ABSTRACT
In addition to the numerous immunological and nutritional benefits that breast milk offers to infants, its proportion in the diet must be limited or even excluded in the case of inborn errors of amino acid metabolism (IEM). The objective of the study was to expand knowledge about breastfeeding and the degree of contribution of breast milk to the feeding of infants with IEM before and after the introduction of expanded newborn screening. A retrospective single-centre study was conducted on 127 infants born between 1997 and 2020: 66 with phenylketonuria (PKU), 45 with other IEM (non-PKU), all diagnosed through newborn screening (NBS), and 16 non-PKU diagnosed through selective screening (SS). The time of initiation of dietary treatment and the proportion of breast milk in the diet, both expressed and breastfed, with or without intake control, were analysed at 1, 3, and 6 months after birth. For 47% of the newborns in Groups 1 and 2, the dietary treatment was started before the 10th day of life; in Group 3, the dietary treatment was started after the 10th day of life for all children. During the first month of life, the proportion of infants receiving breast milk was higher in the NBS-PKU (74%) and the NBS non-PKU (80%) groups, compared with 38% in the SS non-PKU infants. In the subsequent months of life, the proportion of infants receiving human milk (either from the breast or a bottle) declined in all groups. This decline occurred more in bottle-fed rather than directly breast-fed infants. Our observations indicate that the model of feeding from a bottle with expressed milk may have had an adverse effect on maintaining lactation and may have contributed to a faster transition to formula milk. Maintaining lactation and extending the period of feeding the infant with human milk in the first 6 months of life is possible by breastfeeding on demand, under regular biochemical monitoring: preferably weekly in PKU infants, and at least every 2-4 weeks in infants with other IEM.
Subject(s)
Breast Feeding , Milk, Human , Neonatal Screening , Phenylketonurias , Humans , Infant, Newborn , Retrospective Studies , Phenylketonurias/diet therapy , Female , Neonatal Screening/methods , Male , Infant , Amino Acid Metabolism, Inborn Errors , Infant Nutritional Physiological PhenomenaABSTRACT
The diagnosis of Mendelian disorders has notably advanced with integration of whole exome and genome sequencing (WES and WGS) in clinical practice. However, challenges in variant interpretation and uncovered variants by WES still leave a substantial percentage of patients undiagnosed. In this context, integrating RNA sequencing (RNA-seq) improves diagnostic workflows, particularly for WES inconclusive cases. Additionally, functional studies are often necessary to elucidate the impact of prioritized variants on gene expression and protein function. Our study focused on three unrelated male patients (P1-P3) with ATP6AP1-CDG (congenital disorder of glycosylation), presenting with intellectual disability and varying degrees of hepatopathy, glycosylation defects, and an initially inconclusive diagnosis through WES. Subsequent RNA-seq was pivotal in identifying the underlying genetic causes in P1 and P2, detecting ATP6AP1 underexpression and aberrant splicing. Molecular studies in fibroblasts confirmed these findings and identified the rare intronic variants c.289-233C > T and c.289-289G > A in P1 and P2, respectively. Trio-WGS also revealed the variant c.289-289G > A in P3, which was a de novo change in both patients. Functional assays expressing the mutant alleles in HAP1 cells demonstrated the pathogenic impact of these variants by reproducing the splicing alterations observed in patients. Our study underscores the role of RNA-seq and WGS in enhancing diagnostic rates for genetic diseases such as CDG, providing new insights into ATP6AP1-CDG molecular bases by identifying the first two deep intronic variants in this X-linked gene. Additionally, our study highlights the need to integrate RNA-seq and WGS, followed by functional validation, in routine diagnostics for a comprehensive evaluation of patients with an unidentified molecular etiology.
Subject(s)
Introns , RNA, Messenger , Humans , Male , Introns/genetics , RNA, Messenger/genetics , Vacuolar Proton-Translocating ATPases/genetics , Congenital Disorders of Glycosylation/genetics , Congenital Disorders of Glycosylation/diagnosis , Congenital Disorders of Glycosylation/pathology , Mutation , Whole Genome Sequencing , Exome Sequencing , Sequence Analysis, RNA , Intellectual Disability/genetics , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Child , RNA Splicing/genetics , Child, PreschoolABSTRACT
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Aromatic-L-Amino-Acid Decarboxylases , Humans , Prevalence , Dopamine/metabolism , Genotype , Amino Acid Metabolism, Inborn Errors/epidemiology , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acids/geneticsABSTRACT
Regulation of H2S homeostasis in humans is poorly understood. Therefore, we assessed the importance of individual enzymes in synthesis and catabolism of H2S by studying patients with respective genetic defects. We analyzed sulfur compounds (including bioavailable sulfide) in 37 untreated or insufficiently treated patients with seven ultrarare enzyme deficiencies and compared them to 63 controls. Surprisingly, we observed that patients with severe deficiency in cystathionine ß-synthase (CBS) or cystathionine γ-lyase (CSE) - the enzymes primarily responsible for H2S synthesis - exhibited increased and normal levels of bioavailable sulfide, respectively. However, an approximately 21-fold increase of urinary homolanthionine in CBS deficiency strongly suggests that lacking CBS activity is compensated for by an increase in CSE-dependent H2S synthesis from accumulating homocysteine, which suggests a control of H2S homeostasis in vivo. In deficiency of sulfide:quinone oxidoreductase - the first enzyme in mitochondrial H2S oxidation - we found normal H2S concentrations in a symptomatic patient and his asymptomatic sibling, and elevated levels in an asymptomatic sibling, challenging the requirement for this enzyme in catabolizing H2S under physiological conditions. Patients with ethylmalonic encephalopathy and sulfite oxidase/molybdenum cofactor deficiencies exhibited massive accumulation of thiosulfate and sulfite with formation of large amounts of S-sulfocysteine and S-sulfohomocysteine, increased renal losses of sulfur compounds and concomitant strong reduction in plasma total cysteine. Our results demonstrate the value of a comprehensive assessment of sulfur compounds in severe disorders of homocysteine/cysteine metabolism and provide evidence for redundancy and compensatory mechanisms in the maintenance of H2S homeostasis.
Subject(s)
Hydrogen Sulfide , Humans , Hydrogen Sulfide/metabolism , Cysteine , Sulfides/metabolism , Homeostasis , Sulfur , HomocysteineABSTRACT
Aromatic amino acid decarboxylase (AADC) deficiency is a rare monogenic disease, often fatal in the first decade, causing severe intellectual disability, movement disorders and autonomic dysfunction. It is due to mutations in the gene coding for the AADC enzyme responsible for the synthesis of dopamine and serotonin. Using whole exome sequencing, we have identified a novel homozygous c.989C > T (p.Pro330Leu) variant of AADC causing AADC deficiency. Pro330 is part of an essential structural and functional element: the flexible catalytic loop suggested to cover the active site as a lid and properly position the catalytic residues. Our investigations provide evidence that Pro330 concurs in the achievement of an optimal catalytic competence. Through a combination of bioinformatic approaches, dynamic light scattering measurements, limited proteolysis experiments, spectroscopic and in solution analyses, we demonstrate that the substitution of Pro330 with Leu, although not determining gross conformational changes, results in an enzymatic species that is highly affected in catalysis with a decarboxylase catalytic efficiency decreased by 674- and 194-fold for the two aromatic substrates. This defect does not lead to active site structural disassembling, nor to the inability to bind the pyridoxal 5'-phosphate (PLP) cofactor. The molecular basis for the pathogenic effect of this variant is rather due to a mispositioning of the catalytically competent external aldimine intermediate, as corroborated by spectroscopic analyses and pH dependence of the kinetic parameters. Altogether, we determined the structural basis for the severity of the manifestation of AADC deficiency in this patient and discussed the rationale for a precision therapy.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Aromatic-L-Amino-Acid Decarboxylases , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/metabolism , Aromatic-L-Amino-Acid Decarboxylases/deficiency , Aromatic-L-Amino-Acid Decarboxylases/genetics , Aromatic-L-Amino-Acid Decarboxylases/metabolism , Catalysis , Dopamine/metabolism , HumansABSTRACT
Biotinidase deficiency (BD) is a rare autosomal recessive metabolic disease. Previously the disease was identified only by clinical signs and symptoms, and since recently, it has been included in newborn screening programs (NBS) worldwide, though not commonly. In Europe, BD prevalence varies highly among different countries, e.g., from 1:7 116 in Turkey to 1:75 842 in Switzerland. This paper aimed to present the molecular spectrum of BD (profound and partial forms) in Polish patients diagnosed within the national NBS of 1,071,463 newborns. The initial suspicion of BD was based on an abnormal biotinidase activity result determined in a dry blood spot (DBS) by colorimetric and by fluorimetric methods while biochemical verification was determined by serum biotinidase activity (as quantitative analysis). The final diagnosis of BD was established by serum enzyme activity and the BTD gene direct sequencing. The obtained results allowed for the estimation of disease prevalence (1:66,966 births, while 1:178,577 for profound and 1:107,146 for partial forms), and gave novel data on the molecular etiology of BD.
Subject(s)
Biotinidase Deficiency , Biotinidase/genetics , Biotinidase Deficiency/diagnosis , Biotinidase Deficiency/epidemiology , Biotinidase Deficiency/genetics , Humans , Infant, Newborn , Mutation , Neonatal Screening/methods , Poland/epidemiology , PrevalenceABSTRACT
More than 650 inherited metabolic diseases may present with epilepsy or seizures. These diseases are often multisystem, life-long and induce complex needs of patients and families. Multidisciplinary care involves all stages of disease management: diagnostics, specific or symptomatic, acute and chronic treatments, and integrated care that takes into account not only medical, but also manifold psychosocial, educational, vocational and other needs of patients and their caregivers. Care coordination is indispensable to ensure smooth transitions of care across life and disease stages, including management of emergencies, transition from pediatric to adult services and palliative care. Care pathways are highly diverse and have to find the right balance between highly specialized and locally provided services. While multidisciplinary teams consist of many professionals, a named supervising physician in a highly specialized healthcare setting and a care coordinator are highly important. As the greatest burden of care always falls onto the shoulders of patients and/or families, patient empowerment should be a part of every care pathway and include provision of required information, involvement into common decision-making, patient's and family's education, support for self-management, liaison with peer support groups and emotional/ psychological support. Due to the rarity and complexity of these diseases, sufficient expertise may not be available in a national healthcare system and cross-border services (virtual or physical) in the recently developed European Reference Networks should be ensured through the proper organization of referral systems in each EU and EEA country. Finally, digital technologies are particularly important in the provision of services for patients with rare diseases and can significantly increase the availability of highly specialized services and expertise.
ABSTRACT
COVID-19 pandemic is an organisational challenge for both healthcare providers and patients. People with rare inherited metabolic disorders (IMD) and rare autoinflammatory diseases (AD) are vulnerable patients whose well-being is deeply connected with regular follow-ups. This study aimed to assess how e one year of coronavirus pandemic has impacted the treatment of patients with IMD and AD in Poland. Surveys were distributed to all healthcare providers that coordinate the treatment of IMD and AD patients. Thirty-two responders (55%) answered the survey. They provide care to 1726 patients with IMD/AD, including 246 patients on dedicated treatment. In 35% of units, the regular appointments were disrupted, primarily because of patient infection. In 18 hospitals, remote visits were implemented, but only 66.6% of patients used this form of consultation. In 14/32 hospitals, administration of the therapy was delayed (median: 17.4 days). Forty-four patients suffered from SARS-COV-2 infection, in majority with mild symptoms. However, four adult patients developed complications, and one died following a SARS-COV-2 infection. Although most hospitals managed to maintain regular visits during the pandemic, more comprehensive implementation of telemedicine and switch to oral therapy or home infusions would be a reasonable solution for the current epidemic situation.
ABSTRACT
PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 µg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.
Subject(s)
Adrenal Insufficiency/diagnosis , Adrenal Insufficiency/physiopathology , Phosphotransferases (Phosphomutases)/blood , Adolescent , Adrenal Insufficiency/etiology , Adult , Child , Child, Preschool , Congenital Disorders of Glycosylation , Female , Glycosylation , Humans , Infant , Male , Middle Aged , Phosphotransferases (Phosphomutases)/genetics , Pituitary-Adrenal System/physiology , Prospective Studies , Risk Factors , Young AdultABSTRACT
Classic galactosemia (OMIM #230400) is an autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the galactose-1-phosphate uridylyltransferase gene (GALT; 606999) on chromosome 9p13. Its diagnosis is established by detecting elevated erythrocyte galactose-1-phosphate concentration, reduced erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity. Biallelic pathogenic variants in the GALT gene is confirmed by DNA analysis. Our paper presents molecular characteristics of 195 Polish patients diagnosed with galactosemia I, intending to expand the current knowledge of this rare disease's molecular etiology. To the best of our knowledge, the described cohort of galactosemia patients is the largest single-center cohort presented so far.
Subject(s)
Galactosemias , Galactosemias/genetics , Homozygote , Humans , Nucleotidyltransferases , Poland , UTP-Hexose-1-Phosphate Uridylyltransferase/geneticsABSTRACT
BACKGROUND: Most white matter diseases present on magnetic resonance imaging as focal or diffuse T2-hyperintensities. However, in a few of them, radially oriented stripes of low (relatively normal) signal intensity are observed within diffusely affected T2-hyperintense cerebral white matter and are called "tigroid pattern" in the literature. The fornix is a tiny white matter fibers bundle playing crucial role in cognitive functioning, easily overlooked on magnetic resonance imaging and not described in inborn errors of metabolism. CASE PRESENTATION: We present a case of glutaric aciduria type 1 with a follow-up of over nine years. The course of the disease is presented in three magnetic resonance scans at the age of 8 and 21 months, and 10 years, with diffusion restriction in the fornix in scan 1 and 2 and with tigroid pattern in scan 3. Despite appropriate diet and supplementation, injury of white matter progressed achieving diffuse stage with tigroid pattern. Psychological tests revealed deficits in patient's specific cognitive skills, most likely related to damage to the fornix. CONCLUSIONS: To our knowledge, this is the first report of tigroid pattern of white matter involvement in glutaric aciduria type 1 and the first report of forniceal injury in this disease which seems to be correlated with patient's low functioning in all kinds of memory skills, previously not reported in glutaric aciduria type 1.
Subject(s)
Glutarates , Leukoencephalopathies , Amino Acid Metabolism, Inborn Errors , Brain/diagnostic imaging , Brain Diseases, Metabolic , Glutaryl-CoA Dehydrogenase/deficiency , Humans , Leukoencephalopathies/diagnostic imaging , Magnetic Resonance ImagingABSTRACT
Methylmalonic aciduria is treated with a natural protein-restricted diet with adequate energy intake to sustain metabolic balance. Natural protein is a source of methylmalonic acid precursors, and intake is individually modified according to the severity and clinical course of the disease. The experience and approach to MMA treatment in European centers is variable with different amounts of natural protein and precursor-free l-amino acids being prescribed, although the outcome appears independent of the use of precursor-free l-amino acids. Further long-term outcome data is necessary for early treated patients with MMA. This case study, a woman with MMA followed from birth to the age of 35 years, including pregnancy, illustrates the long-term course of the disease and lifetime changes in dietary treatment. A low natural protein diet (1.5 g-1.0 g/kg/day) was the foundation of treatment, but temporary supplementation with precursor-free l-amino acids, vitamin-mineral mixture, and energy supplements were necessary at different timepoints (in childhood, adolescence, adulthood and pregnancy). Childhood psychomotor development was slightly delayed but within the normal range in adulthood. There were few episodes of metabolic decompensation requiring IV glucose, but at age 27 years, she required intensive care following steroid treatment. In pregnancy, she remained stable but received intensive biochemical and medical follow-up. This successful long-term follow-up of a patient with MMA from childhood, throughout pregnancy, delivery, and postpartum confirms that careful clinical, biochemical, and dietetic monitoring is crucial to ensure a favourable outcomes in MMA. Personalized treatment is necessary according to the individual clinical course. Knowledge about long-term treatment and clinical outcome is important information to influence future MMA clinical guidelines.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Adolescent , Adult , Amino Acid Metabolism, Inborn Errors/drug therapy , Diet , Dietary Supplements , Female , Humans , Methylmalonic Acid , PregnancyABSTRACT
Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients.
Subject(s)
Disease Management , Galactose/therapeutic use , Glycogen Storage Disease/diagnosis , Glycogen Storage Disease/drug therapy , Adult , Cardiomyopathies/complications , Cardiomyopathies/pathology , Cleft Palate/complications , Cleft Palate/pathology , Consensus , Glycogen Storage Disease/complications , Glycogen Storage Disease/enzymology , Humans , Hypoglycemia/complications , Infant , International Cooperation , Muscular Diseases/complications , Muscular Diseases/pathologyABSTRACT
(1) Background: Molybdenum cofactor deficiency type B (MOCODB, #252160) is a rare autosomal recessive metabolic disorder characterized by intractable seizures of neonatal-onset, muscular spasticity, accompanying with hypouricemia, elevated urinary sulfite levels and craniofacial dysmorphism. Thirty-five patients were reported to date. (2) Methods: Our paper aimed to delineate the disease genotype by presenting another patient, in whom a novel, in-frame variant within the MOCS2 gene was identified. (3) Results: Exome sequencing led to the identification of a novel variant in the MOCS2 gene-c.472_477del of unknown significance (VUS). (4) Conclusions: To prove the clinical significance of the mentioned variant, analysis of the possible mutation consequences on molecular level with the use of the available crystal structure of the human molybdopterin synthase complex was of great importance. Moreover, a potential pathomechanism resulting from a molecular defect was presented, giving original insight into the current knowledge on this rare disease, including treatment options.
ABSTRACT
Quantitative estimates for the global impact of COVID-19 on the diagnosis and management of patients with inborn errors of metabolism (IEM) are lacking. We collected relevant data from 16 specialized medical centers treating IEM patients in Europe, Asia and Africa. The median decline of reported IEM related services in March 1st-May 31st 2020 compared to the same period in 2019 were as high as 60-80% with a profound impact on patient management and care for this vulnerable patient group. More representative data along with outcome data and guidelines for managing IEM disorders under such extraordinary circumstances are needed.
Subject(s)
COVID-19/prevention & control , Delivery of Health Care/statistics & numerical data , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/therapy , Africa/epidemiology , Asia/epidemiology , COVID-19/epidemiology , COVID-19/virology , Comorbidity , Delivery of Health Care/methods , Delivery of Health Care/trends , Europe/epidemiology , Humans , Infant, Newborn , Mass Screening/methods , Mass Screening/statistics & numerical data , Metabolism, Inborn Errors/epidemiology , Neonatal Screening/methods , Pandemics , Phenylketonurias/diagnosis , Phenylketonurias/epidemiology , Phenylketonurias/therapy , SARS-CoV-2/physiologyABSTRACT
INTRODUCTION: To avoid the risk of intellectual disabilities, newborns in Poland are screened for phenylketonuria and are recommended to start a life-long phenylalanine-restricted diet shortly after birth. The aim of this paper is to evaluate the health care for patients with classical phenylketonuria in Poland. MATERIAL AND METHODS: We reviewed the National Health Fund's reporting data concerning information on healthcare services for patients with classical phenylketonuria (PKU), which were reported to the payer by the healthcare service providers between 2009 and 2015. The analysis was prepared within the framework of mapping the health care needs of patients with metabolic diseases published in December 2016 (http://www.mapypotrzebzdrowotnych.mz.gov.pl/). RESULTS: A total of 2706 patients with PKU (including 1180 children) were registered in the healthcare system in the period covered. The estimated national prevalence of PKU was 1 per 7758 live births. Paediatric patients up to 12 moths of age accounted for over 40% of all visits to outpatient clinics. Patients over 28 years of age accounted for only 1% of all PKU patients receiving specialist outpatient care. There were twice as many clinics providing health care to children than to adults. The majority of adult patients received healthcare from the same providers as children. Sixty-nine percent of adults and 64% of children were treated in the two largest outpatient centres. There were 12 deaths, with a median age of 63 years. The working-age adults accounted for 50% of the deaths. CONCLUSIONS: Adult patients with PKU do not receive sufficient healthcare. The discontinuation of healthcare by adults with PKU can result from the lack of an adequate transition process from paediatric to adult care.
Subject(s)
Financial Management , Phenylketonurias , Transition to Adult Care , Adult , Humans , Infant , Infant, Newborn , Phenylketonurias/therapy , Poland , PrevalenceABSTRACT
Genetic disorders are the leading cause of infant morbidity and mortality. Due to the large number of genetic diseases, molecular and phenotype heterogeneity and often severe course, these diseases remain undiagnosed. In infants with a suspected acute monogenic disease, rapid whole-exome sequencing (R-WES) can be successfully performed. R-WES (singletons) was performed in 18 unrelated infants with a severe and/or progressing disease with the suspicion of genetic origin hospitalized in an Intensive Care Unit (ICU). Blood samples were also collected from the parents. The results from the R-WES were available after 5-14 days. A conclusive genetic diagnosis was obtained in 13 children, corresponding to an overall diagnostic yield of 72.2%. For nine patients, R-WES was used as a first-tier test. Eight patients were diagnosed with inborn errors of metabolism, mainly mitochondrial diseases. In two patients, the disease was possibly caused by variants in genes which so far have not been associated with human disease (NARS1 and DCAF5). R-WES proved to be an effective diagnostic tool for critically ill infants in ICUs suspected of having a genetic disorder. It also should be considered as a first-tier test after precise clinical description. The quickly obtained diagnosis impacts patient's medical management, and families can receive genetic counseling.
ABSTRACT
3-methylglutaconic aciduria includes a heterogeneous group of inborn errors of metabolism. The disease may have various clinical presentations, as can duplication 5q. We present the case of a 13-year-old boy with 3-methylglutaconic aciduria and duplication 5q. The main symptoms included myopathy, weakness, spastic paresis intensified mostly in the lower limbs, and intellectual disability. Additional studies showed elevated levels of 3-methylglutaconic acid in urine and ammonia in plasma. A duplication in region 5q23.3q31.1 was found in array-based comparative genomic hybridization. Next-generation sequencing did not reveal any pathological mutation. On the basis of the clinical picture and the results of biochemical and genetic tests 3-methylglutaconic aciduria type IV with duplication 5q was diagnosed.