NGLY1 Deficiency: A Rare Newly Described Condition with a Typical Presentation.
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ABSTRACT:
SUBMITTER: Dabaj I
PROVIDER: S-EPMC7996810 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Pathogenic variants in the NGLY1 gene are associated with a Congenital Disorder of Deglycosylation (CDDG) characterized by delays in reaching developmental milestones, complex hyperkinetic movement disorder, transient elevation of transaminases, and alacrima or hypolacrima. To date, only few cases of NGLY1 deficiency have been identified and reported in the literature. This report highlights a first child of non-consanguineous parents with no relevant family history who presented with hypotonia and poor weight gain since birth. At 2 months, the child developed paroxysmal cervical dystonia, posteriorly resolving spontaneously by age of 3. Subsequently, delays in reaching developmental milestones, ataxia, dyskinesia, visual impairment due to cone rod retinal dystrophy, low triglycerides, and persistently elevated liver transaminases were observed. Extensive etiological investigation was performed, including array-CGH and metabolic evaluation with no abnormalities to note. Trio whole exome analysis identified a homozygous pathogenic variant of the NGLY1 gene, c.1891del (p.Gln631Serfs*7), consistent with CDDG. Both parents were confirmed to be heterozygous carriers. The authors discuss in this case, the clinical presentation, the diagnostic challenges, and review other relevant NGLY1 deficiency cases previously reported in the literature. This case, along with the previous reported in the literature, indicates that pathogenic variants in NGLY1 cause a recognizable phenotype and should be considered in patients with a typical presentation. It also suggests that decreased sweating is not present universally in these patients.
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Project description:INTRODUCTION:Cyclopia (alobar holoprosencephaly) (OMIM% 236100) is a rare and lethal complex human malformation, resulting from incomplete cleavage of prosencephalon into right and left hemispheres occurring between the 18th and the 28th day of gestation. Holoprosencephaly occurs in 1/16,000 live births, and 1/250 during embryogenesis. Approximately 1.05 in 100,000 births are identified as infants with cyclopia, including stillbirths. Cyclopia typically presents with a median single eye or a partially divided eye in a single orbit, absent nose, and a proboscis above the eye. Extracranial malformations described in stillbirths with cyclopia include polydactyl, renal dysplasia, and an omphalocele. The etiology of this rare syndrome, which is incompatible with life, is still largely unknown. Most cases are sporadic. Heterogeneous risk factors have been implicated as possible causes. CASE PRESENTATION:A live full-term baby with birth weight of 2900 g, product of cesarean section because of severe fetal bradycardia, was born at Prince Hashem Military Hospital - Zarqa city/Jordan. This newborn was the first baby to a non-consanguineous family, and a healthy 18-year-old mother, with no history of drug ingestion or febrile illnesses during pregnancy. Antenatal history revealed severe hydrocephalus diagnosed early by intrauterine ultrasound but the pregnancy was not terminated because of the lack of medical legitimization in the country. On examination, the newborn was found to have a dysmorphic face, with a median single eye, absence of nose, micrognathia, and a proboscis above the eye, all of which made cyclopia the possible initial diagnosis. Multiple unusual abdominal defects were present that include a huge omphalocele containing whole liver and spleen, urinary bladder extrophy, and undefined abnormal external genitalia, which called for urgent confirmation. Brain MRI was done and revealed findings consistent with alobar holoprosencephaly (cyclopia). CONCLUSION:Presentation of cyclopia is not fully exposed and new cyclopian syndromes still can appear. The prenatal diagnosis of cyclopia can be made early by ultrasound, and the awareness of the spectrum of sonographic findings of cyclopia can improve the accuracy of prenatal diagnosis. The legitimization of pregnancy termination for indexed cases in many countries around the world should be revised.
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Project description:CDKL5 deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the X-linked cyclin-dependent kinase 5 (CDKL5) gene. This rare disorder occurs more frequently in females than in males. The incidence is estimated to be approximately 1: 40,000-60,000 live births. So far, 50 cases have been described in boys. The clinical course in males tends to be more severe and is often associated with death in the first or second decade of life. The authors present an unreported 2.5-year-old male patient with drug-resistant epilepsy who was diagnosed with a de novo mutation in the CDKL5 gene. First seizures developed in the fifth week of life and have progressed steadily since then. The child's psychomotor development was strongly delayed, and generalized hypotonia was noticed since birth. Brain MRI showed areas of incomplete myelination, posterior narrowing of the corpus callosum, a pineal cyst of up to 3 mm, and open islet lids. Intensive antiseizure medications (ASMs), a ketogenic diet, and steroid therapy were not successful. Short-term improvement was achieved with the implantation of a vagal nerve stimulator (VNS). Due to the progressive course of the disease, the boy requires frequent modification of ASMs.
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Project description:N-Glycanase 1 (NGLY1) deficiency is a congenital disorder caused by mutations in the NGLY1 gene. Because systemic Ngly1-/- mice with a C57BL/6 (B6) background are embryonically lethal, studies on the mechanism of NGLY1 deficiency using mice have been problematic. In this study, B6-Ngly1-/+ mice were crossed with Japanese wild mice-originated Japanese fancy mouse 1 (JF1) mice to produce viable F2 Ngly1-/- mice from (JF1×B6)F1 Ngly1-/+ mice. Systemic Ngly1-/- mice with a JF1 mouse background were also embryonically lethal. Hybrid F1 Ngly1-/- (JF1/B6F1) mice, however, showed developmental delay and motor dysfunction, similar to that in human patients. JF1/B6F1 Ngly1-/- mice showed increased levels of plasma and urinary aspartylglycosamine, a potential biomarker for NGLY1 deficiency. JF1/B6F1 Ngly1-/- mice are a useful isogenic animal model for the preclinical testing of therapeutic options and understanding the precise pathogenic mechanisms responsible for NGLY1 deficiency.
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Project description:Chiropractors expect the typical patient to recover fully or to improve quickly with treatment if relapses occur. However, a mismatch between expectations and outcome would have a negative effect on both the chiropractors' professional self-esteem and patients' satisfaction with care. The prevalence of three types of recovery patterns among patients with non-specific low back pain (LBP) was calculated: 1: A full sustained recovery. 2: Initial recovery, but with one or several relapses followed by a period of recovery. 3: No initial recovery, but at least one period of recovery during the six month course of the study. Also, the number of patients classified as recovered at the end of the study was calculated.In this Swedish clinical observational study from 2008 to 2009, an automated text message system (SMS-Track®) was used to ask chiropractic patients weekly for 6 months about the number of days their LBP had bothered them during the past week. Data were analyzed blindly by two researchers by viewing individual graphs and was performed twice.In all 176 of 262 patients with non-specific LBP were included in the analysis. 1) Twenty percent of patients (CI: 15.3-26.9) made a full sustained recovery. 2) A further 20% (CI: 14.8-26.2) recovered initially but experienced a relapse, followed by at least one new period of full recovery. 3) Twenty-three percent (CI: 17.3-29.3) of patients failed to recovery initially but experienced recovery some time during the study. 4) Thirty-seven percent (CI: 30.3-44.1) had no periods of recovery, and were therefore classified as having a non-favorable course. At the end of the study, 41% (CI: 34.1-48.1) were classified as recovered.The results from this study can be used to introduce a realistic approach to chiropractic care in LBP, which should reduce disappointments among both chiropractors and patients. There was no "typical" recovery pattern. Trajectories were, in fact, spread over several subgroups with somewhat more than half reporting a favorable course but only one fifth enjoyed early and sustained recovery. Further, from a research perspective, the end-of -study status does not well depict the outcome experienced by patients.
| S-EPMC5549290 | biostudies-other
Project description:Molecular methods are increasingly used to identify pathogens that are difficult to cultivate. We report a case of disseminated infection with "Mycobacterium tilburgii," a proposed species that has never been cultivated. The case illustrates the diagnostic utility of sequence analysis of the 16S rRNA gene directly from clinical specimens.
| S-EPMC2681830 | biostudies-literature
Project description:Mutations in human N-glycanase 1 (NGLY1) cause the first known congenital disorder of deglycosylation (CDDG). Patients with this rare disease, which is also known as NGLY1 deficiency, exhibit global developmental delay and other phenotypes including neuropathy, movement disorder, and constipation. NGLY1 is known to regulate proteasomal and mitophagy gene expression through activation of a transcription factor called "nuclear factor erythroid 2-like 1" (NFE2L1). Loss of NGLY1 has also been shown to impair energy metabolism, but the molecular basis for this phenotype and its in vivo consequences are not well understood. Using a combination of genetic studies, imaging, and biochemical assays, here we report that loss of NGLY1 in the visceral muscle of the Drosophila larval intestine results in a severe reduction in the level of AMP-activated protein kinase ? (AMPK?), leading to energy metabolism defects, impaired gut peristalsis, failure to empty the gut, and animal lethality. Ngly1-/- mouse embryonic fibroblasts and NGLY1 deficiency patient fibroblasts also show reduced AMPK? levels. Moreover, pharmacological activation of AMPK signaling significantly suppressed the energy metabolism defects in these cells. Importantly, the reduced AMPK? level and impaired energy metabolism observed in NGLY1 deficiency models are not caused by the loss of NFE2L1 activity. Taken together, these observations identify reduced AMPK signaling as a conserved mediator of energy metabolism defects in NGLY1 deficiency and suggest AMPK signaling as a therapeutic target in this disease.
| S-EPMC7769621 | biostudies-literature
Project description:N-glycanase 1 (NGLY1) deficiency is a rare inherited disorder characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, motor deficits, and other neurological symptoms. The underlying mechanisms of the NGLY1 phenotype are poorly understood, and no effective therapy is currently available. Similar to human patients, the rat model of NGLY1 deficiency, Ngly1-/-, shows developmental delay, movement disorder, somatosensory impairment, scoliosis, and learning disability. Here we show that single intracerebroventricular administration of AAV9 expressing human NGLY1 cDNA (AAV9-hNGLY1) to Ngly1-/- rats during the weaning period restored NGLY1 expression in the brain and spinal cord, concomitant with increased enzymatic activity of NGLY1 in the brain. hNGLY1 protein expressed by AAV9 was found predominantly in mature neurons, but not in glial cells, of Ngly1-/- rats. Strikingly, intracerebroventricular administration of AAV9-hNGLY1 normalized the motor phenotypes of Ngly1-/- rats assessed by the rota-rod test and gait analysis. The reversibility of motor deficits in Ngly1-/- rats by central nervous system (CNS)-restricted gene delivery suggests that the CNS is the primary therapeutic target organs for NGLY1 deficiency, and that the Ngly1-/- rat model may be useful for evaluating therapeutic treatments in pre-clinical studies.
| S-EPMC8201687 | biostudies-literature
Project description:ObjectivesTogether with the lysosomal storage diseases, NGLY1 deficiency is a congenital disorder of deglycosylation (NGLY1-CDDG). Since the first report in 2012, 26 patients have been described. All but one were diagnosed by exome or genome sequencing; the remaining one was identified by finding an increased concentration of an urinary marker.The aim of this study was to describe the clinical, biochemical, and molecular features of the first Polish patient diagnosed with NGLY1-CDDG, to provide an overview of the literature and to propose a diagnostic algorithm.ResultsA Polish patient presented with global developmental delay, hyperkinetic movement disorder, stagnation of head growth, hypolacrimia, elevated serum transaminases, and hypolipidemia in infancy. Whole exome sequencing revealed two heterozygous nonsense variants in the NGLY1 gene (a novel and an unreported). Literature review revealed global developmental disability in all reported patients, and hyperkinetic movements as well as alacrima/hypolacrima in nearly all.ConclusionsNGLY1-CDDG should be considered in patients with developmental disability associated with a hyperkinetic movement disorder and alacrimia/hypolacrima. Absence of the latter two symptoms does not rule out this diagnosis.
| S-EPMC7012742 | biostudies-literature
Project description: Not available
| S-EPMC11016977 | biostudies-literature