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PubMed2024

Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder.

PURPOSE: The function of FAM177A1 and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1 to be a critical immune-associated gene. One previous case study has linked FAM177A1 to a neurodevelopmental disorder in 4 siblings. METHODS: We identified 5 individuals from 3 unrelated families with biallelic variants in FAM177A1. The physiological function of FAM177A1 was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort. RESULTS: These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA sequencing and metabolomic data sets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation. CONCLUSION: Our data shed light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity.

Humans↗
PubMed2026

Identification of the Genomic Etiology of Unexplained Congenital Problems in Pediatric Patients: First Reported Case With Coffin-Siris Syndrome and Sialuria From India.

Coffin-Siris syndrome (CSS) (OMIM:614608) is a rare genetic disorder characterized by global developmental delay (GDD), speech impediment, coarse facial features, and hypoplastic or absent fifth fingernails/toenails. Genetic variants in the SMARCB1 gene are associated with CSS, benign tumors (schwannomas), and rhabdoid tumor predisposition syndrome. Genetic variants in the GNE gene are associated with the autosomal dominant sialuria (OMIM#269921), a rare inborn error of metabolism resulting in high levels of free sialic acid. Here we present case reports of two siblings: patient 1 (10 years) and patient 2 (2 years). While both siblings showed GDD and dysmorphic features such as hypotelorism and large ears, patient #1 exhibited additional phenotypes. Whole exome sequencing identified a heterozygous pathogenic variant, NM_003073.5:c.1096C>T (p.Arg366Cys), in the SMARCB1 gene in both siblings. In addition, patient 1 harbored a heterozygous likely pathogenic variant, NM_005476.7:c.2086G>A (p.Val696Met), in the GNE gene, which was absent in patient 2. The co-occurrence of the GNE variant may contribute to the increased severity of the phenotype in patient 1. This study is the first report worldwide of the co-occurrence of two extremely rare disorders. These findings highlight the complexity of genomic contributions while also emphasizing the value of genomic sequencing for congenital problems.

Coffin–Siris syndrome↗
PubMed1996

Multiple roles for dopamine in Drosophila development.

Manipulation of dopamine levels by inhibition of tyrosine hydroxylase activity was accomplished in Drosophila melanogaster larval instars by feeding enzyme inhibitors for a 24-hr period. Behavioral assays performed immediately after treatment demonstrated that larval phototaxis, salt aversion, and heptanol preference were unaffected by reduced levels of dopamine. Within a few hours of treatment, the larvae ceased exploratory behavior and were unresponsive to external stimuli; these larvae eventually died. This behavior is strikingly similar to that displayed by dopamine-deficient transgenic mice. Treated larvae placed immediately onto normal food (to replenish dopamine levels) showed significant developmental delays and decreased fertility as adults. The lethality, developmental retardation, and decrease in fertility were reversed by addition of L-DOPA to inhibitor-containing food, suggesting that these effects were due solely to inhibition of tyrosine hydroxylation. Depletion of dopamine in newly eclosed females resulted in abnormally developed ovaries. These results suggest that the enzymatic function of tyrosine hydroxylase is vital and that reduced levels of dopamine result in akinesia and lethality, developmental retardation, and decreased fertility.

Animals↗
PubMedDate not supplied

Hemimegalencephaly: evaluation with positron emission tomography.

We performed positron emission tomographic (PET) studies with 2-deoxy-2[18F]fluoro-D-glucose in 8 children with hemimegalencephaly (HME). HME is a developmental brain malformation associated with epilepsy, hemianopsia, and varying degrees of developmental delay. We hypothesized that the relatively poor overall developmental outcome of surgically hemispherectomized HME patients as a group, compared to children undergoing hemispherectomy for Sturge-Weber syndrome or chronic focal encephalitis, is related to dysfunction of the structurally "normal" non-HME side and that PET would be helpful in the pre-surgical evaluation of HME patients with intractable epilepsy. Visual analysis of the non-HME side on PET clearly revealed evidence of cortical hypometabolism in 4 patients compared to controls. Seven children underwent epilepsy surgery. One child had a glucose metabolic pattern suggesting a cortical lamination defect in the non-HME hemisphere, bilateral independent seizure onset, and was not considered to be a surgical candidate. We found a general correlation between the pattern of glucose utilization in the less affected hemisphere and prognosis. Although the follow-up periods are short, it is recommended that HME children with intractable epilepsy undergo hemispherectomy in the first year of life in order to allow maximal brain plasticity to occur; however, preoperative evaluation should also include an assessment of the integrity of the non-HME hemisphere.

Brain↗
PubMed2001

Developmental assessment-based surgical intervention for intractable epilepsies in infants and young children.

PURPOSE: To define the most appropriate time for surgery for medically intractable epilepsies in infants and young children. METHODS: First we examined retrospectively the changes in developmental quotients (DQs) during the clinical course and the clinical factors affecting the DQ in 39 consecutive patients younger than 15 years, who underwent surgical treatment for intractable epilepsy. Second, we examined prospectively five new patients for early detection of developmental arrest or regression by periodic developmental assessments and whether this could lead to early surgical intervention, eventually resulting in minimal developmental defects. RESULTS: Retrospective studies revealed that the DQ progressively decreased with age and that the reduction of DQ was related to continuing frequent seizures in many patients. The prospective studies demonstrated that periodic developmental assessments could detect the reduction of DQ at 5 months or later after onset of frequent seizures in three patients. In two other patients, operations were performed before reduction of DQs, and their postoperative DQ levels were normal. The post-operative recovery of DQ was complete in one patient whose operation was performed 3 months after reduction of DQ, whereas it was incomplete in two others whose operations were carried out at 12 and 14 months after reduction, respectively. Furthermore, three patients with normal developmental outcome had shorter periods between the onset of frequent seizures and the operation (< or = 7 months) than those of two patients with developmental delay (> or = 17 months). CONCLUSIONS: To minimize the developmental defects, periodic developmental assessments should be initiated when frequent seizures have occurred, and surgery should be considered as soon as possible when DQ reduction is recognized.

Child, Preschool↗
PubMed1988

47,XXX: what is the prognosis?

Eleven unselected 47,XXX girls, now 15 to 22 years of age, have been observed from birth in a prospective study of children with sex chromosome anomalies. A description of their growth and development is presented. The 47,XXX infants were not generally distinguishable from chromosomally normal children in the first year of life, even though there was a slight delay in neuromotor development. By 2 years of age, developmental delays in speech and language often became evident, and speech therapy was often necessitated in the preschool years. Early school problems included speech and language deficiencies, lack of coordination, poor academic performance, and immature behavior; these persisted throughout the school years. By high school age, a 47,XXX girl was generally tall and often subject to somatic complaints. Sexual development was generally normal. Seven of the 11 propositae had a diagnosed psychiatric disorder or disturbance at some time during adolescence. Variability within this syndrome is great; one proposita is in college and another is mentally retarded. The frequency of the diagnosis of the 47,XXX karyotype by genetic amniocentesis is estimated to be 1/1000, the same incidence as in the newborn population. Expectant parents must be counseled as to the significance of this karyotype and prognostic information must be given. Suggested guidelines are included.

Adaptation, Psychological↗
PubMed2005

[Diagnosis of speech retardation and early intervention].

In the diagnosis of speech retardation, not only speech production and comprehension, but the assessment of interpersonal relationships is important as an indicator of non-language development. The newly revised K method developmental examination ("Shinban K-shiki Kensahou") is widely used as an assessment for preschool children. I think the Enjouji method analytical developmental examination for infant and preschool children ("Enjouji-shiki Bunsekiteki Kensahou") is a simple and useful examination scale of developmental delay because it includes the category of interpersonal relationship. Developmental language disorder (DLD) is the most frequently noted (4.3%) in the general population as seen in our research of speech retardation of 1 year-6 month examination in Ota-ku district. Some academic societies of children warn that TV watching for a long time causes speech retardation or psychiatric disorders, but it seems to me that this influence is of limited significance. To assess autism adequately we made a checklist that includes concrete behavioral abnormalities based on the criteria of DSM-IV. The criteria of DLD are diverse and are not currently standardized now. I proposed, therefore, a criterion by unifying them.

Child, Preschool↗
PubMed1981

The predictive validity of a simple two item developmental screening test for three year olds.

A simple two item developmental screening test for three year old children is described, together with its predictive validity when used with 937 children being followed in the Dunedin Multidisciplinary Child Development Study. Data are presented to show that the test screened out 6.9 percent of the three year old children and more than half of them gained very low scores on at least one test of intelligence, motor or language development two years later. The screening test successfully identified from one half to three-quarters of all the children who gained very low five year scores in intelligence, motor or language development at age five. The two item screening test is recommended for use by doctors, nurses, teachers or social workers, as a simple method of identifying three year old children in need of further assessment because of suspected developmental delays.

Child, Preschool↗
PubMed1995

Allogeneic bone marrow transplantation for fucosidosis.

Bone marrow transplantation was performed on an 8-month-old boy who was diagnosed as having fucosidosis following the diagnosis of the disease in his older brother. Although he was asymptomatic and his development was normal, abnomalities were found on an MRI scan prior to transplant. In the absence of a suitable related donor, an unrelated volunteer donor was used. Conditioning for the transplant consisted of busulphan and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of in vitro T cell-depletion of the bone marrow and in vivo administration of cyclosporin. The post-transplant period was complicated by moderately severe graft-versus-host disease. Engraftment was documented by the presence of donor levels of alpha-fucosidase, donor blood group and tissue type (difference in the DQ antigen), and chromosomal polymorphism pattern of donor origin. Eighteen months after transplant, there is evidence of mild neurodevelopmental delay. By contrast, his elder sibling showed far greater developmental delay at the same age. The patient's MRI scan shows improvement. We believe this to be the first case of human fucosidosis treated by bone marrow transplantation.

Bone Marrow Transplantation↗
PubMed1997

New autosomal-recessive syndrome of Leber congenital amaurosis, short stature, growth hormone insufficiency, mental retardation, hepatic dysfunction, and metabolic acidosis.

We report on a new autosomal-recessive syndrome in 4 Japanese children in 2 families. The key manifestations are Leber congenital amaurosis, short stature, growth hormone insufficiency, mental retardation, hepatic dysfunction, metabolic acidosis, and autosomal-recessive inheritance. There were no consanguineous marriages. Abnormal eye movements were noticed neonatally, and ophthalmological examinations showed no visual acuity, pigmentary retinal degeneration, and nonrecordable electroretinograms in all cases. Inadequate weight gain and short stature gradually became apparent after birth, and at present the height range is -4.6 - -7.2 SD (standard deviations). Developmental delay was noted at age 4 months, and the developmental quotient is 50-70 at present. Deterioration of development and convulsions were not recognized. Elevated serum aminotransferase levels and metabolic acidosis were also found at age 4 months. Proximal renal tubular acidosis was clarified by bicarbonate tolerance tests in 1 case, and may have caused metabolic acidosis. Growth hormone secretion was insufficient by insulin tolerance test in 3 cases. One year of growth hormone therapy in 2 cases did not affect growth velocity. Hepatic dysfunction and metabolic acidosis ameliorated later. No renal cysts were found. A cranial computed tomographic scan and magnetic resonance imaging showed normal findings. Amino acids, organic acids, and very long chain fatty acid levels in plasma were all normal in the 3 cases examined. Histopathological and mitochondrial DNA analyses showed no evidence of mitochondrial disorders.

Acidosis↗
PubMed1991

Distinct subsets of accessory cells activate Thy-1+ triple negative (CD3-, CD4-, CD8-) cells and Th-1 delayed-type hypersensitivity effector T cells.

The SJL strain of mice possess a unique developmental delay in the ability to exhibit delayed-type hypersensitivity (DTH) responses after immunization with a wide variety of Ag. Similar to other models of DTH, the adoptive transfer of syngeneic Ag-pulsed macrophages from DTH-responsive mice into these DTH-unresponsive mice results in the activation of Ag-specific, CD4+ DTH effector Th1 T cells. The absence of other defects in APC-dependent immune responses indicate that the macrophages is the sole APC required for the induction of DTH effector T cells in SJL mice. The defect occurs during the sensitization phase of the DTH response; however, it has not been determined whether a Th cell, which is required for the induction of CD4+ DTH effector T cells, was present in the DTH unresponsive SJL mice. In this study, we have determined that the Thy-1+ helper cell is induced upon Ag stimulation of nonresponder mice and present evidence for the existence of an accessory cell distinct from the macrophage that induces CD4+ DTH effector T cells. Our data indicate that CD4+ DTH effector T cells are induced in an Ag-specific and MHC-restricted manner by an adherent macrophage that expresses the Mac-1+, Mac-2-, Mac-3+, I-A+ phenotype. Adoptive transfer of as few as 100 of the Mac-1+, Mac-2-, or Mac-3+ subsets from DTH responsive donors to DTH unresponsive recipients is able to overcome the DTH deficit. The activation of CD4+ DTH effector T cells in the SJL mouse cells also requires a Thy-1+, Lyt-1+, CD3-, CD4-, CD8-, helper cell. In contrast to the Mac-1+, Mac-3+, I-A+ accessory cell, this helper cell requires an adherent, irradiation resistant, accessory cell that expresses the Mac-1+, Mac-2-, Mac-3-, I-A- surface phenotype for activation. Further, the interaction between this accessory cell and the Thy-1+ helper cell is neither Ag-specific nor MHC restricted. This is the first demonstration of an accessory cell requirement for the Thy-1+, Lyt-1+, B220-, CD4-, CD8-, CD3- DTH Th cell. These data indicate that the activation of the triple negative helper cells and subsequent activation of the CD4+ effector T cells are regulated by two distinct macrophage subpopulations.

Animals↗
PubMed1983

Suppressing aggressive-destructive behavior by delayed overcorrection.

Delayed overcorrection reduced the aggressive-destructive behavior of a developmentally delayed adolescent when it was added to previously ineffective procedures of differential reinforcement (tokens and token-removal) of other behavior. The delayed contingency was necessary because target behaviors occurred exclusively in the absence of the only family member who could overpower the subject. A multiple baseline design across two levels of problem-behavior severity indicated that delayed overcorrection effectively suppressed the aggressive-destructive episodes. The results support the notion that delayed contingencies can effectively suppress target behaviors.

Adolescent↗
PubMed2005

Is mom too sensitive? Impact of maternal stress during gestation.

Studies have documented the detrimental impact of gestational and postpartum maternal stress on the developing offspring. In susceptible individuals, stress has been associated with everything from brain developmental delays to emotionality and behavior disorders. Understanding the genetics and developmental window of greatest stress sensitivity is vital to providing the best preventative care and therapeutic targets. Corticotropin-releasing factor (CRF) and its receptors (CRFR1 and CRFR2) are the key regulators of the endocrine stress response and are critical in maintenance of organismal homeostasis. Dysregulation of these stress pathways can result in an increased sensitivity to stress. Mice deficient for CRFR2 show such a dysregulation and have been found to be a valuable genetic model of increased stress sensitivity. Initial comparisons utilizing this mouse model in studies examining maternal behaviors and cross-fostering outcome validate the complex nature-nurture contribution. Using this model, altered stress responsivity in offspring appears to require both a genetic predisposition to stress sensitivity and a postnatal environment that influences it.

Animals↗
PubMed1998

Approaching the management of the neonatal intensive care unit graduate through history and physical assessment.

NICU graduates, often ex-premature infants, offer unusual challenges to the primary care provider. History and physical assessment require an organized approach with meticulous attention to detail. These infants are at high risk for multiple problems including growth delays, nutrition and feeding problems, pulmonary sequelae, neurological sequelae and developmental delays, vision and hearing disturbances, as well as abnormalities in parent-infant bonding. This article emphasizes particular aspects of the history and physical examination that signify pathophysiology and sequelae common to the NICU graduate.

Bronchopulmonary Dysplasia↗
PubMed2005

Acute bilateral striatal necrosis with rotavirus gastroenteritis and inborn metabolic predisposition.

We present a 9-month-old male with acute rotavirus gastroenteritis who developed an acute encephalopathy with focal seizures and developmental regression. Magnetic resonance imaging showed bilateral striatal necrosis and raised glutarylcarnitine levels on tandem mass spectrometry of a (crisis) blood spot, and chromatography of organic acids revealed increased urinary excretion of dicarboxylic acid. Skin biopsy demonstrated a partial decrease in glutaryl-CoA dehydrogenase activity. The case was not typical for either rotavirus encephalitis/rotavirus-associated encephalopathy or for glutaric aciduria type I. The patient has developmental delay and continues to receive physiotherapy, speech therapy, and local developmental follow-up.

Brain Diseases, Metabolic, Inborn↗
PubMed1985

A distinct variant of intermediate maple syrup urine disease.

Branched chain alpha-ketoacid dehydrogenase (BCKAD) deficiency, or maple syrup urine disease (MSUD), can be categorized as classical, intermediate, intermittent or thiamine responsive, based on generally concordant in vitro BCKAD activity and severity of phenotype. We present clinical and enzymatic data on a boy with intermediate maple syrup urine disease, and suggest that he represents a novel category of mutation. He presented at age 10 months in ketoacidotic coma, with a history of irritability, poor feeding and growth and developmental delay. Branched chain amino acid restriction effected normal growth and developmental parameters by age 42 months. In contrast to previous patients with intermediate MSUD, his fibroblasts and fibroblast extracts failed to decarboxylate [1-14C]-alpha-ketoisovalerate (KIV). The defect is not in mitochondrial transport of substrate, but rather in the catalytic activity of the E1 component of the BCKAD. Disrupted cells of the proband exhibited negligible BCKAD activity over a wide range of keto acid substrate concentrations, irrespective of the presence of added thiamine pyrophosphate (TPP). These results differ from the sigmoidal kinetics observed using classical MSUD extracts, and the hyperbolic kinetics with control preparations under the same assay conditions. We propose that the structurally altered enzyme possesses reduced but not negligible activity in vivo, and exists as an unstable complex in vitro under assay conditions used, even in the presence of added TPP.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMedDate not supplied

Developmental disabilities: genetic implications.

Knowledge and new techniques in genetics can aid in a better understanding of developmental disabilities. Through new treatments and better assessment skills, individuals with disorders such as phenylketonuria (PKU), Down syndrome, and fragile X syndrome are having diagnoses sooner and are living into adulthood. With the passage of public law 99.457, early intervention services are mandated for those who are 3 years old or younger and are developmentally delayed or at risk for delay. Organizations for paraprofessionals and professionals in the arena of developmental disabilities and genetics exist to create a forum for future action, awareness, and direction.

Child↗
PubMedDate not supplied

Developmental rounds: an intervention strategy for hospitalized infants.

Infants who experience prolonged or repeated hospitalization are at risk for developmental delays. Federal mandates for early intervention include the initiation of developmental intervention during hospitalization. Developmental Rounds is a creative strategy to address the unique needs of high risk infants and their families and to promote continuity of care and community referrals for developmental intervention.

Child, Hospitalized↗