absent speech

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: 

Epileptic Encephalopathy, Early Infantile 48

Clinical Characteristics
Ocular Features: 

Poor eye contact is present from infancy.  Optic atrophy has been reported in several patients and features of retinitis pigmentosa were present in sibs of one family.

Systemic Features: 

Infants usually present with hypotonia and feeding difficulties.  Global developmental delay is also noted early and becomes more obvious with time.  Seizures are often seen early and become intractable.  Many individuals have microcephaly.  Hypermobility with dyskinesias and hyporeflexia are often present.  Speech is generally absent and many individuals are unable to sit or walk.

Brain imaging often shows atrophy of the cerebrum and cerebellum accompanied by enlarged ventricles and a thin corpus callosum.

Genetics

Homozygous or compound heterozygous mutations in the AP3B2 gene (15q25.2) can be responsible for this condition.

For another somewhat similar condition see early onset epileptic encephalopathy 28 (616211) with autosomal recessive inheritance.  For an autosomal dominant condition with a similar clinical picture, see early onset epileptic encephalopathy 47 (617166).

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

Assoum M, Philippe C, Isidor B, Perrin L, Makrythanasis P, Sondheimer N, Paris C, Douglas J, Lesca G, Antonarakis S, Hamamy H, Jouan T, Duffourd Y, Auvin S, Saunier A, Begtrup A, Nowak C, Chatron N, Ville D, Mireskandari K, Milani P, Jonveaux P, Lemeur G, Milh M, Amamoto M, Kato M, Nakashima M, Miyake N, Matsumoto N, Masri A, Thauvin-Robinet C, Riviere JB, Faivre L, Thevenon J. Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy. Am J Hum Genet. 2016 Dec 1;99(6):1368-1376.

PubMed ID: 
27889060

Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield

Anazi S, Maddirevula S, Faqeih E, Alsedairy H, Alzahrani F, Shamseldin HE, Patel N, Hashem M, Ibrahim N, Abdulwahab F, Ewida N, Alsaif HS, Al Sharif H, Alamoudi W, Kentab A, Bashiri FA, Alnaser M, AlWadei AH, Alfadhel M, Eyaid W, Hashem A, Al Asmari A, Saleh MM, AlSaman A, Alhasan KA, Alsughayir M, Al Shammari M, Mahmoud A, Al-Hassnan ZN, Al-Husain M, Osama Khalil R, Abd El Meguid N, Masri A, Ali R, Ben-Omran T, El Fishway P, Hashish A, Ercan Sencicek A, State M, Alazami AM, Salih MA, Altassan N, Arold ST, Abouelhoda M, Wakil SM, Monies D, Shaheen R, Alkuraya FS. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry. 2016 Jul 19. doi: 10.1038/mp.2016.113. [Epub ahead of print].

PubMed ID: 
27431290
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