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PubMed1999

Characterization of a complex chromosomal rearrangement in a patient with a typical catlike cry and no other clinical findings of cri-du-chat syndrome.

We report on the clinical, cytogenetic, and molecular cytogenetic findings in a 4-year-old girl who was evaluated for developmental delay and a catlike cry from birth. No other findings of cri-du-chat syndrome were present. Karyotype analysis demonstrated a de novo deletion and inverted duplication of the 5p region. The abnormality was confirmed and further defined by detailed FISH analysis using cosmid and lambda phage clones previously mapped to distinct regions of 5p. The analyses documented deletion of 5p15.3-->pter and an inverted duplication of 5p14-->5p15.3. The deleted segment on 5p contains the region implicated in the isolated catlike cry feature of the cri-du-chat syndrome, confirming that the genes involved in the catlike cry map to the distal end of 5p. Except for the catlike cry and possibly the developmental delay that may be due to the deletion of 5p, the duplication of 5p14-->5p15.3 in this patient did not present with additional anomalies. This study further demonstrates the usefulness of the molecular cytogenetic approach for characterizing complex chromosome rearrangements. Such analyses of patients with an isolated catlike cry can avoid an incorrect diagnosis of the cri-du-chat syndrome, which is associated with a more severe prognosis.

Child, Preschool↗

PubMed1982

Control of adolescents' arbitrary matching-to-sample by positive and negative stimulus relations.

In Experiment 1, four developmentally delayed adolescents were taught an A-B matching-to-sample task with nonidentical stimuli: given Sample A1, select Comparison B1; given A2, select B2. During nonreinforced test trials, appropriate matching occurred when B stimuli appeared as samples and A stimuli as comparisons, i.e., the sample and comparison functions were symmetrical (B-A matching). During A-B or B-A matching test trials in which familiar samples and correct comparisons were presented along with novel comparisons, the subjects selected the correct comparisons. In tests with familiar samples and both incorrect and novel comparisons, subjects selected the novel comparisons, demonstrating control by both positive ("matching") and negative ("nonmatching") stimulus relations in A-B and B-A arrays. In Experiment 2, 12 developmentally delayed subjects were taught a two-stage arbitrary-matching task (e.g., A-B, C-B matching). Test sessions showed sample-comparison symmetry (e.g., B-A, B-C matching) and derived sample-comparison relations (e.g., A-C, C-A matching) for 11 subjects. These subjects also demonstrated control by positive and negative stimulus relations in the derived relations.

Adolescent↗

PubMed1989

Exposure of rats to ethanol from postnatal days 4 to 8: alterations of cholinergic neurochemistry in the cerebral cortex and corpus striatum at day 20.

Male and female rat pups were administered ethanol (3 g/kg/dose) twice daily by intragastric intubation between postnatal Day (PN) 4 and 8. Pups were maternally reared throughout the exposure period and until sacrifice on PN20. The consequences of this growth spurt exposure to ethanol were measured by an impact upon body growth, as well as upon specific growth parameters and cholinergic neurochemical factors within the cerebral cortex and corpus striatum. Specific endpoints included muscarinic receptor binding dynamics, acetylcholinesterase (AChE) and choline acetyltransferase (CAT) activities, regional wet weights, and subcellular protein content. In male pups, ethanol resulted in a significant enhancement of body weight gain and an increase in striatal but not cortical mass. Additionally, ethanol exposure resulted in a significant increase in striatal muscarinic receptor affinity, regardless of gender. This was accompanied by evidence of a significantly greater density of striatal muscarinic receptors in males versus females, regardless of treatment. Overall, the ethanol-associated effects are suggestive of a drug-induced developmental delay. Gender-specific, treatment-independent differences were also detected in the developing brain regions. Thus, regardless of treatment, cerebral cortical S1-level protein content was found to be significantly greater in males than in females. Furthermore, there were gender-based, significant differences in AChE activity within the striatum of control pups (males greater than females). Ethanol exposure resulted in a loss of this gender-based difference. We conclude that the cholinergic neurochemical development occurring in the striatum of the female rat brain between PN4 and 8 is exquisitely sensitive to ethanol-induced developmental delays which are not remediable by 12 subsequent days of maternal rearing in the absence of ethanol exposure.

Acetylcholinesterase↗

PubMed2000

Methylenetetrahydrofolate reductase deficiency: importance of early diagnosis.

Methylenetetrahydrofolate reductase deficiency is the most common inborn error of folate metabolism and should be suspected when homocystinuria is combined with hypomethioninemia. The main clinical findings are neurologic signs such as severe developmental delay, marked hypotonia, seizures, microcephaly, apnea, and coma. Most patients present in early life. The infantile form is severe, with rapid deterioration leading to death usually within 1 year. Treatment with betaine has been shown to be efficient in lowering homocysteine concentrations and returning methionine to normal, but the clinical response is variable. We report two brothers with methylenetetrahydrofolate reductase deficiency: the first was undiagnosed and died at 8 months of age from neurologic deterioration and apnea, while his brother, who was treated with betaine from the age of 4 months, is now 3 years old and has developmental delay.

Betaine↗

PubMed1981

Developmental language disability as a consequence of prenatal exposure to ethanol.

Two pre-school-aged patients with a history of prenatal exposure to ethanol had abnormal head size and developmental delay. Both children were strikingly similar in physical appearance, behavior, and cognitive dysfunction. Facial features were typical of fetal alcohol syndrome. Head circumference greater than 97th percentile without hydrocephalus and no evidence of prenatal or postnatal growth failure were unusual for ethanol teratogenicity. Each child had a similar pattern of verbal and behavioral dysfunctions characterized by (1) marked hypervigilence, (2) distractability, and (3) cognitive confusion manifested as anxiety and behavioral disorganization. It is suggested that a history of prenatal exposure to ethanol associated with (1) large head circumference, (2) facial features of fetal alcohol syndrome, and (3) early developmental delay, particularly in language acquisition, and impaired modulation of attention and arousal may represent a possible new effect of alcohol teratogenicity.

Child, Preschool↗

PubMed1999

Fragile X syndrome with FMR1 and FMR2 deletion.

We report a 13 year old boy with fragile X syndrome resulting from a de novo deletion of the FMR1 and FMR2 genes extending from (and including) DXS7536 proximally to FMR2 distally. The patient has severe developmental delay, epilepsy, and behavioural difficulties, including autistic features. He has epicanthic folds, in addition to facial features typical of fragile X syndrome, and marked joint hypermobility. We compare our patient to the three other cases reported in which both FMR1 and FMR2 are deleted. This case has the smallest deletion reported to date. All four patients have epilepsy and a more severe degree of mental retardation than is usual in fragile X syndrome resulting from FMR1 triplet repeat expansion. Three of the patients have joint laxity and two have epicanthic folds. We suggest that these features, in particular severe developmental delay and epilepsy, may form part of the characteristic phenotype resulting from deletion of both FMR1 and FMR2 genes. The diagnosis in this case was delayed because routine cytogenetics showed no abnormality and standard molecular tests for FMR1 triplet repeat expansion (PCR and Southern blotting) failed. Further DNA studies should be undertaken to investigate for a deletion where clinical suspicion of fragile X syndrome is strong and routine laboratory tests fail.

Adolescent↗

PubMed2024

Upregulation versus loss of function of NTRK2 in 44 affected individuals leads to 2 distinct neurodevelopmental disorders.

PURPOSE: Heterozygous pathogenic variants in NTRK2 (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of NTRK2-related disorders and to delineate the clinical presentation. METHODS: We reported an extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported. RESULTS: Our analysis led to splitting the cohort into 2 entities. CONCLUSION: One group had variants in the cholesterol-binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A>G p.(Tyr434Cys). These variants probably lead to upregulation of tropomyosin receptor kinase B activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variants that presumably disturb the 3D structure of the protein leading to loss of function. These individuals had a remarkably milder phenotype of developmental delay, obesity, and hyperphagia.

Humans↗

PubMed2001

MECP2 gene analysis in classical Rett syndrome and in patients with Rett-like features.

OBJECTIVE: To discuss the diagnostic criteria for Rett syndrome based on mutational screening of the methyl-CpG-binding protein 2 gene ( MECP2 ) in patients with classic Rett syndrome and patients with Rett-like features. METHODS: Thirty-nine patients with classical Rett syndrome, one with preserved speech variant (PSV), and 12 patients with developmental delay and some features of Rett syndrome were recruited for sequence analysis of the MECP2 gene coding region. The phenotype of the patients was correlated with the presence and type of the mutation as well as the X-chromosome inactivation (XCI) pattern. RESULTS: found in 100% of the patients with classical Rett syndrome originating from Finland. One novel mutation, P127L, was detected in a patient with PSV. No mutations were found in other cases. The XCI status was found to be random in 72% of the patients with classical Rett syndrome, including the patient with PSV and all patients with developmental delay informative for the analysis. CONCLUSIONS: An MECP2 mutation can be found in almost every patient with classical Rett syndrome. More patients need to be analyzed in order to clarify the mutation prevalence in patients with atypical Rett syndrome and in patients with mental retardation.

Adolescent↗

PubMed2002

A severe connatal form of Pelizaeus Merzbacher disease in a Czech boy caused by a novel mutation (725C>A, Ala242Glu) at the 'jimpy(msd) codon' in the PLP gene.

Pelizaeus Merzbacher disease (PMD) is an X-linked recessive disorder of the central nervous system myelination caused by mutations involving the proteolipid protein gene (PLP). Early nystagmus and developmental delay, progressive pyramidal, cerebellar and dystonic signs as well as white matter changes in brain MRI are typical for PMD. The PLP gene can be affected by two major types of mutations. A duplication of the whole PLP gene is the most common mutation and results usually in the milder classical phenotype, whereas point mutations in PLP gene often result in the rarer and more severe connatal form of PMD. The PLP protein is a higly conserved across species and is identical in human, mouse and rat. We describe a 13-year-old Czech boy with an early and severe developmental delay. His maternal uncle died at the age of one year and was also early and severely psychomotoricly retarded. The patient was the first child of healthy unrelated parents born after an uneventful pregnancy and delivery in 1988. Hyperbilirubinemia and bronchopneumonia and early stridor complicated his neonatal period. Diffuse hypotonia, nystagmus, psychomotor retardation, visual and hearing impairment have been observed in the patient since the age of 6 weeks. White matter abnormalities, cortical and periventricular atrophy were detected by MRI at the age of 6 and 11 years, respectively. Despite these signs and results an accurate clinical diagnosis was unclear until the age of 11 years. Last neurological examination in 1999 showed no nystagmus anymore, but extremely dystrophic limbs, truncal deformation, due to severe scoliosis, tetraplegia with hyperreflexia in C5C7 and areflexia L2S2 and positive pyramidal signs. The boy had no visual or speech contact. DNA tests followed the clinical suspicion for PMD. At first, duplication of PLP gene was excluded by quantitative comparative PCR. Direct sequencing of PLP gene detected a novel mutation in exon 6, a missense mutation 725C-->A (Ala242Glu) in the patient and in his mother and later also in his maternal grandmother. The same codon, but to valine (Ala242Val) is mutated in jimpy(msd) mouse, which is the frequently used animal model for PMD. Prenatal diagnosis for the next pregnancy has been offered to the family. The patient died recently at the age of 13 years due to respiratory failure. Our results support the data on the importance of this conserved amino acid alanine at codon 242.

Child↗

PubMed1995

Hypercalciuria and nephrocalcinosis in the oculocerebrorenal syndrome.

The oculocerebrorenal (Lowe) syndrome is an X-linked recessive disorder characterized by congenital cataracts, hypotonia, developmental delay, poor growth and renal tubular dysfunction. Although the disorder has been mapped to chromosome Xq24-26, the underlying metabolic defect remains unknown. The renal component of the Lowe syndrome comprises tubular dysfunction, that is tubular proteinuria and generalized aminoaciduria progressing to the renal Fanconi syndrome, with later glomerular disease. Clinical problems typically include polyuria, acidosis, hypophosphatemia with rickets and eventually end stage renal disease. Hypercalciuria and its sequelae (nephrocalcinosis and nephrolithiasis) have not been described as cardinal features of the untreated disorder although they reportedly complicate vitamin D and calcium therapy of rickets. We discuss 5 boys with congenital cataracts, hypotonia, developmental delay, failure to thrive and the renal Fanconi syndrome who were diagnosed with the Lowe syndrome and in whom hypercalciuria was documented at diagnosis. We conclude that hypercalciuria and its sequelae may occur commonly in patients with the Lowe syndrome as a component of tubular dysfunction or a complication of therapy.

Calcium↗

PubMed1998

Mosaic trisomy 16 ascertained through amniocentesis: evaluation of 11 new cases.

Trisomy 16, once thought to result uniformly in early pregnancy loss, has been detected in chorionic villus samples (CVS) from on-going pregnancies and was initially ascribed to a second, nonviable pregnancy. Prenatally detected trisomy 16 in CVS and its resolution to disomy has led to the reexamination of the viability of trisomy 16. This study evaluates 11 cases of mosaic trisomy 16 detected through second trimester amniocentesis. In 9 of the 11 cases, amniocenteses were performed in women under the age of 35 because of abnormal levels of maternal serum alpha-fetoprotein (MSAFP) or maternal serum human chorionic gonadotropin (MShCG). The other two amniocenteses were performed for advanced maternal age. Five of the 11 pregnancies resulted in liveborn infants, and six pregnancies were electively terminated. The liveborn infants all had some combination of intrauterine growth retardation (IUGR), congenital heart defects (CHD), or minor anomalies. Two of them died neonatally because of complications of severe congenital heart defects. The three surviving children have variable growth retardation, developmental delay, congenital anomalies, and/or minor anomalies. In the terminated pregnancies, the four fetuses evaluated by ultrasound or autopsy demonstrated various congenital anomalies and/or IUGR. Cytogenetic and fluorescent in situ hybridization studies identified true mosaicism in 5 of 10 cases examined, although the abnormal cell line was never seen in more than 1% of cultured lymphocytes. Placental mosaicism was seen in all placentas examined and was associated with IUGR in four of seven cases. Maternal uniparental disomy was identified in three cases. Mosaic trisomy 16 detected through amniocentesis is not a benign finding but associated with a high risk of abnormal outcome, most commonly IUGR, CHD, developmental delay, and minor anomalies. The various outcomes may reflect the diversity of mechanisms involved in the resolution of this abnormality. As 80% of these patients were ascertained because of the presence of abnormal levels of MSAFP or MShCG, the increased use of maternal serum screening should bring more such cases to clinical attention.

Amniocentesis↗

PubMed1997

Long-term form identification vision after early, closed, lensectomy-vitrectomy for stage 5 retinopathy of prematurity.

PURPOSE: Form identification vision after early, closed, lensectomy-vitrectomy for retinopathy of prematurity (ROP) stage 5 open funnel retinal detachment is reported from a database that included 45 eyes of 27 infants. The focus of this report is the verbal responses at a mean age of 7.0 years for nine nonamblyopic (preferred) eyes of nine preterm infants with minimal developmental delay (good central nervous system function). METHODS: All 45 eyes underwent initial cryotherapy for threshold ROP to the avascular retina to decrease the angiogenic stimulus (mean postconceptual age = 34.8 weeks) and subsequently underwent multiple cryotherapy sessions to the avascular retina and shunt with scleral buckling to decrease retinal traction (mean postconceptual age = 38.0 weeks). When tractional retinal detachment occurred with an open funnel, each eye underwent an early, closed, lensectomy-vitrectomy (mean postconceptual age = 45.7 weeks). The 34 eyes with a successful anatomic result were fitted with contact lenses as soon as possible after surgery. RESULTS: The nine nonamblyopic eyes of nine preterm infants with minimal developmental delay had the following visual acuities using Allen figures or Snellen test types: one eye 20/80, one eye 20/200, two eyes 20/400, three eyes 20/800, and two eyes 20/ 1600. CONCLUSION: These nine eyes support the thesis that form identification vision can be obtained by early vitrectomy for ROP stage 5 open funnel retinal detachments.

Child↗

PubMed1999

Molecular screening for fragile X syndrome in Thailand.

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. We screened for FXS in 237 Thai males (age < or = 15 years) with developmental delay of unknown cause. We found 16 (6.8%) to have FXS using standard molecular analysis. Wc then studied the extended families of these 16 FXS subjects and 4 other independently ascertained FXS cases. We found that there were at least 35 affected males and 8 affected females. In addition we found that there were at least 31 premutation carrier females and 4 premutation males. The CGG repeats numbers in these premutation individuals ranged from 60 to 125. By comparison, the normal CGG repeats were 19-50 with a heterozygosity of 67.2% in 337 randomly selected males. This study providcs insight into the high incidence of FXS in developmentally delayed Thai males and points the way toward the means of prevention of mental retardation by genetic counseling and prenatal diagnosis.

Adolescent↗

PubMed1994

The role of hemispherectomy in the treatment of holohemispheric hemimegaloencephaly.

The role of hemispherectomy in treating holohemispheric hemimegaloencephaly, a unilateral brain malformation, is still not well defined. The authors describe the cases of five infants presenting with intractable seizures, progressive neurological deficits, and severe developmental delay. Electroencephalography (EEG) showed generalized polyspikes from the megaloencephalic hemisphere and progressive slowing on the opposite side in all children; contralateral seizure spikes occurred in three children. Three of the five children underwent hemispherectomy for intractable seizures before 2 years of age, after which the seizures subsided completely in two children and improved remarkably in the third. Preoperative Wada testing proved useful in evaluating pharmacologically the effect of hemispherectomy on contralateral polyspikes. Postoperative EEG revealed the absence of polyspikes in the operated hemisphere and decreased slowing on the contralateral side. Psychomotor development in the surgically treated infants exceeded that of the children not undergoing hemispherectomy. Of the two children treated medically, one died at 4 years of age in status epilepticus and the other (now 5 years old) has frequent seizures and severe developmental delay. Based on these results, hemispherectomy appears to be a useful procedure for controlling seizures and improving psychomotor development in children with hemimegaloencephaly involving the entire hemisphere. Surgery in infancy can prevent or minimize seizure foci and encephalopathic changes that may develop in the contralateral hemisphere. Staging the procedure and exercising meticulous hemostasis make surgery relatively safe in infants who otherwise may have significant blood loss associated with increased blood flow to the megaloencephalic hemisphere.

Anticonvulsants↗

PubMed2006

2q24-q31 deletion: report of a case and review of the literature.

We report a patient with a de novo interstitial deletion of the long arm of chromosome 2 involving bands 2q24.3-q31.1. The patient shows postnatal growth retardation, microcephaly, ptosis, down-slanting palpebral fissures, long eyelashes and micrognathia. Halluces are long, broad and medially deviated, while the other toes are laterally deviated and remarkably short with hypoplastic phalanges. She also showed developmental delay, seizures, lack of eye contact, stereotypic and repetitive hand movements and sleep disturbances with breath holding. Prenatal and three independent postnatal karyotypes were normal. Array-CGH analysis allowed us to identify and characterize a "de novo" 2q interstitial deletion of about 10.4Mb, involving segment between cytogenetic bands 2q24.3 and 2q31.1. The deletion was confirmed by quantitative PCR. About 30 children with 2q interstitial deletion have been reported. The deletion described here is overlapping with 15 of these cases. We have attempted to compare the clinical features of our patient with 15 overlapping cases. The emerging phenotypes include low birth weight, postnatal growth retardation, mental retardation and developmental delay, microcephaly, and peculiar facial dysmorphisms. Peculiar long and broad halluces with an increased distance between the first and the second toe are ("sandal gap" sign) present in most of the described patients. The gene content analysis of the deleted region revealed the presence of some genes that may be indicated as good candidates in generating both neurological and dysmorphic phenotype in the patient. In particular, a cluster of SCNA genes is located within the deleted region and it is known that loss of function mutations in SCNA1 gene cause a severe form of epilepsy.

Abnormalities, Multiple↗

PubMed1999

Skeletal muscle mitochondrial defects in nonspecific neurologic disorders.

A group of 25 children (5 months to 20 years of age) presenting with intractable seizures, developmental delay, and severe hypotonia, who did not fall into the known categories of mitochondrial encephalomyopathies, underwent muscle biopsy for evaluation of mitochondrial function and were compared with age-matched control subjects. Biopsied skeletal muscle was analyzed for six mitochondrial enzyme-specific activities, mitochondrial DNA point mutations and deletions, and mitochondrial DNA levels. The data reveal a high incidence of specific mitochondrial enzyme activity defects. Reduced activity levels were evident in complex I (11 patients), III (24 patients), IV (nine patients), and V (10 patients). Two patients also exhibited pronounced reduction in mitochondrial DNA levels (80% reduction compared with control subjects). Two patients manifested increased levels of 5-kb and 7.4-kb mitochondrial DNA deletions. Pathogenic mutations previously described in association with mitochondrial encephalomyopathies were not evident. The data suggest that mitochondrial dysfunction, including extensive defects in specific enzyme activities, may be frequently present in children with seizures, developmental delay, and hypotonia that do not fall within the known mitochondrial encephalomyopathies. These mitochondrial deficiencies can be primarily ascertained by biochemical analysis and are rarely accompanied by mitochondrial ultrastructural changes. The molecular basis of these defects, their role in these disorders, and potential treatment warrant further study.

Adult↗

PubMed1990

Lower serum thyroxine levels in rats following prenatal exposure to ethanol.

Fetal alcohol syndrome (FAS) is noted for poor growth, developmental delays, and mental retardation. In animals, prenatal alcohol exposure alters anatomical, physiological, and neurochemical maturation and produces behavioral changes similar to those in children. Since thyroid hormones are critical trophic factors for normal somatic and neural maturation, and since fetal thyroid hormones are profoundly affected by acute maternal ethanol administration, we hypothesized that postnatal effects of prenatal alcohol exposure may be related to abnormal thyroid hormone development. We report here that young rats exposed to alcohol in utero have significantly lower serum total thyroxine (T4) concentrations than normal and pair-fed control rats. The results suggest prenatal ethanol exposure may compromise thyroid development in ways not attributable to undernutrition or developmental delays alone. Lowered total T4 levels may be a teratogenic outcome of prenatal alcohol exposure, which could contribute to impaired growth, altered neural organization, and behavioral dysfunction.

Alcohol Drinking↗

PubMed2005

ATR-16 due to a de novo complex rearrangement of chromosome 16.

We describe a child with ATR-16 [alpha-thalassemia (thal)/mental retardation], who was referred for genetic evaluation because of minor anomalies and developmental delay. Cytogenetic analysis demonstrated a de novo complex rearrangement of chromosome 16. Fluorescence in situ hybridization (FISH) analysis, using chromosome 16 subtelomeric probes, showed that this patient had a deletion of the distal short arm of chromosome 16 that contains the alpha-globin genes and a duplication of 16q. Analysis of the alpha-globin locus by Southern blot showed a half normal dose of the alpha-globin gene. Microsatellite marker studies revealed that the duplicated 16q region was maternal in origin. Hematological studies revealed anemia, hypochromia and occasional cells with Hb H inclusion bodies. A hematological screening for alpha-thal should be considered in patients with mild developmental delay and a suggestive phenotype of ATR-16 with microcytic hypochromic anemia and normal iron status. The stellate pattern of the iris, a new finding in our patient, may contribute to a better clinical delineation of both syndromes, ATR-16 and/or duplication of 16qter.

Chromosome Aberrations↗