Unexplained Developmental Delay Research Articles

Analysis of genetic etiology in a patient with 1p36 deletion syndrome in conjunct with Snijders Blok-Campeau syndrome

To explore the genetic basis for a patient with unexplained developmental delay and special facial features. A male patient admitted to the Maternal and Child Health Care Hospital of Gansu Province on May 27, 2021 due to infertility was selected as the study subject. Clinical data of the patient was collected, and genomic DNA was extracted from peripheral blood samples from the patient and his parents. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing. The patient was found to harbor a 2.54 Mb deletion in 1p36.33p36.32 and a heterozygous c.1123G>C (p.E375Q) variant of the CHD3 gene, neither of which was detected in his parents. The patient was diagnosed with Snijders Blok-Campeau syndrome in conjunct with 1p36 deletion syndrome, which has enabled genetic counseling for his family.

Clinicobiochemical Profile and Outcome of Children with Small Molecule Neurometabolic Disorders: A Tertiary Care Hospital Experience from India

AbstractInborn Errors of Metabolism (IEM), though heterogenous, are not uncommon. Neurologic manifestations predominate. Without universal newborn screening, early diagnosis and treatment may lessen neuromorbidity. Hence, this study was done to understand small molecule neurometabolic disorders' presentation, diagnostic clues, and outcome.Small molecule neurometabolic disorder was diagnosed in 45 children (postneonatal onset) over 14 years (2008–2022) in a tertiary care hospital. Clinical and laboratory data were retrospectively analyzed.There were 26 boys and 19 girls. The median age at diagnosis was 19 months (interquartile range [IQR] 8–38 months). The median diagnostic delay was 12 months in chronic encephalopathy (IQR 1–24 months) and 1 month (IQR 0.2–5.5 months) in the acute encephalopathy group (p ≤ 0.01). The presentation mode was chronic encephalopathy/myopathy in 29 (64.4%) and acute encephalopathy in 11 (24.4%). Diagnostic clues included unexplained developmental delay (n = 27, 60%), tone abnormalities (n = 26, 57.7%), movement disorder and ataxia (n = 16, 35.5%), acute encephalopathy (n = 11, 24.4%), neuroregression (n = 10, 22.2%), macrocephaly (n = 10, 22.2%), and alopecia (n = 4, 8.9%). Diagnostic/suggestive blood-spot tandem mass spectrometry (TMS) was seen in 34/38 (89.5%) children. Neuroimaging helped clinch the diagnosis in 17 (47%) children. Diagnostic categories were organic acidemias (n = 25, 55.6%), urea cycle disorders (n = 11, 24.4%), aminoacidopathies (n = 5, 11.1%), and fatty acid oxidation disorders (n = 4, 8.9%). The neurodevelopmental outcome was normal in 13 (28.8%), mild delay in 12 (26.6%), severe delay in 11 (24.4%), 3 deaths (6.6%), and 6 (13.3%) children being lost to follow-up. Overall, the outcome was favorable in 55% of cases.Unexplained developmental delay with tone abnormalities with or without movement disorders is a joint presentation of late-onset neurometabolic diseases. Neuroimaging studies and laboratory tests like blood-spot TMS help identify many small molecule disorders.

Application of array comparative genomic hybridization in clinical diagnostics of intellectual disability/developmental delay in children

Background: This study was designed to analyze and evaluate the potential pathogenic genomic imbalance in children with unexplained intellectual disability (ID) and/or developmental delay (DD) and its association with phenotypes, and to investigate the value of array-based comparative genomic hybridization (array-CGH). Methods: A total of 72 Children with ID/DD were evaluated by array-CGH for detection of genomic copy number variations (CNVs). Results: The results of the array-CGH revealed that 10(14%) of the 72 patients had pathogenic CNVs, in that six cases had pathogenic CNV in a single chromosome, 2 cases had multiple microdeletions and 2 cases had combined microdeletion and microduplication, 2 cases had pathogenic CNVs in chromosome 1p36 and Xq28 region. One case had variation of unknown significance in chromosome region 15q11.2. Large bands of copy neutral loss of heterozygosity were detected in 2 cases comprising more than 10% of genome. Conclusions: Array-CGH being a high-throughput and rapid tool, allows for the etiological diagnosis in some of the children with unexplained ID/DD.

Allan-Herndon-Dudley syndrome in Hong Kong: Implication for newborn screening

BackgroundAllan-Herndon-Dudley syndrome (MCT 8 deficiency) is an X-linked recessive condition caused by hemizygous pathogenic variants in SLC16A2 encoding the monocarboxylate transporter 8 (MCT8). Patients present with global developmental delay and neurological impairment, and abnormal serum thyroid function tests. The drug, 3,3′,5 triiodothyroacetic acid (TRIAC), was recently demonstrated to improve the endocrinological profile. Improvement in diagnostic approach is key to earlier start of treatment. Patient findingsWe described four Chinese patients with MCT8 deficiency undergoing different diagnostic odysseys. Their initial presentation included global developmental delay and dystonia. Patient 2 also had epilepsy. Patients 1 and 2 presented with two novel variants: (1)hemizygous NM_006517.4(SLC16A2):c.1170 + 2 T > A; p.(?), and (2)hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17) respectively. Patients 3 and 4 were biological brothers harboring hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17), which was first reported in 2004. We obtained the measurement of triiodothyronine (T3) and reverse T3 (rT3) from dried blood spot samples collected on Day 1 of life from Patient 1 and studied the biomarkers (rT3 and T3/rT3 ratio) proposed by Iwayama et al. for the detection of MCT8 deficiency at birth. Our data verified the significantly reduced rT3 level in Patient 1, compared with healthy newborns, although low T3 level and comparable T3/rT3 ratio with controls were detected. SummaryPatients with MCT8 deficiency often undergo diagnostic odysseys. An early diagnosis could be missed by a normal newborn thyroid function screening result based on biochemical measurement of TSH and/or T4/fT4. Early detection of rT3 is key to improving current diagnostic approach. ConclusionWe recommend that full thyroid function profile (TSH, T4/fT4, T3/fT3, rT3) be considered early for all pediatric patients presenting with unexplained developmental delay and/or dystonia. The potential inclusion of rT3 measurement in newborn screening may prove promising.

Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities-A Narrative Review.

Unexplained global developmental delay (GDD) and intellectual disabilities (ID) together affect nearly 2% of the pediatric population. Establishing an etiologic diagnosis is crucial for disease management, prognostic evaluation, and provision of physical and psychological support for both the patient and the family. Advancements in genome sequencing have allowed rapid accumulation of gene-disorder associations and have accelerated the search for an etiologic diagnosis for unexplained GDD/ID. We reviewed recent studies that utilized genome-wide analysis technologies, and we discussed their diagnostic yield, strengths, and limitations. Overall, exome sequencing (ES) and genome sequencing (GS) outperformed chromosomal microarrays and targeted panel sequencing. GS provides coverage for both ES and chromosomal microarray regions, providing the maximal diagnostic potential, and the cost of ES and reanalysis of ES-negative results is currently still lower than that of GS alone. Therefore, singleton or trio ES is the more cost-effective option for the initial investigation of individuals with GDD/ID in clinical practice compared to a staged approach or GS alone. Based on these updated evidence, we proposed an evaluation algorithm with ES as the first-tier evaluation for unexplained GDD/ID.

Pathogenic Copy Number Variations Involved in the Genetic Etiology of Syndromic and Non-Syndromic Intellectual Disability-Data from a Romanian Cohort.

The investigation of unexplained global developmental delay (GDD)/intellectual disability (ID) is challenging. In low resource settings, patients may not follow a standardized diagnostic process that makes use of the benefits of advanced technologies. Our study aims to explore the contribution of chromosome microarray analysis (CMA) in identifying the genetic etiology of GDD/ID. A total of 371 Romanian patients with syndromic or non-syndromic GDD/ID, without epilepsy, were routinely evaluated in tertiary clinics. A total of 234 males (63.07%) and 137 (36.93%) females, with ages ranging from 6 months to 40 years (median age of 5.5 years), were referred for genetic diagnosis between 2015 and 2022; testing options included CMA and/or karyotyping. Agilent Technologies and Oxford Gene Technology CMA workflows were used. Pathogenic/likely pathogenic copy number variations (pCNVs) were identified in 79 patients (21.29%). Diagnosis yield was comparable between mild ID (17.05%, 22/129) and moderate/severe ID 23.55% (57/242). Higher rates were found in cases where facial dysmorphism (22.97%, 71/309), autism spectrum disorder (ASD) (19.11%, 26/136) and finger anomalies (20%, 27/96) were associated with GDD/ID. GDD/ID plus multiple congenital anomalies (MCA) account for the highest detection rates at 27.42% (17/62). pCNVs represent a significant proportion of the genetic causes of GDD/ID. Our study confirms the utility of CMA in assessing GDD/ID with an uncertain etiology, especially in patients with associated comorbidities.

CEP104 gene may involve in the pathogenesis of a new developmental disorder other than joubert syndrome.

The CEP104 gene (OMIM: 616,690) encodes the centrosome protein 104 (CEP104) that is involved in cilia function. Pathogenic variants in this gene have been described in four patients diagnosed with Joubert syndrome (JBTS) 25. Here, we challenged the concept that pathogenic variants in CEP104 gene are only involved in the development of JBTS 25. In a clinical setting, whole-exome sequencing (WES) was applied to investigate pathogenic variants in patients with unexplained developmental delay or intellectual disability (DD/ID).WES revealed a novel homozygous nonsense variant (c.643C > T) in CEP104 (NM _014704.3) in a girl with mild intellectual disability, hypotonia, and imbalanced gait. Her brain MRI data did not show molar tooth sign (MTS) or any other brain anomalies. Our study introduced a novel variant in the CEP104 gene that results in an ID phenotype other than JBTS25. Comparison of her phenotype with that of eight previously published DD/ID patients harboring pathogenic variants in CEP104 gene revealed that more than half of them did not show JBTS related symptoms. Therefore, we suggest that the CEP104 gene might also be involved in a disorder other than JBTS 25, a point that deserves to be emerged in the OMIM database.

Unusual precocious diagnosis of Duchenne muscular dystrophy by SNP-array in a 6-month old baby

Microdeletions and microduplications are involved in many cases of malformations, developmental delay (DD), autism (A) and growth disturbances (GD). Molecular karyotyping (MC) performed by microarray technology is a valuable method frequently used to elucidate the etiology of these clinical expressions, essentially contributing to the diagnosis of rare genetic diseases produced by DNA copy number variations (CNVs). MC has offered a higher diagnostic yield for genetic testing of patients with unexplained DD, A and GD than a G-banded karyotype, primarily because of its higher sensitivity in detecting submicroscopic deletions and duplications. In addition, the molecular karyotype approach using the SNP-array method also allows highlighting the regions of loss of heterozygosity and uniparental disomy, which are the basis of some genetic syndromes. In this paper we will present a rare case of a 6 months old boy, referred for MC due to global developmental delay, axial hypotonia, with limbs hypertonia, heart malformation (atrial septal defect). SNP-Array analysis identified a 606,3 Kb microdeletion in the Xp21.1 region, that contains 39 exons of dystrophin gene. This finding was confirmed also with additional MLPA testing. In conclusion, it is an unusual, precocious diagnosis of Duchenne muscular dystrophy, during first year of life, referred for atypical presentation, main clinical feature being global developmental delay.

Genetic Analysis of Children With Unexplained Developmental Delay and/or Intellectual Disability by Whole-Exome Sequencing.

Background: Whole-exome sequencing (WES) has been recommended as a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders (NDDs). We aimed to identify the genetic causes of 17 children with developmental delay (DD) and/or intellectual disability (ID). Methods: WES and exome-based copy number variation (CNV) analysis were performed for 17 patients with unexplained DD/ID. Results: Single-nucleotide variant (SNV)/small insertion or deletion (Indel) analysis and exome-based CNV calling yielded an overall diagnostic rate of 58.8% (10/17), of which diagnostic SNVs/Indels accounted for 41.2% (7/17) and diagnostic CNVs accounted for 17.6% (3/17). Conclusion: Our findings expand the known mutation spectrum of genes related to DD/ID and indicate that exome-based CNV analysis could improve the diagnostic yield of patients with DD/ID.

Clinical and genetic profile of children with unexplained intellectual disability/developmental delay and epilepsy

ObjectiveThis study was conducted to evaluate the validity of performing whole exome sequencing in children with unexplained intellectual disability (ID), developmental delay (DD), and epilepsy. MethodsWe enrolled 61 Iranian children with unexplained DD/ID, and epilepsy with no etiologic diagnosis. 64 % of cases were male and 36 % were female, with a mean age of 6.2 years (range, 38 days to 15 years). Approximately 79 % of patients were born to consanguineous parents or had non-related parents from a highly inbred local region. Whole-exome sequencing analysis followed by Sanger sequencing was performed in all patients. ResultsPathogenic/likely pathogenic variants were identified in 59% (36/61) of patients, consisting of 26 novel and 14 known alterations. Variants of unknown significance were observed in 6.5 % (4/61) of patients. Variants in 28 genes have not been previously reported in Iranian patients with ID. Several additional phenotypes, mostly microcephaly, were common in 57.4 % of cases. Additionally, epilepsy was refractory in 40 % of patients. Three groups of brain anomalies consisting of brain dysgenesis, brain atrophy, and leukodystrophy were identified in our cohort. Mutations in genes implicated in cellular metabolic pathways were the most common, followed by ion channel/ion transporter and transcription pathways. DiscussionHigh-throughput DNA sequencing of the Iranian population with a high rate of parental consanguinity is a valuable strategy for identifying genetic etiology in children with unexplained ID/DD and epilepsy. Determining the genetic basis and most commonly involved pathways may help to identify novel genes and targeted antiepileptic treatments.

19.3 DDX3X SYNDROME: A WINDOW INTO STUDYING AUTISM SPECTRUM DISORDER IN GIRLS

DDX3X syndrome is a recently identified genetic disorder that accounts for 1% to 3% of cases of unexplained developmental delay (DD) and/or intellectual disability (ID) in females and is a significant cause of autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored.

Screening for Inherited Metabolic Disorders by Tandem Mass Spectrometry May Miss L-2 Hydroxy Glutaric Aciduria: A Report of Two Cases

AbstractL-2 hydroxy glutaric aciduria (L-2HGA) is an autosomal recessive neurometabolic disorder. It is characterized by a variety of clinical features and typical radiological features which aids in diagnosis. We report two cases that presented with unexplained intellectual impairment and seizures. Magnetic resonance imaging (MRI) brain showed characteristic features of L-2HGA. Tandem mass spectrometry was negative in both cases. Genetic analysis was done based on typical imaging features which confirmed the diagnosis of L-2HGA. For patients with unexplained developmental delay and typical MRI features, a high degree of suspicion is necessary to confirm the diagnosis with targeted genetic analysis.

Prospective and detailed behavioral phenotyping in DDX3X syndrome

BackgroundDDX3X syndrome is a recently identified genetic disorder that accounts for 1–3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored.MethodsWe carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions.ResultsEighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype–phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants.LimitationsSample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder.ConclusionThis study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype–phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes.

Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing.

Whole-exome sequencing (WES) enables identification of pathogenic variants, including copy number variants (CNVs). In this study, we performed WES in 101 Japanese patients with unexplained developmental delay (DD) or intellectual disability (ID) (63 males and 38 females), 98 of them with trio-WES. Pathogenic variants were identified in 54 cases (53.5%), including four cases with pathogenic CNVs. In one case, a pathogenic variant was identified by reanalysis of exome data; and in two cases, two molecular diagnoses were identified. Among 58 pathogenic variants, 49 variants occurred de novo in 48 patients, including two somatic variants. The accompanying autism spectrum disorder and external ear anomalies were associated with detection of pathogenic variants with odds ratios of 11.88 (95% confidence interval [CI] 2.52-56.00) and 3.46 (95% CI 1.23-9.73), respectively. These findings revealed the importance of reanalysis of WES data and detection of CNVs and somatic variants in increasing the diagnostic yield for unexplained DD/ID. In addition, genetic testing is recommended when patients suffer from the autism spectrum disorder or external ear anomalies, which potentially suggests the involvement of genetic factors associated with gene expression regulation.

Wiedemann-Steiner syndrome due to novel nonsense variant of KMT2A gene in a case

To explore the genetic basis for a child with unexplained global developmental delay (GDD), seizure, and facial deformity. Whole exome sequencing (WES) was carried out for the patient. Candidate variants were verified by Sanger sequencing of the patient and his parents. WES revealed that the patient has carried a previously unreported de novo heterozygous nonsense c.4906C>T (p.Arg1636Ter) variant of the KMT2A gene, Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.4906C>T variant of KMT2A gene was predicted to be pathogenic (PVS1+ PS2+ PM2+PP3). The heterozygous nonsense c.4906C>T (p.Arg1636Ter) variant of the KMT2A gene probably underlay the disease in the child. Above finding has enriched the spectrum of pathogenic variants of the KMT2A gene.

Intellectual disability and dysmorphisms in a child with 14q32.31-q32.33 deletion: a case report

INTRODUCTION: Intellectual disability and global developmental delay are frequent causes of genetic consultation requested by pediatricians. Around 30% of severe intellectual disability and 70% of mild intellectual disability do not present a defined diagnosis. OBJECTIVES: Chromosome microarray comparative genomic hybridization test is now the standard diagnosis for patients presenting unexplained global developmental delay or intellectual disability, autism spectrum disorders, and multiple congenital anomalies due to the tests sensibility, increasing the chance for a diagnosis and elucidating size and region affected. CASE REPORT: This paper reports a girl with intellectual disability, prominent hypotonia, postnatal growth retardation and several dysmorphisms with a small subtelomeric 14q terminal deletion whose diagnosis was sought during six years and only became possible through the chromosome microarray test.

A rare thyroid disorder mimicking mitochondrial disease

<p>Introduction. Patients affected with Allan-Herndon-Dudley syndrome (AHDS) have a deficiency of monocarboxylate transporter 8 (MCT8), a protein primarily responsible for the transport of triiodothyronine (T3) into the brain. This X-linked disorder affects almost exclusively males with clinical presentation encompassing developmental delay, axial hypotonia, dystonia, poor head control, quadriplegia and absence of speech. Case reports. Patient 1 is a male child referred to a hospital investigation at 11 months due to severe developmental delay and elevated blood ammonia level (163 mcmol/L). Hypotonia and dystonic movements were noted at admission, with facial dysmorphic features. Laboratory findings revealed increased blood lactate (17.2 mmol/L), alanine (533 mcmol/L) and ammonia (391 mcmol/L) concentrations. Serum creatine-kinase levels showed substantial increase over the course of hospitalization up to 6,855 IU/L. Clinical exome sequencing detected a novel hemizygous frameshift insertion c.1456insC in gene SLC16A2, predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Segregation genetic testing of the family members revealed that mother, maternal uncle and maternal grandmother carry the same mutation in SLC16A2. The boy`s mother experienced learning difficulties through childhood while maternal uncle is severely affected by AHDS. Patient 2 is a boy referred to clinical geneticist due to severe psychomotor delay of unknown etiology. Moderate serum lactate elevation was the only laboratory abnormality during initial investigations. Diagnosis of AHDS was established by clinical exome sequencing, and subsequent hormonal evaluation revealed increased triiodothyronine (T3) level which corresponds well to genetic diagnosis. Conclusion. Presence of lactic acidosis and/or hyperammonemia in children with severe developmental delay is not specific for inborn disorders of energy production, such as mitochondrial disease. Clinicians should consider thyroid hormones profiling in cases of unexplained severe developmental delay in male children, especially if associated with axial hypotonia and dystonic movements.</p>

Detection of Copy Number Variants by Short Multiply Aggregated Sequence Homologies

Chromosomal microarray testing is indicated for patients with diagnoses including unexplained developmental delay or intellectual disability, autism spectrum disorders, and multiple congenital anomalies. The short multiply aggregated sequence homologies (SMASH) genomic assay is a novel next-generation sequencing technology that performs copy number analysis at resolution similar to high-coverage whole genome sequencing but requires far less capacity. We benchmarked the performance of SMASH on a panel of genomic DNAs containing known copy number variants (CNVs). SMASH was able to detect pathogenic copy number variants of ≥10 kb in 77 of 77 samples. No pathogenic events were seen in 32 of 32 controls, indicating 100% sensitivity and specificity for detecting pathogenic CNVs >10 kb. Repeatability (interassay precision) and reproducibility (intra-assay precision) were assessed with 13 samples and showed perfect concordance. We also established that SMASH had a limit of detection of 20% for detection of large mosaic CNVs. Finally, we analyzed seven blinded specimens by SMASH analysis and successfully identified all pathogenic events. These results establish the efficacy of the SMASH genomic assay as a clinical test for the detection of pathogenic copy number variants at a resolution comparable to chromosomal microarray analysis.

Chromosomal Microarray Analysis in Turkish Patients with Unexplained Developmental Delay and Intellectual Developmental Disorders.

Aneuploids, copy number variations (CNVs), and single nucleotide variants in specific genes are the main genetic causes of developmental delay (DD) and intellectual disability disorder (IDD). These genetic changes can be detected using chromosome analysis, chromosomal microarray (CMA), and next-generation DNA sequencing techniques. Therefore; In this study, we aimed to investigate the importance of CMA in determining the genomic etiology of unexplained DD and IDD in 123 patients. For 123 patients, chromosome analysis, DNA fragment analysis and microarray were performed. Conventional G-band karyotype analysis from peripheral blood was performed as part of the initial screening tests. FMR1 gene CGG repeat number and methylation analysis were carried out to exclude fragile X syndrome. CMA analysis was performed in 123 unexplained IDD/DD patients with normal karyotypes and fragile X screening, which were evaluated by conventional cytogenetics. Forty-four CNVs were detected in 39 (39/123=31.7%) patients. Twelve CNV variant of unknown significance (VUS) (9.75%) patients and 7 CNV benign (5.69%) patients were reported. In 6 patients, one or more pathogenic CNVs were determined. Therefore, the diagnostic efficiency of CMA was found to be 31.7% (39/123). Today, genetic analysis is still not part of the routine in the evaluation of IDD patients who present to psychiatry clinics. A genetic diagnosis from CMA can eliminate genetic question marks and thus alter the clinical management of patients. Approximately one-third of the positive CMA findings are clinically intervenable. However, the emergence of CNVs as important risk factors for multiple disorders increases the need for individuals with comorbid neurodevelopmental conditions to be the priority where the CMA test is recommended.

Disturbances of Amino Acid Metabolism in Neurologic Disorders detected by fluorescent high performance liquid chromotograghy (HPLC) in Baghdad - IRAQ

Background:Amino acid disorders are a major group of inborn error metabolism (IEM) with variable clinical presentation; its diagnosis constitutes a real challenge in a community with high consanguinity rate and no systematic newborn screening.
 Objectives: to provide data about amino acid disorders detected in high-risk Iraqi children by using quantitative amino acid fluorescent high performance liquid chromatography (HPLC) analysis.
 Type of the study: Cross-sectional study.
 Methods: a descriptive cross sectional study from 1st February to 1st December 2014, at Neurological ward and clinic of the Children Welfare teaching Hospital, in Baghdad - Iraq. Plasma specimens of 500 patients, with clinical suspicion of inborn error of metabolism (IEM) because of unexplained neurological deficits, unexplained developmental delay, recurrent coma and/or Neuro-degeneration, hair changes and/or lethargy, poor feeding, vomiting and selected cases of autistic spectrum syndrome or with positive screening, were analyzed for amino acids by high performance liquid chromatography (HPLC). The amino acid disorders were confirmed in fifty patients were; clinical data of patients were reported and analyzed statistically.
 Results: out of 500 patients visiting the neurological outpatient and ward, clinical and neurological finding were recorded as well as the family history and/or other symptoms suggestive of aminoacidopathy, Sixty patients were confirmed their diagnosis as amino acid disorders, ten patients were excluded because they lost the follow up or there is no solid base for a causal relationship between detected abnormal amino acids and neurological disorders, therefore only 50 patients were
 
 enrolled in the study. Patients with Phenylketonuria were the most frequent 24 (48%), homocystinuria 14 (28%), maple syrup urine disease 9 (18%) & other amino acid disorder, (Citrullinemia, non-ketotic hyperglycinemia & Tyrosinemia) 1for each disorder (2%). Considerable delay in diagnosis was noticed which lead to variable neurological abnormalities in most patients and the psychomotor delay was the main clinical presentation at time of diagnosis 34 (68%).
 Conclusion: in the absence of newborn screening, the majority of Aminoacidopathies cases was still diagnosed clinically, but delayed. The importance of clinical awareness and accurate biochemical analysis were the key tools for diagnosis and the necessity for a comprehensive national newborn screening program.