We report clinical and biochemical finding from three unrelated patients presenting ONCE (Optic Neuropathy, Cardiomyopathy and Encephalopathy with lactic acidosis and combined oxidative ...phosphorylation deficiency) syndrome. Whole‐exome sequencing (WES) of the three patients and the healthy sister of one of them was used to identify the carry gene. Clinical and biochemical findings were used to filter variants, and molecular, in silico and genetic studies were performed to characterize the candidate variants. Mitochondrial DNA (mtDNA) defects involving mutations, deletions or depletion were discarded, whereas WES uncovered a double homozygous mutation in the MTO1 gene (NM_001123226:c.1510C>T, p.R504C, and c.1669G>A, p.V557M) in two of the patients and the homozygous mutation p.R504C in the other. Therefore, our data confirm p.R504C as pathogenic mutation responsible of ONCE syndrome, and p.V557M as a rare polymorphic variant.
The R504C mutation in MTO1 gene is the responsible of ONCE syndrome (Optic Neuropathy, Cardiomyopathy and Encephalopathy with lactic acidosis and combined OXPHOS deficiency) and V557M is a rare polymorphic variant.
Identification of very long-chain acyl-CoA dehydrogenase deficiency is possible in the expanded newborn screening (NBS) due to the increase in tetradecenoylcarnitine (C14:1) and in the C14:1/C2, ...C14:1/C16, C14:1/C12:1 ratios detected in dried blood spots. Nevertheless, different confirmatory tests must be performed to confirm the final diagnosis. We have revised the NBS results and the results of the confirmatory tests (plasma acylcarnitine profiles, molecular findings, and lymphocytes VLCAD activity) for 36 cases detected in three Spanish NBS centers during 4 years, correlating these with the clinical outcome and treatment. Our aim was to distinguish unambiguously true cases from disease carriers in order to obtain useful diagnostic information for clinicians that can be applied in the follow-up of neonates identified by NBS.
Increases in C14:1 and of the different ratios, the presence of two pathogenic mutations, and deficient enzyme activity in lymphocytes (<12% of the intra-assay control) identified 12 true-positive cases. These cases were given nutritional therapy and all of them are asymptomatic, except one. Seventeen individuals were considered disease carriers based on the mild increase in plasma C14:1, in conjunction with the presence of only one mutation and/or intermediate residual activity (18–57%). In addition, seven cases were classified as false positives, with normal biochemical parameters and no mutations in the exonic region of ACADVL. All these carriers and the false positive cases remained asymptomatic. The combined evaluation of the acylcarnitine profiles, genetic results, and residual enzyme activities have proven useful to definitively classify individuals with suspected VLCAD deficiency into true-positive cases and carriers, and to decide which cases need treatment.
Summary Background & aims Mitochondrial diseases (MD) are the most frequent inborn errors of metabolism. In affected tissues, MD can alter cellular oxygen consumption rate leading to potential ...decreases in whole-body resting energy expenditure (REE), but data on pediatric children are absent. We determined, using indirect calorimetry (IC), whole-body oxygen consumption (VO2 ), carbon dioxide production (VCO2 ), respiratory quotient (RQ) and REE in pediatric patients with MD and healthy controls. Another goal was to assess the accuracy of available predictive equations for REE estimation in this patient population. Methods IC data were obtained under fasting and resting conditions in 20 MD patients and 27 age and gender-matched healthy peers. We determined the agreement between REE measured with IC and REE estimated with Schofield weight and FAO/WHO/UNU equations. Results Mean values of VO2 , VCO2 (mL·min−1 ·kg−1 ) or RQ did not differ significantly between patients and controls ( P = 0.085, P = 0.055 and P = 0.626 respectively). Accordingly, no significant differences ( P = 0.086) were found for REE (kcal·day−1 kg−1 ) either. On the other hand, although we found no significant differences between IC-measured REE and Schofield or FAO/WHO/UNU-estimated REE, Bland–Altman analysis revealed wide limits of agreement and there were some important individual differences between IC and equation-derived REE. Conclusions VO2 , VCO2 , RQ and REE are not significantly altered in pediatric patients with MD compared with healthy controls. The energy demands of pediatric patients with MD should be determined based on IC data in order to provide the best possible personalized nutritional management for these children.
We present the nutritional and pharmacological management of a 2-year-old girl with a severe form of propionic acidaemia and a genitourinary embryonal rhabdomyosarcoma. This association has not been ...described before, nor the utilization of chemotherapy in patients with propionic acidaemia.
The patient is a girl with neonatal onset of propionic acidaemia, homozygous for the c.2041-2924del3889 mutation in PCCA gene. At 23 months of age she was diagnosed with genitourinary embryonal rhabdomyosarcoma. Conservative surgery, brachytherapy and nine cycles of chemotherapy with iphosphamide, vincristine and actinomycin were recommended by oncologists. Due to the possibility that the child could present decompensations, we elaborated three different courses of treatment: when the patient was stable (treatment 1), intermittent bolus feeding through gastrostomy, containing 70 kcal/kg/day and 1.4 g/kg/day of total protein (0.6 g/kg/day of natural protein and 0.8 g/kg/day of amino acid-based formula) was prescribed; on the chemotherapy-days (treatment 2), diet consisted on continuous feeding, with the same energy and amino acid-based formula but half of natural protein intake; in case of decompensation (treatment 3), we increased by 10% the energy intake, and completely stopped natural protein in the diet but maintaining the amino acid-based formula. On chemotherapy- days carnitine was increased from 100 mg/kg/day to 150 mg/kg/day, and N-carbamylglutamate was added.
Through the 7 months with chemotherapy the patient did not suffer decompensations, while she maintained good nutritional status.
Enteral continuous feeding by gastrostomy, amino acid-based formula, and preventive use of N-carbamylglutamate during chemotherapy-days are the principal measures we propose in these situations.
La enfermedad de Niemann-Pick tipo C está causada por un defecto en el transporte intracelular de colesterol que produce un acúmulo de lípidos en los lisosomas de diferentes tejidos. Es una ...enfermedad rara, debida generalmente a mutaciones en el gen
NPC1 y solo unos pocos casos se asocian a mutaciones en el gen
NPC2. Frecuentemente se manifiesta en la edad pediátrica, presentando gran variabilidad en las manifestaciones clínicas. La enfermedad conduce a un deterioro neurológico con diferentes síntomas que están relacionados con la edad. Una colestasis neonatal transitoria, la aparición de esplenomegalia y/o hepatomegalia pueden preceder en años a los síntomas neurológicos.
Presentamos los 6 casos diagnosticados en nuestra unidad en los últimos 20 años. Se han revisado las manifestaciones clínicas, los hallazgos neurorradiológicos (RM) y el análisis molecular de todos ellos.
Todos se presentaron antes de los 6 años y 5 casos tuvieron afectación hepática y/o colestasis en el periodo neonatal. En 2 casos se detectó ascitis en el periodo prenatal. La presencia de esplenomegalia se objetivó en 5 casos. En todos los casos se detectaron mutaciones en el gen
NPC1.
Es importante el conocimiento de esta enfermedad y la identificación de los síntomas clínicos precoces para poder diagnosticarla precozmente, lo que conllevaría a un tratamiento adecuado, pudiendo evitar procedimientos innecesarios. Por otra parte es importante asesorar adecuadamente a las familias y proporcionar un consejo genético.
Niemann-Pick type C is a lysosomal storage disorder caused by a defect in intracellular trafficking of cholesterol. It is a rare disease, usually caused by mutations in
NPC1 gene, but in some cases by mutations in
NPC2 gene. Usually it is present in the paediatric age with a great variability of clinical manifestations. This disease leads to neurological degeneration with various age-related symptoms. Transient neonatal cholestasis, the appearance of splenomegaly and/or hepatomegaly may occur years before the neurological symptoms.
We report 6 cases diagnosed in our unit in the last 20 years. We reviewed the clinical manifestations, neuroradiological findings (MRI) and molecular analysis of all of them.
The disease began before 6 years of age and 5 cases had liver dysfunction and cholestasis in the neonatal period. Ascites was detected in 2 cases in prenatal period. Five cases have or had splenomegaly. Mutations in
NPC1 gene were detected in all of them.
It is important to understand this disease and the identification of early clinical symptoms to make an early diagnosis, leading to appropriate treatment and avoiding unnecessary tests. Moreover, it is important to suitably advise families and provide them with genetic counselling.
Niemann-Pick type C is a lysosomal storage disorder caused by a defect in intracellular trafficking of cholesterol. It is a rare disease, usually caused by mutations in NPC1 gene, but in some cases ...by mutations in NPC2 gene. Usually it is present in the paediatric age with a great variability of clinical manifestations. This disease leads to neurological degeneration with various age-related symptoms. Transient neonatal cholestasis, the appearance of splenomegaly and/or hepatomegaly may occur years before the neurological symptoms.
We report 6 cases diagnosed in our unit in the last 20 years. We reviewed the clinical manifestations, neuroradiological findings (MRI) and molecular analysis of all of them.
The disease began before 6 years of age and 5 cases had liver dysfunction and cholestasis in the neonatal period. Ascites was detected in 2 cases in prenatal period. Five cases have or had splenomegaly. Mutations in NPC1 gene were detected in all of them.
It is important to understand this disease and the identification of early clinical symptoms to make an early diagnosis, leading to appropriate treatment and avoiding unnecessary tests. Moreover, it is important to suitably advise families and provide them with genetic counselling.
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