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INTRODUCTION: Tyrosinaemia type I is a rare hereditary metabolic disease caused by deficiency of the enzyme involved in the breakdown of tyrosine. Since the use of nitisinone in addition to diet in 1992, survival rates have increased significantly, but more and more socio-emotional problems have become apparent. The aim of the study was the assessment the relationship between variations in serum tyrosine and phenylalanine levels and measurements of socio-emotional functioning and determination of patients' IQs. THE AIM OF THE STUDY: was the assessment the relationship between variations in serum tyrosine and phenylalanine levels and measurements of socio-emotional functioning and determination of patients' IQs. MATERIAL AND METHODS: Twelve children were studied, from a single centre, born between 1994 and 2012, treated with nitisinone and a low-phenylalanine and -tyrosine diet. The psychological evaluation was conducted using the parent form of the Child Behaviour Checklist (CBCL)/4-18. Additionally, the patients' IQs were measured using the Stanford-Binet 5 (SB5) Intelligence Scale. Statistical analyses were performed using PAWS software suite version 26. We found that phenylalanine variability over time correlated with measures of emotional and behavioural functioning. This relationship holds true for externalising behaviour, associated with the experience of maladjustment and aggression. Total score intellectual and cognitive function was within the norm for all patients. CONCLUSIONS: To maintain better quality of life for patients and their families in terms of emotional and behavioural functioning, it may be important to avoid spikes (significant fluctuations) in phenylalanine levels. Regular, detailed psychological evaluations are recommended to detect potential problems and implement interventions aimed at achieving the best possible individual development and realise the intellectual and behavioural potential, thereby improving the patient's and her family's quality of life.
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Fenilalanina , Tirosinemias , Humanos , Tirosinemias/sangue , Tirosinemias/psicologia , Criança , Masculino , Feminino , Fenilalanina/sangue , Pré-Escolar , Adolescente , Tirosina/sangue , Cicloexanonas/uso terapêutico , Emoções , Qualidade de Vida , Nitrobenzoatos/uso terapêutico , Comportamento Infantil/psicologiaRESUMO
BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder associated with pathogenic variants in SLC19A3 gene. The clinical picture includes symptoms of subacute encephalopathy (e.g. confusion, dysphagia, dysarthria, and seizures), which respond very well to early treatment with thiamine and biotin. METHOD: A retrospective review of clinical characteristics, magnetic resonance imaging and molecular findings in 3 patients with BTBGD. RESULTS: The first symptoms in all patients occurred at 12-24 months of age and they had subacute encephalopathy, ataxia and dystonia. The baseline magnetic resonance imaging demonstrated abnormal signal intensity in the basal ganglia with atrophy and necrosis of the basal ganglia during follow-up in two patients. One patient was diagnosed and the treatment was initiated after a long period from symptoms onset and he is currently severely affected, with dystonia, quadriparesis and seizures. The other two patients were diagnosed early in life and are currently stable on treatment, without the clinical symptoms. Genetic testing demonstrated pathogenic variants in SLC19A3 gene. CONCLUSION: To avoid diagnostic errors and delayed or incorrect treatment, BTBGD must be recognized early. Adequate prompt treatment gives the chance of significant clinical improvement. Unexplained encephalopathy and MRI abnormalities including bilateral abnormal signal in the basal ganglia should alert the clinician to consider BTBGD in the differential, and the treatment with biotin and thiamine should be introduced immediately.
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Congenital disorders of glycosylation (CDG) are a growing, heterogeneous group of genetic disorders caused by a defect in the glycoprotein synthesis. The first and still widely used method for routine CDG screening was isoelectric focusing (IEF) of serum transferrin. Dried blood spot (DBS) testing is commonly used in newborn screening procedures to detect inborn errors of metabolism. The aim of this study was to demonstrate the reliability of the IEF method in DBS testing. Dried blood spot testing can help in the postmortem diagnosis of CDG disorders when other material is unavailable. The patterns and concentrations of transferrin isoforms in serum and DBS are comparable, and slight differences do not affect interpretation of results.
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Defeitos Congênitos da Glicosilação/sangue , Defeitos Congênitos da Glicosilação/diagnóstico , Teste em Amostras de Sangue Seco/métodos , Programas de Rastreamento/métodos , Transferrina/análise , Estudos de Casos e Controles , Humanos , Focalização Isoelétrica/métodos , Isoformas de Proteínas/análise , Reprodutibilidade dos TestesRESUMO
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.
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INTRODUCTION: Methylmalonic Aciduria (MMA) is a heterogeneous group of rare diseases leading to accumulation of methylmalonic acid in body fluids. One of the causes of the disease is the methylmalonic aciduria, cblA type (cblA - type MMA), conditioned by a mutation in the MMAA gene, which is essential for the proper functioning of a cofactor of the methylmalonyl-CoA mutase. The symptoms of the disease, depending on the cause, may manifest themselves at different ages. Most patients are sensitive to high doses of hydroxycobalamin, which is associated with better prognosis. MATERIAL AND METHOD: The purpose of the study was to retrospectively analyze the clinical picture and effects of treatment of patients with methylmalonic aciduria related to mutation in the MMAA gene. RESULTS: Five patients with diagnosed cblA - type MMA were presented. At the time of diagnosis the median of age was 18.8â¯months, but the symptoms had already appeared since infancy, as recurrent vomiting and delayed psychomotor development. Significant excretion of methylmalonic acid in urine and metabolic acidosis traits with significantly increased anionic gap were observed in all patients. All of them were sensitive to the treatment with vitamin B12. The median of therapy duration and observation is 12.2â¯years. During the treatment, good metabolic control was achieved in all patients, but their cognitive development is delayed. Three patients have renal failure and pharmacologically treated arterial hypertension. CONCLUSIONS: Patients with a mutation in the MMAA gene are sensitive to treatment with hydroxocobalamine, but the inclusion of appropriate treatment does not protect against neurodevelopmental disorders and chronic kidney disease.
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OBJECTIVES: Although hearing loss is a well-known symptom of mitochondria-related disorders, it is not clear how often it is a congenital and cochlear impairment. The Newborn Hearing Screening Program (NHSP) enables to distinguish congenital cochlear deafness from an acquired hearing deficit. The initial aim of the study was to research the frequency of the congenital cochlear hearing loss among patients with various gene defects resulting in mitochondrial disorders. The research process brought on an additional gain: basing on our preliminary study group of 80 patients, in 12 patients altogether we identified two defected genes responsible for mitochondrial disorders, whose carriers did not pass the NHSP. Finally, these patients were diagnosed with the congenital cochlear deafness. MATERIAL AND METHODS: The results of the NHSP in the patients with mitochondrial disorders diagnosed in our tertiary reference center were analyzed. Only the cases with confirmed mutations were qualified for the study group. The NHSP database included 80 patients with mutations in 31 different genes: 25 nuclear-encoded and 6 mtDNA-encoded. We searched the literature for the presence of a congenital hearing impairment (CHI) in mitochondrial disorders caused by changes in 278 already known genes. RESULTS: For 68 patients from the study group the NHSP test indicated a proper cochlear function and thus suggested normal hearing. For 12 mitochondrial patients, the NHSP test indicated the requirement for the further audiological diagnosis, and finally CHI was confirmed in 8 of them. This latter subset included patients with pathogenic variants in RRM2B and SERAC1, known as "deafness-causing genes". Contrary to our initial expectations, the patients carrying mutations in other "deafness-causing genes": MPV17, POLG, COX10, as well as other mitochondria-related genes, all reported in literature, did not indicate any CHI following the NHSP test. CONCLUSION: Our study indicates that the cochlear CHI is a phenotypic feature of the RRM2B and SERAC1 related defects. The diagnosis of the CHI following the NHSP allows to early distinguish those defects from other mitochondria-related disorders in which the NHSP test result is correct. Wider studies are needed to assess the significance of this observation.
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Hidrolases de Éster Carboxílico/genética , Proteínas de Ciclo Celular/genética , Surdez/genética , Perda Auditiva Neurossensorial/genética , Doenças Mitocondriais/genética , Ribonucleotídeo Redutases/genética , Adolescente , Criança , Pré-Escolar , DNA Mitocondrial , Surdez/congênito , Feminino , Perda Auditiva Neurossensorial/congênito , Testes Auditivos , Heterozigoto , Hospitais , Humanos , Lactente , Recém-Nascido , Masculino , Doenças Mitocondriais/complicações , Doenças Mitocondriais/diagnóstico , Mutação , Triagem Neonatal , PolôniaRESUMO
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.
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Citrulina/sangue , Transtornos do Crescimento/etiologia , Estado Nutricional , Nutrição Parenteral no Domicílio , Síndrome do Intestino Curto/dietoterapia , Adolescente , Densidade Óssea , Criança , Pré-Escolar , Colestase , Estudos de Coortes , Feminino , Humanos , Lactente , Testes de Função Hepática , Masculino , Síndrome do Intestino Curto/sangue , Síndrome do Intestino Curto/complicações , Vitamina D/sangueRESUMO
OBJECTIVE: 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. METHODS: This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. RESULTS: Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learned to walk (68%). Seventy-nine percent suffered hearing loss, 58% never learned to speak, and nearly all had significant intellectual disability (88%). Magnetic resonance imaging features were accordingly homogenous, with bilateral basal ganglia involvement (98%); the characteristic "putaminal eye" was seen in 53%. The urinary marker 3-methylglutaconic aciduria was present in virtually all patients (98%). Supportive treatment focused on spasticity and drooling, and was effective in the individuals treated; hearing aids or cochlear implants did not improve communication skills. INTERPRETATION: MEGDHEL syndrome is a progressive deafness-dystonia syndrome with frequent and reversible neonatal liver involvement and a strikingly homogenous course of disease. Ann Neurol 2017;82:1004-1015.
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Hidrolases de Éster Carboxílico/genética , Surdocegueira/diagnóstico por imagem , Surdocegueira/genética , Progressão da Doença , Distonia/diagnóstico por imagem , Distonia/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Mutação/genética , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Surdocegueira/terapia , Distonia/terapia , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/terapia , Masculino , Atrofia Óptica/terapia , Adulto JovemRESUMO
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. .
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Doenças dos Gânglios da Base/patologia , Encéfalo/patologia , Proteínas de Membrana Transportadoras/genética , Doenças dos Gânglios da Base/genética , Humanos , Recém-Nascido , Masculino , MutaçãoRESUMO
Recently, CLPB deficiency has been shown to cause a genetic syndrome with cataracts, neutropenia, and 3-methylglutaconic aciduria. Surprisingly, the neurological presentation ranges from completely unaffected to patients with virtual absence of development. Muscular hypo- and hypertonia, movement disorder and progressive brain atrophy are frequently reported. We present the foetal, peri- and neonatal features of 31 patients, of which five are previously unreported, using a newly developed clinical severity scoring system rating the clinical, metabolic, imaging and other findings weighted by the age of onset. Our data are illustrated by foetal and neonatal videos. The patients were classified as having a mild (n = 4), moderate (n = 13) or severe (n = 14) disease phenotype. The most striking feature of the severe subtype was the neonatal absence of voluntary movements in combination with ventilator dependency and hyperexcitability. The foetal and neonatal presentation mirrored the course of disease with respect to survival (current median age 17.5 years in the mild group, median age of death 35 days in the severe group), severity and age of onset of all findings evaluated. CLPB deficiency should be considered in neonates with absence of voluntary movements, respiratory insufficiency and swallowing problems, especially if associated with 3-methylglutaconic aciduria, neutropenia and cataracts. Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients. The neonatal presentation of CLPB deficiency predicts the course of disease in later life, which is extremely important for counselling.
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Catarata/metabolismo , Endopeptidase Clp/deficiência , Erros Inatos do Metabolismo/metabolismo , Neutropenia/metabolismo , Adolescente , Adulto , Atrofia/metabolismo , Encefalopatias , Criança , Pré-Escolar , Feminino , Feto/metabolismo , Humanos , Hiperecplexia/metabolismo , Lactente , Recém-Nascido , Masculino , Transtornos dos Movimentos/metabolismo , Fenótipo , Adulto JovemRESUMO
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.
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Doença da Deficiência da Carbamoil-Fosfato Sintase I/urina , Glutaratos/urina , Doença da Deficiência da Carbamoil-Fosfato Sintase I/diagnóstico , Doença da Deficiência da Carbamoil-Fosfato Sintase I/genética , Feminino , Humanos , Recém-Nascido , Masculino , Mutação , LinhagemRESUMO
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.
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Exoma/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Pediatria , Análise de Sequência de DNA/métodos , Biópsia , Criança , Pré-Escolar , DNA Mitocondrial/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/genética , Músculos/patologia , Mutação/genética , LinhagemRESUMO
INTRODUCTION: Biotinidase deficiency (BTD) is an inborn error of biotin metabolism inherited as an autosomal recessive trait. Due to the, biotinidase deficiency, biotin is not recycled. Individuals with BTD usually exhibit neurological and cutaneous abnormalities unless treated with biotin. Supplementation with biotin may either ameliorate or if early introduced even prevent symptoms when introduced presymptomatically. PATIENTS AND METHODS: Since 1991, 22 Polish patients from 19 families have been diagnosed with BTD. In 16 children the diagnosis had been suspected on the basis of clinical signs: skin lesions, hyperventilation, seizures, spasticity, and laboratory investigation (elevated lactate and metabolites on urine organic acids profile). The defect was enzymatically (serum biotinidase activity measurement) and genetically (tested for mutations in the BTD gene) confirmed afterwards. All patients were treated with biotin. Urine organic acids analysis (GC/MS) for 3-hydroxizovaleric acid was used for patients' monitoring. Neurological, audiological and ophthalmological evaluation has been conducted once a year. RESULTS: In 5 symptomatic patients a progressive optic nerve atrophy had already been noted at the time of treatment initiation. In these patients sensorineural hearing loss has also been diagnosed despite biotin supplementation. Asymptomatic patients treated with biotin supplementation presented no signs or symptoms of BTD. Supplementation with biotin slows the progression of BTD in symptomatic patients, but does not reverse nerve atrophy. Nonetheless, introduction of the treatment with biotin during presymptomatic stage of the disease prevents the onset of symptoms including optic atrophy and hearing loss. Homozygosity for the p.Leu215Phe mutation in BTD gene seems to be frequent in patients from the North-Eastern region of Poland and is connected with the hearing loss. CONCLUSION: Since the prognosis for individuals diagnosed with BTD is good, provided they are treated before symptoms occur, it is justified to add this metabolic disorder to the panel of conditions screened under the national newborn screening programme in Poland.
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UNLABELLED: 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.
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DNA Mitocondrial/genética , Doença de Leigh/diagnóstico , Doença de Leigh/genética , Mutação/genética , Síncope/diagnóstico , Síncope/genética , Adolescente , Evolução Fatal , Humanos , Doença de Leigh/complicações , Masculino , Síncope/etiologiaRESUMO
Barth syndrome (BTHS) is an X-linked mitochondrial defect characterised by dilated cardiomyopathy, neutropaenia and 3-methylglutaconic aciduria (3-MGCA). We report on two affected brothers with c.646G > A (p.G216R) TAZ gene mutations. The pathogenicity of the mutation, as indicated by the structure-based functional analyses, was further confirmed by abnormal monolysocardiolipin/cardiolipin ratio in dry blood spots of the patients as well as the occurrence of this mutation in another reported BTHS proband. In both brothers, 2D-echocardiography revealed some features of left ventricular noncompaction (LVNC) despite marked differences in the course of the disease; the eldest child presented with isolated cardiomyopathy from late infancy, whereas the youngest showed severe lactic acidosis without 3-MGCA during the neonatal period. An examination of the patients' fibroblast cultures revealed that extremely low mitochondrial membrane potentials (mtΔΨ about 50 % of the control value) dominated other unspecific mitochondrial changes detected (respiratory chain dysfunction, abnormal ROS production and depressed antioxidant defense). 1) Our studies confirm generalised mitochondrial dysfunction in the skeletal muscle and the fibroblasts of BTHS patients, especially a severe impairment in the mtΔΨ and the inhibition of complex V activity. It can be hypothesised that impaired mtΔΨ and mitochondrial ATP synthase activity may contribute to episodes of cardiac arrhythmia that occurred unexpectedly in BTHS patients. 2) Severe lactic acidosis without 3-methylglutaconic aciduria in male neonates as well as an asymptomatic mild left ventricular noncompaction may characterise the ranges of natural history of Barth syndrome.
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Síndrome de Barth/complicações , Síndrome de Barth/fisiopatologia , Potencial da Membrana Mitocondrial , Síndrome de Barth/diagnóstico , Síndrome de Barth/etiologia , Células Cultivadas , Criança , Pré-Escolar , Humanos , Masculino , Músculo Esquelético/patologia , IrmãosRESUMO
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.
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Perda Auditiva Neurossensorial/genética , Adenina/química , Adolescente , Adulto , Idade de Início , Encéfalo/patologia , DNA/análise , Análise Mutacional de DNA , DNA Mitocondrial/genética , Feminino , Guanina/química , Perda Auditiva Neurossensorial/epidemiologia , Heterozigoto , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Mutação , Polônia , Fatores SexuaisRESUMO
UNLABELLED: 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 muscle 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.
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Catalase/metabolismo , Surdez/metabolismo , Fibroblastos/metabolismo , Glutaratos/urina , Doença de Leigh/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Pré-Escolar , Surdez/complicações , Surdez/fisiopatologia , Feminino , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Doença de Leigh/complicações , Doença de Leigh/fisiopatologia , Doenças Mitocondriais/complicações , Doenças Mitocondriais/metabolismoRESUMO
BACKGROUND: POLG (polymerase gamma) gene mutations lead to a variety of neurological disorders, including Alpers-Huttenlocher syndrome (AHS). The diagnostic triad of AHS is: resistant epilepsy, liver impairment triggered by sodium valproate (VA), and mitochondrial DNA depletion. MATERIAL/METHODS: A cohort of 28 children with mitochondrial encephalopathy and liver failure was qualified for retrospective study of mitochondrial DNA depletion and POLG mutations. RESULTS: The p.W748S POLG gene mutation was revealed in 2 children, the only ones in the cohort who fulfilled the AHS criteria. Depletion of mtDNA (16% of control value) was confirmed post mortem in available liver tissue and was not detected in the muscle. The disease started with drug-resistant seizures, failure to thrive and developmental regression at the ages of 7 and 18 months, respectively. Irreversible liver failure developed after VA administration. Co-existence of epilepsy, VA liver toxicity, lactic acidemia and muscle respiratory chain dysfunction led finally to the diagnosis of mitochondrial disorder (and AHS suspicion). CONCLUSIONS: Our results confirm, for the first time, the occurrence of a pathology caused by POLG gene mutation(s) in the Polish population. POLG mutation screening and mtDNA depletion assessment should be included in differential diagnosis of drug-resistant epilepsy associated with a hepatopathy.
Assuntos
DNA Polimerase Dirigida por DNA/genética , Esclerose Cerebral Difusa de Schilder/complicações , Resistência a Medicamentos , Epilepsia/complicações , Fígado/patologia , Mutação/genética , Ácido Valproico/efeitos adversos , Substituição de Aminoácidos/genética , Criança , DNA Polimerase gama , Esclerose Cerebral Difusa de Schilder/enzimologia , Esclerose Cerebral Difusa de Schilder/patologia , Epilepsia/tratamento farmacológico , Epilepsia/enzimologia , Evolução Fatal , Feminino , Humanos , Lactente , Fígado/efeitos dos fármacos , Mudanças Depois da Morte , Espectrofotometria , Ácido Valproico/uso terapêuticoRESUMO
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 pathogenicity, 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.
Assuntos
Glucose/metabolismo , Homeostase/genética , Sobrecarga de Ferro/genética , Falência Hepática/enzimologia , Mutação/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Autopsia , DNA Mitocondrial/genética , Feminino , Homozigoto , Humanos , Lactente , Recém-Nascido , Falência Hepática/genética , MasculinoRESUMO
UNLABELLED: Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a fatty acid oxidation disorder with especially high mortality and uncertain long-term outcome. The aim of the study was to analyze the influence of diagnostic approach on survival in 59 affected children. Referral to a metabolic center was replaced over time by urine/blood testing in centralized metabolic laboratory (selective screening) and by pilot tandem mass spectrometry newborn screening (NBS). Molecular analysis revealed the prevalent mutation in the HADHA gene in all 58 examined cases. Twenty patients died. The number of detections and number of deaths were respectively 9 and 4 (44%) in the patients recognized by differential diagnosis, 28 and 9 (32%) - by selective screening, and 11 and 1 (9%) - by NBS. In 80% of cases the death occurred before or within 3 weeks from the identification. Urgent and active metabolic service remarkably influenced the surviving. The current age of 39 survivors is 0.5 to 23 yrs (mean 7.2 yrs). The disease frequency estimated on the patients number was 1: 115 450, whereas in the pilot NBS - 1: 109 750 (658 492 neonates tested). Interestingly, the phenylalanine level in asymptomatic neonates frequently exceeded the cut-off values. CONCLUSIONS: 1) Urgent metabolic intervention decreases mortality of LCHAD-deficient patients, but the prognosis is still uncertain. 2) Emergent metabolic reporting and service are crucial also for the survival of neonates detected by NBS. 3) The nationwide selective screening appeared efficient in LCHADD detection in the country. 4) Transient mild hyperphenylalaninaemia may occur in LCHAD-deficient newborns.