psychomotor delay

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

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

Encephalopathy, Early-Onset, With Brain Atrophy and Thin Corpus Callosum

Clinical Characteristics
Ocular Features: 

Optic atrophy is present in many patients and may be present early since lack of visual tracking or eye contact may be noted at birth.  Sparse eyebrows, upslanting palpebral fissures, and hypertelorism have also been reported.

Systemic Features: 

Severe hypotonia is present at birth often causing respiratory distress in the neonate.  Spasticity can develop later.  Growth failure with progressive microcephaly is present in infants.  Brain imaging often reveals diffuse atrophy of structures including the cerebellum, brainstem, spinal cord, and cerebrum.  Tongue fasciculations have been observed.   Micrognathia and widely spaced teeth are sometimes present.  Several patients have died during infancy.

Genetics

Homozygous mutations in the TBCD (17q25.3) are responsible for this disorder.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment has been reported.

References
Article Title: 

Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy

Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, Baas F, Piemonte F, Dallapiccola B, Graham JM Jr, Saunders CJ, Bertini E, Kahn RA, Koolen DA, Tartaglia M. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):962-973.

PubMed ID: 
27666370

Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy

Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, Kakita A, Imagawa E, Shiina M, Ogata K, Okuno-Yuguchi J, Fueki N, Ogiso Y, Suzumura H, Watabe Y, Imataka G, Leong HY, Fattal-Valevski A, Kramer U, Miyatake S, Kato M, Okamoto N, Sato Y, Mitsuhashi S, Nishino I, Kaneko N, Nishiyama A, Tamura T, Mizuguchi T, Nakashima M, Tanaka F, Saitsu H, Matsumoto N. Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):950-961.

PubMed ID: 
27666374

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: 

Encephalopathy Due To Defective Mitochondrial And Peroxisomal Fission 2

Clinical Characteristics
Ocular Features: 

Visual impairment and optic atrophy are usually present.  Visual-evoked potentials may be negative or slowed severely.  Some degree of ophthalmoparesis is often present while frank external ophthalmoplegia can develop in the second year of life.  In one patient aged 7 years, MRI showed increased T2 signals in the optic radiation.

Systemic Features: 

Microcephaly becomes evident in the first year of life and seizures can appear in this period as well.  General developmental delays are present.  There may be evidence of Leigh-like basal ganglia disease.  Dysphagia may require the placement of a gastroscopy tube.  Truncal hypotonia can be so severe that sitting and head control are not possible.  However, there is often spasticity and hyperreflexia in the limbs.  EEG recordings show hypsarrhythmia.

Brain MRI may show increased T2 signaling in the global pallidus, thalamus, and the subthalamic nucleus.

Patients may never be able to sit or walk and usually do not develop speech.  

Genetics

Homozygous or compound heterozygous truncating mutations in the MFF gene (mitochondrial fission factor) (2q36.3) is responsible for this condition.  Patients with EMPF2 may have abnormally elongated and tubular mitochondria and peroxisomes in fibroblasts.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available for the general disorder.  Gastrostomy tubes may be required to maintain adequate nutrition.  Airway hygiene is important.  Respiratory complications can be a factor in the early demise of children.

References
Article Title: 

Leukodystrophy, Hypomyelinating, 13

Clinical Characteristics
Ocular Features: 

Several individuals in one family have been observed with optic atrophy, nystagmus and visual impairment.

Systemic Features: 

Head circumference is normal at birth but later in childhood falls behind in growth.  Neurodevelopment seems to plateau without regression.  Feeding difficulties may be present from birth and may require gastroscopy tube placement.  Motor skills are delayed and expressive language may never develop.  General irritability and increased muscle tone with hyperreflexia are usually present eventually resulting in joint contractures. 

EEGs , electromyography, and nerve conduction studies have been normal in 3 patients.  A brain MRI in one patient showed a leukodystrophic pattern in periventricular areas.  Variable cardiac malfunctions such as heart failure, LVH, and pericarditis were observed in several patients.

Sudden death following a short febrile illness has been reported to occur in three of the six affected children before the age of 15 years. 

Genetics

Homozygous mutations in the C11ORF73 gene (11q14.2) are responsible for this disorder.  Three unrelated families of Ashkenazi Jewish descent have been reported.

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Hyperphosphatasia with Mental Retardation Syndrome 6

Clinical Characteristics
Ocular Features: 

Congenital cataracts may be present.  The eyes appear deeply-set and strabismus has been seen in severely affected cases.   

Systemic Features: 

Two families have been reported.  The range of severity in symptoms is wide.  Birth may occur prematurely especially in the presence of polyhydramnios.  Postnatal development can be complicated by seizures, chronic lung disease, developmental regression, and renal disease.  Poor growth secondary to feeding difficulties have been reported.  Death can occur in early childhood.

Dysmorphic features include a short neck, bitemporal narrowing, depressed nasal bridge, and proximal limb shortening.  Osteopenia, flexion contractures, and hip dysplasia may be present.  Dilatation of the renal collecting system with increased echogenicity have been reported.  Creatine kinase and serum alkaline phosphatase may be increased and muscle histology shows small, atrophic fibers with increased fibrosis and considerable variations in fiber size.

Genetics

Homozygous mutations in the PIGY gene (4q22.1) resulting in deficiencies of glycosylphosphatidylinositol synthesis have been associated with this condition.  

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No effective treatment has been reported.

References
Article Title: 

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Ilkovski B, Pagnamenta AT, O'Grady GL, Kinoshita T, Howard MF, Lek M, Thomas B, Turner A, Christodoulou J, Sillence D, Knight SJ, Popitsch N, Keays DA, Anzilotti C, Goriely A, Waddell LB, Brilot F, North KN, Kanzawa N, Macarthur DG, Taylor JC, Kini U, Murakami Y, Clarke NF. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies. Hum Mol Genet. 2015 Nov 1;24(21):6146-59.

PubMed ID: 
26293662

Hypotonia, Infantile, with Psychomotor Retardation and Characteristic Facies 3

Clinical Characteristics
Ocular Features: 

Deep-set eyes with highly arched eyebrows have been described and poor fixation can be present.  Cortical visual impairment has been described.

Systemic Features: 

The neurologic abnormalities become evident soon after birth.  Hypotonia and decreased reflexes may be present early and often there is little psychomotor development subsequently.  Some patients have no or very little speech and may never sit, stand, or walk.  However, there is considerable variation in the clinical picture and other individuals are able to walk and may live into the third decade.  Brain imaging reveals a variety of abnormalities including cerebellar and cerebral hypoplasia.  Respiratory difficulties and poor feeding are often present.

The facial dysmorphism may include brachycephaly with a broad forehead and narrowing of the temporal regions.  The nose may be small and the mouth appears large in the presence of micrognathia and a thin upper lip.

Genetics

This is an autosomal recessive condition as the result of homozygous or compound heterozygous mutations in the TBCK gene (4q24). 

Other similar conditions include IHPRF2 (616801) (with homozygous mutations in UNC80 and IHPRF1 (615419) (with homozygous mutations in NALCN) whose ocular features may include strabismus, nystagmus, and poor visual fixation.    

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is available.

References
Article Title: 

Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia

Bhoj EJ, Li D, Harr M, Edvardson S, Elpeleg O, Chisholm E, Juusola J, Douglas G, Guillen Sacoto MJ, Siquier-Pernet K, Saadi A, Bole-Feysot C, Nitschke P, Narravula A, Walke M, Horner MB, Day-Salvatore DL, Jayakar P, Vergano SA, Tarnopolsky MA, Hegde M, Colleaux L, Crino P, Hakonarson H. Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia. Am J Hum Genet. 2016 Apr 7;98(4):782-8.

PubMed ID: 
27040691

Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy

Chong JX, Caputo V, Phelps IG, Stella L, Worgan L, Dempsey JC, Nguyen A, Leuzzi V, Webster R, Pizzuti A, Marvin CT, Ishak GE, Ardern-Holmes S, Richmond Z; University of Washington Center for Mendelian Genomics, Bamshad MJ, Ortiz-Gonzalez XR, Tartaglia M, Chopra M, Doherty D. Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy. Am J Hum Genet. 2016 Apr 7;98(4):772-81.

PubMed ID: 
27040692

Developmental Delay with Short Stature, Dysmorphic Features, and Sparse Hair

Clinical Characteristics
Ocular Features: 

Patients may have downward-slanting lid fissures, hypertelorism, epicanthal folds, and sparse eyebrows and eyelashes.

Systemic Features: 

Patients have scaphocephaly with or without craniosynostosis and facial dysmorphism with a depressed nasal bridge and micrognathia.  Short stature, sparse hair, and developmental delay are characteristic.  Hypoplastic toenails and dental anomalies are present.  Brain imaging may show Dandy-Walker malformations and cerebellar vermis hypoplasia.  The kidneys may have focal interstitial nephritis and there may be intermittent hematuria and proteinuria in the presence of otherwise normal renal function.  Cardiac septal defects have been noted.

Genetics

Homozygous mutations in the DPH1 gene (17p13.3) are responsible for this disorder.  Two families have been reported with this condition. 

Pedigree: 
Autosomal recessive
Treatment
Treatment Options: 

No treatment is known.

References
Article Title: 

Matching two cohorts validates DPH1 as a gene responsible for autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies

Loucks CM, Parboosingh JS, Shaheen R, Bernier FP, McLeod DR, Seidahmed MZ, Puffenberger EG, Ober C, Hegele RA, Boycott KM, Alkuraya FS, Innes AM. Matching two independent cohorts validates DPH1 as a gene responsible for autosomal recessive intellectual disability with short stature, craniofacial, and ectodermal anomalies. Hum Mutat. 2015 Oct;36(10):1015-9.

PubMed ID: 
26220823

Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families

Alazami AM, Patel N, Shamseldin HE, Anazi S, Al-Dosari MS, Alzahrani F, Hijazi H, Alshammari M, Aldahmesh MA, Salih MA, Faqeih E, Alhashem A, Bashiri FA, Al-Owain M, Kentab AY, Sogaty S, Al Tala S, Temsah MH, Tulbah M, Aljelaify RF, Alshahwan SA, Seidahmed MZ, Alhadid AA, Aldhalaan H, AlQallaf F, Kurdi W, Alfadhel M, Babay Z, Alsogheer M, Kaya N, Al-Hassnan ZN, Abdel-Salam GM, Al-Sannaa N, Al Mutairi F, El Khashab HY, Bohlega S, Jia X, Nguyen HC, Hammami R, Adly N, Mohamed JY, Abdulwahab F, Ibrahim N, Naim EA, Al-Younes B, Meyer BF, Hashem M, Shaheen R, Xiong Y, Abouelhoda M, Aldeeri AA, Monies DM, Alkuraya FS. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 2015 Jan 13;10(2):148-61.

PubMed ID: 
25558065

Pages

Subscribe to RSS - psychomotor delay