strabismus

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

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

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

Birk-Landau-Perez Syndrome

Clinical Characteristics
Ocular Features: 

Patients have oculomotor apraxia, saccadic pursuits, lack of fixation, and ptosis.  No pigmentary changes were seen in the fundi but the optic nerves have not been described.

Systemic Features: 

This is a progressive disorder in which psychomotor regression and loss of speech develop by 1 to 2 years of age, often appearing as the first sign of abnormalities.  Cognitive impairment can progress to profound intellectual disability.  Older patients have limb and truncal ataxia and experience frequent falls.  Muscle tone in the limbs is increased and children often exhibit dyskinesia, dystonia, and axial hypotonia.  General muscle weakness is often present.  No abnormalities have been seen on brain imaging.

Some patients develop a nephropathy with renal insufficiency, hypertension, and hyperechogenic kidneys though deterioration of the renal disease is slow.  Renal biopsy in one patient revealed tubulointerstitial nephritis but no individuals have reached end-stage renal failure.

Genetics

Homozygous mutations in the SLC30A9 gene (4p13) are responsible for this disorder.  A single multigenerational consanguineous Bedouin family of 6 affected individuals has been reported with a transmission pattern consistent with autosomal recessive inheritance.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment for the general disorder has been reported.  Electrolytes should be monitored and metabolic issues resulting from kidney malfunction may need to be addressed.

References
Article Title: 

Gabriele-de Vries Syndrome

Clinical Characteristics
Ocular Features: 

A number of nondiagnostic signs occur in the periocular structures as part of the general facial dysmorphism.  There is a general fullness to the periocular area, most evident in the upper eyelids.  The lid fissures slant downward and the eyebrows are sparse.  Strabismus is often present.  Ptosis has been noted in a few individuals.

Systemic Features: 

Systemic signs are inconsistent and highly variable.  Intrauterine growth is usually below average.  Feeding problems are evident from birth.  The facial dysmorphology is highlighted by a high, broad forehead and accentuated by micrognathia and midface hypoplasia.  The ears are posteriorly rotated.  General development is delayed and milestones, if achieved, are delayed.  Behavioral problems can be manifest as anxiety and some individuals have features of the autism spectrum.  Abnormal movements such as tremor and dystonia are sometimes present.

Brain imaging may reveal delayed myelination, frontal gliosis, white matter abnormalities, and enlarged ventricles.

Genetics

Heterozygous mutations in the YY1 gene (14q32) have been identified in this condition.  The gene is a transcription factor that acts both as a repressor and an activator in specific circumstances.  Virtually all cases occur de novo.

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

No effective generalized treatment has been reported.

References
Article Title: 

YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Gabriele M, Vulto-van Silfhout AT, Germain PL, Vitriolo A, Kumar R, Douglas E, Haan E, Kosaki K, Takenouchi T, Rauch A, Steindl K, Frengen E, Misceo D, Pedurupillay CRJ, Stromme P, Rosenfeld JA, Shao Y, Craigen WJ, Schaaf CP, Rodriguez-Buritica D, Farach L, Friedman J, Thulin P, McLean SD, Nugent KM, Morton J, Nicholl J, Andrieux J, Stray-Pedersen A, Chambon P, Patrier S, Lynch SA, Kjaergaard S, Torring PM, Brasch-Andersen C, Ronan A, van Haeringen A, Anderson PJ, Powis Z, Brunner HG, Pfundt R, Schuurs-Hoeijmakers JHM, van Bon BWM, Lelieveld S, Gilissen C, Nillesen WM, Vissers LELM, Gecz J, Koolen DA, Testa G, de Vries BBA. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction. Am J Hum Genet. 2017 Jun 1;100(6):907-925.

PubMed ID: 
28575647

Muscular Dystrophy, Congenital, with Cataracts and Intellectual Disability

Clinical Characteristics
Ocular Features: 

Cataracts have been diagnosed by 6 months of age and may be congenital in origin. Several patients have had strabismus.

Systemic Features: 

Progressive muscle weakness begins in early childhood.  Hypotonia is usually present at birth followed by atrophy of the proximal muscles (especially in the lower limbs).  Muscle weakness progresses for several years and may stabilize but not before severe gait difficulties occur.  Most adult patients are confined to a wheelchair.  No cardiac involvement occurs although respiratory weakness is often present.  Serum creatine kinase is usually elevated and biopsied muscle fibers show dystrophic changes and increased variability in fiber size with vacuolization.

Other signs in some individuals are contractures, scoliosis, seizures, short stature, cognitive deficits (usually mild), and spinal rigidity.  Paradoxically, some patients have limb spasticity and hyperreflexia with pyramidal signs.  No cerebellar signs are present.

Genetics

This condition results from homozygous or compound heterozygous mutations in the INPP5K gene (17p13).  

See Marinesco-Sjogren Syndrome for a disorder with a somewhat similar clinical presentation plus cerebellar signs.  It is caused by a different mutation, however.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

Cataracts have been surgically removed in several patients by the age of two years.  Physical therapy may be beneficial.  Selected individuals could benefit from release of contractures.

References
Article Title: 

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment

Wiessner M, Roos A, Munn CJ, Viswanathan R, Whyte T, Cox D, Schoser B, Sewry C, Roper H, Phadke R, Marini Bettolo C, Barresi R, Charlton R, Bonnemann CG, Abath Neto O, Reed UC, Zanoteli E, Araujo Martins Moreno C, Ertl-Wagner B, Stucka R, De Goede C, Borges da Silva T, Hathazi D, Dell'Aica M, Zahedi RP, Thiele S, Muller J, Kingston H, Muller S, Curtis E, Walter MC, Strom TM, Straub V, Bushby K, Muntoni F, Swan LE, Lochmuller H, Senderek J. Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment. Am J Hum Genet. 2017 Mar 2;100(3):523-536.

PubMed ID: 
28190456

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

Osborn DP, Pond HL, Mazaheri N, Dejardin J, Munn CJ, Mushref K, Cauley ES, Moroni I, Pasanisi MB, Sellars EA, Hill RS, Partlow JN, Willaert RK, Bharj J, Malamiri RA, Galehdari H, Shariati G, Maroofian R, Mora M, Swan LE, Voit T, Conti FJ, Jamshidi Y, Manzini MC. Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjogren Syndrome and Dystroglycanopathy. Am J Hum Genet. 2017 Mar 2;100(3):537-545.

PubMed ID: 
28190459

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

Spastic Paraplegia 78

Clinical Characteristics
Ocular Features: 

Reduced upgaze with nystagmus and strabismus have been reported.  

Systemic Features: 

This progressive neurodegenerative disorder usually has its onset in young adults but the signs and symptoms are highly variable.  Ambulation and gait difficulties combined with spasticity and lower limb weakness are common signs.  Ataxia and dysarthria are also important signs.  Some individuals have dementia while others have only mild cognitive impairment.  Some individuals have mild signs of Parkinsonism.

Brain imaging may show cerebellar and cortical atrophy with a thin corpus callosum. 

Genetics

This condition results from homozygous or compound heterozygous mutations in the ATP13A2 gene (1p36.13).

The same gene is also mutated in the Kufor-Rakeb syndrome (606693), an early-onset form of Parkinsonism.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

Estrada-Cuzcano A, Martin S, Chamova T, Synofzik M, Timmann D, Holemans T, Andreeva A, Reichbauer J, De Rycke R, Chang DI, van Veen S, Samuel J, Schols L, Poppel T, Mollerup Sorensen D, Asselbergh B, Klein C, Zuchner S, Jordanova A, Vangheluwe P, Tournev I, Schule R. Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78). Brain. 2017 Feb;140(Pt 2):287-305.

PubMed ID: 
28137957

Genetic and phenotypic characterization of complex hereditary spastic paraplegia

Kara E, Tucci A, Manzoni C, Lynch DS, Elpidorou M, Bettencourt C, Chelban V, Manole A, Hamed SA, Haridy NA, Federoff M, Preza E, Hughes D, Pittman A, Jaunmuktane Z, Brandner S, Xiromerisiou G, Wiethoff S, Schottlaender L, Proukakis C, Morris H, Warner T, Bhatia KP, Korlipara LV, Singleton AB, Hardy J, Wood NW, Lewis PA, Houlden H. Genetic and phenotypic characterization of complex hereditary spastic paraplegia. Brain. 2016 Jul;139(Pt 7):1904-18.

PubMed ID: 
27217339

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