ABSTRACT
The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo. TSC2-deficient macrophages formed mTORC1-dependent granulomatous structures in vitro and showed constitutive proliferation that was mediated by the neo-expression of cyclin-dependent kinase 4 (CDK4). Moreover, mTORC1 promoted metabolic reprogramming via CDK4 toward increased glycolysis while simultaneously inhibiting NF-κB signaling and apoptosis. Inhibition of mTORC1 induced apoptosis and completely resolved granulomas in myeloid TSC2-deficient mice. In human sarcoidosis patients, mTORC1 activation, macrophage proliferation and glycolysis were identified as hallmarks that correlated with clinical disease progression. Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1-dependent granulomatous disease with clinical implications for sarcoidosis.
Subject(s)
Granuloma/immunology , Macrophages/immunology , Multiprotein Complexes/metabolism , Sarcoidosis/immunology , TOR Serine-Threonine Kinases/metabolism , Tumor Suppressor Proteins/metabolism , Animals , Cell Line , Cyclin-Dependent Kinase 4/metabolism , Disease Progression , Granuloma/drug therapy , Humans , Macrophages/drug effects , Mechanistic Target of Rapamycin Complex 1 , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA, Small Interfering/genetics , Sarcoidosis/drug therapy , Signal Transduction , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/geneticsABSTRACT
Elevated total plasma homocysteine (hyperhomocysteinemia) is a marker of cardiovascular, thrombotic, and neuropsychological disease. It has multiple causes, including the common nutritional vitamin B12 or folate deficiency. However, some rare but treatable, inborn errors of metabolism (IEM) characterized by hyperhomocysteinemia can be missed due to variable presentations and the lack of awareness. The aim of this study is to identify undiagnosed IEM in adults with significantly elevated homocysteine using key existing clinical data points, then IEM specific treatment can be offered to improve outcome. We conducted a retrospective study with data mining and chart review of patients with plasma total homocysteine >30 µmol/L over a two-year period. We offer biochemical and genetic testing to patients with significant hyperhomocysteinemia without a clear explanation to diagnose IEM. We identified 22 subjects with significant hyperhomocysteinemia but no clear explanation. Subsequently, we offered genetic testing to seven patients and diagnosed one patient with classic homocystinuria due to cystathionine beta-synthase deficiency. With treatment, she lowered her plasma homocysteine and improved her health. This study stresses the importance of a thorough investigation of hyperhomocysteinemia in adults to identify rare but treatable IEM. We propose a metabolic evaluation algorithm for elevated homocysteine levels.
Subject(s)
Homocystinuria , Hyperhomocysteinemia , Metabolism, Inborn Errors , Humans , Adult , Female , Folic Acid , Retrospective Studies , Vitamin B 12/therapeutic use , Hyperhomocysteinemia/diagnosis , Hyperhomocysteinemia/genetics , Homocystinuria/diagnosis , Homocystinuria/genetics , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , HomocysteineABSTRACT
3q29 deletion syndrome (3q29del) is a rare genomic disorder caused by a 1.6 Mb deletion (hg19, chr3:195725000-197350000). 3q29del is associated with neurodevelopmental and psychiatric phenotypes, including an astonishing >40-fold increased risk for schizophrenia, but medical phenotypes are less well-described. We used the online 3q29 registry of 206 individuals (3q29deletion.org) to recruit 57 individuals with 3q29del (56.14% male) and requested information about musculoskeletal phenotypes with a custom questionnaire. 85.96% of participants with 3q29del reported at least one musculoskeletal phenotype. Congenital anomalies were most common (70.18%), with pes planus (40.35%), pectus excavatum (22.81%), and pectus carinatum (5.26%) significantly elevated relative to the pediatric general population. 49.12% of participants reported fatigue after 30 min or less of activity. Bone fractures (8.77%) were significantly elevated relative to the pediatric general population. Participants commonly report receiving medical care for musculoskeletal complaints (71.93%), indicating that these phenotypes impact quality of life for individuals with 3q29del. This is the most comprehensive description of musculoskeletal phenotypes in 3q29del to date, suggests ideas for clinical evaluation, and expands our understanding of the phenotypic spectrum of this syndrome.
Subject(s)
Developmental Disabilities , Intellectual Disability , Humans , Child , Male , Female , Developmental Disabilities/genetics , Chromosome Deletion , Quality of Life , Intellectual Disability/epidemiology , Intellectual Disability/genetics , Intellectual Disability/psychology , Phenotype , SyndromeABSTRACT
Trisomy 18, sometimes called Edwards syndrome, occurs in about 1 in 6000 live births and causes multiple birth defects in affected infants. The extra copy of chromosome 18 causes the altered expression of many genes and leads to severe skeletal, cardiovascular and neurological systems malformations as well as other medical problems. Due to the low rate of survival and the massive genetic imbalance, little research has been aimed at understanding the molecular consequences of trisomy 18 or considering potential therapeutic approaches. Our research is the first study to characterize whole-genome expression in fibroblast cells obtained from two patients with trisomy 18 and two matched controls, with follow-up expression confirmation studies on six independent controls. We show a detailed analysis of the most highly dysregulated genes on chromosome 18 and those genome-wide. The identified effector genes and the dysregulated downstream pathways provide hints of possible genotype-phenotype relationships to some of the most common symptoms observed in trisomy 18. We also provide a possible explanation for the sex-specific differences in survival, a unique characteristic of trisomy 18. Our analysis of genome-wide expression data moves us closer to understanding the molecular consequences of the second most common human autosomal trisomy of infants who survive to term. These insights might also translate to the understanding of the etiology of associated birth defects and medical conditions among those with trisomy 18.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 18/genetics , Fibroblasts/metabolism , Gene Expression Regulation/genetics , Trisomy 18 Syndrome/genetics , Cells, Cultured , Female , Genetic Association Studies , Genome-Wide Association Study , Genomics , Genotype , Humans , Infant , Infant, Newborn , Male , Phenotype , RNA-Seq , Trisomy 18 Syndrome/etiology , Trisomy 18 Syndrome/pathologyABSTRACT
Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurodevelopmental disorder characterized by variable expressivity. TSC results from inactivating variants within the TSC1 or TSC2 genes, leading to constitutive activation of mechanistic target of rapamycin complex 1 signaling. Using a mouse model of TSC (Tsc2-RG) in which the Tsc2 gene is deleted in radial glial precursors and their neuronal and glial descendants, we observed increased ornithine decarboxylase (ODC) enzymatic activity and concentration of its product, putrescine. To test if increased ODC activity and dysregulated polyamine metabolism contribute to the neurodevelopmental defects of Tsc2-RG mice, we used pharmacologic and genetic approaches to reduce ODC activity in Tsc2-RG mice, followed by histologic assessment of brain development. We observed that decreasing ODC activity and putrescine levels in Tsc2-RG mice worsened many of the neurodevelopmental phenotypes, including brain growth and neuronal migration defects, astrogliosis and oxidative stress. These data suggest a protective effect of increased ODC activity and elevated putrescine that modify the phenotype in this developmental Tsc2-RG model.
Subject(s)
Neurons/metabolism , Ornithine Decarboxylase/genetics , Tuberous Sclerosis/genetics , Animals , Animals, Newborn , Brain/metabolism , Brain/pathology , Disease Models, Animal , Humans , Mice , Mutation/genetics , Neuroglia/metabolism , Neuroglia/pathology , Neurons/pathology , Phenotype , Polyamines/metabolism , Tuberous Sclerosis/pathology , Tuberous Sclerosis Complex 1 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/geneticsABSTRACT
D-2-hydroxyglutaric aciduria (D-2-HGA) is a rare neurometabolic disease with two main subtypes, caused by either inactivating variants in D2HGDH (type I) or germline gain of function variants in IDH2 (type II), that result in accumulation of the same toxic metabolite, D-2-hydroxyglutarate. The main clinical features of both are neurologic, including developmental delay, hypotonia, and seizures. Dilated cardiomyopathy is a unique feature thus far only reported in type II. As somatic variants in IDH2 are frequently identified in several different types of cancer, including acute myeloid leukemia (AML), a link between cancer and this metabolic disease has been proposed; however, there is no reported cancer in patients with either type of D-2-HGA. Murine models have demonstrated how D-2-hydroxyglutarate alters metabolism and epigenetics, a potential mechanism by which this metabolite may cause cancer and cardiomyopathy. Here, we report the first case of both AML and dilated cardiomyopathy in a pediatric patient with D-2-HGA type I, who was treated with an anthracycline-free regimen. This report may expand the clinical spectrum of this rare metabolic disease and provide insight on long-term surveillance and care. However, this case is complicated by the presence of a complex chromosomal rearrangement resulting in a 25.5 Mb duplication of 1q41 and a 2.38 Mb deletion of 2q37.3. Thus, the direct causal relationship between D-2-HGA and leukemogenesis or cardiomyopathy warrants further scrutiny.
Subject(s)
Brain Diseases, Metabolic, Inborn , Cardiomyopathies , Cardiomyopathy, Dilated , Leukemia, Myeloid, Acute , Metabolic Diseases , Urogenital Abnormalities , Animals , Brain Diseases, Metabolic, Inborn/complications , Brain Diseases, Metabolic, Inborn/diagnosis , Brain Diseases, Metabolic, Inborn/genetics , Cardiomyopathies/complications , Cardiomyopathy, Dilated/complications , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/genetics , Child , Humans , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Mice , Rare DiseasesABSTRACT
PURPOSE: To understand the consequences of the 3q29 deletion on medical, neurodevelopmental, psychiatric, brain structural, and neurological sequalae by systematic evaluation of affected individuals. To develop evidence-based recommendations using these data for effective clinical care. METHODS: Thirty-two individuals with the 3q29 deletion were evaluated using a defined phenotyping protocol and standardized data collection instruments. RESULTS: Medical manifestations were varied and reported across nearly every organ system. The most severe manifestations were congenital heart defects (25%) and the most common were gastrointestinal symptoms (81%). Physical examination revealed a high proportion of musculoskeletal findings (81%). Neurodevelopmental phenotypes represent a significant burden and include intellectual disability (34%), autism spectrum disorder (38%), executive function deficits (46%), and graphomotor weakness (78%). Psychiatric illness manifests across the lifespan with psychosis prodrome (15%), psychosis (20%), anxiety disorders (40%), and attention deficit-hyperactivity disorder (ADHD) (63%). Neuroimaging revealed structural anomalies of the posterior fossa, but on neurological exam study subjects displayed only mild or moderate motor vulnerabilities. CONCLUSION: By direct evaluation of 3q29 deletion study subjects, we document common features of the syndrome, including a high burden of neurodevelopmental and neuropsychiatric phenotypes. Evidence-based recommendations for evaluation, referral, and management are provided to help guide clinicians in the care of 3q29 deletion patients.
Subject(s)
Autism Spectrum Disorder , Intellectual Disability , Psychotic Disorders , Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/genetics , Child , Chromosome Deletion , Developmental Disabilities/genetics , Humans , Intellectual Disability/diagnosis , Intellectual Disability/geneticsABSTRACT
Hypotrichosis-lymphedema-telangiectasia syndrome (HLTS) is a rare condition caused by pathogenic variants in the SOX18 gene. SOX18 plays a key role in angio- and lymphangiogenesis due to its expression in venous endothelial cells from which the lymphatic system develops. It is also expressed in embryonic hair follicles, heart, and vascular smooth muscle cells. The main clinical symptoms of HLTS include sparse hair, alopecia totalis, lymphedema, most often affecting lower limbs, and telangiectatic lesions. Only 10 patients with a SOX18 pathogenic variant have been described that presented with additional features such as hydrocele, renal failure, arterial or pulmonary hypertension, aortic dilatation, and facial dysmorphism. Here, we summarize these phenotypic variations and report an additional HLTS patient, with a 14-nucleotide de novo duplication in SOX18 and congenital ileal atresia, a feature not previously associated with HLTS.
Subject(s)
Genetic Predisposition to Disease , Hypotrichosis/genetics , Lymphangiogenesis/genetics , Lymphedema/genetics , SOXF Transcription Factors/genetics , Telangiectasis/genetics , Adolescent , Child , Child, Preschool , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Gene Duplication/genetics , Humans , Hypotrichosis/physiopathology , Infant , Infant, Newborn , Lymphedema/physiopathology , Male , Telangiectasis/physiopathologyABSTRACT
3q29 deletion syndrome (3q29del) is a recurrent deletion syndrome associated with neuropsychiatric disorders and congenital anomalies. Dysmorphic facial features have been described but not systematically characterized. This study aims to detail the 3q29del craniofacial phenotype and use a machine learning approach to categorize individuals with 3q29del through analysis of 2D photos. Detailed dysmorphology exam and 2D facial photos were ascertained from 31 individuals with 3q29del. Photos were used to train the next-generation phenotyping algorithm DeepGestalt (Face2Gene by FDNA, Inc, Boston, MA) to distinguish 3q29del cases from controls and all other recognized syndromes. Area under the curve of receiver operating characteristic curves (AUC-ROC) was used to determine the capacity of Face2Gene to identify 3q29del cases against controls. In this cohort, the most common observed craniofacial features were prominent forehead (48.4%), prominent nose tip (35.5%), and thin upper lip vermillion (25.8%). The FDNA technology showed an ability to distinguish cases from controls with an AUC-ROC value of 0.873 (p = 0.006) and led to the inclusion of 3q29del as one of the supported syndromes. This study found a recognizable facial pattern in 3q29del, as observed by trained clinical geneticists and next-generation phenotyping technology. These results expand the potential application of automated technology such as FDNA in identifying rare genetic syndromes, even when facial dysmorphology is subtle.
Subject(s)
Biological Variation, Population/genetics , Craniofacial Abnormalities/genetics , Genetic Predisposition to Disease , Intellectual Disability/genetics , Adolescent , Adult , Algorithms , Child , Child, Preschool , Chromosomes, Human, Pair 3/genetics , Craniofacial Abnormalities/pathology , Face , Female , Humans , Intellectual Disability/pathology , Male , Phenotype , Sequence Deletion/genetics , Young AdultABSTRACT
Tuberous sclerosis complex (TSC) is an autosomal dominant neurodevelopmental disorder and the quintessential disorder of mechanistic Target of Rapamycin Complex 1 (mTORC1) dysregulation. Loss of either causative gene, TSC1 or TSC2, leads to constitutive mTORC1 kinase activation and a pathologically anabolic state of macromolecular biosynthesis. Little is known about the organ-specific metabolic reprogramming that occurs in TSC-affected organs. Using a mouse model of TSC in which Tsc2 is disrupted in radial glial precursors and their neuronal and glial descendants, we performed an unbiased metabolomic analysis of hippocampi to identify Tsc2-dependent metabolic changes. Significant metabolic reprogramming was found in well-established pathways associated with mTORC1 activation, including redox homeostasis, glutamine/tricarboxylic acid cycle, pentose and nucleotide metabolism. Changes in two novel pathways were identified: transmethylation and polyamine metabolism. Changes in transmethylation included reduced methionine, cystathionine, S-adenosylmethionine (SAM-the major methyl donor), reduced SAM/S-adenosylhomocysteine ratio (cellular methylation potential), and elevated betaine, an alternative methyl donor. These changes were associated with alterations in SAM-dependent methylation pathways and expression of the enzymes methionine adenosyltransferase 2A and cystathionine beta synthase. We also found increased levels of the polyamine putrescine due to increased activity of ornithine decarboxylase, the rate-determining enzyme in polyamine synthesis. Treatment of Tsc2+/- mice with the ornithine decarboxylase inhibitor α-difluoromethylornithine, to reduce putrescine synthesis dose-dependently reduced hippocampal astrogliosis. These data establish roles for SAM-dependent methylation reactions and polyamine metabolism in TSC neuropathology. Importantly, both pathways are amenable to nutritional or pharmacologic therapy.
Subject(s)
Brain/metabolism , Metabolomics , Tuberous Sclerosis/metabolism , Animals , Brain/pathology , Cystathionine/genetics , Cystathionine beta-Synthase/genetics , DNA Methylation/genetics , Disease Models, Animal , Eflornithine/administration & dosage , Humans , Mechanistic Target of Rapamycin Complex 1/genetics , Methionine Adenosyltransferase/genetics , Mice , Neurons/metabolism , Neurons/pathology , Polyamines/metabolism , Putrescine/biosynthesis , S-Adenosylmethionine/metabolism , Tuberous Sclerosis/genetics , Tuberous Sclerosis/pathology , Tuberous Sclerosis Complex 1 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/geneticsABSTRACT
Cartilage oligomeric matrix protein (COMP) is a large, multifunctional extracellular protein that, when mutated, is retained in the rough endoplasmic reticulum (ER). This retention elicits ER stress, inflammation, and oxidative stress, resulting in dysfunction and death of growth plate chondrocytes. While identifying the cellular pathologic mechanisms underlying the murine mutant (MT)-COMP model of pseudoachondroplasia, increased midline-1 (MID1) expression and mammalian target of rapamycin complex 1 (mTORC1) signaling was found. This novel role for MID1/mTORC1 signaling was investigated since treatments shown to repress the pathology also reduced Mid1/mTORC1. Although ER stress-inducing drugs or tumor necrosis factor α (TNFα) in rat chondrosarcoma cells increased Mid1, oxidative stress did not, establishing that ER stress- or TNFα-driven inflammation alone is sufficient to elevate MID1 expression. Since MID1 ubiquitinates protein phosphatase 2A (PP2A), a negative regulator of mTORC1, PP2A was evaluated in MT-COMP growth plate chondrocytes. PP2A was decreased, indicating de-repression of mTORC1 signaling. Rapamycin treatment in MT-COMP mice reduced mTORC1 signaling and intracellular retention of COMP, and increased proliferation, but did not change inflammatory markers IL-16 and eosinophil peroxidase. Lastly, mRNA from tuberous sclerosis-1/2-null mice brain tissue exhibiting ER stress had increased Mid1 expression, confirming the relationship between ER stress and MID1/mTORC1 signaling. These findings suggest a mechanistic link between ER stress and MID1/mTORC1 signaling that has implications extending to other conditions involving ER stress.
Subject(s)
Achondroplasia , Cartilage Oligomeric Matrix Protein , Drug Delivery Systems , Mechanistic Target of Rapamycin Complex 1 , Achondroplasia/drug therapy , Achondroplasia/genetics , Achondroplasia/pathology , Animals , Biomarkers/metabolism , Cartilage Oligomeric Matrix Protein/genetics , Cartilage Oligomeric Matrix Protein/metabolism , Cell Line, Tumor , Chondrocytes/metabolism , Chondrocytes/pathology , Disease Models, Animal , Endoplasmic Reticulum Stress/genetics , Endoplasmic Reticulum, Rough/genetics , Endoplasmic Reticulum, Rough/metabolism , Endoplasmic Reticulum, Rough/pathology , Eosinophil Peroxidase/genetics , Eosinophil Peroxidase/metabolism , Humans , Inflammation Mediators/metabolism , Interleukin-16/genetics , Interleukin-16/metabolism , Mechanistic Target of Rapamycin Complex 1/genetics , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Mice, Transgenic , Mutation/genetics , Protein Phosphatase 2/genetics , Protein Phosphatase 2/metabolism , Proteins/genetics , Proteins/metabolism , Rats , Signal Transduction/genetics , Sirolimus/pharmacology , Tuberous Sclerosis Complex 1 Protein/genetics , Tuberous Sclerosis Complex 1 Protein/metabolism , Tuberous Sclerosis Complex 2 Protein/genetics , Tuberous Sclerosis Complex 2 Protein/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Ubiquitin-Protein LigasesABSTRACT
The long-term consequences and need for therapy in children with short-chain acyl-CoA dehydrogenase deficiency (SCADD) or isobutyryl-CoA dehydrogenase deficiency (IBDD) identified via newborn screening (NBS) remains controversial. Initial clinical descriptions were severe; however, while most cases identified through NBS have remained asymptomatic, clinical concerns have been raised in these populations. It is not clear whether these children are asymptomatic because of the success of NBS, or because the normal clinical course of these disorders is relatively benign. To evaluate these possibilities in our program, we evaluated the clinical outcomes of children with SCADD or IBDD identified by the Georgia NBS compared to the health status of a healthy age-matched control group. We also assessed parental anxiety during a phone interview both subjectively and objectively using the Pediatric Inventory for Parents (PIP), a validated measure of illness-related parental stress. The general health of 52 SCADD and nine IBDD cases from 2007 to 2016 were compared to the general health of unaffected control children obtained through the Centers for Disease Control and Prevention (CDC) parent listserv. We also collected statements from parents who participated in a phone survey regarding events they experienced during and after their diagnostic process. Overall, the children with SCADD and IBDD had no major health problems. There was no significant difference in cognitive development (pâ¯=â¯.207). We identified a slightly higher incidence of reported neonatal hypoglycemia in the SCADD group; two of these occurred in the context of maternal diabetes. All interviewed parents reported extreme anxiety during the diagnostic period and current feelings of uncertainty about their child's future. PIP scores for all six caregivers who responded to that portion of the survey were consistent with some degree of parental stress. The greatest reported stressor was the unknown long-term impact of the illness. All children with SCADD and IBDD had no significant long-term sequelae. The phone interviews revealed substantial parental anxiety about the identification and follow-up of SCADD and IBDD. Based on our findings, the anxiety parents experience may be unwarranted given that we see no disease-associated morbidity or mortality in these children. Consideration should be given to the removal of these conditions from NBS panels, or if that is not possible, clinicians could educate parents on the benign nature of these diagnoses and release them from follow-up without treatment.
Subject(s)
Acyl-CoA Dehydrogenase/deficiency , Amino Acid Metabolism, Inborn Errors/diagnosis , Anxiety/etiology , Lipid Metabolism, Inborn Errors/diagnosis , Neonatal Screening/psychology , Parents/psychology , Acyl-CoA Dehydrogenase/genetics , Amino Acid Metabolism, Inborn Errors/complications , Amino Acid Metabolism, Inborn Errors/genetics , Anxiety/epidemiology , Child , Child, Preschool , Cohort Studies , Female , Genetic Variation , Georgia/epidemiology , Humans , Infant , Infant, Newborn , Lipid Metabolism, Inborn Errors/complications , Lipid Metabolism, Inborn Errors/genetics , Male , Surveys and QuestionnairesABSTRACT
Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.
Subject(s)
Abnormalities, Multiple/genetics , Calcinosis/genetics , Ear Diseases/genetics , Genetic Predisposition to Disease , Intellectual Disability/genetics , Megalencephaly/genetics , Muscular Atrophy/genetics , Nerve Tissue Proteins/genetics , Transcription Factors/genetics , 3-Hydroxyacyl CoA Dehydrogenases/genetics , Abnormalities, Multiple/pathology , Acetyl-CoA C-Acyltransferase/genetics , Adolescent , Adult , Calcinosis/pathology , Carbon-Carbon Double Bond Isomerases/genetics , Child , Child, Preschool , Ear Diseases/pathology , Enoyl-CoA Hydratase/genetics , Face/abnormalities , Female , Genetic Association Studies , Heterozygote , Humans , Infant , Intellectual Disability/pathology , Male , Megalencephaly/pathology , Middle Aged , Mitochondria/genetics , Mitochondria/pathology , Muscular Atrophy/pathology , Mutation , Mutation, Missense/genetics , Phenotype , Racemases and Epimerases/genetics , Testicular Neoplasms , Young AdultABSTRACT
BACKGROUND: 3q29 deletion syndrome is associated with a range of medical, neurodevelopmental, and psychiatric phenotypes. The deletion is usually de novo but cases have been reported where the deletion is inherited from apparently unaffected parents. The presence of these unaffected or mildly affected individuals suggests there may be an ascertainment bias for severely affected cases of 3q29 deletion syndrome, thus the more deleterious consequence of the 3q29 deletion may be overestimated. However, a substantial fraction of 3q29 deletion syndrome morbidity is due to psychiatric illness. In many case reports, probands and transmitting parents are not systematically evaluated for psychiatric traits. Here we report results from a systematic phenotyping protocol for neurodevelopmental and neuropsychiatric traits applied to all 3q29 deletion carriers in a multiplex family. CASE PRESENTATION: Through the 3q29 registry at Emory University, a multiplex family was identified where three offspring had a paternally inherited 3q29 deletion. We evaluated all 4 3q29 deletion family members using our previously described standardized, systematic phenotyping protocol. The transmitting parent reported no psychiatric history, however upon evaluation he was discovered to meet criteria for multiple psychiatric diagnoses including previously undiagnosed schizoaffective disorder. All four 3q29 deletion individuals in the pedigree had multiple psychiatric diagnoses that interfered with quality of life and prohibited successful academic and occupational functioning. Cognitive ability for all individuals was average or below average, but within the normal range. CONCLUSIONS: This is the first case report of inherited 3q29 deletion syndrome where all affected individuals in the pedigree have been comprehensively and systematically evaluated for neurodevelopmental and psychiatric symptoms, using a standard battery of normed instruments administered by expert clinicians. Our investigation reveals that individuals with 3q29 deletion syndrome may have psychiatric morbidity that is debilitating, but only apparent through specialized evaluation by an expert. In the absence of appropriate evaluation, individuals with 3q29 deletion syndrome may suffer from psychiatric illness but lack avenues for access to care. The individuals evaluated here all have cognition in the normal range alongside multiple psychiatric diagnoses each, suggesting that cognitive ability alone is not a representative proxy for 3q29 deletion-associated disability. These results require replication in a larger cohort of individuals with 3q29 deletion syndrome.
Subject(s)
Intellectual Disability/genetics , Mental Disorders/genetics , Pedigree , Psychotic Disorders/genetics , Chromosome Deletion , Chromosomes, Human, Pair 3/genetics , Developmental Disabilities/genetics , Humans , Intellectual Disability/psychology , Male , Mental Disorders/physiopathology , Phenotype , Psychotic Disorders/diagnosis , Quality of Life , SyndromeABSTRACT
The Polycomb repressive complex 2 is an epigenetic writer and recruiter with a role in transcriptional silencing. Constitutional pathogenic variants in its component proteins have been found to cause two established overgrowth syndromes: Weaver syndrome (EZH2-related overgrowth) and Cohen-Gibson syndrome (EED-related overgrowth). Imagawa et al. (2017) initially reported a singleton female with a Weaver-like phenotype with a rare coding SUZ12 variant-the same group subsequently reported two additional affected patients. Here we describe a further 10 patients (from nine families) with rare heterozygous SUZ12 variants who present with a Weaver-like phenotype. We report four frameshift, two missense, one nonsense, and two splice site variants. The affected patients demonstrate variable pre- and postnatal overgrowth, dysmorphic features, musculoskeletal abnormalities and developmental delay/intellectual disability. Some patients have genitourinary and structural brain abnormalities, and there may be an association with respiratory issues. The addition of these 10 patients makes a compelling argument that rare pathogenic SUZ12 variants frequently cause overgrowth, physical abnormalities, and abnormal neurodevelopmental outcomes in the heterozygous state. Pathogenic SUZ12 variants may be de novo or inherited, and are sometimes inherited from a mildly-affected parent. Larger samples sizes will be needed to elucidate whether one or more clinically-recognizable syndromes emerge from different variant subtypes.
Subject(s)
Growth Disorders/genetics , Phenotype , Polycomb Repressive Complex 2/genetics , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Intellectual Disability/genetics , Male , Mutation , Neoplasm Proteins , Transcription FactorsABSTRACT
PURPOSE: To characterize clinical characteristics and genotypes of patients in the ADVANCE study of 4000 L-scale alglucosidase alfa (NCT01526785), the largest prospective United States Pompe disease cohort to date. METHODS: Patients aged ≥1 year with confirmed Pompe disease previously receiving 160 L alglucosidase alfa were eligible. GAA genotypes were determined before/at enrollment. Baseline assessments included histories/physical exams, Gross Motor Function Measure-88 (GMFM-88), pulmonary function tests, and cardiac assessments. RESULTS: Of 113 enrollees (60 male/53 female) aged 1-18 years, 87 had infantile-onset Pompe disease (IOPD) and 26 late-onset (LOPD). One hundred eight enrollees with GAA genotypes had 215 pathogenic variants (220 including combinations): 118 missense (4 combinations), 23 splice, 35 nonsense, 34 insertions/deletions, 9 duplications (1 combination), 6 other; c.2560C>T (n = 23), c.-32-13T>G (n = 13), and c.525delT (n = 12) were most common. Four patients had previously unpublished variants, and 14/83 (17%) genotyped IOPD patients were cross-reactive immunological material-negative. All IOPD and 6/26 LOPD patients had cardiac involvement, all without c.-32-13T>G. Thirty-two (26 IOPD, 6 LOPD) were invasively ventilated. GMFM-88 total %scores (mean ± SD, median, range): overall 46.3 ± 33.0% (47.9%, 0.0-100.0%), IOPD 41.6 ± 31.64% (38.9%, 0.0-99.7%), LOPD: 61.8 ± 33.2 (70.9%, 0.0-100.0%). CONCLUSION: ADVANCE, a uniformly assessed cohort comprising most US children and adolescents with treated Pompe disease, expands understanding of the phenotype and observed variants in the United States.
Subject(s)
Glycogen Storage Disease Type II/epidemiology , Glycogen Storage Disease Type II/genetics , alpha-Glucosidases/genetics , Adolescent , Child , Child, Preschool , Cohort Studies , Enzyme Replacement Therapy/methods , Female , Genotype , Humans , Infant , Male , Phenotype , Prospective Studies , United States/epidemiology , alpha-Glucosidases/metabolismABSTRACT
Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis.
Subject(s)
DNA, Mitochondrial/genetics , Heredodegenerative Disorders, Nervous System , Liver Diseases , Membrane Proteins/genetics , Mitochondrial Diseases , Mitochondrial Proteins/genetics , Peripheral Nervous System Diseases , Heredodegenerative Disorders, Nervous System/diagnosis , Heredodegenerative Disorders, Nervous System/genetics , Heredodegenerative Disorders, Nervous System/metabolism , Humans , Liver/metabolism , Liver Diseases/diagnosis , Liver Diseases/genetics , Liver Diseases/metabolism , Mitochondria/genetics , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/metabolism , Mutation , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/metabolismABSTRACT
PURPOSE: Pompe disease results from lysosomal acid α-glucosidase (GAA) deficiency and its associated glycogen accumulation and muscle damage. Alglucosidase alfa (recombinant human GAA (rhGAA)) received approval in 2006 as a treatment for Pompe disease at the 160 L production scale. In 2010, larger-scale rhGAA was approved for patients up to 8 years old without cardiomyopathy. NCT01526785 evaluated 4,000 L rhGAA efficacy/safety in US infantile- or late-onset Pompe disease (IOPD, LOPD) patients up to 1 year old transitioned from 160 L rhGAA. METHODS: A total of 113 patients (87 with IOPD; 26 with LOPD) received 4,000 L rhGAA for 52 weeks dosed the same as previous 160 L rhGAA. Efficacy was calculated as the percentage of patients stable/improved at week 52 (without death, new requirement for invasive ventilation, left ventricular mass z-score increase >1 if baseline was >2, upright forced vital capacity decrease ≥15% predicted, or Gross Motor Function Measure-88 decrease ≥8 percentage points). Safety evaluation included an extension ≤20 months. RESULTS: Week 52 data was available for 104 patients, 100 of whom entered the extension. At week 52, 87/104 (83.7%) were stable/improved. Overall survival was 98.1% overall, 97.6% IOPD, 100% LOPD; 92.4% remained invasive ventilator-free (93.4% IOPD, 88.7% LOPD). Thirty-five patients had infusion-associated reactions. Eight IOPD patients died of drug-unrelated causes. CONCLUSIONS: Most Pompe disease patients were clinically stable/improved after transitioning to 4,000 L rhGAA. Safety profiles of both rhGAA forms were consistent.
Subject(s)
Glycogen Storage Disease Type II/drug therapy , Recombinant Proteins/administration & dosage , alpha-Glucosidases/administration & dosage , Age of Onset , Child , Child, Preschool , Dose-Response Relationship, Drug , Female , Glycogen Storage Disease Type II/genetics , Glycogen Storage Disease Type II/pathology , Humans , Infant , Infant, Newborn , Kaplan-Meier Estimate , Male , Recombinant Proteins/adverse effects , alpha-Glucosidases/adverse effectsABSTRACT
Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI.
Subject(s)
Chemical and Drug Induced Liver Injury/diagnosis , Chemical and Drug Induced Liver Injury/etiology , Fructose Intolerance/chemically induced , Fructose-Bisphosphate Aldolase/genetics , Infant Formula/adverse effects , Mutation , Female , Fructose Intolerance/complications , Fructose-Bisphosphate Aldolase/deficiency , Homozygote , Humans , Infant , Infant, Newborn , Male , PrognosisABSTRACT
We describe 2 children with cobalamin G disease, a disorder of vitamin B12 metabolism with normal serum B12 levels. They presented with megaloblastic anemia progressing rapidly to severe thrombotic microangiopathy. In infants presenting with acute thrombotic microangiopathy, cobalamin disorders should be considered early as diagnosis and targeted treatment can be lifesaving.