psychomotor delay

Spastic Paraplegia with Psychomotor Retardation and Seizures

Clinical Characteristics
Ocular Features: 

The eyes are usually deeply set.  Nothing is known regarding visual acuity.  Strabismus is a common feature.  Retinal dystrophy (not further described) has been reported in 4 of 8 patients described.  The ERG in one individual was read as consistent with cone-rod dystrophy.

Systemic Features: 

Newborns are hypotonic and severe psychomotor retardation is evident a few months later.  Truncal ataxia and progressive lower limb spasticity are seen later.  Mobility is significantly impaired and many individuals are confined to bed or a wheelchair and never walk.  Dysarthria is frequently present and some individuals have a neurosensory hearing loss.  Myoclonic seizures may be evident.  Kyphoscoliosis, macrocephaly, and various foot deformities have been described.

CT scans of the brain may show generalized cerebral atrophy and a hypoplastic corpus callosum.  The ventricles may be enlarged and the EEG confirms the occurrence of myoclonic as well as tonic-clonic and focal epilepsy.

Genetics

This is an autosomal recessive disorder caused by homozygous or compound heterozygous mutations in the HACE1 gene (6q16).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for this condition but physical therapy and assistive devices such as hearing and visual aids may be helpful.

References
Article Title: 

DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Akawi N, McRae J, Ansari M, Balasubramanian M, Blyth M, Brady AF, Clayton S, Cole T, Deshpande C, Fitzgerald TW, Foulds N, Francis R, Gabriel G, Gerety SS, Goodship J, Hobson E, Jones WD, Joss S, King D, Klena N, Kumar A, Lees M, Lelliott C, Lord J, McMullan D, O'Regan M, Osio D, Piombo V, Prigmore E, Rajan D, Rosser E, Sifrim A, Smith A, Swaminathan GJ, Turnpenny P, Whitworth J, Wright CF, Firth HV, Barrett JC, Lo CW, FitzPatrick DR, Hurles ME; DDD study. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nat Genet. 2015 Nov;47(11):1363-9.

PubMed ID: 
26437029

HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome

Hollstein R, Parry DA, Nalbach L, Logan CV, Strom TM, Hartill VL, Carr IM, Korenke GC, Uppal S, Ahmed M, Wieland T, Markham AF, Bennett CP, Gillessen-Kaesbach G, Sheridan EG, Kaiser FJ, Bonthron DT. HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome. J Med Genet. 2015 Dec;52(12):797-803.

PubMed ID: 
26424145

CHOPS Syndrome

Clinical Characteristics
Ocular Features: 

There is usually some degree of proptosis and apparent hypertelorism.  The eyebrows are bushy and the eyelashes are luxurious.  One of three patients had cataracts and another had mild optic atrophy.

Systemic Features: 

The overall facial appearance may resemble Cornelia de Lange syndrome with hypertrichosis and a coarse, round facies.  Head circumference is low normal.  Septal defects and a patent ductus arteriosus are often present.  Laryngeal and tracheal malacia predispose to recurrent pulmonary infections and chronic lung disease.  Skeletal dysplasia includes brachydactyly and anomalous vertebral bodies resulting in short stature (3rd percentile).  Genitourinary abnormalities include cryptorchidism, horseshoe kidney, and vesiculoureteral reflux.  Delayed gastric emptying and reflux have been reported.

Genetics

Heterozygous mutations in the AFF4 gene (5q31.1) have been identified in 3 unrelated individuals with this condition.  No familial cases have been identified.  The gene is a core component of the super elongation complex that is critical to transcriptional elongation during embryogenesis.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

There is no treatment for the general disorder.  Tracheostomy was required in 2 of three reported patients. 

References
Article Title: 

Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin

Izumi K, Nakato R, Zhang Z, Edmondson AC, Noon S, Dulik MC, Rajagopalan R, Venditti CP, Gripp K, Samanich J, Zackai EH, Deardorff MA, Clark D, Allen JL, Dorsett D, Misulovin Z, Komata M, Bando M, Kaur M, Katou Y, Shirahige K, Krantz ID. Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet. 2015 Apr;47(4):338-44.

PubMed ID: 
25730767

Basel-Vanagaite-Smirin-Yosef Syndrome

Clinical Characteristics
Ocular Features: 

The eyes appear abnormally far apart.  Ptosis, microcornea, congenital cataracts, sparse eyebrows, and strabismus are usually present.  Epicanthal folds are often seen.

Systemic Features: 

Psychomotor development is severely delayed and with delay or absence of milestones.  DTRs are often hyperactive but some infants are described as hypotonic.  Some individuals have seizures.  There may be a nevus flammeus simplex lesion on the forehead and body hair is sparse.  Cleft palate, cardiac septal defects, hypospadius, thin corpus callosum and cerebral ventricular dilation have been observed.  The upper lip may have a tented morphology with everted lower lip vermilion. A short philtrum is common. 

Genetics

A homozygous missense mutation in the MED25 gene (19q13.33) has been reported and the transmission pattern is consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No known treatment has been reported.

References
Article Title: 

Homozygous MED25 mutation implicated in eye-intellectual disability syndrome

Basel-Vanagaite L, Smirin-Yosef P, Essakow JL, Tzur S, Lagovsky I, Maya I, Pasmanik-Chor M, Yeheskel A, Konen O, Orenstein N, Weisz Hubshman M, Drasinover V, Magal N, Peretz Amit G, Zalzstein Y, Zeharia A, Shohat M, Straussberg R, Monte D, Salmon-Divon M, Behar DM. Homozygous MED25 mutation implicated in eye-intellectual disability syndrome. Hum Genet. 2015 Jun;134(6):577-87.

PubMed ID: 
25792360

3-methylglutaconic Aciduria with Cataracts, Neurologic Involvement and Neurtropenia

Clinical Characteristics
Ocular Features: 

Descriptions of ocular findings have been limited.  Congenital nuclear cataracts have been described in one patient but lens opacities have been noted in others.

Systemic Features: 

There is considerable heterogeneity in the phenotype with some patients having minimal signs and living to adulthood whereas others succumb to their disease in the first year of life.  The onset of progressive encephalopathy usually occurs in infancy as evidenced by various movement abnormalities and psychomotor delays.  Neonatal hypotonia sometimes progresses to spasticity.  However, other infants are neurologically normal.  Delayed psychomotor development, ataxia, seizures, and dystonia may be seen.  Brain imaging may reveal cerebellar and cerebral atrophy along with brain stem abnormalities.  Neuronal loss, diffuse gliosis, and microvacuolization have been seen on neuropathologic examination.  Dysphagia is common.  Severe neutropenia and recurrent infections may begin in infancy as well.

Increased amounts of 3-methylglutaconic acid are found in the urine while the bone marrow may contain evidence of arrested granulopoiesis. 

Genetics

This autosomal recessive disorder results from homozygous or compound heterozygous mutations in the CLPB gene (11q13.4).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported for this condition.

References
Article Title: 

CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder

Wortmann SB, Zietkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lucke T, Ounap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA. CLPB mutations cause 3-methylglutaconic aciduria, progressive brain atrophy, intellectual disability, congenital neutropenia, cataracts, movement disorder. Am J Hum Genet. 2015 Feb 5;96(2):245-57.

PubMed ID: 
25597510

Peroxisomol Fatty Acyl-CoA Reductase 1 Disorder

Clinical Characteristics
Ocular Features: 

At least some patients have cataracts which may be congenital in origin.  Highly arched eyebrows are part of the facial dysmorphism.

Systemic Features: 

Neonatal hypotonia is common while postnatal psychomotor development, somatic growth delay, microcephaly, and seizures become evident later.  The coarse facial dysmorphism includes large ears, a flattened nasal root, thin upper lip, a long philtrum, and a flattening of the nasal root.  Cognitive deficits are often present and some individuals have significant mobility problems. 

Red blood cell plasmalogen may be decreased.

Genetics

This condition results from homozygous or compound heterozygous mutations in FAR1 gene (11p15.2) resulting in complete loss of enzyme activity consistent with a defect in peroxisomes.

There is some clinical resemblance to rhizomelic chondrodysplasia punctata (215100) in which congenital cataracts also occur but lacks the skeletal features and results from a different mutation. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the generalized condition but physical therapy and special education could be helpful.  Cataract removal is an option that may be considered.

References
Article Title: 

Epileptic Encephalopathy, Early Infantile 28

Clinical Characteristics
Ocular Features: 

Infants with this lethal neuropathy often have minimal or absent eye contact from birth.  Responses to visual stimuli are often but not always absent.  Optic atrophy may be present and the ERG is abnormal in some individuals. The retinas may have "abnormal" pigmentation while scotopic and photopic flash ERG responses are reduced as are visual evoked potentials indicating delayed visual maturation with severe macular and optic nerve dysfunction. 

Systemic Features: 

Seizures begin within weeks after birth and are resistant to pharmacological treatment.  There is no spontaneous motility and little or no psychomotor development.  Normal developmental milestones are usually not achieved.  Spasticity and hyperreflexia are often present but some newborn infants are hypotonic.  MRI imaging reveals cortical atrophy with hippocampal hypoplasia and a hypoplastic corpus callosum. Progressive microcephaly has been described.

Infants generally do not live beyond two years of age and may die within weeks or a few months. Pulmonary dysfunction can be a significant cause of morbidity. 

Genetics

The transmission pattern is consistent with autosomal recessive inheritance.  Homozygous and compound heterozygous mutations in the WWOX gene (16q23) have been found in several families.

Among the limited number of patients reported, at least two with compound heterozygous mutations had normal brain imaging, appropriate visual responses, and some ability to interact with their environment.  Profound psychomotor delays, however, remained.  Hypotonia replaced spasticity as a neurological feature in some infants.

The same gene is mutated in autosomal recessive spinocerebellar ataxia 12 (614322), a less severe condition in which gaze-evoked nystagmus occurs.

Other forms of epileptic encephalopathy have been reported (see 617105, 617106, and 617113) including Early Onset Epileptic Encephalopathy 48 (617276).  For an autosomal dominant form of epileptic encephalopathy in this database, see Epileptic Encephalopathy, Early Onset 47 (617166).

 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known for this condition.

References
Article Title: 

WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

Mignot C, Lambert L, Pasquier L, Bienvenu T, Delahaye-Duriez A, Keren B, Lefranc J, Saunier A, Allou L, Roth V, Valduga M, Moustaine A, Auvin S, Barrey C, Chantot-Bastaraud S, Lebrun N, Moutard ML, Nougues MC, Vermersch AI, Heron B, Pipiras E, Heron D, Olivier-Faivre L, Gueant JL, Jonveaux P, Philippe C. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation. J Med Genet. 2015 Jan;52(1):61-70..

PubMed ID: 
25411445

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

Orofaciodigital Syndrome IX

Clinical Characteristics
Ocular Features: 

Multiple forms of orofaciodigital syndrome are recognized but this one (type IX, originally reported as VIII) is of ophthalmological interest because of the retinal anomalies.  Gurrieri’s original report calls these “retinochoroideal lacunae of colobomatous origin” similar to those found in Aicardi syndrome (304050).  These were further described as hypopigmented and atrophic appearing.  Synophyrs and hypertelorism have been noted and the ears may be low-set.

Systemic Features: 

Facial, oral, digital, psychomotor delays, and skeletal anomalies are major systemic features of OFD IX.  The oral manifestations include a high arched palate, cleft lip (sometimes subtle), bifid tongue, hemartomas on the tongue, abnormal tongue frenulation, and dental anomalies (supernumerary teeth).  Digital anomalies consist of mild syndactyly and occasionally polydactyly, brachydactyly, and bifid large toes.  Some patients have short stature.  Psychomotor delay is common and some patients have been described as mentally retarded.

Genetics

This is most likely an autosomal recessive condition since multiple sibs of both sexes have been identified.  Nothing is known of the locus or specific mutation.

Gurrieri’s name is attached to another syndrome (Gurrieri syndrome [601187]) with entirely different oculoskeletal features.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Specific malformations may need correction but there is no treatment for the overall disease.

References
Article Title: 

Microphthalmia, Syndromic 3

Clinical Characteristics
Ocular Features: 

Microphthalmia or clinical anophthalmia is the major ocular malformation in this disorder but optic nerve hypoplasia or even aplasia may also be present.  Colobomas and congenital cataracts may be seen.

Systemic Features: 

Esophageal atresia and sometimes tracheoesophageal fistula sometimes coexist. The ears can be low-set and malformed and sensorineural hearing loss is often present.  Facial palsy has been reported.  The penis may be small and combined with cryptorchidism while physical growth retardation is common.  Other less common malformations include cleft palate, vertebral anomalies, cardiac anomalies, body asymmetry, and microcephaly.  A few patients have had radiologically evident CNS malformations such as dilated ventricles, hippocampal hypoplasia, abnormal white matter, and holoprosencephaly.  However, intellectual development and function have been normal in other patients.

Genetics

This is an autosomal dominant disorder secondary to heterozygous mutations in the SOX2 gene (3q26.33).  Chromosomal aberrations involving this region of chromosome 3 have also been found.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Depending upon the severity of malformations, life expectancy can be normal but some patients have died in the neonatal period.  Certain defects such as those of the heart, palate and esophagus can be surgically repaired.  Hearing device can be helpful but no treatment is available for the eyeball malformations.

References
Article Title: 

Microphthalmia, Syndromic 2

Clinical Characteristics
Ocular Features: 

Microphthalmia with congenital cataracts are the outstanding ocular features of this syndrome.  Some patients have glaucoma.  Blepharophimosis, ptosis, and ankyloblepharon have also been reported.

Systemic Features: 

Facial dysmorphism, dental anomalies and cardiac defects are consistently present.  The face may appear elongated while the nose can be short with a broad tip and long philtrum.  The primary teeth often persist into the second decade but oligodontia, hyperdontia, and dental radiculomegaly may be seen as well.  Reported cardiac defects include ASD, VSD and floppy valves.  Some patients have cleft palate.  Renal, and intestinal malformations have also been described and some patients exhibit psychomotor delays.

Genetics

This is an X-linked disorder secondary to a mutation in the BCOR gene at Xp11.4.  Because virtually all patients are female, it has been suggested that this is an X-linked dominant mutation with lethality in hemizygous males (mother-daughter transmission has been reported).  This is one of several disorders [others being Incontinentia pigmenti (308300)and focal dermal hypoplasia (305600)] in which skewed X-chromosome inactivation has been demonstrated.

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

Cataracts can be removed and glaucoma requires treatment.

References
Article Title: 

Pages

Subscribe to RSS - psychomotor delay