seizures

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

Mental Retardation, AD 31

Clinical Characteristics
Ocular Features: 

A variety of ocular dysmorphisms have been described in this disorder including up-slanting lid fissures, epicanthal folds, hypertelorism, and telecanthus.  Ptosis was described in 1 patient.  Strabismus, nystagmus, and disconjugate gaze have been observed.  Visual acuity has not been reported but "variable visual impairment" has been described.  One patient was considered to have cortical visual impairment.

Systemic Features: 

Neonatal hypotonia and feeding difficulties are among the first signs along with seizure-like activity (50%) including infantile spasms.  EEG anomalies are present in the majority of individuals.  Gastroscopy tubes may be required in a significant minority of patients.  Hypotonic or myopathic facies is common.  Apneic episodes may be seen in the neonatal period and most infants have respiratory difficulties in the first year of life which may improve during this period.  Learning difficulties and features of autism are common.  Some patients are unable to walk while others have an ataxic or broad-based gait.  Speech may be absent or severely limited.  The forehead is prominent while the hard palate is usually highly vaulted.

Brain MRIs may show delayed myelination but such scans have been described as normal in other individuals.  Enlarged ventricles, a thin corpus callosum, and periventricular white matter changes may also be present.   Neuropathologic studies have revealed chronic inflammatory changes around the arterioles of deep while matter.

Genetics

Heterozygous mutations in the PURA gene (5q31) have been identified in this disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Expanding the neurodevelopmental phenotype of PURA syndrome

Lee BH, Reijnders MRF, Abubakare O, Tuttle E, Lape B, Minks KQ, Stodgell C, Bennetto L, Kwon J, Fong CT, Gripp KW, Marsh ED, Smith WE, Huq AM, Coury SA, Tan WH, Solis O, Mehta RI, Leventer RJ, Baralle D, Hunt D, Paciorkowski AR. Expanding the neurodevelopmental phenotype of PURA syndrome. Am J Med Genet A. 2018 Jan;176(1):56-67.

PubMed ID: 
29150892

De novo mutations in PURA are associated with hypotonia and developmental delay

Tanaka AJ, Bai R, Cho MT, Anyane-Yeboa K, Ahimaz P, Wilson AL, Kendall F, Hay B, Moss T, Nardini M, Bauer M, Retterer K, Juusola J, Chung WK. De novo mutations in PURA are associated with hypotonia and developmental delay. Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000356. doi: 10.1101/mcs.a000356.

PubMed ID: 
27148565

Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome

Lalani SR, Zhang J, Schaaf CP, Brown CW, Magoulas P, Tsai AC, El-Gharbawy A, Wierenga KJ, Bartholomew D, Fong CT, Barbaro-Dieber T, Kukolich MK, Burrage LC, Austin E, Keller K, Pastore M, Fernandez F, Lotze T, Wilfong A, Purcarin G, Zhu W, Craigen WJ, McGuire M, Jain M, Cooney E, Azamian M, Bainbridge MN, Muzny DM, Boerwinkle E, Person RE, Niu Z, Eng CM, Lupski JR, Gibbs RA, Beaudet AL, Yang Y, Wang MC, Xia F. Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. Am J Hum Genet. 2014 Nov 6;95(5):579-83.

PubMed ID: 
25439098

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: 

Hypotonia, Infantile, with Psychomotor Retardation And Characteristic Facies 2

Clinical Characteristics
Ocular Features: 

Anomalies of periocular structures are part of the characteristic facial morphology.  The lid fissures slant downward and epicanthal folds are with ptosis are generally present.  Strabismus and nystagmus are characteristic features.

Systemic Features: 

This is a severe congenital neurodevelopmental disorder with global delay, hypotonia, and characteristic facies.  It is usually present at birth and soon manifest as a profound intellectual delay.  Most patients do not develop speech or independent motor skills.  Feeding difficulties are evident early and often require gastric tube placement for nutrition.  Failure to thrive is common.   Most patients have seizures of a tonic-clonic or atonic type which may be controlled with medication. 

Microcephaly, brachycephaly, plagiocephaly, and brachycephaly have been described.  A high forehead with frontal bossing, facial hypotonia, triangular facies have been described.  The ears are low-set and posteriorly rotated.  The upper lip is often thin and the mouth is commonly open.  The neck appears short, the nose is bulbous while the nasal bridge is prominent and the nares may be anteverted.

Brain imaging is normal in some patients but there is evidence of generalized cerebral atrophy, with a thin corpus callosum and decreased myelination in others.  Variable features include scoliosis, hip contractures, muscle wasting, and dyskinesias are sometimes seen.

Genetics

This disorder is caused by homozygous or compound heterozygous mutations in the UNC80 gene (2q34).  

For somewhat similar disorders see IHPRF1 (615419) and IHPRF3 (616900).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability

Stray-Pedersen A, Cobben JM, Prescott TE, Lee S, Cang C, Aranda K, Ahmed S, Alders M, Gerstner T, Aslaksen K, Tetreault M, Qin W, Hartley T, Jhangiani SN, Muzny DM, Tarailo-Graovac M, van Karnebeek CD; Care4Rare Canada Consortium; Baylor-Hopkins Center for Mendelian Genomics, Lupski JR, Ren D, Yoon G. Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability. Am J Hum Genet. 2016 Jan 7;98(1):202-9.

PubMed ID: 
26708751

UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN

Perez Y, Kadir R, Volodarsky M, Noyman I, Flusser H, Shorer Z, Gradstein L, Birnbaum RY, Birk OS. UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN. J Med Genet. 2016 Jun;53(6):397-402.

PubMed ID: 
26545877

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

Encephalopathy, Progressive, Early-Onset, wtih Brain Atrophy and Spasticity

Clinical Characteristics
Ocular Features: 

Optic atrophy or cortical visual impairment with lack of visual tracking have been described in all patients.

Systemic Features: 

Microcephaly is evident at birth with global developmental delay and hearing loss.  One patient of 3 reported in 2 unrelated families had brief flexion seizures at 5 months.  Developmental regression and stagnation may become evident within the first months of life.  The EEG showed a hypsarrhythmia pattern.  Truncal hypotonia, spasticity, dystonia and/or myoclonus, scoliosis, and dysphagia are also features.  Two of the three reported patients had seizures. 

Brain MRI showed a pattern of pontine hypoplasia, partial agenesis of the corpus callosum, modified frontal gyri and diffuse cortical atrophy with enlarged ventricles have been described.  The cerebellum seems to be spared.

Genetics

Homozygous or compound heterozygous mutations in the TRAPPC12 gene (2p25.3) were found in 3 children in 2 unrelated families with this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Ayme-Gripp Syndrome

Clinical Characteristics
Ocular Features: 

Most patients have congenital cataracts which may be mild and "oil drop" in appearance.  The eyes appear far apart, the eyebrows are broad, and the palpebral fissures may slant upward or downward.  Ptosis has been reported.  Aphakic glaucoma has been reported in one juvenile who had unilateral cataract surgery at 5 months of age.

Systemic Features: 

The phenotype is heterogeneous and not all patients have all features.  The facial features are said to resemble those of the Down syndrome with brachycephaly, a high forehead, and a flat midface with shallow orbits and malar hypoplasia.  The ears are small, low-set, and posteriorly rotated.  The nose is short and the nasal bridge is broad and flat.  The mouth is small and the upper lip is thin.  The scalp hair may be sparse and the nails sometimes appear dystrophic.

The fingers are sometimes brachydactylous and tapered.  Short stature is common and the joints may have limited motion.  Dislocation of the radial heads is seen rarely while radioulnar synostosis has been seen in a few individuals.  Postnatal short stature is common.

Seizures often occur.  The ventricles appear large and cerebral atrophy has been reported.  Intellectual disability and mental retardation are common. However, at least one individual attended university although he had been diagnosed in childhood with Asberger disease.   Neurosensory hearing loss is common.

Genetics

This autosomal dominant condition results from heterozygous mutations in the MAF (16q32.2) gene.  At least one mother/son transmission event has been reported.

Many of the same features are seen in what has been called the Fine-Lubinsky syndrome (601353) but without mutations in the MAF gene.  It may not be a unique disorder.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No general treatment has been reported but specific anomalies such as cataracts should be addressed.

References
Article Title: 

Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies

Niceta M, Stellacci E, Gripp KW, Zampino G, Kousi M, Anselmi M, Traversa A, Ciolfi A, Stabley D, Bruselles A, Caputo V, Cecchetti S, Prudente S, Fiorenza MT, Boitani C, Philip N, Niyazov D, Leoni C, Nakane T, Keppler-Noreuil K, Braddock SR, Gillessen-Kaesbach G, Palleschi A, Campeau PM, Lee BH, Pouponnot C, Stella L, Bocchinfuso G, Katsanis N, Sol-Church K, Tartaglia M. Mutations Impairing GSK3-Mediated MAF Phosphorylation Cause Cataract, Deafness, Intellectual Disability, Seizures, and a Down Syndrome-like Facies. Am J Hum Genet. 2015 May 7;96(5):816-25.

PubMed ID: 
25865493

PEHO-Like Syndrome

Clinical Characteristics
Ocular Features: 

Poor visual fixation and attention has been noted during the first 6 months of life.  Optic atrophy has been described and epicanthal folds may be present.

Systemic Features: 

General hypotonia with developmental delay and progressive microcephaly are evident in the first 6-12 months of life.  Seizures may be present at birth or within the first month of life.  Edema of the feet, hands, and face are also present at birth.  Cognitive deficits and motor delays are usually evident during infancy.  The central hypotonia may be accompanied by peripheral spasticity.  Kyphoscoliosis often develops.  Other dysmorphic features include micrognathia, narrow forehead, short nose, and open mouth.

Brain imaging reveals coarse pachygyria, polymicrogyria, and dilated ventricles with hypoplastic corpus callosum and pons.  Cerebellar hypoplasia was found in one child. 

Genetics

This presumed autosomal recessive disorder is associated with homozygous mutations in the CCDC88A gene (2p16.1).  Three affected children have been reported in a consanguineous family.

A somewhat similar disorder known as PEHO syndrome (260565) results from homozygous mutations in the ZNHIT3 gene. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

The PEHO syndrome

Riikonen R. The PEHO syndrome. Brain Dev. 2001 Nov;23(7):765-9. Review.

PubMed ID: 
11701291

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