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1.
Nutrients ; 11(10)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640267

RESUMO

The standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet, supplemented with Phe-free protein substitutes; however, adult patients often show poor adherence to therapy. Alternative treatment options include the use of large neutral amino acids (LNAA). The aim of this study was to determine the Phe, tyrosine (Tyr), and Phe/Tyr ratio in a cohort of sub-optimally controlled adult patients with classical PKU treated with a new LNAA formulation. Twelve patients received a Phe-restricted diet plus a slow-release LNAA product taken three times per day, at a dose of 1 g/kg body weight (mean 0.8 ± 0.24 g/kg/day), over a 12-month period. The product is in a microgranulated formulation, which incorporates all amino acids and uses sodium alginate as a hydrophilic carrier to prolong its release. This LNAA formulation provides up to 80% of the total protein requirement, with the rest of the protein supplied by natural food. Patients had fortnightly measurements of Phe and Tyr levels over a 12-month period after the introduction of LNAA. All patients completed the 12-month treatment period. Overall, adherence to the new LNAA tablets was very good compared with a previous amino acid mixture, for which taste was a major complaint by patients. Phe levels remained unchanged (p = 0.0522), and Tyr levels increased (p = 0.0195). Consequently, the Phe/Tyr ratio decreased significantly (p < 0.05) in the majority of patients treated. In conclusion, LNAA treatment increases Tyr levels in sub-optimally controlled adult PKU patients, while offering the potential to improve their adherence to treatment.

2.
Ital J Pediatr ; 45(1): 71, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186032

RESUMO

The original article contains an unintended omission of a statement of competing interests. As such, the authors would like to declare the following complete statement of competing interests.

3.
J Neural Transm (Vienna) ; 126(6): 739-757, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31076915

RESUMO

Status dystonicus (SD) is a rare and potentially life-threatening condition requiring intensive care management. Deep brain stimulation (DBS) has emerged as an effective treatment for SD refractory to medical management, but its application in this field is still limited. Here, we report the long-term outcome of four pediatric patients treated with DBS at the University Hospital of Padua, Italy, for SD refractory to medications. In addition, we present the results of a systematic literature review aimed at identifying published cases of SD treated with DBS, with focus on motor outcome. In our cohort, two children were affected by methylmalonic acidemia and suffered acute basal ganglia lesions, while the other two carried a pathogenic mutation in GNAO1 gene. DBS target was subthalamic nucleus (STN) in one case and globus pallidus internus (GPi) in three. All patients experienced SD resolution within 8-19 days after surgery. Mean post-operative follow-up was 5 years. We identified in the literature 53 additional SD cases treated with DBS (median age at DBS implantation: 12 years) with reported positive outcome in 51 and resolution of SD in a mean of 17 days after surgery. Our findings indicate that DBS is an effective treatment for SD refractory to medications, even in patients with acute basal ganglia lesions; STN can be an appropriate target when GPi is damaged. Moreover, data from long-term follow-up show that SD recurrences can be significantly reduced in frequency or abolished after DBS implantation.

4.
Clin Chem Lab Med ; 57(12): 1863-1874, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31091195

RESUMO

Background Lysosphingolipids, the N-deacylated forms of sphingolipids, have been identified as potential biomarkers of several sphingolipidoses, such as Gaucher, Fabry, Krabbe and Niemann-Pick diseases and in GM1 and GM2 gangliosidoses. To date, different methods have been developed to measure various lysosphingolipids (LysoSLs) in plasma. Here, we present a novel liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for a simultaneous quantification of LysoSLs (HexSph, LysoGb3, LysoGM1, LysoGM2, LysoSM and LysoSM509) in dried blood spot (DBS). This LC-MS/MS method was used to compare the levels of LysoSLs in DBS and plasma in both affected patients and healthy controls. Methods Lysosphingolipids were extracted from a 3.2 mm diameter DBS with a mixture of methanol:acetonitrile:water (80:15:5, v/v) containing internal stable isotope standards. Chromatographic separation was performed using a C18 column with a gradient of water and acetonitrile both with 0.1% formic acid in a total run time of 4 min. The compounds were detected in the positive ion mode electrospray ionization (ESI)-MS/MS by multiple reaction monitoring (MRM). Results The method was validated on DBS to demonstrate specificity, linearity, lowest limit of quantification, accuracy and precision. The reference ranges were determined in pediatric and adult populations. The elevated levels of LysoSLs were identified in Gaucher disease (HexSph), Fabry disease (LysoGb3), prosaposin deficiency (HexSph and LysoGb3) and Niemann-Pick disease types A/B and C (LysoSM and LysoSM509). The correlation in the levels between DBS and plasma was excellent for LysoGb3 and HexSph but poor for LysoSM and LysoSM509. Conclusions Despite the fact that plasma LysoSLs determination remains the gold standard, our LC-MS/MS method allows a rapid and reliable quantification of lysosphingolipids in DBS. The method is a useful tool for the diagnosis of different sphingolipidoses except for Niemann-Pick type C.

5.
J Inherit Metab Dis ; 42(6): 1192-1230, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30982989

RESUMO

In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years that have elapsed since the first guideline was published, abundant novel information has accumulated, experience on newborn screening for some UCDs has widened, a novel hyperammonemia-causing genetic disorder has been reported, glycerol phenylbutyrate has been introduced as a treatment, and novel promising therapeutic avenues (including gene therapy) have been opened. Several factors including the impact of the first edition of these guidelines (frequently read and quoted) may have increased awareness among health professionals and patient families. However, under-recognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research.

6.
J Inherit Metab Dis ; 42(1): 93-106, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30740724

RESUMO

BACKGROUND: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.

7.
Neurol Sci ; 40(6): 1279-1281, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30762167

RESUMO

Fabry disease (FD) is an X-linked monogenic disorder caused by mutations in the GLA gene which leads to a deficiency of the functionally active lysosomal α-galactosidase A enzyme. Here, we report on a family of five members: unaffected parents, one unaffected son, and another son and daughter both carrying the same mutation (p.G138E) in the GLA gene. Genotype analysis using intragenic GLA markers confirmed the maternal origin of the mutation. The affected son and daughter carried the same mutation; however, it was not detected in the peripheral blood, buccal cells, and urinary sediment cells of their mother. Moreover, the unaffected son without the alteration in the GLA gene carried the same maternal chromosome X (disease-associated) haplotype. To the best of our knowledge, this study represents the first case of maternal germline mosaicism in FD.


Assuntos
Doença de Fabry/genética , Mutação em Linhagem Germinativa , Mosaicismo , alfa-Galactosidase/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
8.
J Inherit Metab Dis ; 42(2): 209-219, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30690773

RESUMO

Newborn screening for phenylketonuria (PKU) and early introduction of dietary therapy has been remarkably successful in preventing the severe neurological features of PKU, including mental retardation and epilepsy. However, concerns remain that long-term outcome is still suboptimal, particularly in adult patients who are no longer on strict phenylalanine-restricted diets. With our systematic literature review we aimed to describe the neurological phenotype of adults with early-treated phenylketonuria (ETPKU). The literature search covered the period from 1 January 1990 up to 16 April 2018, using the NLM MEDLINE controlled vocabulary. Of the 643 records initially identified, 83 were included in the analysis. The most commonly reported neurological signs were tremor and hyperreflexia. The overall quality of life (QoL) of ETPKU adults was good or comparable to control populations, and there was no evidence for a significant incidence of psychiatric disease or social difficulties. Neuroimaging revealed that brain abnormalities are present in ETPKU adults, but their clinical significance remains unclear. Generally, intelligence quotient (IQ) appears normal but specific deficits in neuropsychological and social functioning were reported in early-treated adults compared with healthy individuals. However, accurately defining the prevalence of these deficits is complicated by the lack of standardized neuropsychological tests. Future research should employ standardized neurological, neuropsychological, and neuroimaging protocols, and consider other techniques such as advanced imaging analyses and the recently validated PKU-specific QoL questionnaire, to precisely define the nature of the impairments within the adult ETPKU population and how these relate to metabolic control throughout life.

9.
Parkinsonism Relat Disord ; 61: 207-210, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30337205

RESUMO

INTRODUCTION: Clathrins play a key role in endocytosis, recycling, and trafficking as well as the generation of presynaptic vesicles. We report a new clinical condition associated with a de novo variant in the CLTC gene, which encodes the clathrin heavy polypeptide. CASE REPORT: This 30-year-old woman presented with a developmental disorder during childhood that progressed to mild cognitive decline in late childhood and relapsing-remitting hypokinetic-rigid syndrome with severe achalasia, weight loss, and mood disorder in adulthood. 123I-Ioflupane SPECT was normal. Blood phenylalanine was slightly increased and PAH sequencing revealed compound heterozygosity for two variants, p.[Asp151Glu]:[Thr380Met]. CSF examination unexpectedly detected a remarkable reduction of homovanillic, 5-hydroxyindolacetic, and 5-methylthetrahydrofolic acids, which could not be ascribed to any alteration of tetrahydrobiopterin and related biogenic amine pathways. METHODS: Trio-based exome sequencing was performed. RESULT: A de novo missense variant (c.2669C > T/p.Pro890Leu) was detected in CLTC. Treatment with biogenic amine precursors was ineffective, while the inhibitor of MAO-A selegiline resulted in persistent clinical improvement. CONCLUSIONS: We suggest CLTC defect as a new disorder of biogenic amine trafficking, resulting in neurodevelopmental derangement and movement disorder. Neurotransmitter depletion in CSF may be a biomarker of this disease, and selegiline a possible treatment option.

10.
Ital J Pediatr ; 44(Suppl 2): 126, 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30442156

RESUMO

Newborn screening (NBS) methods and therapeutic options have become increasingly available for mucopolysaccharidoses (MPS), and there is a clear evidence that early intervention significantly improves the outcome. It is recommended that mucopolysaccharidosis type I (MPS I) is included in the US newborn screening panel, and this is currently underway in some NBS programs in the world. The key factors in recommending MPS I for inclusion in NBS are the strongly improved efficacy of early-onset therapy and the improved performance of screening tests. Two studies on MPS I screening have been conducted in Italy. In the Tuscany-Umbria pilot NBS, eight infants were confirmed positive, and alpha-L-iduronidase (IDUA) gene molecular analysis showed that seven had either homozygosity or compound heterozygosity for pseudodeficiency alleles. p.Ala79Thr and p.His82Gln changes were demonstrated in four and three infants, respectively, six of which were of African origin. Only one infant had transitory elevation of urine glycosaminoglycans (GAGs) (by quantitative analysis) and she is in follow-up at the time of writing. In the North East Italy experience, there was one affected newborn for 66,491 screened. In this patient treatment started at 1 month of age. In the North East Italy experience the incidence of pseudodeficiency was very high (1:6044), with a high incidence of pseudodeficiency from patients of African origin.A significant problem that is encountered in the follow-up of infants with abnormal NBS and variants of unknown significance (VUS) on molecular analysis results relates to those who cannot be positively identified as either affected or unaffected. Long-term follow-up of these infants, and of those detected with late-onset disorders, will be essential to document the true risks and benefits of NBS. The availability of treatments in MPS II, IVA, VI, and VII with a better clinical outcome when started early in life, and the availability of a combined multiple assay for MPS, may be a prerequisite for new pilot NBS studies in the near future.


Assuntos
Mucopolissacaridose I/diagnóstico , Triagem Neonatal , Humanos , Recém-Nascido , Valor Preditivo dos Testes
11.
Int J Mol Sci ; 19(12)2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30477121

RESUMO

Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. α-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, α-Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease.


Assuntos
Doença de Fabry/genética , Glicolipídeos/genética , Mutação , Esfingolipídeos/genética , alfa-Galactosidase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Biomarcadores , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
12.
Sci Rep ; 8(1): 15436, 2018 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-30337552

RESUMO

N-acetylglutamate synthase deficiency (NAGSD, MIM #237310) is an autosomal recessive disorder of the urea cycle that results from absent or decreased production of N-acetylglutamate (NAG) due to either decreased NAGS gene expression or defective NAGS enzyme. NAG is essential for the activity of carbamylphosphate synthetase 1 (CPS1), the first and rate-limiting enzyme of the urea cycle. NAGSD is the only urea cycle disorder that can be treated with a single drug, N-carbamylglutamate (NCG), which can activate CPS1 and completely restore ureagenesis in patients with NAGSD. We describe a novel sequence variant NM_153006.2:c.-3026C > T in the NAGS enhancer that was found in three patients from two families with NAGSD; two patients had hyperammonemia that resolved upon treatment with NCG, while the third patient increased dietary protein intake after initiation of NCG therapy. Two patients were homozygous for the variant while the third patient had the c.-3026C > T variant and a partial uniparental disomy that encompassed the NAGS gene on chromosome 17. The c.-3026C > T sequence variant affects a base pair that is highly conserved in vertebrates; the variant is predicted to be deleterious by several bioinformatics tools. Functional assays in cultured HepG2 cells demonstrated that the c.-3026C > T substitution could result in reduced expression of the NAGS gene. These findings underscore the importance of analyzing NAGS gene regulatory regions when looking for molecular causes of NAGSD.


Assuntos
Aminoácido N-Acetiltransferase/genética , Elementos Facilitadores Genéticos , Variação Genética , Distúrbios Congênitos do Ciclo da Ureia/etiologia , Aminoácido N-Acetiltransferase/metabolismo , Sequência de Bases , Criança , Pré-Escolar , Feminino , Humanos , Hiperamonemia , Prognóstico , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/patologia
13.
EMBO Mol Med ; 10(10)2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30190335

RESUMO

TIMM50 is an essential component of the TIM23 complex, the mitochondrial inner membrane machinery that imports cytosolic proteins containing a mitochondrial targeting presequence into the mitochondrial inner compartment. Whole exome sequencing (WES) identified compound heterozygous pathogenic mutations in TIMM50 in an infant patient with rapidly progressive, severe encephalopathy. Patient fibroblasts presented low levels of TIMM50 and other components of the TIM23 complex, lower mitochondrial membrane potential, and impaired TIM23-dependent protein import. As a consequence, steady-state levels of several components of mitochondrial respiratory chain were decreased, resulting in decreased respiration and increased ROS production. Growth of patient fibroblasts in galactose shifted energy production metabolism toward oxidative phosphorylation (OxPhos), producing an apparent improvement in most of the above features but also increased apoptosis. Complementation of patient fibroblasts with TIMM50 improved or restored these features to control levels. Moreover, RNASEH1 and ISCU mutant fibroblasts only shared a few of these features with TIMM50 mutant fibroblasts. Our results indicate that mutations in TIMM50 cause multiple mitochondrial bioenergetic dysfunction and that functional TIMM50 is essential for cell survival in OxPhos-dependent conditions.


Assuntos
Encefalopatias/fisiopatologia , Proteínas de Membrana Transportadoras/genética , Doenças Mitocondriais/fisiopatologia , Mutação , Fosforilação Oxidativa , Encefalopatias/diagnóstico , Encefalopatias/patologia , Sobrevivência Celular , Células Cultivadas , Feminino , Fibroblastos/patologia , Teste de Complementação Genética , Humanos , Lactente , Itália , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/patologia
14.
Mol Genet Metab Rep ; 16: 39-45, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30069431

RESUMO

Dietary treatment is the cornerstone of therapy for phenylketonuria (PKU), but adherence to low- phenylalanine diet progressively decreases after adolescence. We designed a survey to characterize the dietary habits of Italian adult PKU patients and to identify psychological factors influencing disease perception and adherence to diet. Participants to the survey (n = 111; response rate 94%) were asked to complete a structured questionnaire. Patients appeared to have an altered perception and awareness of the disease. About 40% of them did not consider PKU a disease and, despite declaring regular monitoring of phenylalanine levels (85%), nearly half of them reported a high plasma value over the last 6 months (>600 µmol/L, 48%) or were unable to specify it (31%). Adherence to PKU diet was unsatisfactory, with increased consumption of natural protein sources and reduced daily use of amino-acid supplements (<4-5 times/day in 82% patients). In addition to the intrinsic characteristics of AA formula (palatability, ease of use), the most important factor influencing their consumption was the increased social pressure associated with their use (55%). Plasma phenylalanine periodical measurements (61%) and examinations at metabolic centers (49%) were considered relevant for compliance to diet. In Italian adult PKU patients dietary management was found to be inadequate, likely due to inappropriate perception and knowledge of the disease, and lack of awareness of the negative impact of poor metabolic control in adult life. Clinicians should consider implementing more intense and tailored educational measures, as well as structured transitional care processes.

15.
Orphanet J Rare Dis ; 13(1): 120, 2018 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-30025539

RESUMO

BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.


Assuntos
Acidose/genética , Acidose/metabolismo , Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Debilidade Muscular/genética , Debilidade Muscular/metabolismo , Riboflavina/uso terapêutico , Acidose/patologia , Atividades Cotidianas , Acil-CoA Desidrogenase/genética , Acil-CoA Desidrogenase/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Cardiomiopatia Hipertrófica/patologia , Complexo I de Transporte de Elétrons/metabolismo , Feminino , Humanos , Masculino , Doenças Mitocondriais/patologia , Debilidade Muscular/tratamento farmacológico , Debilidade Muscular/patologia , Prognóstico
16.
Eur J Paediatr Neurol ; 22(6): 1042-1053, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30005813

RESUMO

BACKGROUND: The ALDH7A1 gene is known to be responsible for autosomal recessive pyridoxine-dependent epilepsy (OMIM 266100). The phenotypic spectrum of ALDH7A1 mutations is very heterogeneous ranging from refractory epilepsy and neurodevelopmental delay, to multisystem neonatal disorder. AIM: The present study aims at describing the phenotype associated with a novel homozygous ALDH7A1 mutation and the spectrum of brain malformations associated with pyridoxine-dependent epilepsy. METHODS: We conducted a literature review on the Internet database Pubmed (up to November 2017) searching for ALDH7A1 mutations associated with brain malformations and brain MRI findings. RESULTS: We present the case of two siblings, children of related parents. The proband presented neonatal focal seizures not responding to conventional antiepileptic drugs. Electroencephalography showed a suppression burst pattern and several multifocal ictal patterns, responsive to pyridoxine. Brain MRI was normal. Molecular analysis by targeted next-generation sequencing panel for epileptic encephalopathy disclosed a homozygous missense mutation of ALDH7A1. The same mutation was then found in a stored sample of DNA from peripheral blood of an older sister dead 3 years earlier. This girl presented a complex brain malformation diagnosed with a foetal MRI and had neonatal refractory seizures with suppression burst pattern. She died at 6 months of age. LITERATURE REVIEW: The brain abnormalities most frequently reported in pyridoxine-dependent epilepsy include: agenesia/hypoplasia of the corpus callosum, not specific white matter abnormalities, large cisterna magna, ventriculomegaly, haemorrhages, cerebellum hypoplasia/dysplasia, and, more rarely, dysplasia of the brainstem and hydrocephalus. DISCUSSION AND CONCLUSIONS: ALDH7A1 mutations have been associated to different brain abnormalities, documented by MRI only in few cases. The study cases expand the clinical spectrum of ALDH7A1 associated conditions, suggesting to look for ALDH7A1 mutations not only in classical phenotypes but also in patients with brain malformations, mainly if there is a response to a pyridoxine trial.


Assuntos
Aldeído Desidrogenase/genética , Encéfalo/anormalidades , Epilepsia/genética , Epilepsia/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Mutação de Sentido Incorreto , Fenótipo , Irmãos
17.
Orphanet J Rare Dis ; 13(1): 32, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29422078

RESUMO

BACKGROUND: Enzyme replacement therapy (ERT) has deeply modified the clinical history of Infantile Onset Pompe Disease (IOPD). However, its long-term effectiveness is still not completely defined. Available data shows a close relationship between clinical outcome and patients' cross-reactive immunological status (CRIM), being CRIM-negative status a negative prognostic factor. At the same time limited data are available on the long-term treatment in CRIM-positive infants. METHODS: A retrospective multicentre observational study was designed to analyse the long-term effectiveness of ERT in IOPD. Thirteen Italian centres spread throughout the country were involved and a cohort of 28 patients (15 females, 13 males, born in the period: February 2002-January 2013) was enrolled. IOPD diagnosis was based on clinical symptoms, enzymatic and molecular analysis. All patients received ERT within the first year of life. Clinical, laboratory, and functional data (motor, cardiac and respiratory) were collected and followed for a median period of 71 months (5 years 11 months). RESULTS: Median age at onset, diagnosis and start of ERT were 2, 3 and 4 months, respectively. CRIM status was available for 24/28 patients: 17/24 (71%) were CRIM-positive. Nineteen patients (67%) survived > 2 years: 4 were CRIM-negative, 14 CRIM-positive and one unknown. Six patients (5 CRIM-positive and one unknown) never needed ventilation support (21,4%) and seven (6 CRIM-positive and one unknown: 25%) developed independent ambulation although one subsequently lost this function. Brain imaging study was performed in 6 patients and showed peri-ventricular white matter abnormalities in all of them. Clinical follow-up confirmed the better prognosis for CRIM-positive patients, though a slow, progressive worsening of motor and/or respiratory functions was detected in 8 patients. CONCLUSIONS: These data are the result of the longest independent retrospective study on ERT in IOPD reported so far outside clinical trials. The data obtained confirmed the better outcome of the CRIM-positive patients but at the same time, showed the inability of the current therapeutic approach to reverse or stabilize the disease progression. The results also evidenced the involvement of central nervous system in Pompe disease. To better understand the disease clinical history and to improve treatment efficacy larger multicentre studies are needed as well as the development of new therapeutic approaches.


Assuntos
Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , alfa-Glucosidases/uso terapêutico , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Itália , Masculino , Proteínas Recombinantes , Estudos Retrospectivos , alfa-Glucosidases/administração & dosagem
19.
Ital J Pediatr ; 44(1): 18, 2018 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-29368648

RESUMO

Several disorders should be considered in the case of newborns and infants experiencing acute or recurrent symptoms after food ingestion. Immune-mediated adverse food reactions are the most frequent and always to be considered. Nevertheless, in the extensive differential diagnosis, clinicians should also include inherited metabolic disorders (IMDs).This review reports clinical features and diagnostic aspects of the most common IMDs that may present with acute manifestations triggered by food intake. Major focus will be amino acid and protein metabolism defects and carbohydrate disorders.Nowadays, for many of these disorders the risk of an acute presentation triggered by food has been decreased by the introduction of expanded newborn screening (NBS). Nevertheless, clinical suspicion remains essential because some IMDs do not have still reliable markers for NBS and a false negative screening result may occur.The aim of this review is to help pediatricians to take these rare inherited disorders into account in the differential diagnosis of acute or recurrent gastrointestinal symptoms related to food intake, which may avoid delayed diagnosis and potentially life-threatening consequences.


Assuntos
Diagnóstico Tardio , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Triagem Neonatal/métodos , Padrões de Prática Médica , Comportamento Alimentar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/terapia , Pediatras , Prevalência , Prognóstico , Medição de Risco
20.
Cogn Neuropsychol ; 35(3-4): 200-208, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29117799

RESUMO

In this study we compared the neuropsychological profile of phenylketonuria (PKU) and human immunodeficiency virus (HIV) to examine the specificity of the executive function (EF) impairment reported in these two patologies. A total of 55 age-matched children and adolescents were assessed, including 11 patients with PKU, 16 patients with HIV and 28 healthy controls, underwent a neuropsychological assessment. Although neither the PKU nor the HIV group scored below the normative ranges, both groups showed lower scores in neuropsychological tests engaging EFs than controls. In addition, compared to patients with PKU the HIV group performed significantly worse in the Trail-Making Test A, Corsi Span and Verbal Fluency. These findings suggest that EF impairments in PKU (a) are limited to EFs (i.e., working memory and attentional shifting), (b) are not simply due to generalized processing speed deficits and


Assuntos
Função Executiva/fisiologia , Testes Neuropsicológicos/normas , Fenilcetonúrias/complicações , Adolescente , Criança , Feminino , Humanos , Masculino , Fenilcetonúrias/patologia
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