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The first-tier genetic testing for developmental and epileptic encephalopathies (DEE) is now increasingly used in routine clinical practice. Antiquitin deficiency, also referred to as pyridoxine-dependent epilepsy (PDE-ALDH7A1), represents an inherited metabolic disorder with the phenotype of an early infantile DEE. In addition to the fact that biochemical biomarkers of PDE-ALDH7A1, including a-aminoadipic semialdehyde dehydrogenase, pipecolic acid (PA), 1-piperideine-6-carboxylate, and 6-oxopipecolate (6-oxo-PIP), are well-characterized, and their analysis and usefulness have some limitations. Here, we describe the case of a newborn presenting with seizures from the first hours of life, who was resistant to standard antiepileptic drugs and was found to be a biallelic compound heterozygote of two clearly pathogenic variants in the ALDH7A1 gene based on targeted next-generation sequencing (NGS). The diagnostic process of PDE-ALDH7A1 was limited by the possibility to determine only urinary PA and 6-oxo-PIP (urinary organic acid profile using the GC-MS method), and the exogenous peak of levetiracetam, due to the fact that it has a similar retention time as 6-oxo-PIP, masked the detection of 6-oxo-PIP. [ABSTRACT FROM AUTHOR]

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Aim: Children with ultra-short bowel syndrome (USBS) have not been extensively studied to date because the condition is rare. The aim of the study was to assess the nutritional status of children with USBS receiving home parenteral nutrition, using citrulline serum concentration and cholestasis.Methods: We studied 17 patients with USBS, with a median age of 6.6 years and median duration of parenteral nutrition of 6.6 years. The study was carried out at The Children's Memorial Health Institute, Warsaw, from January 2014 to January 2015.Results: The median standard deviation score (SDS) was -1.2 for body mass according to chronological age, -1.72 according to height and -0.59 according to height for age. Patients requiring seven days per week parenteral nutrition had a citrulline concentration below 10 μmol/L. Decreased bone-mineral density was observed in 87% of the patients. Low values of 25-hydroxyvitamin D were found in 53% of the children. None of the patients had elevated conjugated bilirubin levels above 34.2 μmol/L.Conclusion: Children with USBS were growth deficient according to their chronological age, with frequent abnormal bone mineralisation and vitamin D deficiency. Children requiring parenteral nutrition seven days a week had citrulline concentrations below 10 μmol/L. Cholestasis was not seen. [ABSTRACT FROM AUTHOR]

The urea cycle disorder carbamoyl phosphate synthetase I deficiency is an important differential diagnosis in the encephalopathic neonate. This intoxication type inborn error of metabolism often leads to neonatal death or severe and irreversible damage of the central nervous system, even despite appropriate treatment. Timely diagnosis is crucial, but can be difficult on routine metabolite level. Here, we report ten neonates from eight families (finally) diagnosed with CPS1 deficiency at three tertiary metabolic centres. In seven of them the laboratory findings were dominated by significantly elevated urinary 3-methylglutaconic acid levels which complicated the diagnostic process. Our findings are both important for the differential diagnosis of patients with urea cycle disorders and also broaden the differential diagnosis of hyperammonemia associated with 3-methylglutaconic aciduria, which was earlier only reported in TMEM70 and SERAC1 defect. [ABSTRACT FROM AUTHOR]

Biotin-thiamine-responsive basal ganglia disease is a severe form of a rare neurogenetic disorder caused by pathogenic molecular variants in the thiamine transporter gene. Nowadays, a potentially effective treatment is known, therefore the early diagnosis is mandatory. The aim of the paper was to assess the contribution of neuropathological and magnetic resonance imaging (MRI) studies to a proper diagnosis. We present the brain study of two Polish patients with SLC19A3 mutations, including (1) an infant with an intriguing "walnut" appearance of the brain autopsied many years before the discovery of the SLC19A3 defect, and (2) a one-year-old patient with clinical features of Leigh syndrome. In patient 2, biotin/thiamine responsiveness was not tested at the time of diagnosis and causal treatment started with one-year delay. The central nervous system lesions found in the patients displayed almost clearly a specific pattern for SLC19A3 defect, as previously proposed in diagnostic criteria. Our study presents a detailed description of neuropathological and MRI findings of both patients. We confirm that the autopsy and/or MRI of the brain is sufficient to qualify a patient with an unknown neuropathological disorder directly for SLC19A3 mutations testing and a prompt trial of specific treatment. [ABSTRACT FROM AUTHOR]

Background: Whole-exome sequencing (WES) has led to an exponential increase in identification of causative variants in mitochondrial disorders (MD).Methods: We performed WES in 113 MD suspected patients from Polish paediatric reference centre, in whom routine testing failed to identify a molecular defect. WES was performed using TruSeqExome enrichment, followed by variant prioritization, validation by Sanger sequencing, and segregation with the disease phenotype in the family.Results: Likely causative mutations were identified in 67 (59.3 %) patients; these included variants in mtDNA (6 patients) and nDNA: X-linked (9 patients), autosomal dominant (5 patients), and autosomal recessive (47 patients, 11 homozygotes). Novel variants accounted for 50.5 % (50/99) of all detected changes. In 47 patients, changes in 31 MD-related genes (ACAD9, ADCK3, AIFM1, CLPB, COX10, DLD, EARS2, FBXL4, MTATP6, MTFMT, MTND1, MTND3, MTND5, NAXE, NDUFS6, NDUFS7, NDUFV1, OPA1, PARS2, PC, PDHA1, POLG, RARS2, RRM2B, SCO2, SERAC1, SLC19A3, SLC25A12, TAZ, TMEM126B, VARS2) were identified. The ACAD9, CLPB, FBXL4, PDHA1 genes recurred more than twice suggesting higher general/ethnic prevalence. In 19 cases, variants in 18 non-MD related genes (ADAR, CACNA1A, CDKL5, CLN3, CPS1, DMD, DYSF, GBE1, GFAP, HSD17B4, MECP2, MYBPC3, PEX5, PGAP2, PIGN, PRF1, SBDS, SCN2A) were found. The percentage of positive WES results rose gradually with increasing probability of MD according to the Mitochondrial Disease Criteria (MDC) scale (from 36 to 90 % for low and high probability, respectively). The percentage of detected MD-related genes compared with non MD-related genes also grew with the increasing MD likelihood (from 20 to 97 %). Molecular diagnosis was established in 30/47 (63.8 %) neonates and in 17/28 (60.7 %) patients with basal ganglia involvement. Mutations in CLPB, SERAC1, TAZ genes were identified in neonates with 3-methylglutaconic aciduria (3-MGA) as a discriminative feature. New MD-related candidate gene (NDUFB8) is under verification.Conclusions: We suggest WES rather than targeted NGS as the method of choice in diagnostics of MD in children, including neonates with 3-MGA aciduria, who died without determination of disease cause and with limited availability of laboratory data. There is a strong correlation between the degree of MD diagnosis by WES and MD likelihood expressed by the MDC scale. [ABSTRACT FROM AUTHOR]

We describe a child with dyslexia and difficulty in school who, at the age of 13 years, began to suffer from several head injuries resulting from falls of uncertain cause. Two years later, the patient developed symptoms of a severe mitochondrial disorder (involving bulbar-pyramidal paralysis, ophthalmoplegia, and hyperlactatemia) that coincided with VPA administration. Brain MR imaging revealed rapidly developing Leigh syndrome (LS), and muscle biopsy showed ragged blue fibres (RBF). A diminished expression of the E1α subunit of pyruvate dehydrogenase was found in muscle homogenate (signal 28.7% of normal). The accurate diagnosis of mitochondrially inherited LS (MILS) and the identification of an almost homoplasmic m.8344G>A mutation in the MTTK gene was delayed due to an initial incorrect diagnosis of epilepsy, misdiagnosis of neuroinfection, and failure to note LS on the first brain MRI. Periods of exacerbation or improvement were observed in association with the administration of certain drugs or procedures (VPA administration or intensive rehabilitation associated with worsening; ketogenic diet associated with remission). However, the random association of these factors with natural disease fluctuations cannot be excluded. Conclusions: 1) To improve the early detection of mitochondrial disorder, we recommend screening for mtDNA (and nDNA) mutations in all patients with LS present on brain MRI. 2) Brain MRI protocols should include diffusion-weighted and T2-weighted imaging, and LS-like changes should be analysed by a neuroradiologist experienced in the field. 3) Additional controlled studies are urgently needed to assess the causal relationship between management strategies and the natural history of the disease. Until the association between VPA and disease exacerbation can be ruled out, VPA should be avoided in patients with these symptoms unless the mitochondrial disorder has been excluded. [ABSTRACT FROM AUTHOR]

Background: The prevalence of isolated hearing loss (HL) associated with the m.3243A.G mutation is unknown. The aim of this study was to assess the frequency and heteroplasmy level of the m.3243A.G mutation in a large group of Polish patients with postlingual bilateral sensorineural HL of unidentified cause. Methodology/Principal Findings: A molecular search was undertaken in the archival blood DNA of 1482 unrelated patients with isolated HL that had begun at ages between 5 and 40 years. Maternal relatives of the probands were subsequently investigated and all carriers underwent audiological tests. The m.3243A.G mutation was found in 16 of 1482 probands (an incidence of 1.08%) and 18 family members. Of these 34 individuals, hearing impairment was detected in 29 patients and the mean onset of HL was at 26 years. Some 42% of the identified m.3243A.G carriers did not develop multisystem symptomatology over the following 10 years. Mean heteroplasmy level of m.3243A.G was lowest in blood at a level of 14% and highest in urine at 58%. These values were independent of the manifested clinical severity of the disease. Conclusions: A single m.3243A.G carrier can usually be found among each 100 individuals who have postlingual hearing loss of unknown cause. Urine samples are best for detecting the m.3243A.G mutation and diagnosing mitochondrially inherited hearing loss. [ABSTRACT FROM AUTHOR]

Association of 3-methylglutaconic aciduria (3-MGCA) with sensorineural deafness and Leigh-like encephalopathy (MEGDEL) was described as a very rare mitochondrial disorder without a known molecular background. We present clinical and biochemical characteristics of a 4.5-year-old girl with a similar association. The clinical course of the disease was as follows: in the neonatal period transient adaptation troubles; at 4-5 mo failure to thrive and hypotonia; at 13 mo: extrapyramidal symptoms, sensorineural deafness, Leigh syndrome on MRI, pigmentary degeneration of retina, episodes of respiratory alkalosis, increased lactate in plasma, urine and brain, and increased excretion of 3-MGCA. Mitochondrial encephalopathy was suspected and muscl e biopsy performed. Only mild lipid accumulation was found by muscle histopathology and histochemistry. Unspecific decrease of respiratory chain complexes was revealed by muscle homogenate spectrophotometry. The in-gel activity assay in the patient's muscle confirmed a combined defect of OXPHOS, particularly indicating suppression of mitochondrial ATP synthase (complex V) activity. Measurements of functional mitochondrial bioenergetic parameters in the patient's fibroblasts revealed a decrease in the mitochondrial membrane potential and activity of the mitochondrial respiratory chain. At the same time, a significant increase of ROS production (cytosolic and mitochondrial superoxide and H2O2) with signs of protein damage (protein carbonylation), and decreased antioxidant defence (SOD1 and SOD2) were observed. Additionally, the catalase amount was surprisingly low in comparison with healthy control and other reference 3-MGCA cases (Barth syndrome). Conclusion: (1) the natural history of the disease in the presented patient confirms the existence of previously reported clinical phenotype of MEGDEL (2) antioxidant defence impairment due to abnormal catalase metabolism/transport may characterize an unknown basic defect which led to the development of MEGDEL association. [ABSTRACT FROM AUTHOR]

Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase ( DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogeneity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDS-associated hypoglycemia; (ii) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates. [ABSTRACT FROM AUTHOR]

Abstract: Infants with deficiency of cytochrome c oxidase (COX) due to SCO2 mutations observed so far usually demonstrated early cardiomyopathy, encephalopathy and lactic acidosis. Milder spinal muscular atrophy-like (SMA-like) phenotype was also rarely reported. The aim is to present 18 Polish patients with SCO2 mutations. Molecular study revealed p.E140K mutation in all cases (on 32 alleles); p.Q53X mutation and novel p.M177T change were identified in single patients. In three families no second mutation was found. Thirteen p.E140K homozygotes presented in infancy with floppiness and remarkable stridor. Survival motor neuron (SMN) gene deletion was excluded. Mild to moderate lactic academia was found. Neurological involvement manifested as spasticity and psychomotor retardation. In some patients strabismus, ptosis and episodes of seizures were seen. During second half of the year chronic respiratory failure with artificial respiration dependency appeared in all homozygotes. Heart involvement was never present at the beginning. Rapidly progressive hypertrophic cardiomyopathy developed in several patients at the terminal stage. The stridor was constant and striking feature. Skeletal muscle biopsy was performed in 16 patients including 11 homozygotes. Four pathological patterns were discerned – from neurogenic muscle changes, including spinal muscular atrophy (SMA) to unspecific findings. Histochemical cytochrome c oxidase (COX) deficit was not a constant feature. Significant decrease in respiratory chain complex IV activity was detected in muscle homogenate by spectrophotometric method only in 7 out of 12 examined cases. Conclusions: 1/Mutations of SCO2 gene should be considered as a possible cause of neurogenic skeletal muscle features (including SMA-like) in infants with encephalomyopathy even in the absence of heart involvement and COX deficit; 2/Inspiratory stridor may be symptomatic of SCO2 gene mutation(s). [Copyright &y& Elsevier]

Isovaleric acidemia (IVA) is an autosomal recessive leucine inborn error of metabolism caused by isovaleryl-CoA dehydrogenase deficiency. The disease has various courses, from severe ones manifesting in newborns to the intermittent form with first manifestation in children and adults. The aim of this study was to analyze clinical and neurological outcomes in Polish patients with IVA. Ten patients diagnosed and treated in The Children's Memorial Health Institute were included in the study. The diagnosis was based on tandem MS (increased level of C5 acylcarnitine) and urine GCMS (increased isovalerylglycine, and 3-hydroxyisovaleric acid). Molecular analysis was performed in seven patients (70%) leading to the detection of pathogenic variants in the IVD gene in all of them. A retrospective analysis of patients' medical records included: demographics, symptoms at diagnosis, medical management, and biochemical and clinical outcomes following therapy. The median follow-up time (median; Q1–Q2) was 2.5 years (1.5–9.0) for newborn screening (NBS) and family screening (FS) children, and 17 years (5.0–20) for symptomatic patients. Five patients were in a good clinical state, four children presented mild neurological symptoms, and one—severely delayed child. In the IVD gene, five known and two novel variants (p.466C>G, c.1132G>A) were identified. Molecular analysis was performed in seven patients leading to identification of biallelic pathogenic variants in the IVD gene in all of them. We can conclude that long-term clinical and neurological outcomes of patients with IVA were satisfactory as a result of an early diagnosis and proper management. Although early treatment did not prevent decompensations, they were milder in these patients. [ABSTRACT FROM AUTHOR]