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Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).
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Proteínas Transportadoras de GABA en la Membrana Plasmática , Estudios de Asociación Genética , Mutación Missense , Humanos , Proteínas Transportadoras de GABA en la Membrana Plasmática/genética , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , FenotipoRESUMEN
A 23-month-old boy with poor growth, developmental delay, and hypotonia presented with acute onset of ataxia and fatigue. Magnetic resonance imaging (MRI) of the brain and spinal cord was performed as part of diagnostic work-up. MRI showed bilateral symmetrical lesions in basal ganglia, midbrain, and brainstem consistent with Leigh syndrome. Signal abnormalities were also present within the cervical cord, with enhancement of multiple cranial, spinal, and cauda equina nerve roots. Genetic testing confirmed compound heterozygosity for two pathogenic variants in SURF1 implicated in Leigh syndrome. Whilst nerve root enhancement has been described in other mitochondrial disorders, we believe this is the first published case of both cranial and spinal nerve root enhancement in Leigh syndrome.
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PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. CONCLUSION: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.
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Ataxia , Convulsiones , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Embarazo , Atención PrenatalRESUMEN
Several studies have shown serum fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) levels are elevated in patients with mitochondrial disease (MD) where myopathy is a feature. In this study we investigated the utility of FGF21 and GDF15 as biomarkers for MD in a phenotypically and genotypically diverse pediatric cohort with suspected MD against a panel of healthy controls and non-mitochondrial disease controls with some overlapping clinical features. Serum was collected from 56 children with MD, 104 children with non-mitochondrial disease (27 neuromuscular, 26 cardiac, 21 hepatic, 30 renal) and 30 pediatric controls. Serum FGF21 and GDF15 concentrations were measured using ELISA, and their ability to detect MD was determined. Median FGF21 and GDF15 serum concentrations were elevated 17-fold and 3-fold respectively in pediatric MD patients compared to the healthy control group. Non-mitochondrial disease controls had elevated serum GDF15 concentrations while FGF21 concentrations were in the normal range. Elevation of GDF15 in a range of non-mitochondrial pediatric disorders limits its use as a MD biomarker. FGF21 was elevated in MD patients with a spectrum of clinical phenotypes, including those without myopathy. Serum FGF21 had an area under the receiver operating characteristic curve of 0.87, indicating good ability to discriminate between pediatric MD and healthy and non-mitochondrial disease controls. Triaging of pediatric MD patients by clinical phenotyping and serum FGF21 testing, followed by massively parallel sequencing, may enable more rapid diagnosis of pediatric MD.
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Factor 15 de Diferenciación de Crecimiento , Enfermedades Mitocondriales , Biomarcadores , Niño , Factores de Crecimiento de Fibroblastos/genética , Factor 15 de Diferenciación de Crecimiento/genética , Humanos , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genéticaRESUMEN
This document provides consensus-based recommendations for general physicians and primary care physicians who diagnose and manage patients with mitochondrial diseases (MD). It builds on previous international guidelines, with particular emphasis on clinical management in the Australian setting. This statement was prepared by a working group of medical practitioners, nurses and allied health professionals with clinical expertise and experience in managing Australian patients with MD. As new treatments and management plans emerge, these consensus-based recommendations will continue to evolve, but current standards of care are summarised in this document.
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Enfermedades Mitocondriales , Nivel de Atención , Australia/epidemiología , Consenso , Guías como Asunto , Humanos , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/terapia , Sociedades MédicasRESUMEN
COX16 is involved in the biogenesis of cytochrome-c-oxidase (complex IV), the terminal complex of the mitochondrial respiratory chain. We present the first report of two unrelated patients with the homozygous nonsense variant c.244C>T(p. Arg82*) in COX16 with hypertrophic cardiomyopathy, encephalopathy and severe fatal lactic acidosis, and isolated complex IV deficiency. The absence of COX16 protein expression leads to a complete loss of the holo-complex IV, as detected by Western blot in patient fibroblasts. Lentiviral transduction of patient fibroblasts with wild-type COX16 complementary DNA rescued complex IV biosynthesis. We hypothesize that COX16 could play a role in the copper delivery route of the COX2 module as part of the complex IV assembly. Our data provide clear evidence for the pathogenicity of the COX16 variant as a cause for the observed clinical features and the isolated complex IV deficiency in these two patients and that COX16 deficiency is a cause for mitochondrial disease.
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Acidosis Láctica , Encefalopatías , Cardiomiopatías , Deficiencia de Citocromo-c Oxidasa , Hepatopatías , Proteínas de la Membrana/genética , Proteínas Mitocondriales/genética , Acidosis Láctica/genética , Cardiomiopatías/genética , Deficiencia de Citocromo-c Oxidasa/genética , Humanos , Recién Nacido , Proteínas Mitocondriales/metabolismoRESUMEN
PURPOSE: The utility of genome sequencing (GS) in the diagnosis of suspected pediatric mitochondrial disease (MD) was investigated. METHODS: An Australian cohort of 40 pediatric patients with clinical features suggestive of MD were classified using the modified Nijmegen mitochondrial disease severity scoring into definite (17), probable (17), and possible (6) MD groups. Trio GS was performed using DNA extracted from patient and parent blood. Data were analyzed for single-nucleotide variants, indels, mitochondrial DNA variants, and structural variants. RESULTS: A definitive MD gene molecular diagnosis was made in 15 cases and a likely MD molecular diagnosis in a further five cases. Causative mitochondrial DNA (mtDNA) variants were identified in four of these cases. Three potential novel MD genes were identified. In seven cases, causative variants were identified in known disease genes with no previous evidence of causing a primary MD. Diagnostic rates were higher in patients classified as having definite MD. CONCLUSION: GS efficiently identifies variants in MD genes of both nuclear and mitochondrial origin. A likely molecular diagnosis was identified in 67% of cases and a definitive molecular diagnosis achieved in 55% of cases. This study highlights the value of GS for a phenotypically and genetically heterogeneous disorder like MD.
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Genoma Mitocondrial , Enfermedades Mitocondriales , Australia , Niño , Mapeo Cromosómico , ADN Mitocondrial/genética , Genoma Mitocondrial/genética , Humanos , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , MutaciónRESUMEN
AIM: Poorer physical and mental health often accompany loss of walking in Duchenne muscular dystrophy. This study assessed the impacts of powered wheelchair standing device (PWSD) use on muscle and joint pain, joint angles when standing and mental health in adolescents with Duchenne muscular dystrophy. METHODS: Fourteen adolescents and parents participated in a stepped wedge design study over 12 months. During a baseline and intervention period, adolescents described pain and mental health, and parents reported their child's mental health. Video data were collected to measure hip, knee and ankle joint angles in the preferred standing position. RESULTS: Compared with baseline and adjusting for covariates, standing wheelchair use was associated with no change in muscle or joint pain or videoed joint angles in standing. Child-reported Strengths and Difficulties total scores decreased (coefficient -3.1, 95% confidence interval -4.6, -1.5); and parent-reported Personal Adjustment and Role Skills Scale total scores increased (coefficient 7.9, 95% confidence interval 3.3-12.5). CONCLUSIONS: PWSD use was associated with maintenance of musculoskeletal status and advantages to mental health. Long-term observations are necessary to improve understanding of how to support wellbeing in adolescents with Duchenne muscular dystrophy.
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Distrofia Muscular de Duchenne , Silla de Ruedas , Adolescente , Niño , Humanos , Padres , Posición de Pie , CaminataRESUMEN
3-Methylglutaconyl-CoA hydratase deficiency (MGA1) is a defect in leucine catabolism, which causes the accumulation of urinary 3-methylglutaconate, with or without 3-hydroxyisovalerate and 3-methylglutarate. It is an ultra-rare condition, with <30 cases published in the literature. It is unclear whether the clinical features seen in reported patients are caused by the biochemical abnormalities, or whether they simply represent an ascertainment bias in patients that come to clinical attention. We reviewed the collective Australian experience of patients with confirmed MGA1, four of whom were diagnosed when asymptomatic through newborn screening (NBS). When our cohort is considered alongside the broader literature, there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder. Some patients have non-specific clinical features (such as autism spectrum disorder [ASD]); however, there are also other family members with ASD in the absence of MGA1, suggesting a multifactorial aetiology. Importantly, all four patients diagnosed through NBS (including three with over 18 years of clinical follow-up) remain asymptomatic in the absence of treatment. Based on the available literature, we suggest that MGA1 represents a biochemical phenotype, with an absence of a childhood clinical phenotype. The burdens of sustained treatment (particularly with intensive dietary leucine restriction) in asymptomatic individuals may be of little benefit, and likely to result in poor compliance. Longer-term follow-up of patients detected via NBS (or biochemical screening of large cohorts of asymptomatic adult individuals) will be required to conclusively prove or disprove the association with adult-onset leukoencephalopathy.
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BACKGROUND: TANGO2 deficiency disorder (TDD) is an autosomal recessive disease associated with metabolic crisis, lethal cardiac arrhythmias, and cardiomyopathy. Data regarding treatment, management, and outcomes of cardiac manifestations of TDD are lacking. OBJECTIVE: The purpose of this study was to describe TDD-related cardiac crises. METHODS: Retrospective multicenter chart review was made of TDD patients admitted with cardiac crises, defined as development of ventricular tachycardia (VT), cardiomyopathy, or cardiac arrest during metabolic crises. RESULTS: Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4-9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all (median 547 ms; IQR 504-600 ms) and a type I Brugada pattern in 8 (26%). Arrhythmias included VT in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. There were 10 deaths (37%), 6 related to arrhythmias. In 5 patients, recalcitrant VT occurred despite use of antiarrhythmic drugs. In 6 patients, arrhythmias were controlled after extracorporeal membrane oxygenation (ECMO) support; 5 of these patients survived. Among 10 patients who survived VT without ECMO, successful treatment included intravenous magnesium, isoproterenol, and atrial pacing in multiple cases and verapamil in 1 patient. Initiation of feeds seemed to decrease VT events. CONCLUSION: TDD-related cardiac crises are associated with a high risk of arrhythmias, cardiomyopathy, cardiac arrest, and death. Although further studies are needed, early recognition and appropriate treatment are critical. Acutely, intravenous magnesium, isoproterenol, atrial pacing, and ECMO as a last resort seem to be the best current treatment options, and early initiation of feeds may prevent VT events.
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Cardiomiopatías , Paro Cardíaco , Taquicardia Ventricular , Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/etiología , Arritmias Cardíacas/terapia , Cardiomiopatías/complicaciones , Cardiomiopatías/diagnóstico , Niño , Paro Cardíaco/etiología , Paro Cardíaco/terapia , Humanos , Isoproterenol , Magnesio , VerapamiloRESUMEN
Mitochondrial diseases can be caused by pathogenic variants in nuclear or mitochondrial DNA-encoded genes that often lead to multisystemic symptoms and can have any mode of inheritance. Using a single test, Genome Sequencing (GS) can effectively identify variants in both genomes, but it has not yet been universally used as a first-line approach to diagnosing mitochondrial diseases due to related costs and challenges in data analysis. In this article, we report three patients with mitochondrial disease molecularly diagnosed through GS performed on DNA extracted from blood to demonstrate different diagnostic advantages of this technology, including the detection of a low-level heteroplasmic pathogenic variant, an intragenic nuclear DNA deletion, and a large mtDNA deletion. Current technical improvements and cost reductions are likely to lead to an expanded routine diagnostic usage of GS and of the complementary "Omic" technologies in mitochondrial diseases.
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ADN/sangre , Variación Genética , Enfermedades Mitocondriales/diagnóstico , Secuenciación Completa del Genoma/métodos , Adolescente , Preescolar , Diagnóstico Precoz , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Enfermedades Mitocondriales/sangre , Enfermedades Mitocondriales/genéticaRESUMEN
Pyridoxine-dependent epilepsy (PDE) is a potentially treatable vitamin-responsive epileptic encephalopathy. The most prevalent form of PDE is due to an underlying genetic defect in ALDH7A1 encoding Antiquitin (ATQ), an enzyme with α-aminoadipic semialdehyde dehydrogenase (AASADH) activity which facilitates cerebral lysine degradation. Devastating outcomes including intellectual disability and significant developmental delays are still observed in 75% to 80% of pyridoxine responsive individuals with good seizure control, potentially attributable to the accumulation of toxic intermediates α-aminoadipic semialdehyde (AASA) and its cyclic form Δ1-piperideine-6-carboxylate (P6C) in plasma, urine and CSF. Thus, adjunct treatment strategies incorporating lysine restriction and arginine supplementation, separately or in combination with pyridoxine have been attempted to enhance seizure control and improve cognitive function. We describe a 4 year old girl with classical PDE who demonstrated significant improvements in clinical, neurological and developmental outcomes including absence of clinical seizures and cessation of antiepileptic medications since age 3 months, normalisation of EEG, significant improvement in the white matter signal throughout the cerebrum on neuroimaging and significant reduction in urine P6C and pipecolic acid levels post- combined therapy with lysine restricted diet in conjunction with pyridoxine and folinic acid. Lysine restriction was well tolerated with impressive compliance and plasma lysine levels remained within the lower reference ranges; mean level 70 µmol/L (ref range 52-196 µmol/L). This case further emphasizes the benefit of early dietary intervention as an effective adjunct in the management of PDE.
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BACKGROUND: Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome. METHODS: We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible. RESULTS: Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%). CONCLUSIONS: Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy.
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Epilepsia , Enfermedades Genéticas Congénitas , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Malformaciones del Sistema Nervioso , Trastornos del Sueño-Vigilia , Factores de Transcripción/genética , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Electroencefalografía , Epilepsia/diagnóstico , Epilepsia/etiología , Epilepsia/genética , Epilepsia/fisiopatología , Femenino , Enfermedades Genéticas Congénitas/complicaciones , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/fisiopatología , Humanos , Lactante , Masculino , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/etiología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/fisiopatología , Estudios Retrospectivos , Fases del Sueño/fisiología , Trastornos del Sueño-Vigilia/diagnóstico , Trastornos del Sueño-Vigilia/etiología , Trastornos del Sueño-Vigilia/genética , Trastornos del Sueño-Vigilia/fisiopatología , Síndrome , Adulto JovenRESUMEN
Nonketotic hyperglycinemia (NKH) is a devastating inborn error of glycine metabolism caused by deficient activity of the glycine cleavage enzyme. Classically, patients present with lethargy, hypotonia, myoclonic jerks, transient respiratory depression in the first week of life and often progress to death. Surviving infants have profound psychomotor retardation, refractory epilepsy and poor quality of life. Currently, no effective therapeutic avenues exist for severe NKH. Ketogenic diet (KD) has been trialled only in a small group of patients with neonatal NKH and early myoclonic encephalopathy, in whom significant improvements in seizure control were reported. We describe an infant with classical neonatal NKH who presented on the third day of life with hypotonia, poor feeding, respiratory insufficiency resulting in ventilatory support and seizures with burst-suppression pattern on electroencephalogram (EEG). KD initiated at age 6 months for intractable seizures, lead to a dramatic decrease in seizure frequency, EEG improvements, normalisation of plasma glycine levels, reduced spasticity and improved quality of life. KD may be a valuable treatment modality for refractory seizure control in classical NKH.
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Dieta Cetogénica/métodos , Epilepsia/dietoterapia , Hiperglicinemia no Cetósica/dietoterapia , Epilepsia/congénito , Humanos , Hiperglicinemia no Cetósica/complicaciones , Recién Nacido , MasculinoRESUMEN
Duchenne muscular dystrophy is a common neuromuscular disorder involving progressive muscle weakness. A powered wheelchair standing device provides capacity to stand despite increasing muscle weakness. This study used qualitative methods to explore how adolescents with Duchenne muscular dystrophy used a powered wheelchair standing device in their daily lives. Semi-structured interviews were conducted with 12 adolescents, 11 parents and 11 teachers. Qualitative thematic analysis using a grounded theory framework was conducted to identify emerging domains. "Capacity to be able" was the central theme that emerged across the dataset: the introduction of the powered wheelchair standing device at a time when motor skills were declining enabled the adolescent to maintain and sometimes extend his independence. There were four underlying themes including (1) Independence, (2) Health, (3) Comfort, and (4) Community belonging and involvement. Each theme was illustrated in data collected from adolescents, parents and teachers. The device appeared to mitigate some of the challenges of progressive muscle weakness by providing the option for the individual with Duchenne muscular dystrophy to choose when and where to stand for participation in a range of activities, beyond what would be possible with existing therapeutic regimes involving standing frames.
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Debilidad Muscular/fisiopatología , Distrofia Muscular de Duchenne/fisiopatología , Dispositivos de Autoayuda , Silla de Ruedas , Adolescente , Niño , Participación de la Comunidad/métodos , Femenino , Humanos , Masculino , Debilidad Muscular/rehabilitación , Enfermedades Neuromusculares/rehabilitación , Padres/psicologíaRESUMEN
PNPT1 (PNPase-polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic PNPT1 variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype-phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects. Recently, it has been suggested that PNPase can lead to activation of an innate immune response. To better understand the clinical and molecular spectrum of patients with bi-allelic PNPT1 variants, we captured detailed clinical and molecular phenotypes of all 17 patients reported in the literature, plus seven new patients, including a 78-year-old male with the longest reported survival. A functional follow-up of genomic sequencing by cDNA studies confirmed a splicing defect in a novel, apparently synonymous, variant. Patient fibroblasts showed an accumulation of mitochondrial unprocessed PNPT1 transcripts, while blood showed an increased interferon response. Our findings suggest that functional analyses of the RNA processing function of PNPase are more sensitive than testing downstream defects in oxidative phosphorylation (OXPHPOS) enzyme activities. This research extends our knowledge of the clinical and functional consequences of bi-allelic pathogenic PNPT1 variants that may guide management and further efforts into understanding the pathophysiological mechanisms for therapeutic development.
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Gastrointestinal (GI) manifestations of post-natally acquired cytomegalovirus (CMV) in preterm neonates can vary from mild diarrhoea to severe necrotising enterocolitis. However, the suspicion of CMV-related GI disease remains low. Mild CMV disease localised to the GI tract may go undiagnosed initially until a more obvious complication such as strictures manifest. A case of CMV-associated enteritis in an extremely preterm neonate is presented. The diagnosis was established after the histopathology of the surgical specimen showed the presence of CMV inclusion bodies. Testing the stool specimen for CMV to establish the diagnosis when the pathology is limited to the GI tract is also discussed.
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Infecciones por Citomegalovirus/complicaciones , Enteritis/complicaciones , Enfermedades del Íleon/etiología , Enfermedades del Prematuro/etiología , Adulto , Bacteroides fragilis/aislamiento & purificación , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/diagnóstico , Diagnóstico Diferencial , Enteritis/virología , Heces/virología , Femenino , Humanos , Enfermedades del Íleon/fisiopatología , Enfermedades del Íleon/terapia , Recién Nacido , Recien Nacido Prematuro , Enfermedades del Prematuro/fisiopatología , Enfermedades del Prematuro/terapia , Masculino , Embarazo , Complicaciones Hematológicas del Embarazo , Nacimiento Prematuro , Sepsis/virología , Resultado del Tratamiento , Australia OccidentalRESUMEN
Nonketotic hyperglycinemia, also known as glycine encephalopathy (OMIM #605899), is an autosomal recessive disorder of glycine metabolism resulting from a defect in the glycine cleavage system. We report two novel mutations of the glycine decarboxylase (GLDC) gene observed in a compound heterozygous state in a neonate of mixed Maori and Caucasian parentage: c.395C>T p.(Ser132Leu) in exon 3, and c.256-?_334+?del p.(Ser86Valfs*119), resulting in an out-of-frame deletion of exon 2. Additionally, we describe our experience of implementing the ketogenic diet, alongside standard pharmacological therapy, and highlight its potential therapeutic benefit in severe nonketotic hyperglycinemia, particularly in seizure management.
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BACKGROUND: Our objective was to study demographic features, clinical features, and karyotype analyses of patients with Down syndrome (DS). Our study design was a retrospective analysis, while the study was conducted in the Genetic Clinic of a tertiary-care teaching hospital. METHODS: Retrospective analysis of cases referred to the Genetic Clinic was performed. Case proformas of the patients presenting with phenotypic features of DS were analyzed. The following information was recorded from the proformas: age at presentation; sex; maternal age; craniofacial and other physical features; presence and type of congenital heart disease; gastrointestinal abnormalities, and results of cytogenetic evaluation. Clinical features in neonates with DS were separately analyzed. RESULTS: Analysis included cases of DS presenting over a period of 7.5 years; a total of 524 patients were studied (303 males and 221 females; M:F ratio 1.37:1). Average age at presentation was 19.4 months (range: 1 day-26 years). Average maternal age at birth of the affected child was 26.8 years (range: 16-45 years). Craniofacial features noted in >50% of the cases included mongoloid slant (83.9%), ear abnormalities (66.9%), epicanthic folds (56.9%), and flat facial profile (50.9%). A total of 76.3% cases had hypotonia. Characteristic limb and dermatoglyphic anomalies were seen in less than one half of cases. These included sandle sign (46.2%), unilateral or bilateral simian crease (33.2%), clinodactyly (36.1%), and brachydactyly (11.1%). Ophthalmologic abnormalities included hypertelorism (33.9%), nystagmus (3.2%), Brushfield spots (3.2%), squint (2.7%), and cataracts (1.9%). Congenital heart disease was clinically diagnosed in 96 cases (18.3%). The nature of the cardiac defect was ascertained by color Doppler examination and/or 2D-echocardiography in 58 cases. The most common cardiac anomalies were ventricular septal defect (25.8%), tetralogy of Fallot (15.5%), and atrial septal defect (12.1%). Gastrointestinal anomalies were noted in seven cases and included three cases with imperforate anus, two with Hirschsprung disease, and one each with duodenal atresia and Morgagni hernia. Results of cytogenetic abnormalities were available in 42.2%. Free trisomy (non-dysjunction) was present in 95%, 3.2% had translocation, and 1.8% were mosaics. In neonates, common features noted were mongoloid slant, ear abnormalities, flat facial profile, hypotonia, sandle sign, and clinodactyly+/-brachydactyly. CONCLUSIONS: All characteristic craniofacial and physical features of DS need not be present in every case. Major features noted in the present study were mongoloid slant, ear abnormalities, epicanthic folds, flat facies, and hypotonia. Congenital heart disease was present in 18.3% of cases, with ventricular septal defect being the most common type of defect. Non-dysjunction was the most common cause of the chromosomal anomaly.