autosomal recessive

Neu-Laxova Syndrome 2

Clinical Characteristics
Ocular Features: 

The eyes appear prominent, an effect that is sometimes exaggerated by absent or malformed eyelids.

Systemic Features: 

Intrauterine growth retardation is common and infants are born with significant deformities including microcephaly, limb malformations, flexion deformities, ichthyosis, and edema of the hands and feet.   Brain malformations may be present as well.

Genetics

This disorder has a transmission pattern consistent with autosomal recessive inheritance.  Homozygous or compound heterozygous mutations in the PSAT1 gene (9q21.2) are responsible. 

This condition has similar features to Neu-Laxova syndrome 1 (256520) but is less severe and results from a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Neu-laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway

Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjold M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, Zenker M. Neu-laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet. 2014 Sep 4;95(3):285-93.

PubMed ID: 
25152457

Neu-Laxova Syndrome 1

Clinical Characteristics
Ocular Features: 

The globes are prominent, an appearance that is exaggerated sometimes by absence of the eyelids or ectropion.  The lashes may be absent in other patients.  Cloudy corneas and cataracts have been described.

Systemic Features: 

This is a lethal dysplasia-malformation syndrome in which some infants are stillborn while others do not live beyond a few days.  The placenta is often small and the umbilical cord is short.  Decreased fetal movements and polyhydramnios are often noted.  Microcephaly can be striking at birth but there is overall intrauterine growth retardation.  The skin is ichthyotic and dysplastic containing excess fatty tissue beneath the epidermis.  Digits are often small and may be fused (syndactyly).  There is generalized edema with ‘puffiness’ of the hands and feet.  The lungs are frequently underdeveloped and cardiac defects such as septal openings, patent ductus arteriosus and transposition of great vessels are common.  Males often have cryptorchidism while females have a bifid uterus and renal dysgenesis has been reported.

The face is dysmorphic with prominent globes (in spite of microphthalmia), the ears are large and malformed, the forehead is sloping, the nose is flattened and the jaw is small.  Some infants have a cleft lip and palate while the mouth is round and gaping.  The neck is usually short.

Severe brain malformations such as lissencephaly, cerebellar hypoplasia, and dysgenesis/agenesis of the corpus callosum are frequently present.

Genetics

This is an autosomal recessive disorder secondary to mutations in the PHGDH gene (1p12).

This condition has some clinical overlap with Neu-Laxova syndrome 2 (616038) but the latter is less severe and is caused by a different mutation.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Neu-laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway

Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjold M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, Zenker M. Neu-laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. Am J Hum Genet. 2014 Sep 4;95(3):285-93.

PubMed ID: 
25152457

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: 

Corneal Dystrophy, Band-Shaped

Clinical Characteristics
Ocular Features: 

Symptoms of ocular irritation with tearing, conjunctival injection and decreased vision can be present at birth but more often is evident later in the first decade of life.  The band is located in the cornea in the palpebral fissure area in a horizontal pattern.  Apparently no other lesions are present in the eye.    

Systemic Features: 

None reported.

Genetics

Only three families with familial, isolated band keratopathy have been reported.  These were described in the mid-twentieth century and it is possible that they had underlying ocular and corneal disease.  In one family 3 of 9 children, the product of a first-cousin mating, were affected consistent with autosomal recessive inheritance.  In two of these the keratopathy was first noted during puberty while it was present at birth in the third child.

 In another family the band keratopathy was seen in a brother and sister at 11 and 16 years old.

In the third family a father and son were affected.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Topically applied EDTA solutions are sometimes effective in removing lesions consisting of calcium deposits but this has not been reported to be effective in the hereditary form of band keratopathy. 

References
Article Title: 

Cranial Dysinnervation Disorders with Strabismus and Arthrogryposis

Clinical Characteristics
Ocular Features: 

Strabismus and/or ophthalmoplegia are important features of a group of conditions known as cranial dysinnervation disorders.  Ptosis, Duane syndrome, V pattern exotropia and various degrees of ophthalmoplegia may be seen.  There may be considerable asymmetry in the manifestations in the two eyes.  Epicanthal folds, blepharophimosis, and hypermetropia are sometimes present.  Some patients have corneal leukomas, keratoglobus, high corneal astigmatism, and dysplastic optic disks. 

A pigmentary retinopathy and folds in the macula with an abnormal ERG has been reported.  Subnormal vision has been reported in some patients.

Systemic Features: 

Patients are often short in stature with pectus excavatum, spine stiffness, highly arched palate, and club feet.  Limited forearm rotation and wrist extension may be present.  The fingers appear long and often have contractures while the palmar and phalangeal creases may be absent.  Camptodactyly and clinodactyly are common.  Deep tendon reflexes are often hyporeactive and decreased muscle mass has been noted.  The muscles seem "firm" to palpation.  Restrictive lung disease has been reported.  Hearing loss is experienced by some individuals.

Genetics

Distal arthrogryposis type 5D is caused by homozygous or compound heterozygous mutations in the ECEL1 gene located at 2q36.  However, a similar phenotype (albeit with more severe ocular manifestations) results from heterozygous mutations in PIEZO2 (18p11).  Heterozygous mutations in the PIEZO2 gene have also been reported to cause distal arthrogryposis type 3 (Gordon syndrome [114300]) and Marden-Walker syndrome (248700) and all of these may be simply phenotypical variations of the same disorder.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for this condition.  Patients with subnormal vision may benefit from low vision aids and selective surgery may be helpful in reducing the physical restrictions from physical deformities.

References
Article Title: 

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5

McMillin MJ, Beck AE, Chong JX, Shively KM, Buckingham KJ, Gildersleeve HI, Aracena MI, Aylsworth AS, Bitoun P, Carey JC, Clericuzio CL, Crow YJ, Curry CJ, Devriendt K, Everman DB, Fryer A, Gibson K, Giovannucci Uzielli ML, Graham JM Jr, Hall JG, Hecht JT, Heidenreich RA, Hurst JA, Irani S, Krapels IP, Leroy JG, Mowat D, Plant GT, Robertson SP, Schorry EK, Scott RH, Seaver LH, Sherr E, Splitt M, Stewart H, Stumpel C, Temel SG, Weaver DD, Whiteford M, Williams MS, Tabor HK, Smith JD, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5. Am J Hum Genet. 2014 May 1;94(5):734-44.

PubMed ID: 
24726473

Roberts Syndrome

Clinical Characteristics
Ocular Features: 

The eyes often appear prominent as the result of shallow orbits.  Hypertelorism and microphthalmia can be present.  The sclerae can have a bluish hue.   Cataracts and central corneal clouding plus scleralization and vascularization of the peripheral corneas are sometimes seen.  Lid colobomas and down-slanting palpebral fissures may be present.

Systemic Features: 

Failure of both membranous and long bones to grow properly lead to a variety of abnormalities such as craniosynostosis, hypomelia, syndactyly, oligodactyly, malar hypoplasia, short neck, micrognathia, and cleft lip and palate.  The long bones of the limbs may be underdeveloped or even absent.  Contractures of elbow, knee, and ankle joints are common as are digital anomalies.  Low birth weight and slow postnatal growth rates are usually result in short stature.  The hair is often sparse and light-colored. 

Mental development is impaired and some children are diagnosed to have mental retardation.  Cardiac defects are common.  Facial hemangiomas are often present as are septal defects and sometimes a patent ductus arteriosus.  External genitalia in both sexes appear enlarged.  The kidneys may be polycystic or horseshoe-shaped.

Genetics

This is an autosomal recessive condition caused by mutations in the ESCO2 gene (8p21.1).  Mutations in the same gene are also responsible for what some have called the SC phocomelia syndrome (269000) which has a similar but less severe phenotype.  Some consider the two disorders to be variants of the same condition and they are considered to be the same entity in this database.  The gene product is required for structural maintenance of centromeric cohesion during the cell cycle.  Microscopic anomalies of the centromeric region (puffing of the heterochromatic regions) are sometimes seen during cell division.

The Baller-Gerold syndrome (218600) has some phenotypic overlap with Roberts syndrome but is caused by mutations in a different gene (RECQL4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Severely affected infants may be stillborn or die in infancy.  Other individuals live to adulthood.  There is no treatment for this condition beyond specific correction of individual anomalies.

References
Article Title: 

Myopia and Deafness

Clinical Characteristics
Ocular Features: 

High myopia (6-11D) is usually diagnosed during infancy or in the first year of life.  Nine patients so far reported have ranged in age from 13 to 60 years if age.  Vitreoretinal degeneration has not been reported.

Systemic Features: 

Prelingual hearing loss has been identified in all patients, ranging in severity from moderate to severe.  No other neurological problems have been found.  CT scans of the temporal bone are normal.  No developmental delays or cognitive deficits have been identified.

Genetics

SLITRK family genes code for membrane proteins, expressed primarily in neural tissues. Mutations in SLITRK6 in the reported families cause loss of function.  In cultured cells from rodents the protein product impacts synapse induction and neurite modulation.  In Slitrk6 knockout mice, there is a reduction of cochlear innervations with reduced startle responses and impaired brainstem responses.  Axial length in these mice is normal at birth but adults have a significant increase in eye size.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

The refractive error should be corrected and assistive hearing devices may be helpful.

References
Article Title: 

SLITRK6 mutations cause myopia and deafness in humans and mice

Tekin M, Chioza BA, Matsumoto Y, Diaz-Horta O, Cross HE, Duman D, Kokotas H, Moore-Barton HL, Sakoori K, Ota M, Odaka YS, Foster J 2nd, Cengiz FB, Tokgoz-Yilmaz S, Tekeli O, Grigoriadou M, Petersen MB, Sreekantan-Nair A, Gurtz K, Xia XJ, Pandya A, Patton MA, Young JI, Aruga J, Crosby AH. SLITRK6 mutations cause myopia and deafness in humans and mice. J Clin Invest. 2013 May 1;123(5):2094-102.

PubMed ID: 
23543054

Spastic Ataxia 2

Clinical Characteristics
Ocular Features: 

Horizontal nystagmus is present in some patients.

Systemic Features: 

Cerebellar ataxia, dysarthria, and spasticity of the lower limbs appear in the first two decades of life.  The spasticity may involve all 4 limbs late in life.  Cognition is not impacted. Cervical dystonia has been noted. No consistent changes have been found on brain imaging.  The neurologic signs are slowly progressive although patients may remain ambulatory.

Tremor, clonus, and extrapyramidal chorea has been seen in several families with what has been called spastic paraplegia-58 which may be the same disorder as SPAX2 since mutations are found in the same gene (KIF1C).  Symptoms and prognosis are similar in these conditions except for the reported presence of developmental delay and mild mental retardation in some individuals diagnosed to have SPG58.

Genetics

This is an autosomal recessive condition as the result of homozygous mutations in the KIF1C gene (17p13.2).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment for this disease is available although speech and physical therapy may be helpful.

References
Article Title: 

Motor protein mutations cause a new form of hereditary spastic paraplegia

Caballero Oteyza A, Battaloglu E, Ocek L, Lindig T, Reichbauer J, Rebelo AP, Gonzalez MA, Zorlu Y, Ozes B, Timmann D, Bender B, Woehlke G, Zuchner S, Schols L, Schule R. Motor protein mutations cause a new form of hereditary spastic paraplegia. Neurology. 2014 May 7. [Epub ahead of print].

PubMed ID: 
24808017

Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

Novarino G, Fenstermaker AG, Zaki MS, Hofree M, Silhavy JL, Heiberg AD, Abdellateef M, Rosti B, Scott E, Mansour L, Masri A, Kayserili H, Al-Aama JY, Abdel-Salam GM, Karminejad A, Kara M, Kara B, Bozorgmehri B, Ben-Omran T, Mojahedi F, Mahmoud IG, Bouslam N, Bouhouche A, Benomar A, Hanein S, Raymond L,Forlani S, Mascaro M, Selim L, Shehata N, Al-Allawi N, Bindu PS, Azam M, Gunel M, Caglayan A, Bilguvar K, Tolun A, Issa MY, Schroth J, Spencer EG, Rosti RO, Akizu N, Vaux KK, Johansen A, Koh AA, Megahed H, Durr A, Brice A, Stevanin G, Gabriel SB, Ideker T, Gleeson JG. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science. 2014 Jan 31;343(6170):506-11.

PubMed ID: 
24482476

Alkaptonuria

Clinical Characteristics
Ocular Features: 

Ocular signs of this disease are present in two out of three patients.  Black or bluish pigmented patches may be noted in the sclerae by the fourth decade. The pigmentation is most evident just anterior to the insertion of the medial and lateral rectus muscles.  It is claimed that brown pigment spots resembling 'oil drops' near the opaque portion of the limbus are diagnostic but they are often not present until the 4th or 5th decades.  Nevertheless, these ocular signs on average precede systemic signs by about 15 years and are therefore diagnostically useful.  The pigmentation has no impact on vision. Hyperpigmentation of the anterior chamber angle with elevated intraocular pressure has been reported.  An increased incidence of central vein occlusion has been suggested.  Progressive astigmatism is sometimes seen.  Staining of the tarsal plates may be seen in the eyelids.

Systemic Features: 

Ochronosis (dark pigmentation in connective tissue) as the result of homogentisic acid (HGA) accumulation is a useful sign but does not appear until the 4th decade.  As a result the joint cartilage becomes fragile leading to disabling and chronic symptoms of arthritis especially in the spine and large joints.  Symptoms usually begin in the third or fourth decade and the degeneration of the ochronotic intervertebral disks may result in significant loss of height.  Back pain, kyphosis, and decreased lumbar flexion are common.  Usually smaller joints such as those of the digits are not affected sufficiently to cause symptoms.

Tendons, ligaments, and other fibrous tissue such as sclerae and heart valves are all susceptible to degenerative changes.  The discoloration in skin hue can also be seen in the axillae, nail beds, pinnae, forehead, tympanic membranes, genital areas, and buccal mucosa.  Clothing may become stained from discolored perspiration.

HGA in the urine oxidizes and turns dark and parents may note staining of diapers in the newborn period.  The urine also becomes alkaline.  Plasma levels of HGA are also elevated.  Urolithiasis may occur.

Genetics

This metabolic disease is among the first inborn errors of metabolism described.  Virchow had early described the yellowish discoloration of connective tissue seen under the microscope.  William Bateson at the beginning of the 20th century suggested the heritability of this condition to the British physician Sir Archibald Garrod who then described this syndrome in 1902 as the first human disease whose transmission pattern conformed to mendelian autosomal recessive inheritance based on his understanding of Mendel's laws.

Homozygosity of mutations in the HGD gene (3q13.33) coding for homogentisate 1,2-dioxygenase is responsible for the phenotype.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Nitisinone reduces the production of HGA and can lower urinary levels up to 95% but may lead to elevated plasma tyrosine that rarely results in the deposition of corneal crystals.  Long-term benefits of nitisinone remain unknown. Others have tried dietary reduction of tyrosine and phenylalanine with reduction in HGA levels but the long term impact on the rate of tissue degradation remains unknown.    

Additional treatment is directed at specific damaged sites.  Calcified valves (often aortic) may need to be replaced.  Large joints such as hips, shoulders, and knees often require replacement for pain relief.  Stones in the urinary tract may need to be removed.  Ophthalmologists should keep such patients under observation for progressive astigmatism and the risk of elevated intraocular pressure.

It may be prudent to avoid contact sports and minimize heavy weight lifting to limit trauma to joint cartilage.

References
Article Title: 

Natural history of alkaptonuria

Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphey MD, Fitzpatrick DL, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA. Natural history of alkaptonuria. N Engl J Med. 2002 Dec 26;347(26):2111-21.

PubMed ID: 
12501223

The molecular basis of alkaptonuria

Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, Renedo M, Fernandez-Ruiz E, Penalva MA, Rodriguez de Cordoba S. The molecular basis of alkaptonuria. Nat Genet. 1996 Sep;14(1):19-24.

PubMed ID: 
8782815

Pseudoxanthoma Elasticum-Like Disease

Clinical Characteristics
Ocular Features: 

Retinitis pigmentosa has been diagnosed clinically and confirmed by ERG studies in some patients. The fundi in a few individuals have the typical angioid streaks and/or peau d’orange changes. The impact on visual acuity and its prognosis has not been systematically studied.

Systemic Features: 

The skin changes resulting from fragmentation and aberrant mineralization of connective tissue, particularly elastic fibers, resemble those seem in classic pseudoxanthoma elasticum. These include the presence of yellowish papules or leathery plaques with dot-like depressions (‘chicken skin’). However, the skin changes are more widespread and involve trunk as well as limbs and flexural areas. Ultrastructurally the elastic fibers are more severely fragmented than those in classic PXE.

Many patients in addition have deficiencies in vitamin K-dependent clotting factors such as II, VII, IX, and X. Epistaxis, spontaneous gingival bleeding and severe vaginal hemorrhages may occur. Cerebral aneurysms, vascular occlusions, and atherosclerotic plaques in the lower extremities have been reported in a few patients.

Genetics

Classic pseudoxanthoma elasticum is due to homozygous mutations in the ABCC6 (ATP-binding cassette subfamily C member 6) gene. However, in the PXE-like condition described here homozygous or compound heterozygous mutations in the GGCX (gamma-glutamyl carboxylase) gene (2p11.2) are responsible. Some heterozygous GGCX individuals in families with this genotype who are also heterozygous for ABCC6 mutations (doubly heterozygous) may have similar skin features. Thus the condition described here may also be a digenic disorder in some individuals.

Pseudoxanthoma elasticum-like disease is an autosomal recessive disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

There is no treatment for the connective tissue defect but individual problems such as subretinal neovascularization, hemorrhages, and vascular occlusions may respond to appropriate therapy.

References
Article Title: 

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