genet. 2012 Feb 10;90(2):331-9.

PubMed ID: 
22325362

Retinitis Pigmentosa and Mental Retardation

Clinical Characteristics

Ocular Features

The lenses may have pleomorphic white axial opacities but in other patients can be totally opacified.  Optic atrophy is present and vision may be reduced to light perception but nystagmus is absent.  Evidence suggests that vision loss is progressive.  Some patients have extensive posterior synechiae while others have been noted to have sluggish pupils.  High myopia is a feature. The retinal pigmentation has a typical retinitis pigmentosa picture with attenuated retinal vessels and equatorial bone spicule pigmentation located in the midperiphery while the macula can have a bull’s eye appearance.   

Systemic Features

Early development may seem normal but developmental milestones are usually delayed.  Postnatal microcephaly and growth deficiency with mental retardation and early hypotonia are typical features.  The mental retardation may be severe.  Scoliosis and arachnodactyly have been noted and hypogonadism has been reported.  Speech may not develop and mobility is sometimes limited.

Genetics

The family pattern suggests autosomal recessive inheritance.  Homozygosity mapping has identified in a region of chromosome 8 (8q21.2-22.1) that overlaps the region for Cohen syndrome () but no specific mutated gene has been identified.      

Treatment Options

None.

References

Horn D, Krebsov?deg A, Kunze J, Reis A. Homozygosity mapping in a family with microcephaly, mental retardation, and short stature to a Cohen syndrome region on 8q21.3-8q22.1: redefining a clinical entity. Am J Med Genet. 2000 Jun 5;92(4):285-92.

PubMed ID: 
10842298

Mirhosseini SA, Holmes LB, Walton DS. Syndrome of pigmentary retinal degeneration, cataract, microcephaly, and severe mental retardation. J Med Genet.1972 Jun;9(2):193-6

PubMed ID: 
5046629

Cataracts, Congenital with Corneal Opacity and Glaucoma

Clinical Characteristics

Ocular Features

The ocular features are evident at birth or within the first year of life and may be asymmetrical.  The phenotype is heterogeneous but does not appear to be progressive.  The anterior chambers are of normal depth and the fundi are normal when visualization is possible.  The corneal opacification is usually denser peripherally and resembles corneoscleralization but it can extend centrally to a variable degree.  In individuals with glaucoma and buphthalmos the cornea is more opaque and usually vascularized. In such eyes the cornea is thinned.  In most patients the corneal diameters were 5-8 mm in diameter but in those with elevated pressures the anterior segment was obviously buphthalmic. Iridocorneal adhesions may be present.  The lenses are cataractous but the capsules are normal.  Microphthalmia has been reported in some patients.  Vision is often in the range of hand motions.    

Systemic Features

None.

Genetics

Homozygous mutations in PXDN (2p25.3) encoding peroxidasin are believed responsible for this autosomal recessive condition.  Mammalian peroxidasin localizes to the endoplasmic reticulum but is also found in the extracellular matrix and is believed important to the maintainence of basement membrane integrity.  The protein is one of several that aids in the extracellular breakdown of hydrogen peroxide and free radicals.  In mouse eyes it localizes to the corneal and lens epithelium but its role in maintaining transparency of the lens and cornea is unknown.

Treatment Options

No information regarding treatment is available but cataract and corneal surgery may be beneficial.   

References

Choi A, Lao R, Ling-Fung Tang P, Wan E, Mayer W, Bardakjian T, Shaw GM, Kwok PY, Schneider A, Slavotinek A. Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis. Eur J Hum Genet. 2014 Jun 18. doi: 10.1038/ejhg.2014.119. [Epub ahead of print] PubMed PMID: 24939590.

PubMed ID: 
24939590

Khan K, Rudkin A, Parry DA, Burdon KP, McKibbin M, Logan CV, Abdelhamed ZI, Muecke JS, Fernandez-Fuentes N, Laurie KJ, Shires M, Fogarty R, Carr IM, Poulter JA, Morgan JE, Mohamed MD, Jafri H, Raashid Y, Meng N, Piseth H, Toomes C, Casson RJ, Taylor GR, Hammerton M, Sheridan E, Johnson CA, Inglehearn CF, Craig JE, Ali M. Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma. Am J Hum Genet. 2011 Sep 9;89(3):464-73.

PubMed ID: 
21907015

Leukoencephalopathy with Vanishing White Matter

Clinical Characteristics

Ocular Features

Optic atrophy is a common feature and blindness is often the result.

Systemic Features

Onset of symptoms may occur at any time from 1.5 years of age to adulthood.  Early psychomotor development may be normal but developmental milestones such as walking and crawling are often delayed.  Patients with a later onset often have a milder course.  Progression is chronic but often episodic with exacerbations following infection and blunt head trauma. Mental stress, even of a relatively minor nature such as fright, may likewise cause a worsening of symptoms.  Such episodes can lead to loss of consciousness or even coma.  Cerebellar ataxia and spasticity are common.  Epilepsy may occur but is uncommon.  Motor function is more severely impaired compared with mental deterioration.  The MRI reveals a diffuse leukoencephalopathy as well as focal and cystic degeneration of white matter which may be present before the onset of symptoms.  Cerebellar atrophy primarily involving the vermis is common.  Behavioral problems, psychiatric symptoms, and even signs of dementia have been reported.  The vast majority of patients have cognitive disabilities and many become severely handicapped and immobile.  Early onset disease in children often leads to death within a few years whereas adults with later onset may live for many years.       

Females with leukoencephalopathy who live to puberty may experience ovarian failure, a condition sometimes called ovarioleukodystrophy.

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in one of a group of five genes (EIF2B) located on chromosomes 1,2,3,12, and 14 encoding subunits of translation initiation factor 2B.    

Treatment Options

There is no effective treatment for the neurologic disease.  Ocular treatment for cataracts has not been reported.

References

Alsalem A, Shaheen R, Alkuraya FS. Vanishing white matter disease caused by EIF2B2 mutation with the presentation of an adrenoleukodystrophy phenotype. Gene. 2012 Jan 17. [Epub ahead of print]

PubMed ID: 
22285377

Labauge P, Horzinski L, Ayrignac X, Blanc P, Vukusic S, Rodriguez D, Mauguiere F, Peter L, Goizet C, Bouhour F, Denier C, Confavreux C, Obadia M, Blanc F, de S?(r)ze J, Fogli A, Boespflug-Tanguy O. Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases. Brain. 2009 Aug;132(Pt 8):2161-9.

PubMed ID: 
19625339

Cataracts, Hearing Loss, and Neurodegeneration

Clinical Characteristics

Ocular Features

Congenital cataracts are the important ocular feature in this syndrome.

Systemic Features

Hearing loss is an important part of this syndrome.  Severe hypomyelination and hypoplasia are seen on MRI.  Marked developmental delay and early death are also seen.  Reduced ceruloplasmin secretion and low serum copper are present.

Genetics

This is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in SLC33A1 (3q25) encoding an acetylCoA transporter (AT-1).  The defect in hepatic cells results in reduced ceruloplasmin secretion with low serum copper.  Wilson disease (277900), Menkes disease (309400), and aceruloplasminemia (604290), other disorders of copper metabolism, have similar blood findings but due to different mechanisms.

Heterozygous mutations in SLC33A1 result in an autosomal dominant form of spastic paraplegia (SPG42) (612539). No ocular abnormalities have been reported in SPG42 though.

Treatment Options

No information on treatment has been reported.

References

Huppke P, Brendel C, Kalscheuer V, Korenke GC, Marquardt I, Freisinger P, Christodoulou J, Hillebrand M, Pitelet G, Wilson C, Gruber-Sedlmayr U, Ullmann R, Haas S, Elpeleg O, N?ornberg G, N?ornberg P, Dad S, M??ller LB, Kaler SG, G?SSrtner J. Mutations in SLC33A1 Cause a Lethal Autosomal-Recessive Disorder with Congenital Cataracts, Hearing Loss, and Low Serum Copper and Ceruloplasmin. Am J Hum Genet. 2012 Jan 13;90(1):61-8.

PubMed ID: 
22243965

Spherophakia, Isolated

Clinical Characteristics

Ocular Features

Small, spherical lenses are characteristic of this entity.  Lenticular myopia is usually present but no increased axial length.  Glaucoma has been reported in several individuals and speculated to be due to pupillary block.  No buphthalmos or angle anomalies were present.  The lens may sublux into the vitreous cavity.

Systemic Features

No skeletal, cardiovascular or metabolic disease is present.

Genetics

Isolated spherophakia is an autosomal recessive disorder resulting from homozygous mutations in LTBP2 (13q24.1-q32.12).  Parental consanguinity was present in reported families. 

Spherophakia is a clinically and genetically heterogeneous disorder and usually found in association with systemic findings.  It is commonly seen in the Weill-Marchesani syndrome 1 (277600), in Weill Marchesani syndrome 2 (608328), in the Weill-Marchesani-Like syndrome (613195), in a condition known as ‘megalocornea, ectopia lentis, and spherophakia’ (?), another one called 'spherophakia and hernia' (157150), sulfite oxidase deficiency (272300), primary congenital glaucoma D (613086) and in a syndrome known as ‘spherophakia and metaphyseal dysplasia’ (157151).

Treatment Options

The lenses may require extraction for secondary glaucoma and/or visual rehabilitation.

References

Kumar A, Duvvari MR, Prabhakaran VC, Shetty JS, Murthy GJ, Blanton SH. A homozygous mutation in LTBP2 causes isolated microspherophakia. Hum Genet. 2010 Oct;128(4):365-71.

PubMed ID: 
20617341

Ben Yahia S, Ouechtati F, Jelliti B, Nouira S, Chakroun S, Abdelhak S, Khairallah M. Clinical and genetic investigation of isolated microspherophakia in a consanguineous Tunisian family. J Hum Genet. 2009 Sep;54(9):550-3.

PubMed ID: 
19696795

Weill-Marchesani-Like Syndrome

Clinical Characteristics

Ocular Features

Several families have been reported in which the ocular features were similar to Weill-Marchesani syndromes WMS1 and WMS2 but lacked most of the skeletal features.  The ocular abnormalities included: myopia, ectopia lentis, spherophakia, and glaucoma.  Shallow anterior chambers and peripheral iris synechiae are often present. Axial length ranges from 21 to 23 mm.

Systemic Features

Short stature is a feature of this syndrome but brachydactyly and decreased joint mobility are not present.  Height is usually below the 25th percentile and often at the third or 5th percentile.

 

Genetics

This is an autosomal recessive disorder resulting from mutations in ADAMTS17 (15q26.3).  See also Weill-Marchesani Syndrome 1 (277600), and Weill-Marchesani Syndrome 2 (608328) for other conditions with clinical similarities but caused by different mutations.

Homozygous mutations in LTBP2 (14q24.3) have also been found in this disorder and in WMS1 (277600).

Treatment Options

Glaucoma requires the usual treatments.  The lens may need to be removed for visual rehabilitation and/or lens induced glaucoma.

References

Haji-Seyed-Javadi R, Jelodari-Mamaghani S, Paylakhi SH, Yazdani S, Nilforushan N, Fan JB, Klotzle B, Mahmoudi MJ, Ebrahimian MJ, Chelich N, Taghiabadi E, Kamyab K, Boileau C, Paisan-Ruiz C, Ronaghi M, Elahi E. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum Mutat. 2012 Apr 26. doi: 10.1002/humu.22105. [Epub ahead of print] PubMed PMID: 22539340.

PubMed ID: 
22539340

Morales J, Al-Sharif L, Khalil DS, Shinwari JM, Bavi P, Al-Mahrouqi RA, Al-Rajhi A, Alkuraya FS, Meyer BF, Al Tassan N. Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am J Hum Genet. 2009 Nov;85(5):558-68.

PubMed ID: 
19836009

Ataxia with Oculomotor Apraxia 1

Clinical Characteristics

Ocular Features

Patients with this disorder have difficulty initiating voluntary ocular movements upon command or when following targets (oculomotor apraxia).  Gaze changes are often initiated first by head thrusting, followed by saccadic eye movements.  One may test for this by holding the head whereupon the patient is unable to move the eyes.  Ocular apraxia is often evident a few years after symptoms of ataxia are noted and may progress to external ophthalmoplegia.  Most patients have exaggerated blinking.

Systemic Features

The ataxia is cerebellar in origin with onset usually in the first decade of life (mean age of onset 4.3 years. It is associated with peripheral axonal neuropathy and hypoalbuminemia. Gait imbalance is usually the first symptom followed by upper limb dysmetria.  Other variable signs include dysarthria, choreiform or athetoid movements, facial grimacing, tongue and limb fasciculations, areflexia, and distal sensory deficits.   All symptoms are progressive and ambulation is lost within a decade of onset.  Cerebellar atrophy may be seen on MRI and the EMG shows evidence of axonal neuropathy.  Mental function is normal in most patients but some have cognitive impairments.

Genetics

Mutations in the APTX gene (9p21.1) encoding aprataxin are responsible for this autosomal recessive condition. 

There is evidence of clinical and genetic heterogeneity.  At least two loci are involved, with the mutation at 9p13 causing an earlier onset of disease (first decade), and hypoalbuminemia, while the second one, ataxia with oculomotor apraxia 2  [606002]) at 9q34 causes a disorder of later onset (2nd or third decade) in which oculomotor apraxia is an inconsistent finding.  Oculomotor apraxia is more consistently found in the disorder described here.  Cogan-type oculomotor apraxia (257550) lacks other neurologic signs.

Oculomotor apraxia may be the presenting sign in Gaucher disease (230800, 230900, 231000). 

The ocular phenotype is similar to that seen in ataxia-telangiectasia (208900).

Treatment Options

No specific treatment is available although physical therapy can be helpful.

References

Amouri R, Moreira MC, Zouari M, El Euch G, Barhoumi C, Kefi M, Belal S, Koenig M, Hentati F. Aprataxin gene mutations in Tunisian families. Neurology. 2004 Sep 14;63(5):928-9.

PubMed ID: 
15365154

Barbot C, Coutinho P, Chor?PSo R, Ferreira C, Barros J, Fineza I, Dias K, Monteiro J, Guimar?PSes A, Mendon?ssa P, do C?(c)u Moreira M, Sequeiros J. Recessive ataxia with ocular apraxia: review of 22 Portuguese patients. Arch Neurol. 2001 Feb;58(2):201-5.

PubMed ID: 
11176957

Retinitis Pigmentosa with Ataxia

Clinical Characteristics

Ocular Features

Pigmentary retinopathy has been noted by 6 months of age. Typical symptoms of retinitis pigmentosa are reported by early childhood.  The visual fields are progressively constricted and a ring scotoma can be plotted.  Night blindness and visual acuity loss are evident in the first decade of life and progressively worsen leading to severe handicaps by the third.  Fundus pigmentation in the midperiphery becomes more prominent and in at least some patients the pattern consists of typical bone spicules.  Cellophane maculopathy has been described.

Systemic Features

Proprioceptive deficits and areflexia appear in early childhood and ataxia worsens as individuals mature.  Scoliosis and general weakness and wasting become prominent manifestations.  Sensory neuropathy with loss of vibratory and position sense, astereognosia, and agraphesthesia can become apparent in the first decade of life.  Walking is delayed and gait abnormalities are clearly evident by the second decade leading to orthopedic deformities such as scoliosis.  Unassisted walking becomes impossible.  The intrinsic hand and foot muscles also have mild weakness.  Sural nerve biopsy may reveal loss of large myelinated fibers.  Hyperintense signals in the posterior spinal columns can be seen on MRI.  No anatomic changes have been described in the cerebrum or cerebellum.

Genetics

This is an autosomal recessive disorder resulting from homozygous mutations in FLVCR1 (1q32.2-q41).  This disorder has some clinical similarities to Biemond 1 syndrome but differs in the inheritance pattern and the molecular basis.

Treatment Options

No specific treatment is available but physical therapy and low vision aids may improve the quality of life.

References

Rajadhyaksha AM, Elemento O, Puffenberger EG, Schierberl KC, Xiang JZ, Putorti ML, Berciano J, Poulin C, Brais B, Michaelides M, Weleber RG, Higgins JJ. Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa. Am J Hum Genet. 2010 Nov 12;87(5):643-54.

PubMed ID: 
21070897

Higgins JJ, Morton DH, Patronas N, Nee LE. An autosomal recessive disorder with posterior column ataxia and retinitis pigmentosa. Neurology. 1997 Dec;49(6):1717-20.

PubMed ID: 
9409377