mental retardation

Baraitser-Winter Syndrome 2

Clinical Characteristics
Ocular Features: 

Hypertelorism, high arched eyebrows, ptosis, and  colobomas occur in the majority of individuals.

Systemic Features: 

Short stature, postnatal microcephaly, lissencephaly, intellectual disability, seizures, and sensorineural hearing loss are common.

Genetics

This syndrome can be considered to be an autosomal dominant disorder secondary to heterozygous mutations in the ACTG1 gene (17q25.3).  However, all patients have been sporadic.

Mutations in ACTG1 are also responsible for autosomal dominant progressive nonsyndromic hearing loss.  

A similar but unique condition known as Baraitser-Winter syndrome 1 (243310) is caused by heterozygous mutations in the ACTB gene. 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment but special education, hearing devices, and physical therapy may be helpful.

References
Article Title: 

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases

Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, Allanson J, Brunner H, Bertola D, Chassaing N, David A, Devriendt K, Eftekhari P, Drouin-Garraud V, Faravelli F, Faivre L, Giuliano F, Guion Almeida L, Juncos J, Kempers M, Eker HK, Lacombe D, Lin A, Mancini G, Melis D, Lourenco CM, Siu VM, Morin G, Nezarati M, Nowaczyk MJ, Ramer JC, Osimani S, Philip N, Pierpont ME, Procaccio V, Roseli ZS, Rossi M, Rusu C, Sznajer Y, Templin L, Uliana V, Klaus M, Van Bon B, Van Ravenswaaij C, Wainer B, Fry AE, Rump A, Hoischen A, Drunat S, Riviere JB, Dobyns WB, Pilz DT. Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Eur J Hum Genet. 2014 Jul 23.

PubMed ID: 
25052316

De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome

Riviere JB, van Bon BW, Hoischen A, Kholmanskikh SS, O'Roak BJ, Gilissen C, Gijsen S, Sullivan CT, Christian SL, Abdul-Rahman OA, Atkin JF, Chassaing N, Drouin-Garraud V, Fry AE, Fryns JP, Gripp KW, Kempers M, Kleefstra T, Mancini GM, Nowaczyk MJ, van Ravenswaaij-Arts CM, Roscioli T, Marble M, Rosenfeld JA, Siu VM, de Vries BB, Shendure J, Verloes A, Veltman JA, Brunner HG, Ross ME, Pilz DT, Dobyns WB. De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. Nat Genet. 2012 Feb 26;44(4):440-4.

PubMed ID: 
22366783

Microphthalmia, Syndromic 4

Clinical Characteristics
Ocular Features: 

In several generations of an Irish family, 7 males with clinical anophthalmia were identified.  Ankyloblepharon was also present and X-rays of the orbits were identified.

Systemic Features: 

One patient was born with a cleft soft palate and had preauricular skin tags.  All individuals were considered to be mentally retarded with IQ's less than 50.

Genetics

MCOPS4 is an X-linked condition based on a single reported family.  The responsible mutation has not been identified but a locus (Xq27-q28) likely to contain the gene has been identified by multipoint linage analysis.

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

No treatment is known.

References
Article Title: 

Trichomegaly Plus Syndrome

Clinical Characteristics
Ocular Features: 

Eyelashes are described as ‘long’, and the eyebrows are bushy.  The majority of individuals have poor vision secondary to severe receptor dysfunction.  Night blindness and severe photophobia are features in some cases.  Both retinal and choroidal atrophy have been diagnosed in the first 5 years of life and most patients have a progressive and extensive pigmentary retinopathy.

Systemic Features: 

Scalp alopecia and sparse body hair is common in spite of the trichomegaly of the eyebrows and eyelashes.  Frontal bossing has been noted in some patients.  Pituitary dysfunction is suggested by low growth hormone levels, features of hypogonadotropic hypogonadism, and possibly hypothyroidism.

Some deficit of cognitive function is usually present and a few patients have been described as mentally retarded.  There is evidence of progressive neurological damage both centrally and peripherally. Developmental milestones are often achieved late and some individuals have been observed to regress during the first decade of life.  The peripheral neuropathy includes both sensory and motor components.  Sensory nerve action potentials may be lost in the first decade while early motor functions may regress during the same period.  Several patients have had evidence of progressive cerebellar ataxia.

Genetics

Compund heterozygous mutations in PNPLA6 (19p13.2), coding for neuropathy target esterase, have been found in several patients presumed to have this condition.  Autosomal recessive inheritance has been proposed on the basis of a single family in which an affected brother and sister were born to first cousin parents.   

The relationship of this disorder to that found in two cousins, offspring of consanguineous matings, described as ‘cone-rod congenital amaurosis associated with congenital hypertrichosis: an autosomal recessive condition’ (204110 ) is unknown.  They were described as having visual impairment from birth and profound photophobia.  Fundus changes were minimal with a bull’s eye pattern of pigment changes in the macula described as indicative of a rod-cone congenital amaurosis.  ERG responses were unrecordable.  These individuals apparently did not have other somatic, psychomotor or neurologic deficits.

Mutations in PNPLA6 occur in other conditions including a form of Bardet-Biedl Syndrome (209900), and Boucher-Neuhauser Syndrome (215470) also known as Chorioretinopathy, Ataxia, Hypogonadism Syndrome in this database.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for this condition although growth hormone and testosterone supplementation have been reported to have the appropriate selective effects.

References
Article Title: 

Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes

Hufnagel RB, Arno G, Hein ND, Hersheson J, Prasad M, Anderson Y, Krueger LA, Gregory LC, Stoetzel C, Jaworek TJ, Hull S, Li A, Plagnol V, Willen CM, Morgan TM, Prows CA, Hegde RS, Riazuddin S, Grabowski GA, Richardson RJ, Dieterich K, Huang T, Revesz T, Martinez-Barbera JP, Sisk RA, Jefferies C, Houlden H, Dattani MT, Fink JK, Dollfus H, Moore AT, Ahmed ZM. Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. J Med Genet. 2015 Feb;52(2):85-94.

PubMed ID: 
25480986

Feingold Syndrome 1

Clinical Characteristics
Ocular Features: 

Short, narrow palpebral fissures have been reported (73%).  The fissures may be up slanting and epicanthal folds have been noted.   

Systemic Features: 

The face can appear asymmetrical and triangular and the head is small in 89% of individuals.  Micrognathia is usually present and the lips appear full.  The nasal bridge is broad and the nostrils are anteverted.  The ears are often low-set and rotated posteriorly.  Syndactyly of the toes is common (97%) and the fingers are often anomalous (particularly 5th finger clinodactyly and brachydactyly) with hypoplastic thumbs.  Shortening of the 2nd and 5th middle phalanx of the fingers is especially common.  True short stature is uncommon but 60% are below the 10th centile.  Rare individuals have a sensorineural hearing loss.

Tracheoesophageal fistulas are often present, together with atresia of the duodenum and sometimes the esophagus as well.  Cardiac, renal, and vertebral malformations are seen in a minority of patients.

Intelligence may be normal but more often is below average and learning difficulties are often present.

Genetics

This is an autosomal dominant disorder secondary to mutations in the MYCN gene (2p24.3).

MYCN is up regulated in some patients with retinoblastoma (180200).

Feingold syndrome 2 (614326) is caused by hemizygous deletions of the MIR17HG gene but no ocular signs have been reported.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no known treatment for the syndrome but surgery can be important for some of the external and internal malformations. Special education and treatment of hearing loss are important.

References
Article Title: 

Genotype-phenotype correlations in MYCN-related Feingold syndrome

Marcelis CL, Hol FA, Graham GE, Rieu PN, Kellermayer R, Meijer RP, Lugtenberg D, Scheffer H, van Bokhoven H, Brunner HG, de Brouwer AP. Genotype-phenotype correlations in MYCN-related Feingold syndrome. Hum Mutat. 2008 Sep;29(9):1125-32.

PubMed ID: 
18470948

Spastic Paraplegia 2

Clinical Characteristics
Ocular Features: 

Nystagmus is common but variable in age of onset, and half of affected individuals have optic atrophy.

Systemic Features: 

This is a complex form of spastic paraplegia in which primarily lower limb spasticity is associated with dysarthria, sensory disturbances, cognitive deficits, muscle wasting and mild ataxia.  There is, however, considerable variability in age of onset and rate of symptom progression.  The first motor symptoms are often evident when children start walking, which is often delayed and clumsy.  However, evidence of spasticity may be present in children under 1 year of age.   Some patients have normal mental functions while others are considered mentally retarded.  The MRI reveals patchy leukodystrophy and degeneration of both corticospinal and spinocerebellar tracks was found in an autopsied individual.  Progression is relentless with many individuals requiring assistive devices such as crutches or walkers by early adult life.

Genetics

This is an X-linked disorder secondary to a mutation in the PLP1 gene at Xq22.2which codes for 2 major proteins found in myelin.  SPG2 is allelic to the more severe Pelizaeus-Merzbacher disease (312080).

Treatment
Treatment Options: 

Mobility devices and physical therapy can be helpful, especially in younger individuals.

References
Article Title: 

IFAP (BRESHECK) Syndrome

Clinical Characteristics
Ocular Features: 

The eyelashes and eyebrow hair is sparse or completely absent.  Keratitis with secondary photophobia is often seen during infancy and progresses to corneal vascularization and scarring, sometimes resembling trachomatous disease.  Cataracts do not seem to be part of this syndrome unlike some other genodermatoses.

Systemic Features: 

Dry, scaly skin and alopecia are usually evident at birth.  There is marked absence of hair throughout the body.  The skin is generally ichthyotic and erythematous, with continuous lamellar desquamation of surface skin.  Generalized follicular hyperkeratosis is present on the scalp, dorsal surface of the limbs and on the abdomen.  Most patients are completely bald.

In some patients the skin, hair and corneal disease is accompanied by severe internal anomalies such as kidney dysplasia, brain anomalies and mental retardation, Hirschsprung disease, cleft palate, external ear malformations, cryptorchidism, and skeletal deformities, a combination of signs that some have called BRESEK/BRESHECK syndrome.  Depending upon how extensive the organ involvement, the prognosis is usually guarded and patients may not live beyond early childhood. 

It is uncertain if IFAP refers to a single disorder or if two disorders are involved (see Genetics).

Genetics

This is generally considered to be an X-linked recessive disorder most likely due to mutations in MBTPS2, at least in patients considered to have the BRESHECK condition.  Female carrier may have some similar skin and hair signs albeit to a lesser degree than males.

Since the amount of MBTPS2 activity has been shown to vary with different mutations, it is possible that all cases of IFAP with or without the added BRESHECK findings are part of the clinical spectrum of a single disorder (variable expressivity).  

Other genodermatoses with severe keratitis are KID syndrome (148210) and Hereditary Mucoepithelial Dysplasia (158310).

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

No effective treatment is known.

References
Article Title: 

MBTPS2 mutation causes BRESEK/BRESHECK syndrome

Naiki M, Mizuno S, Yamada K, Yamada Y, Kimura R, Oshiro M, Okamoto N, Makita Y, Seishima M, Wakamatsu N. MBTPS2 mutation causes BRESEK/BRESHECK syndrome. Am J Med Genet A. 2012 Jan;158A(1):97-102.

PubMed ID: 
22105905

IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response

Oeffner F, Fischer G, Happle R, Konig A, Betz RC, Bornholdt D, Neidel U, Boente Mdel C, Redler S, Romero-Gomez J, Salhi A, Vera-Casano A, Weirich C, Grzeschik KH. IFAP syndrome is caused by deficiency in MBTPS2, an intramembrane zinc metalloprotease essential for cholesterol homeostasis and ER stress response. Am J Hum Genet. 2009 Apr;84(4):459-67.

PubMed ID: 
19361614

Peroxisome Biogenesis Disorder 3B (Infantile Refsum Disease)

Clinical Characteristics
Ocular Features: 

This peroxisomal disorder presents in the first year of life with both systemic and ocular features.  Night blindness is the major ocular feature and at least some have optic atrophy similar to the adult form.  Nystagmus may be present.  Reduction or absence of rod responses on ERG can be used in young children to document the retinopathy. Blindness and deafness commonly occur in childhood.

Systemic Features: 

This disorder is classified as a peroxisomal biogenesis disorder (PBD) associated with the breakdown of phytanic acid.  Ataxia and features of motor neuron disease are evident early.  Hepatomegaly and jaundice may also be an early diagnostic feature as bile acid metabolism is defective.  Infant hypotonia is often seen.  Nonspecific facial dysmorphism has been reported as a feature. The teeth are abnormally large and often have yellowish discoloration.  Postural unsteadiness is evident when patients begin walking.  Diagnosis can be suspected from elevated serum phytanic and pipecolic acid (in 20% of patients) or by demonstration of decreased phytanic acid oxidation in cultured fibroblasts.  Other biochemical abnormalities such as hypocholesterolemia and elevated very long chain fatty acids and trihydroxycholestanoic acid are usually present.  Anosmia and mental retardation are nearly universal features.  Early mortality in infancy or childhood is common although some survive into the 2nd and 3rd decades.

Genetics

This is an autosomal recessive peroxisomal biogenesis disorder (PBD) resulting from mutations in a number of PEX genes (PEX1, PEX2, PEX3, PEX12, PEX26).  It shares many features with other PBDs including those formerly called Zellweger syndrome (214100), rhizomelic chondrodysplasia punctata (215100), and neonatal adrenoleukodystrophy (601539).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment is known.

References
Article Title: 

Mannosidosis, Alpha B

Clinical Characteristics
Ocular Features: 

Many (probably most) patients have lens opacities and some have corneal opacities as well.  Nystagmus and strabismus have been described.  Pigmentary changes of a mottled nature can be present in the posterior pole and may be associated with retinal vessel attenuation and diminished ERG responses.  Retinal thinning can be demonstrated.  A mixture of hypo- and hyperautofluorescence is often visible.  Mild optic atrophy has been seen.  There is evidence for progressive visual loss, even late in life.  Eyebrows appear thick.    

Systemic Features: 

Mannosidosis is a highly variable multisystem disorder.  Onset may be in infancy but in other patients symptoms appear later in the first decade.  Progression of disease is more rapid in individuals with early onset (type 3) with rapid mental, motor deterioration and early death.  The characteristic coarse facial features usually are evident later in milder cases (types 1 and 2) that have mild or moderate intellectual disabilities.  Regardless, mannosidosis is relentlessly progressive with mental deterioration and motor disabilities.  Ataxia is a common feature.  Dental anomalies (diastema), large ears, macroglossia, joint stiffness,, hepatosplenomegaly, enlarged head circumference, hearing loss (sensorineural), increased susceptibility to infections, dysarthria, and spondylolysis may be present.

Genetics

Alpha-mannosidoosis is an autosomal recessive lysosomal storage disorder resulting from mutations in the MAN2B1 gene (19p13.2).  There is another form of mannosidosis known as beta A  (248510) caused by mutations in MANBA but ocular features have not been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Prompt treatment for infections is required and prophylactic vaccinations are indicated.  All individuals should be seen annually and assistive devices such as wheel chairs and hearing aids prescribed when needed.

References
Article Title: 

Retinal and optic nerve degeneration in α-mannosidosis

Matlach J, Zindel T, Amraoui Y, Arash-Kaps L, Hennermann JB, Pitz S. Retinal and optic nerve degeneration in a-mannosidosis. Orphanet J Rare Dis. 2018 Jun 1;13(1):88. doi: 10.1186/s13023-018-0829-z.

PubMed ID: 
29859105

Ocular findings in mannosidosis

Arbisser AI, Murphree AL, Garcia CA, Howell RR. Ocular findings in mannosidosis. Am J Ophthalmol. 1976 Sep;82(3):465-71. PubMed PMID: 961797.

PubMed ID: 
961797

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

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

Pages

Subscribe to RSS - mental retardation