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.
| S-EPMC9776588 | biostudies-literature
Project description:PurposeNGLY1 Deficiency is an ultra-rare, multisystemic disease caused by biallelic pathogenic NGLY1 variants. The aims of this study were to (1) characterize the variants and clinical features of the largest cohort of NGLY1 Deficiency patients reported to date, and (2) estimate the incidence of this disorder.MethodsThe Grace Science Foundation collected genotypic data from 74 NGLY1 Deficiency patients, of which 37 also provided phenotypic data. We analyzed NGLY1 variants and clinical features and estimated NGLY1 disease incidence in the United States (U.S.).ResultsAnalysis of patient genotypes, including 10 previously unreported NGLY1 variants, showed strong statistical enrichment for missense variants in the transglutaminase-like domain of NGLY1 (p < 1.96E-11). Caregivers reported global developmental delay, movement disorder, and alacrima in over 85% of patients. Some phenotypic differences were noted between males and females. Regression was reported for all patients over 14 years old by their caregivers. The calculated U.S. incidence of NGLY1 Deficiency was ~ 12 individuals born per year.ConclusionThe estimated U.S. incidence of NGLY1 indicates the disease may be more common than the number of patients reported in the literature suggests. Given the low frequency of most variants and proportion of compound heterozygotes, genotype/phenotype correlations were not distinguishable.
| S-EPMC9759919 | biostudies-literature
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.
| S-EPMC7897899 | biostudies-literature
Project description:N-glycanase 1 (NGLY1) deficiency is a debilitating, ultra-rare autosomal recessive disorder caused by loss of function of NGLY1, a cytosolic enzyme that deglycosylates other proteins. It is characterized by severe global developmental delay and/or intellectual disability, hyperkinetic movement disorder, transient elevation of transaminases, (hypo)alacrima and progressive, diffuse, length-dependent sensorimotor polyneuropathy. A prospective natural history study (NHS) was conducted to elucidate clinical features and disease course. Twenty-nine participants were enrolled (15 onsite, 14 remotely) and followed for up to 32 months, representing ~29% of the ~100 patients identified worldwide. Participants exhibited profound developmental delays, with almost all developmental quotients below 20 on the Mullen Scales of Early Learning, well below the normative score of 100. Increased difficulties with sitting and standing suggested decline in motor function over time. Most patients presented with (hypo)alacrima and reduced sweat response. Pediatric quality of life was poor except for emotional function. Language/communication and motor skill problems including hand use were reported by caregivers as the most bothersome symptoms. Levels of the substrate biomarker, GlcNAc-Asn (aspartylglucosamine; GNA), were consistently elevated in all participants over time, independent of age. Liver enzymes were elevated for some participants but improved especially in younger patients and did not reach levels indicating severe liver disease. Three participants died during the study period. Data from this NHS informs selection of endpoints and assessments for future clinical trials for NGLY1 deficiency interventions. Potential endpoints include GNA biomarker levels, neurocognitive assessments, autonomic and motor function (particularly hand use), (hypo)alacrima and quality of life.
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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.
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Project description:Angiogenesis is a critical process to form new blood vessels from preexisting vessels under physiologic and pathologic conditions and involves cellular and morphologic changes such as endothelial cell proliferation, migration, and vascular tube formation. Despite evidence that angiogenic factors, including vascular endothelial growth factor and Notch, control various aspects of angiogenesis, the molecular mechanisms underlying gene regulation in blood vessels and surrounding tissues are not fully understood. Importantly, recent studies demonstrate that Forkhead transcription factor Foxc2 directly regulates expression of various genes involved in angiogenesis, CXCR4, integrin beta3, Delta-like 4 (Dll4), and angiopoietin 2, thereby controlling angiogenic processes. Thus, Foxc2 is now recognized as a novel regulator of vascular formation and remodeling. This review summarizes current knowledge about the function of Foxc2 in angiogenesis and discusses prospects for future research in Foxc2-mediated pathologic angiogenesis in cardiovascular disease.
| S-EPMC2674371 | 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