scholarly journals Inborn Errors of Metabolism Associated With Autism Spectrum Disorders: Approaches to Intervention

2021 ◽  
Vol 15 ◽  
Author(s):  
Tamara Žigman ◽  
Danijela Petković Ramadža ◽  
Goran Šimić ◽  
Ivo Barić
Keyword(s):  
Inborn Errors Of Metabolism ◽  
Methylenetetrahydrofolate Reductase ◽  
Autism Spectrum ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Succinic Semialdehyde ◽  
Inborn Errors ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Organic Acidurias ◽  
Semialdehyde Dehydrogenase ◽  
Therapeutic Principles

Increasing evidence suggests that the autism spectrum disorder (ASD) may be associated with inborn errors of metabolism, such as disorders of amino acid metabolism and transport [phenylketonuria, homocystinuria, S-adenosylhomocysteine hydrolase deficiency, branched-chain α-keto acid dehydrogenase kinase deficiency, urea cycle disorders (UCD), Hartnup disease], organic acidurias (propionic aciduria, L-2 hydroxyglutaric aciduria), cholesterol biosynthesis defects (Smith-Lemli-Opitz syndrome), mitochondrial disorders (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes—MELAS syndrome), neurotransmitter disorders (succinic semialdehyde dehydrogenase deficiency), disorders of purine metabolism [adenylosuccinate lyase (ADSL) deficiency, Lesch-Nyhan syndrome], cerebral creatine deficiency syndromes (CCDSs), disorders of folate transport and metabolism (cerebral folate deficiency, methylenetetrahydrofolate reductase deficiency), lysosomal storage disorders [Sanfilippo syndrome, neuronal ceroid lipofuscinoses (NCL), Niemann-Pick disease type C], cerebrotendinous xanthomatosis (CTX), disorders of copper metabolism (Wilson disease), disorders of haem biosynthesis [acute intermittent porphyria (AIP)] and brain iron accumulation diseases. In this review, we briefly describe etiology, clinical presentation, and therapeutic principles, if they exist, for these conditions. Additionally, we suggest the primary and elective laboratory work-up for their successful early diagnosis.

scholarly journals Inborn errors of metabolism in newcomer and refugee populations in Ontario, CA

2019 ◽  
Author(s):  
Srinitya Gannavarapu ◽  
Madhavi Prasad ◽  
Chitra Prasad
Keyword(s):  
Newborn Screening ◽  
Inborn Errors Of Metabolism ◽  
Metabolic Diseases ◽  
Succinic Semialdehyde ◽  
Inherited Disorders ◽  
Inborn Errors ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Refugee Child ◽  
Semialdehyde Dehydrogenase ◽  
Expanding Population

Inborn errors of metabolism (IEM) are a heterogenous group of rare, inherited disorders that impair the biochemical processes involved in metabolism. Many are treated with various restrictive diets in early infancy, prior to the appearance of symptoms to improve the overall outcomes of the affected individuals. Identification of individuals at a risk of developing metabolic disorders through newborn screening (NBS) programs and the subsequent early diagnosis and treatment are an invaluable aspect of healthcare in Canada. Incorporation of Canada’s expanding population of refugees and new immigrants presents with potential challenges and changes. Without the availability of NBS programs in many countries contributing to the refugee influx in Canada, it may be difficult to identify patients who are affected with these rare conditions. This article discusses: 1) the utility of newborn screening and diagnosis of metabolic diseases in immigrant and refugee populations, with complex medical presentations, and 2) a recent diagnosis of succinic semialdehyde dehydrogenase deficiency (an IEM) in a refugee child past the age limit of NBS. An increasingly complicated and diverse refugee population requires a need for revision of existing healthcare practices pertaining to the diagnosis of rare diseases.

Succinic Semialdehyde Dehydrogenase Deficiency

2016 ◽  
Author(s):  
K. Michael Gibson ◽  
Cornelis Jakobs ◽  
Philip L. Pearl
Keyword(s):  
Clinical Manifestations ◽  
Autism Spectrum ◽  
Succinic Semialdehyde ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Respiratory Dysfunction ◽  
Semialdehyde Dehydrogenase ◽  
Acute Decompensation ◽  
Urine Organic Acid ◽  
Succinic Semialdehyde Dehydrogenase Deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency presents with intellectual disability, disproportionate deficit in expressive language, hypotonia, ataxia, and seizures.1,2 (1 Pearl et al 2011; 2 Vogel et al 2012). A diagnosis of autism spectrum disorder frequently occurs, correlated with neuropsychiatric morbidity (ADHD, OCD, PDD). 1,3 The biochemical hallmark, γ‎-hydroxybutyric acid (GHB), is elevated in physiological fluids, as is γ‎-aminobutyrate (GABA) in cerebrospinal fluid (CSF).4,5 Both species are neuroactive. Clinical manifestations are universally present in early childhood, although diagnosis delayed to adulthood has been reported.6 Acute decompensation or complications relate primarily to seizures, intercurrent illnesses sometimes associated with respiratory dysfunction in the setting of hypotonia, or adverse medication responses. Diagnostic confirmation requires urine organic acid analysis (increased GHB) with confirmation via enzyme assay (white cells) and/or molecular characterization of the aldehyde dehydrogenase 5a1 (ALDH5A1) gene.

scholarly journals Succinic Semialdehyde Dehydrogenase Deficiency: Review of the Natural History Study

2021 ◽  
pp. 088307382098126
Author(s):  
Phillip L. Pearl ◽  
Melissa L. DiBacco ◽  
Christos Papadelis ◽  
Thomas Opladen ◽  
Ellen Hanson ◽  
...  
Keyword(s):  
Natural History ◽  
Psychiatric Symptoms ◽  
Epileptiform Activity ◽  
Laboratory Data ◽  
Standard Of Care ◽  
Succinic Semialdehyde ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Natural History Study ◽  
Semialdehyde Dehydrogenase ◽  
Verbal Score

Objective: The SSADHD Natural History Study was initiated in 2019 to define the natural course and identify biomarkers correlating with severity. Methods: The study is conducted by 4 institutions: BCH (US clinical), WSU (bioanalytical core), USF (biostatistical core), and Heidelberg (iNTD), with support from the family advocacy group (SSADH Association). Recruitment goals were to study 20 patients on-site at BCH, 10 with iNTD, and 25 as a standard-of care cohort. Results: At this half-way point of this longitudinal study, 28 subjects have been recruited (57% female, mean 9 years, range 18 months–40 years). Epilepsy is present in half and increases in incidence and severity, as do psychiatric symptoms, in adolescence and adulthood. The average Full Scale IQ (FSIQ) was 53 (Verbal score of 56, Non Verbal score of 49), and half scored as having ASD. Although there was no correlation between gene variant and phenotypic severity, there were extreme cases of lowest functioning in one individual and highest in another that may have genotype-phenotype correlation. The most common EEG finding was mild background slowing with rare epileptiform activity, whereas high-density EEG and magnetoencephalography showed reduction in the gamma frequency band consistent with GABAergic dysfunction. MR spectroscopy showed elevations in the GABA/NAA ratio in all regions studied with no crossover between subjects and controls. Conclusions: The SSADH Natural History Study is providing a unique opportunity to study the complex pathophysiology longitudinally and derive electrophysiologic, neuroimaging, and laboratory data for correlation and to serve as biomarkers for clinical trials and prognostic assessments in this ultra-rare inherited disorder of GABA metabolism.

scholarly journals Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ruixue Zhang ◽  
Rong Qiang ◽  
Chengrong Song ◽  
Xiaoping Ma ◽  
Yan Zhang ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Inborn Errors Of Metabolism ◽  
Northwest China ◽  
Methylmalonic Acidemia ◽  
Shaanxi Province ◽  
Inborn Errors ◽  
Organic Acidurias ◽  
Genetic Characteristics ◽  
Disease Spectrum ◽  
Expanded Newborn Screening

AbstractExpanded newborn screening facilitates early identification and intervention of patients with inborn errors of metabolism (IEMs), There is a lack of disease spectrum data for many areas in China. To determine the disease spectrum and genetic characteristics of IEMs in Xi'an city of Shaanxi province in northwest China, 146152 newborns were screening by MSMS from January 2014 to December 2019 and 61 patients were referred to genetic analysis by next generation sequencing (NGS) and validated by Sanger sequencing. Seventy-five newborns and two mothers were diagnosed with IEMs, with an overall incidence of 1:1898 (1:1949 without mothers). There were 35 newborns with amino acidemias (45.45%, 1:4176), 28 newborns with organic acidurias (36.36%, 1:5220), and 12 newborns and two mothers with FAO disorders (18.18%; 1:10439 or 1:12179 without mothers). Phenylketonuria and methylmalonic acidemia were the two most common disorders, accounting for 65.33% (49/75) of all confirmed newborn. Some hotspot mutations were observed for several IEMs, including PAH gene c.728G>A for phenylketonuria; MMACHC gene c.609G>A and c.567dupT, MMUT gene c.323G>A for methylmalonic acidemia and SLC25A13 gene c.852_855del for citrin deficiency. Our study provides effective clinical guidance for the popularization and application of expanded newborn screening, genetic screening, and genetic counseling of IEMs in this region.

scholarly journals Postmortem Analyses in a Patient With Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): II. Histological, Lipid, and Gene Expression Outcomes in Regional Brain Tissue

2021 ◽  
pp. 088307382098774
Author(s):  
Dana C. Walters ◽  
Regan Lawrence ◽  
Trevor Kirby ◽  
Jared T. Ahrendsen ◽  
Matthew P. Anderson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dehydrogenase Deficiency ◽  
Metabotropic Glutamate Receptor ◽  
Total Phospholipid ◽  
Null Mouse ◽  
Succinic Semialdehyde ◽  
Long Term Effects ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Semialdehyde Dehydrogenase ◽  
Succinic Semialdehyde Dehydrogenase Deficiency

This study has extended previous metabolic measures in postmortem tissues (frontal and parietal lobes, pons, cerebellum, hippocampus, and cerebral cortex) obtained from a 37-year-old male patient with succinic semialdehyde dehydrogenase deficiency (SSADHD) who expired from SUDEP (sudden unexplained death in epilepsy). Histopathologic characterization of fixed cortex and hippocampus revealed mild to moderate astrogliosis, especially in white matter. Analysis of total phospholipid mass in all sections of the patient revealed a 61% increase in cortex and 51% decrease in hippocampus as compared to (n = 2-4) approximately age-matched controls. Examination of mass and molar composition of major phospholipid classes showed decreases in phospholipids enriched in myelin, such as phosphatidylserine, sphingomyelin, and ethanolamine plasmalogen. Evaluation of gene expression (RT2 Profiler PCR Arrays, GABA, glutamate; Qiagen) revealed dysregulation in 14/15 GABAA receptor subunits in cerebellum, parietal, and frontal lobes with the most significant downregulation in ∊, θ, ρ1, and ρ2 subunits (7.7-9.9-fold). GABAB receptor subunits were largely unaffected, as were ionotropic glutamate receptors. The metabotropic glutamate receptor 6 was consistently downregulated (maximum 5.9-fold) as was the neurotransmitter transporter (GABA), member 13 (maximum 7.3-fold). For other genes, consistent dysregulation was seen for interleukin 1β (maximum downregulation 9.9-fold) and synuclein α (maximal upregulation 6.5-fold). Our data provide unique insight into SSADHD brain function, confirming astrogliosis and lipid abnormalities previously observed in the null mouse model while highlighting long-term effects on GABAergic/glutamatergic gene expression in this disorder.

scholarly journals Magnetic Resonance Imaging (MRI) and Spectroscopy in Succinic Semialdehyde Dehydrogenase Deficiency

2021 ◽  
pp. 088307382199129
Author(s):  
Onur Afacan ◽  
Edward Yang ◽  
Alexander P. Lin ◽  
Eduardo Coello ◽  
Melissa L. DiBacco ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Mr Spectroscopy ◽  
Succinic Semialdehyde ◽  
Resonance Imaging ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Semialdehyde Dehydrogenase ◽  
Magnetic Resonance Imaging Mri ◽  
Brain Gaba ◽  
Ssadh Deficiency

Succinic semialdehyde dehydrogenase (SSADH) deficiency is an autosomal recessive disorder of γ-aminobutyric acid (GABA) degradation, resulting in elevations of brain GABA and γ-hydroxybutyric acid (GHB). Previous magnetic resonance (MR) spectroscopy studies have shown increased levels of Glx in SSADH deficiency patients. Here in this work, we measure brain GABA in a large cohort of SSADH deficiency patients using advanced MR spectroscopy techniques that allow separation of GABA from overlapping metabolite peaks. We observed significant increases in GABA concentrations in SSADH deficiency patients for all 3 brain regions that were evaluated. Although GABA levels were higher in all 3 regions, each region had different patterns in terms of GABA changes with respect to age. We also report results from structural magnetic resonance imaging (MRI) of the same cohort compared with age-matched controls. We consistently observed signal hyperintensities in globus pallidus and cerebellar dentate nucleus.

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