intellectual disability

Mental Retardation, AD 57

Clinical Characteristics
Ocular Features: 

Ptosis, strabismus, epicanthal folds, and upslanting lid fissures are often present but there is considerable variation among individuals.  Blepharophimosis, telecanthus, and various refractive errors have also been reported.

Systemic Features: 

There is great variability in the clinical signs among patients.  Most have developmental delays and intellectual disabilities combined with behavioral challenges such as anxiety, obsessive-compulsive disorders and features of autism spectrum disorders.  

Infants and young children may have feeding difficulties but may later develop constipation or diarrhea.  

Skeletal anomalies such as short stature, high palate, craniosynostosis, scoliosis, pes planus, hand contractures, and joint hypermobility have been reported.  The voice may be hoarse.

Genetics

Heterozygous mutations in the TLK2 gene (17q23) are responsible for this condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder

Reijnders MRF, Miller KA, Alvi M, Goos JAC, Lees MM, de Burca A, Henderson A, Kraus A, Mikat B, de Vries BBA, Isidor B, Kerr B, Marcelis C, Schluth-Bolard C, Deshpande C, Ruivenkamp CAL, Wieczorek D; Deciphering Developmental Disorders Study, Baralle D, Blair EM, Engels H, Ludecke HJ, Eason J, Santen GWE, Clayton-Smith J, Chandler K, Tatton-Brown K, Payne K, Helbig K, Radtke K, Nugent KM, Cremer K, Strom TM, Bird LM, Sinnema M, Bitner-Glindzicz M, van Dooren MF, Alders M, Koopmans M, Brick L, Kozenko M, Harline ML, Klaassens M, Steinraths M, Cooper NS, Edery P, Yap P, Terhal PA, van der Spek PJ, Lakeman P, Taylor RL, Littlejohn RO, Pfundt R, Mercimek-Andrews S, Stegmann APA, Kant SG, McLean S, Joss S, Swagemakers SMA, Douzgou S, Wall SA, Kury S, Calpena E, Koelling N, McGowan SJ, Twigg SRF, Mathijssen IMJ, Nellaker C, Brunner HG, Wilkie AOM. De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder. Am J Hum Genet. 2018 Jun 7;102(6):1195-1203.

PubMed ID: 
29861108

Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability

Lelieveld SH, Reijnders MR, Pfundt R, Yntema HG, Kamsteeg EJ, de Vries P, de Vries BB, Willemsen MH, Kleefstra T, Lohner K, Vreeburg M, Stevens SJ, van der Burgt I, Bongers EM, Stegmann AP, Rump P, Rinne T, Nelen MR, Veltman JA, Vissers LE, Brunner HG, Gilissen C. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. 2016 Sep;19(9):1194-6.

PubMed ID: 
27479843

Microcephaly 20, Primary, Autosomal Recessive

Clinical Characteristics
Ocular Features: 

Microphthalmia and optic nerve hypoplasia with "blindness" seem to be common.

Systemic Features: 

Short stature and global developmental delay are usually present.  Poor or absent speech is characteristic and intellectual disability may be severe.  Few individuals can walk.  Foot deformities and hypotonia are often present.  Behavior problems are common having features of ADHD, autism, and aggression.  Foot deformities have been noted. 

Imaging of the brain may reveal cerebellar hypoplasia, a simplified gyral pattern, and absence of the corpus callosum. 

Genetics

Homozygous or compound heterozygous mutations in the KIF14 gene (1q32.1) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic variants in KIF14 cause intellectual disability with microcephaly

Makrythanasis P, Maroofian R, Stray-Pedersen A, Musaev D, Zaki MS, Mahmoud IG, Selim L, Elbadawy A, Jhangiani SN, Coban Akdemir ZH, Gambin T, Sorte HS, Heiberg A, McEvoy-Venneri J, James KN, Stanley V, Belandres D, Guipponi M, Santoni FA, Ahangari N, Tara F, Doosti M, Iwaszkiewicz J, Zoete V, Backe PH, Hamamy H, Gleeson JG, Lupski JR, Karimiani EG, Antonarakis SE. Biallelic variants in KIF14 cause intellectual disability with microcephaly. Eur J Hum Genet. 2018 Mar;26(3):330-339.

PubMed ID: 
29343805

Mutations of KIF14 cause primary microcephaly by impairing cytokinesis

Moawia A, Shaheen R, Rasool S, Waseem SS, Ewida N, Budde B, Kawalia A, Motameny S, Khan K, Fatima A, Jameel M, Ullah F, Akram T, Ali Z, Abdullah U, Irshad S, Hohne W, Noegel AA, Al-Owain M, Hortnagel K, Stobe P, Baig SM, Nurnberg P, Alkuraya FS, Hahn A, Hussain MS. Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. Ann Neurol. 2017 Oct;82(4):562-577.

PubMed ID: 
28892560

Elsahy-Waters Syndrome

Clinical Characteristics
Ocular Features: 

Structural anomalies of periocular tissues are common.  Hypertelorism, proptosis, and telecanthus may be striking.  Colobomas or clefts of the upper lid are frequently seen.  The eyebrows are bushy and synophyrs may be present across a broad nasal bridge.  Megalocornea, downslanting lid fissures, glaucoma and cataracts have also been reported but are uncommon.

Systemic Features: 

The skull has been described as brachycephalic.  The midface is flat due to maxillary hypoplasia. The lower jaw is prominent and some patients have mandibular prognathism.  A bifid uvula or partial clefting of the palate are common.  Low-set and posteriorly rotated ears have been reported as well.

 Both pectus excavatum and pectus carinatum have been described.  The teeth have dysplastic enamel and often have obliterated pulp chambers and dental cysts.  Their roots may be shortened and deformed and they are often lost early.  Vertebrae may have fusion of the spines, particularly in the cervical area.  A mixed type of hearing loss is common and some degree of intellectual disability is often evident, especially in older individuals.  Most males have some degree of hypospadias.  Cryptorchidism has been reported in one individual.

Brain imaging in one case revealed no abnormalities.

Genetics

This disorder results from biallelic mutations in the CDH11 gene (16q21).  The parents have been consanguineous in most reports and no vertical transmission has been documented making autosomal recessive the most likely pattern of inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disorder has been reported.  Eyelid and palatal defects may be surgically repaired and assistive hearing devices may be of benefit.  Special education is also likely to be helpful.

References
Article Title: 

Schurrs-Hoeijmakers Syndrome

Clinical Characteristics
Ocular Features: 

Mild structural variants are common among the periocular structures.  There is marked hypertelorism in many individuals, the eyebrows are full and highly arched, the eyelashes are long, and the lid fissures slant downward.  Ptosis is often evident.  Myopia, nystagmus, and strabismus are frequently noted.  Colobomas have been reported.

Systemic Features: 

There is general psychomotor delay in development.  Intellectual disability (with IQs in the 50s) and hypotonia are common.  Speech is poor and sometimes absent.   Behavioral anomalies such as aggression and features of autism have been reported.  The anterior hairline is low, the mouth is wide with downturned corners, the nose is bulbous, the ears are large and low-set, and the teeth are often widely-spaced.  Cryptorchidism is common among males.

Renal and cardiac defects are common.  Brain MRIs often show cerebellar hypoplasia, enlarged ventricles, and nonspecific white matter changes.

Genetics

No treatment for the general disorder has been published.  Physical and speech therapy might be helpful

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the general disorder has been published.  Physical and speech therapy might be helpful.

References
Article Title: 

Clinical delineation of the PACS1-related syndrome--Report on 19 patients

Schuurs-Hoeijmakers JH, Landsverk ML, Foulds N, Kukolich MK, Gavrilova RH, Greville-Heygate S, Hanson-Kahn A, Bernstein JA, Glass J, Chitayat D, Burrow TA, Husami A, Collins K, Wusik K, van der Aa N, Kooy F, Brown KT, Gadzicki D, Kini U, Alvarez S, Fernandez-Jaen A, McGehee F, Selby K, Tarailo-Graovac M, Van Allen M, van Karnebeek CD, Stavropoulos DJ, Marshall CR, Merico D, Gregor A, Zweier C, Hopkin RJ, Chu YW, Chung BH, de Vries BB, Devriendt K, Hurles ME, Brunner HG; DDD study. Clinical delineation of the PACS1-related syndrome--Report on 19 patients. Am J Med Genet A. 2016 Mar;170(3):670-5.

PubMed ID: 
26842493

Mental Retardation, AD 53

Clinical Characteristics
Ocular Features: 

Dysmorphism of periocular structures includes downward slanting lid fissures, hypertelorism, and epicanthal folds.  Evidence for visual problems comes from visual tracking difficulties in some individuals.  Strabismus is present in a minority of patients.

Systemic Features: 

Delayed global development, cognitive impairment, and intellectual disability are major features of this form of mental retardation.  Hypotonia is present early.  Severe delays in onset of speech and walking are found in all patients and never develop in many individuals.  Behavior problems include, anxiety, hyperactivity, aggression, and autistic traits.  Feeding problems and breathing irregularities have been reported.  Seizures occur in some patients.

Brain MRIs are generally normal although corpus callosum anomalies are sometimes identified.

Genetics

Heterozygous mutations in the CAMK2A gene (5q32) have been found in individuals with this disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the general condition has been reported.

References
Article Title: 

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Kury S, van Woerden GM, Besnard T, Proietti Onori M, Latypova X, Towne MC, Cho MT, Prescott TE, Ploeg MA, Sanders S, Stessman HAF, Pujol A, Distel B, Robak LA, Bernstein JA, Denomme-Pichon AS, Lesca G, Sellars EA, Berg J, Carre W, Busk OL, van Bon BWM, Waugh JL, Deardorff M, Hoganson GE, Bosanko KB, Johnson DS, Dabir T, Holla OL, Sarkar A, Tveten K, de Bellescize J, Braathen GJ, Terhal PA, Grange DK, van Haeringen A, Lam C, Mirzaa G, Burton J, Bhoj EJ, Douglas J, Santani AB, Nesbitt AI, Helbig KL, Andrews MV, Begtrup A, Tang S, van Gassen KLI, Juusola J, Foss K, Enns GM, Moog U, Hinderhofer K, Paramasivam N, Lincoln S, Kusako BH, Lindenbaum P, Charpentier E, Nowak CB, Cherot E, Simonet T, Ruivenkamp CAL, Hahn S, Brownstein CA, Xia F, Schmitt S, Deb W, Bonneau D, Nizon M, Quinquis D, Chelly J, Rudolf G, Sanlaville D, Parent P, Gilbert-Dussardier B, Toutain A, Sutton VR, Thies J, Peart-Vissers LELM, Boisseau P, Vincent M, Grabrucker AM, Dubourg C; Undiagnosed Diseases Network, Tan WH, Verbeek NE, Granzow M, Santen GWE, Shendure J, Isidor B, Pasquier L, Redon R, Yang Y, State MW, Kleefstra T, Cogne B; GEM HUGO; Deciphering Developmental Disorders Study, Petrovski S, Retterer K, Eichler EE, Rosenfeld JA, Agrawal PB, Bezieau S, Odent S, Elgersma Y, Mercier S. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. Am J Hum Genet. 2017 Nov 2;101(5):768-788.

PubMed ID: 
29100089

Epileptic Encephalopathy, Early Infantile 58

Clinical Characteristics
Ocular Features: 

Infants are noted early to have poor fixation and visual following of targets.  Optic nerve hypoplasia is evident on brain MRIs.

Systemic Features: 

Epilepsy and development delay are hallmarks of this condition.  The seizures are of multiple types and have their onset in the first year of life.  The EEG often shows diffuse slowing, multifocal spikes and hypsarrhythmia.  These are often difficult to control.  Severe intellectual disability is usually present.  Feeding difficulties are evident early and slow growth is common.  Hypotonia is common but hyperreflexia and spasticity are also reported.

Brain MRIs show delayed or reduced myelination.  Acquired microcephaly is often seen.

Genetics

De novo heterozygous mutations in the NTRK2 gene (9p21.33) have been found in 4 unrelated individuals.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, Schneider A, Hollingsworth G; Deciphering Developmental Disorders Study, FitzPatrick DR, Donaldson A, Canham N, Blair E, Kerr B, Fry AE, Thomas RH, Shelagh J, Hurst JA, Brittain H, Blyth M, Lebel RR, Gerkes EH, Davis-Keppen L, Stein Q, Chung WK, Dorison SJ, Benke PJ, Fassi E, Corsten-Janssen N, Kamsteeg EJ, Mau-Them FT, Bruel AL, Verloes A, Ounap K, Wojcik MH, Albert DVF, Venkateswaran S, Ware T, Jones D, Liu YC, Mohammad SS, Bizargity P, Bacino CA, Leuzzi V, Martinelli S, Dallapiccola B, Tartaglia M, Blumkin L, Wierenga KJ, Purcarin G, O'Byrne JJ, Stockler S, Lehman A, Keren B, Nougues MC, Mignot C, Auvin S, Nava C, Hiatt SM, Bebin M, Shao Y, Scaglia F, Lalani SR, Frye RE, Jarjour IT, Jacques S, Boucher RM, Riou E, Srour M, Carmant L, Lortie A, Major P, Diadori P, Dubeau F, D'Anjou G, Bourque G, Berkovic SF, Sadleir LG, Campeau PM, Kibar Z, Lafreniere RG, Girard SL, Mercimek-Mahmutoglu S, Boelman C, Rouleau GA, Scheffer IE, Mefford HC, Andrade DM, Rossignol E, Minassian BA, Michaud JL. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Am J Hum Genet. 2017 Nov 2;101(5):664-685.

 

PubMed ID: 
291000083

Epileptic Encephalopathy, Infantile or Early Childhood 2

Clinical Characteristics
Ocular Features: 

Cortical visual impairment or blindness was reported in 3 0f 11 patients.

Systemic Features: 

The hallmark signs of this disorder consist of developmental delay and epilepsy.  Onset of seizures occur in the first decade of life, between birth and 6 years, and consist of a variety of types including focal, multifocal, generalized tonic-clonic, febrile, myoclonic, and atonic.  EEG patterns range from normal, to slow waves, spike waves, and burst suppression patterns.  Seizures may respond to treatment in some individuals whereas others are unresponsive.

Microcephaly, both acquired and congenital, was seen in 7 individuals.  MRI scans are usually normal but some patients have nonspecific white matter abnormalities.  Developmental milestones are seldom achieved but some patients are able to walk and speak with difficulty.   Hypotonia, spasticity, and dyskinesias such as myoclonia, dystonia and ataxia are variably present.

Genetics

Heterozygous missense mutations in the GABRB2 gene (5q34) are responsible for this syndrome.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment for the general condition has been reported.  Seizures may not respond to the usual pharmacologic treatments.

References
Article Title: 

High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Hamdan FF, Myers CT, Cossette P, Lemay P, Spiegelman D, Laporte AD, Nassif C, Diallo O, Monlong J, Cadieux-Dion M, Dobrzeniecka S, Meloche C, Retterer K, Cho MT, Rosenfeld JA, Bi W, Massicotte C, Miguet M, Brunga L, Regan BM, Mo K, Tam C, Schneider A, Hollingsworth G; Deciphering Developmental Disorders Study, FitzPatrick DR, Donaldson A, Canham N, Blair E, Kerr B, Fry AE, Thomas RH, Shelagh J, Hurst JA, Brittain H, Blyth M, Lebel RR, Gerkes EH, Davis-Keppen L, Stein Q, Chung WK, Dorison SJ, Benke PJ, Fassi E, Corsten-Janssen N, Kamsteeg EJ, Mau-Them FT, Bruel AL, Verloes A, Ounap K, Wojcik MH, Albert DVF, Venkateswaran S, Ware T, Jones D, Liu YC, Mohammad SS, Bizargity P, Bacino CA, Leuzzi V, Martinelli S, Dallapiccola B, Tartaglia M, Blumkin L, Wierenga KJ, Purcarin G, O'Byrne JJ, Stockler S, Lehman A, Keren B, Nougues MC, Mignot C, Auvin S, Nava C, Hiatt SM, Bebin M, Shao Y, Scaglia F, Lalani SR, Frye RE, Jarjour IT, Jacques S, Boucher RM, Riou E, Srour M, Carmant L, Lortie A, Major P, Diadori P, Dubeau F, D'Anjou G, Bourque G, Berkovic SF, Sadleir LG, Campeau PM, Kibar Z, Lafreniere RG, Girard SL, Mercimek-Mahmutoglu S, Boelman C, Rouleau GA, Scheffer IE, Mefford HC, Andrade DM, Rossignol E, Minassian BA, Michaud JL. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Am J Hum Genet. 2017 Nov 2;101(5):664-685.

 

PubMed ID: 
291000083

Neurodevelopmental Disorder With or Without Seizures and Gait Abnormalities

Clinical Characteristics
Ocular Features: 

Nystagmus and strabismus are common ocular features.  Optic nerve hypoplasia is present in some individuals.

Systemic Features: 

Symptoms may begin in early infancy or childhood.  Several neonates with irritability, hypertonia, increased startle reflexes, and stiffness have been reported.  Hypotonia may occur in the neonatal period though.  Intellectual disability and severe developmental delay are common and some patients are unable to follow simple commands.  Seizures of variable severity frequently occur at some point.  Speech may be absent.  Some patients are unable to walk while those that do have a clumsy, spastic gait.  Joint contractures may develop.

The most obvious dysmorphic feature are large ears.  Choreiform and stereotypic hand movements are sometimes present.  Feeding difficulties and sleeping problems may be noted.  Cortical atrophy and thinning of the corpus callosum has been seen on brain imaging.  One mildly affected individual was short in stature.

Genetics

Heterozygous mutations in the GRIA4 gene (11q22.3) have been found in 5 unrelated patients.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Neurodevelopmental Disorder, Mitochondrial, with Abnormal Movements and Lactic Acidosis

Clinical Characteristics
Ocular Features: 

Optic atrophy is sometimes present.  Nystagmus, and strabismus are seen in some patients.  A pigmentary retinopathy was found in one individual.

Systemic Features: 

This is a clinically heterogeneous disorder with extensive neurological deficits.  Patients have feeding and swallowing difficulties from the neonatal period.  There is intrauterine growth retardation and postnatally patients usually exhibit psychomotor delays and intellectual disabilities.  Some develop seizures and few achieve normal developmental milestones.  Axial hypotonia is present from early infancy and most patients have muscle weakness and atrophy.  However, there may be spastic quadriplegia which is often associated with dysmetria, tremor, and athetosis.  Ataxia eventually develops in most patients. 

Brain imaging shows cerebral and cerebellar atrophy, enlarged ventricles, white matter defects, and delayed myelination. 

Incomplete metabolic studies suggest there may be abnormalities in mitochondrial oxidative phosphorylation activity in at least some tissues.  Most patients have an elevated serum lactate.

Death in childhood is common.

Genetics

Homozygous and compound heterozygous mutations in the WARS2 gene have been found in several families with this condition.  The considerable variation in the phenotype may at least partially be explained by the fact that an additional variant in the W13G gene is sometimes present which impairs normal localization of the WARS2 gene product within mitochondria.

The transmission pattern in several families is consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported for the general condition.

References
Article Title: 

Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy

Wortmann SB, Timal S, Venselaar H, Wintjes LT, Kopajtich R, Feichtinger RG, Onnekink C, Muhlmeister M, Brandt U, Smeitink JA, Veltman JA, Sperl W, Lefeber D, Pruijn G, Stojanovic V, Freisinger P, V Spronsen F, Derks TG, Veenstra-Knol HE, Mayr JA, Rotig A, Tarnopolsky M, Prokisch H, Rodenburg RJ. Biallelic variants in WARS2 encoding mitochondrial tryptophanyl-tRNA synthase in six individuals with mitochondrial encephalopathy. Hum Mutat. 2017 Dec;38(12):1786-1795.

PubMed ID: 
28905505

Pontocerebellar Hypoplasia 11

Clinical Characteristics
Ocular Features: 

Some patients are reported to have poor eye contact, hyperopia, and strabismus.  Three individuals had colobomas.  Strabismus, poor eye contact, and hyperopia have been noted in some individuals.   

Systemic Features: 

Microcephaly and large ears may be noted at birth.  Some patients have general hypotonia while others have spastic hypertonia.  Neurological features include markedly delayed psychomotor development, truncal and appendicular ataxia, and cognitive delays.  Developmental milestones such as walking, sitting, and speech are delayed.  Some patients have seizures.  A variety of behavior abnormalities have been reported including stereotypical movements, autistic behavior, repetitive motor movements, and poor communication.  Dysarthria and dysphagia are sometimes present.  There seems to be little progression of the neurological manifestations.

Brain MRIs reveal cerebellar hypoplasia and hypoplasia or agenesis of the corpus callosum in most patients.

Genetics

Homozygous mutations in the TBC1D23 gene (3q12.1q12.2) cause this disorder

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development

Ivanova EL, Mau-Them FT, Riazuddin S, Kahrizi K, Laugel V, Schaefer E, de Saint Martin A, Runge K, Iqbal Z, Spitz MA, Laura M, Drouot N, Gerard B, Deleuze JF, de Brouwer APM, Razzaq A, Dollfus H, Assir MZ, Nitchke P, Hinckelmann MV, Ropers H, Riazuddin S, Najmabadi H, van Bokhoven H, Chelly J. Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development. Am J Hum Genet. 2017 Sep 7;101(3):428-440.

PubMed ID: 
28823707

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