microcephaly

Combined Oxidative Phosphorylation Deficiency 32

Clinical Characteristics
Ocular Features: 

Ocular signs are common but variable.  Patients may not make eye contact and sometimes have disconjugate eye movements.  Strabismus (usually exotropia) and nystagmus or often present.

Systemic Features: 

Six patients from 4 unrelated families of mixed ethnic backgrounds have been reported.  Infants within the first 4 to 6 months of life had evidence of developmental delay and neurodevelopmental regression.  Poor feeding and breathing difficulties are often noted in this period.  Other later signs are axial hypotonia, abnormal movements such as tremor, spasticity, hyperkinetic movements, dystonia with eventual regression of milestones.  Joint contractures and kyphoscoliosis may develop. 

Microcephaly was noted in several infants and brain imaging in all patients reveals abnormal T2- weighted signals in the brainstem and specifically in the basal ganglia.  Decreased activity in muscle mitochondrial respiratory complexes I, III, and IV has been documented.  Lactate may be increased in serum and the CSF.  Postmortem studies show brain vascular proliferation and gliosis in basal structures.

Genetics

Homozygous or compound heterozygous mutations in MRPS34 (16p13.3) are the basis for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

Lake NJ, Webb BD, Stroud DA, Richman TR, Ruzzenente B, Compton AG, Mountford HS, Pulman J, Zangarelli C, Rio M, Bodaert N, Assouline Z, Sherpa MD, Schadt EE, Houten SM, Byrnes J, McCormick EM, Zolkipli-Cunningham Z, Haude K, Zhang Z, Retterer K, Bai R, Calvo SE, Mootha VK, Christodoulou J, Rotig A, Filipovska A, Cristian I, Falk MJ, Metodiev MD, Thorburn DR. Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome. Am J Hum Genet. 2017 Aug 3;101(2):239-254.

PubMed ID: 
28777931

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: 

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

Pontocerebellar Hypoplasia 7

Clinical Characteristics
Ocular Features: 

The ocular phenotype has not been fully evaluated.  Optic atrophy, nystagmus, and strabismus have been reported in addition to dysmorphic periocular features such as epicanthal folds, upslanting lid fissures, and a flattened nasal bridge.  Infants frequently do not fix and follow.

Systemic Features: 

Infants may be small at birth and subsequent psychomotor development is delayed.  The ears are large and the palate is highly arched.  Hypotonia is present from birth but spasticity with hyperreflexia may also be seen.  Brain imaging may show a thin corpus callosum as well as olivopontocerebellar hypoplasia.  The ventricles are frequently enlarged.  Patients are frequently irritable with few spontaneous movements.

Genitalia can be ambiguous and are frequently assigned to the female gender because of microphallus, fused scrotum, absent testes, and absence of the uterus.  Many such infants are found to have XY karyotypes.  Infants considered male at birth may subsequently show regression of penile corporeal tissue and may have genitalia that more closely resemble the female gender.  Pelvic imaging and laparoscopy, however, may reveal a uterus, Fallopian tubes and a blind-ending vagina with no gonadal tissue even in individuals with XY karyotypes. 

Genetics

Homozygous or compound heterozygous mutations in the TOE1 gene (1p34.1) are responsible for this condition.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing

Lardelli RM, Schaffer AE, Eggens VR, Zaki MS, Grainger S, Sathe S, Van Nostrand EL, Schlachetzki Z, Rosti B, Akizu N, Scott E, Silhavy JL, Heckman LD, Rosti RO, Dikoglu E, Gregor A, Guemez-Gamboa A, Musaev D, Mande R, Widjaja A, Shaw TL, Markmiller S, Marin-Valencia I, Davies JH, de Meirleir L, Kayserili H, Altunoglu U, Freckmann ML, Warwick L, Chitayat D, Blaser S, Caglayan AO, Bilguvar K, Per H, Fagerberg C, Christesen HT, Kibaek M, Aldinger KA, Manchester D, Matsumoto N, Muramatsu K, Saitsu H, Shiina M, Ogata K, Foulds N, Dobyns WB, Chi NC, Traver D, Spaccini L, Bova SM, Gabriel SB, Gunel M, Valente EM, Nassogne MC, Bennett EJ, Yeo GW, Baas F, Lykke-Andersen J, Gleeson JG. Biallelic mutations in the 3' exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing. Nat Genet. 2017 Mar;49(3):457-464.

PubMed ID: 
28092684

Congenital Heart Defects, Dysmorphic Facies, and Intellectual Developmental Disorder

Clinical Characteristics
Ocular Features: 

The dysmorphic facial features primarily involve the periocular structures.  These include hypertelorism, ptosis, epicanthal folds, strabismus and upslanted palpebral fissures.

Systemic Features: 

Septal defects involving both the atrium and the ventricle are consistently present.  Pulmonary valve abnormalities are present in some patients.

Posteriorly rotated pinnae and a small mouth with a thin upper lip have been observed.  Camptodactyly and clinodactyly are common.  Some patients have mild microcephaly.

Global developmental delay is a consistent feature manifest as delays in walking and speech and eventual intellectual disability.  Feeding difficulties are common.  Hypotonia and hypermobile joints are often noted.  Imaging of the brain may reveal agenesis of the corpus callosum, incomplete formation of the inferior vermis, and leukomalacia of periventricular tissue.

Genetics

Heterozygous mutations have been identified in the CDK13 gene (7p14.1) in seven unrelated individuals.  Heterozygous parents may not have the full phenotype.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the generalized condition.

References
Article Title: 

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Turki SH, Thienpont B, McRae J, Fitzgerald TW, Singh T, Swaminathan GJ, Prigmore E, Rajan D, Abdul-Khaliq H, Banka S, Bauer UM, Bentham J, Berger F, Bhattacharya S, Bu'Lock F, Canham N, Colgiu IG, Cosgrove C, Cox H, Daehnert I, Daly A, Danesh J, Fryer A, Gewillig M, Hobson E, Hoff K, Homfray T; INTERVAL Study., Kahlert AK, Ketley A, Kramer HH, Lachlan K, Lampe AK, Louw JJ, Manickara AK, Manase D, McCarthy KP, Metcalfe K, Moore C, Newbury-Ecob R, Omer SO, Ouwehand WH, Park SM, Parker MJ, Pickardt T, Pollard MO, Robert L, Roberts DJ, Sambrook J, Setchfield K, Stiller B, Thornborough C, Toka O, Watkins H, Williams D, Wright M, Mital S, Daubeney PE, Keavney B, Goodship J; UK10K Consortium., Abu-Sulaiman RM, Klaassen S, Wright CF, Firth HV, Barrett JC, Devriendt K, FitzPatrick DR, Brook JD; Deciphering Developmental Disorders Study., Hurles ME. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet. 2016 Sep;48(9):1060-5.

PubMed ID: 
27479907

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

Intellectual Disability with Dysmorphic Facies and Ptosis

Clinical Characteristics
Ocular Features: 

The eyes appear widely spaced and the lid fissures slant downward.  Ptosis and blepharophimosis are present.  Strabismus is an uncommon feature.

Systemic Features: 

The characteristic facial profile (round, flat) is evident at birth. Microcephaly has been seen in some children.  Low birthweight is common.  Most infants feed poorly with general growth delay and short stature becoming evident in childhood.  Hypotonia and joint hypermobility are constant features.  Gross and fine motor movements appear uncoordinated.  Expressive language is delayed and impaired.  Intellectual disability is mild and achievement of developmental milestones may be delayed.  Seizures are seen in about half of affected individuals.  Brain MRIs may reveal mild white matter anomalies.  Spinal fusion among cervical vertebrae is common.

Individuals may live to adulthood.

Genetics

Heterozygous mutations in the BRPF1 gene (3p25) are responsible for this condition.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

Mattioli F, Schaefer E, Magee A, Mark P, Mancini GM, Dieterich K, Von Allmen G, Alders M, Coutton C, van Slegtenhorst M, Vieville G, Engelen M, Cobben JM, Juusola J, Pujol A, Mandel JL, Piton A. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis. Am J Hum Genet. 2017 Jan 5;100(1):105-116.

PubMed ID: 
27939639

Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation

Yan K, Rousseau J, Littlejohn RO, Kiss C, Lehman A, Rosenfeld JA, Stumpel CT, Stegmann AP, Robak L, Scaglia F, Nguyen TT, Fu H, Ajeawung NF, Camurri MV, Li L, Gardham A, Panis B, Almannai M, Sacoto MJ, Baskin B, Ruivenkamp C, Xia F, Bi W; DDD Study.; CAUSES Study., Cho MT, Potjer TP, Santen GW, Parker MJ, Canham N, McKinnon M, Potocki L, MacKenzie JJ, Roeder ER, Campeau PM, Yang XJ. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation. Am J Hum Genet. 2017 Jan 5;100(1):91-104.

PubMed ID: 
27939640

Optic Atrophy 11

Clinical Characteristics
Ocular Features: 

Optic atrophy is seen as early as 5 years of age but may be congenital in origin as hypoplasia of the optic nerve was present in all patients.  Three of 4 affected children also were myopic.

Systemic Features: 

This is a form of mitochondriopathy with considerable clinical heterogeneity.  A single consanguineous family with 4 affected children of ages 5-16 years of age has been reported.

Common features include short stature, microcephaly (1 had macrocephaly), hearing impairment. Ataxia, dysmetria, and athetotic movements may be present.  Motor and mental development are delayed as is expressive speech.  Intellectual disability is present in all 4 patients.  Leukoencephalopathy was seen in all patients and one had brain atrophy.  Cerebellar hypoplasia was present in 2 of four patients.

Muscle mitochondria in one patient had morphologic changes.  Lactate levels and lactate/pyruvate ratios were elevated in the blood and CSF fluid of three patients.

Genetics

Homozygous mutations in the YME1L1 gene (10p12.1) were responsible for this condition in 4 offspring of a consanguineous Saudi Arabian family.   This is a nuclear encoded mitochondrial gene.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.Hom

References
Article Title: 

Epileptic Encephalopathy, Early Infantile 47

Clinical Characteristics
Ocular Features: 

The fundus is normal early but optic atrophy with narrowed vessels develops eventually.  Cerebral visual impairment has been described.  VEPs were normal at 4 months of age in one patient.

Systemic Features: 

Tonic seizures have their onset in the first month of life.  These become refractory as documented by the EEG which shows severe background slowing, multifocal origins, and hypsarrhythmia.  Psychomotor development is severely delayed and accompanied by profound intellectual disability.  The two reported children were unable to stand and never developed speech.  Feeding difficulties requires tube feeding.  Microcephaly eventually develops along with axial hypotonia and limb ataxia.

Brain MRI was normal at 5 months of age in one individual but at 6 years old showed cerebellar atrophy.  Her younger male sibling at 2 months of age had a normal MRI but cerebellar atrophy was present at 3 years of age.  He died at 3.5 years while his older sib died at age 7 years.

Genetics

Heterozygous mutations in the FGF12 gene (3q28-q29) are responsible for this condition.  One family with 2 affected children has been reported but neither parent carried the mutation in somatic cells suggesting germline mosaicism.

For autosomal recessive forms of early onset epileptic encephalopathy in this database see Epileptic Encephalopathy, Early Infantile 28 (616211) and Epileptic Encephalopathy, Early Infantile 48 (617276).

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No treatment is available for the general condition.  Complete supportive care is required.  Seizures are described as 'refractory' to treatment.

References
Article Title: 

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