Study of paediatric patients with the clinical and biochemical phenotype of glucose transporter type 1 deficiency syndrome.

INTRODUCTION: Glucose transporter type 1 (GLUT1) deficiency syndrome may present a range of phenotypes, including epilepsy, intellectual disability, and movement disorders. The majority of patients present low CSF glucose levels and/or defects in the SLC2A1 gene; however, some patients do not present low CSF glucose or SLC2A1 mutations, and may have other mutations in other genes with compatible phenotypes. AIMS: We describe the clinical, biochemical, and genetic characteristics of the disease and perform a univariate analysis of a group of patients with clinical and biochemical phenotype of GLUT1 deficiency syndrome, with or without SLC2A1 mutations. MATERIAL AND METHODS: The study included 13 patients meeting clinical and biochemical criteria for GLUT1 deficiency syndrome. SLC2A1 sequencing and multiplex ligation-dependent probe amplification were performed; exome sequencing was performed for patients with negative results. RESULTS: Six patients presented the classic phenotype; 2 paroxysmal dyskinesia, 2 complex movement disorders, 2 early-onset absence seizures, and one presented drug-resistant childhood absence epilepsy. Six patients were positive for SLC2A1 mutations; in the other 5, another genetic defect was identified. No significant differences were observed between the 2 groups for age of onset, clinical presentation, microcephaly, intellectual disability, or response to ketogenic diet. Patients with SLC2A1 mutations presented more clinical changes in relation to diet (66.7%, vs 28.6% in the SLC2A1-negative group) and greater persistence of motor symptoms (66% vs 28.6%); these differences were not statistically significant. Significant differences were observed for CSF glucose level (34.5 vs 46mg/dL, P=.04) and CSF/serum glucose ratio (0.4 vs 0.48, P<.05). CONCLUSIONS: GLUT1 deficiency syndrome may be caused by mutations to genes other than SLC2A1 in patients with compatible phenotype, low CSF glucose level, and good response to the ketogenic diet.

Estudio de pacientes pediátricos con fenotipo clínico y bioquímico de síndrome de déficit de transportador de glucosa cerebral (GLUT-1) / Study of paediatric patients with the clinical and biochemical phenotype of glucose transporter type 1 deficiency syndrome

Introducción: El síndrome de déficit del transportador de glucosa cerebral (GLUT1DS) puede presentar fenotipos variados, incluyendo epilepsia, déficit intelectual y trastorno del movimiento. La mayoría presenta hipoglucorraquia y/o defectos en el gen SLC2A1, aunque existen pacientes sin hipoglucorraquia y otros con genética de SLC2A1-negativa, o con defectos en otros genes y fenotipo compatible. Objetivos: Describir las características clínicas, bioquímicas y genéticas y realizar un análisis univariante de un grupo de pacientes con fenotipo clínico y bioquímico de GLUT1DS, con o sin genética SLC2A1-positiva. Material y métodos: Se incluyeron 13 pacientes con criterios clínico-bioquímicos de GLUT1DS. Se realizó secuenciación de SLC2A1 y MLPA. En los casos negativos se realizó exoma clínico. Resultados: Seis presentaron fenotipo clásico, 2 discinesia paroxística, 2 trastornos del movimiento complejo, 2 ausencias precoces y otro presentó epilepsia con ausencias infantiles refractaria a farmacoterapia. Seis fueron SLC2A1-positivos. Y en 5 de los SLC2A1-negativos se identificó otro defecto genético. No hubo diferencias significativas entre los dos grupos en edad de inicio, presentación clínica, microcefalia, discapacidad intelectual ni respuesta a dieta cetogénica. De forma no significativa, los pacientes SCL2A1-positivos presentaron más cambios clínicos en relación con la ingesta (66,7% vs. 28,6%) y mayor persistencia de síntomas motores (66% vs. 28,6%). De forma significativa, presentaron menor glucorraquia (34,5 mg/dl vs. 46 mg/dl, p = 0,04) e índice glucorraquia/glucemia más bajo (0,4 vs. 0,48, p = 0,05) que los SLC2A1-negativos. Conclusiones: GLUT1DS puede ser causado por defectos genéticos en otros genes diferentes de SLC2A1 en pacientes con fenotipo compatible, hipoglucorraquia y buena respuesta a dieta cetogénica. (AU)

Introduction: Glucose transporter type 1 (GLUT1) deficiency syndrome may present a range of phenotypes, including epilepsy, intellectual disability, and movement disorders. The majority of patients present low CSF glucose levels and/or defects in the SLC2A1 gene; however, some patients do not present low CSF glucose or SLC2A1 mutations, and may have other mutations in other genes with compatible phenotypes. Aims: We describe the clinical, biochemical, and genetic characteristics of the disease and perform a univariate analysis of a group of patients with clinical and biochemical phenotype of GLUT1 deficiency syndrome, with or without SLC2A1 mutations. Material and methods: The study included 13 patients meeting clinical and biochemical criteria for GLUT1 deficiency syndrome. SLC2A1 sequencing and multiplex ligation-dependent probe amplification were performed; exome sequencing was performed for patients with negative results. Results: Six patients presented the classic phenotype; 2 paroxysmal dyskinesia, 2 complex movement disorders, 2 early-onset absence seizures, and one presented drug-resistant childhood absence epilepsy. Six patients were positive for SLC2A1mutations; in the other 5, another genetic defect was identified. No significant differences were observed between the 2 groups for age of onset, clinical presentation, microcephaly, intellectual disability, or response to ketogenic diet. Patients ith SLC2A1 mutations presented more clinical changes in relation to diet (66.7% vs. 28.6% in the SLC2A1-negative group) and greater persistence of motor symptoms (66% vs. 28.6%); these differences were not statistically significant. Significant differences were observed for CSF glucose level (34.5 vs. 46 mg/dL, P = .04) and CSF/serum glucose ratio (0.4 vs. 0.48, P < .05). [...] (AU)

Proteostasis regulators as potential rescuers of PMM2 activity.

Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-glycosylation disorder. To date there is no treatment. Following the identification of a number of destabilizing pathogenic variants, our group suggested PMM2-CDG to be a conformational disease. The aim of the present study was to evaluate the possible use of proteostasis network regulators to increase the stability, and subsequently the enzymatic activity, of misfolded PMM2 mutant proteins. Patient-derived fibroblasts transduced with their own PMM2 folding or oligomerization variants were treated with different concentrations of the proteostasis regulators celastrol or MG132. Celastrol treatment led to a significant increase in mutant PMM2 protein concentration and activity, while MG132 had a small effect on protein concentration only. The increase in enzymatic activity with celastrol correlated with an increase in the transcriptional and proteome levels of the heat shock proteins Hsp90 and Hsp70. The use of specific Hsp70 or Hsp90 inhibitors showed the positive effect of celastrol on PMM2 stability and activity to occur through Hsp90-driven modulation of the proteostasis network. The synergistic effect of celastrol and a previously described pharmacological chaperone was also examined, and a mutation-dependent synergistic effect on PMM2 activity was noted. These results provide proof-of-concept regarding the potential treatment of PMM2-CDG by proteostasis regulators, either alone or in combination with pharmacological chaperones.

Study of paediatric patients with the clinical and biochemical phenotype of glucose transporter type 1 deficiency syndrome. / Estudio de pacientes pediátricos con fenotipo clínico y bioquímico de síndrome de déficit de transportador de glucosa cerebral (GLUT-1).

INTRODUCTION: Glucose transporter type 1 (GLUT1) deficiency syndrome may present a range of phenotypes, including epilepsy, intellectual disability, and movement disorders. The majority of patients present low CSF glucose levels and/or defects in the SLC2A1 gene; however, some patients do not present low CSF glucose or SLC2A1 mutations, and may have other mutations in other genes with compatible phenotypes. AIMS: We describe the clinical, biochemical, and genetic characteristics of the disease and perform a univariate analysis of a group of patients with clinical and biochemical phenotype of GLUT1 deficiency syndrome, with or without SLC2A1 mutations. MATERIAL AND METHODS: The study included 13 patients meeting clinical and biochemical criteria for GLUT1 deficiency syndrome. SLC2A1 sequencing and multiplex ligation-dependent probe amplification were performed; exome sequencing was performed for patients with negative results. RESULTS: Six patients presented the classic phenotype; 2 paroxysmal dyskinesia, 2 complex movement disorders, 2 early-onset absence seizures, and one presented drug-resistant childhood absence epilepsy. Six patients were positive for SLC2A1 mutations; in the other 5, another genetic defect was identified. No significant differences were observed between the 2 groups for age of onset, clinical presentation, microcephaly, intellectual disability, or response to ketogenic diet. Patients with SLC2A1 mutations presented more clinical changes in relation to diet (66.7% vs. 28.6% in the SLC2A1-negative group) and greater persistence of motor symptoms (66% vs. 28.6%); these differences were not statistically significant. Significant differences were observed for CSF glucose level (34.5 vs. 46mg/dL, P=.04) and CSF/serum glucose ratio (0.4 vs. 0.48, P<.05). CONCLUSIONS: GLUT1 deficiency syndrome may be caused by mutations to genes other than SLC2A1 in patients with compatible phenotype, low CSF glucose level, and good response to the ketogenic diet.

Miastenia congénita y defecto congénito de la glucosilación por mutaciones en el gen DPAGT1 / Congenital myasthenia and congenital disorders of glycosylation caused by mutations in the DPAGT1 gene

No disponible

Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers.

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.

Protein misfolding diseases: Prospects of pharmacological treatment.

Protein misfolding has been linked to numerous inherited diseases. Loss- and gain-of-function mutations (common features of genetic diseases) may cause the destabilization of proteins, leading to alterations in their properties and/or cellular location, resulting in their incorrect functioning. Misfolded proteins can, however, be rescued via the use of proteostasis regulators and/or pharmacological chaperones, suggesting that treatments with small molecules might be developed for a range of genetic diseases. This work describes the potential of these small molecules in this respect, including for the treatment of congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG).

Tyrosinemia type II: Mutation update, 11 novel mutations and description of 5 independent subjects with a novel founder mutation.

BACKGROUND: Tyrosinemia type II, also known as Richner-Hanhart Syndrome, is an extremely rare autosomal recessive disorder, caused by mutations in the gene encoding hepatic cytosolic tyrosine aminotransferase, leading to the accumulation of tyrosine and its metabolites which cause ocular and skin lesions, that may be accompanied by neurological manifestations, mostly intellectual disability. AIMS: To update disease-causing mutations and current clinical knowledge of the disease. MATERIALS AND METHODS: Genetic and clinical information were obtained from a collection of both unreported and previously reported cases. RESULTS: We report 106 families, represented by 143 individuals, carrying a total of 36 genetic variants, 11 of them not previously known to be associated with the disease. Variants include 3 large deletions, 21 non-synonymous and 5 nonsense amino-acid changes, 5 frameshifts and 2 splice variants. We also report 5 patients from Gran Canaria, representing the largest known group of unrelated families sharing the same P406L mutation. CONCLUSIONS: Data analysis did not reveal a genotype-phenotype correlation, but stressed the need of early diagnosis: All patients improved the oculocutaneous lesions after dietary treatment but neurological symptoms prevailed. The discovery of founder mutations in isolated populations, and the benefits of early intervention, should increase diagnostic awareness in newborns.

Antisense-mediated therapeutic pseudoexon skipping in TMEM165-CDG.

Deficiencies in glycosyltransferases, glycosidases or nucleotide-sugar transporters involved in protein glycosylation lead to congenital disorders of glycosylation (CDG), a group of genetic diseases mostly showing multisystem phenotype. Despite recent advances in the biochemical and molecular knowledge of these diseases, no effective therapy exists for most. Efforts are now being directed toward therapies based on identifying new targets, which would allow to treat specific patients in a personalized way. This work presents proof-of concept for the antisense RNA rescue of the Golgi-resident protein TMEM165, a gene involved in a new type of CDG with a characteristic skeletal phenotype. Using a functional in vitro splicing assay based on minigenes, it was found that the deep intronic change c.792+182G>A is responsible for the insertion of an aberrant exon, corresponding to an intronic sequence. Antisense morpholino oligonucleotide therapy targeted toward TMEM165 mRNA recovered normal protein levels in the Golgi apparatus of patient-derived fibroblasts. This work expands the application of antisense oligonucleotide-mediated pseudoexon skipping to the treatment of a Golgi-resident protein, and opens up a promising treatment option for this specific TMEM165-CDG.

Thirteen years experience with selective screening for disorders in purine and pyrimidine metabolism.

Purine and pyrimidine disorders represent a heterogeneous group with variable clinical symptoms and low prevalence rate. In the last thirteen years, we have studied urine/plasma specimens from about 1600 patients and we have identified 35 patients: eight patients with adenylosuccinate lyase deficiency, eight patients with hypoxanthine-guanine phosphoribosyltransferase deficiency, one patient with purine nucleoside phosphorylase deficiency, ten patients with xanthine dehydrogenase deficiency, six patients with molybdenum cofactor deficiency and two patients with dihydropyrimidine dehydrogenase deficiency. Despite low incidence of these diseases, our findings highlight the importance of including the purine and pyrimidine analysis in the selective screening for inborn errors of metabolism in specialized laboratories, where amino acid and organic acid disorders are simultaneously investigated.

Deficiencia de holocarboxilasa sintetasa de presentación tardía con actividad piruvato carboxilasa normal / Delayed onset holocarboxylase synthetase deficiency with normal pyruvate carboxylase activity

Se presenta un caso de deficiencia de holocarboxilasa sintetasa con actividad piruvato carboxilasa normal en linfocitos en una niña de 8 años con clínica de intoxicación y sin la clásica afectación dermatológica. La identificación de 3 cambios nucleotídicos en el gen HCLS, habiendo sido descrito como mutación patogénica solo uno de ellos, podría estar relacionada con una variante leve de la enfermedad que explicaría la presentación inusual más allá de la época de lactante. El tratamiento con biotina a 40 mg/día, junto con dieta controlada en proteínas, permite un crecimiento físico y un desarrollo psicomotor normales para su edad

We report a case of holocarboxylase synthetase deficiency with normal pyruvate carboxylase activity in the lymphocytes of an 8 year-old girl with clinical toxicity without the classic dermatological involvement. The identification of three nucleotide changes in the holocarboxylase synthetase (HLCS) gene, only one of them described as a pathogenic mutation could be related to a slight variant of the disease that would explain the unusual presentation beyond the age of infant. Treatment with biotin at 40 mg/day with protein controlled diet allows normal physical growth and psychomotor development for their age

[Delayed onset holocarboxylase synthetase deficiency with normal pyruvate carboxylase activity]. / Deficiencia de holocarboxilasa sintetasa de presentación tardía con actividad piruvato carboxilasa normal.

We report a case of holocarboxylase synthetase deficiency with normal pyruvate carboxylase activity in the lymphocytes of an 8 year-old girl with clinical toxicity without the classic dermatological involvement. The identification of three nucleotide changes in the holocarboxylase synthetase (HLCS) gene, only one of them described as a pathogenic mutation could be related to a slight variant of the disease that would explain the unusual presentation beyond the age of infant. Treatment with biotin at 40 mg/day with protein controlled diet allows normal physical growth and psychomotor development for their age.

Functional analysis and in vitro correction of splicing FAH mutations causing tyrosinemia type I.

Hereditary tyrosinemia type I (HT1) is a rare disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway, resulting mainly in hepatic alterations due to accumulation of the toxic metabolites fumarylacetoacetate, maleylacetoacetate and succinylacetone. We have characterized using minigenes four splicing mutations affecting exonic or intronic nucleotides of the FAH gene identified in two HT1 patients. Two of the mutations are novel, c.82-1G>A and c.913G>C and the other two have been previously associated with a splicing defect (c.836A>G and c.1062+5G>A). All mutations were confirmed to affect splicing in minigenes, resulting in exon skipping or activation of a cryptic splice site. We have analyzed the effect of different compounds known to modulate splicing (valproic acid, phenyl butyrate, M344, EIPA, and resveratrol) and the overexpression of splice factors of the SR protein family on the transcriptional profile of the mutant minigenes. For the c.836A>G mutation, a partial recovery of the correctly spliced transcript was observed. These results confirm the relevance of performing functional studies for mutations potentially affecting the splicing process and open the possibility of supplementary therapeutic approaches to diseases caused by splicing defects.

Infantile parkinsonism and GABAergic hypotransmission in a patient with pyruvate carboxylase deficiency.

Pyruvate carboxylase deficiency is a rare metabolic disorder, with three different phenotypes. We aim to report the case of a newborn presenting the severe neonatal form of this deficiency (the B or "French" phenotype, hypokinesia and rigidity being the main features) and the results of the study of classic neurotransmitters involved in movement control. Hyperdopaminergic transmission (both in the cerebrospinal fluid and in the substantia nigra) and hypoGABAergic transmission (in the substantia nigra) were found. Both gamma-aminobutyric acid and dopamine markers were found coexisting in individual neurons of the substantia nigra. This is the first time this phenomenon has been reported in the literature. We discuss the possible role of GABAergic deficiency, its interaction with other neurotransmitters and its implication in neurotransmitter homeostasis. A better comprehension of that field would increase understanding of the pathophysiology of neurological symptoms and neurotransmitter plasticity.

Mild clinical and biochemical phenotype in two patients with PMM2-CDG (congenital disorder of glycosylation Ia).

Phosphomannomutase 2 deficiency (PMM2-CDG) patients may present as mild phenotypes, with the cerebellum frequently involved. In those cases, false-negative results in screening may occur when applying conventional biochemical procedures. Our aim was to report two patients with a diagnosis of PMM2-CDG presenting with mild clinical phenotype. Patient 1-at 9 months of age, she presented with just psychomotor delay, tremor, hypotonia, and slight lipodystrophy. Patient 2-she presented at 8 months of age with psychomotor delay, hand stereotypes, hypotonia, convergent bilateral strabismus, and tremor but no lipodystrophy. Routine biochemical parameters including blood count, clotting factors, proteins, and thyroid hormone were normal in both cases. Cranial MRI evidenced mild cerebellar atrophy with moderate vermis hypoplasia. In case 1, sialotransferrin pattern showed very slightly increased disialotransferrin with no asialotransferrin, and in case 2, the transferrin pattern was impaired in the first study but nearly normal in the second. Nevertheless, in all the samples, quantification of the patterns obtained by capillary zone electrophoresis analysis gave results out of the control range. High residual PMM2 activity was observed in both cases and the genetic analysis showed that patient 1 was heterozygous for c.722G>C (p.C241S) and c.368G>A (p.R123Q) mutations, and patient 2 showed the c.722G>C and the c.470T>C (p.F157S) mutations in the PMM2 gene. We would like to stress the importance of the use of sensitive semiquantitative methods of screening for CDG in order to achieve early identification of patients with mild phenotypes. Intentional tremor was an atypical but remarkable clinical feature in both cases, and the global cerebellar atrophy with vermis hypoplasia reinforced the early clinical suspicion of a PMM2-CDG disease.

Nutritional and Pharmacological Management during Chemotherapy in a Patient with Propionic Acidaemia and Rhabdomyosarcoma Botryoides.

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.

The molecular landscape of phosphomannose mutase deficiency in iberian peninsula: identification of 15 population-specific mutations.

PMM2-CDG is an autosomal recessive disorder and the most frequent form of congenital disorder of N-glycosylation, with more than 100 mutations identified to date. Sixty-six patients from 58 unrelated families were diagnosed as PMM2-CDG (CDG-Ia) based on clinical signs or because of a previous affected sibling. They all presented a type 1 serum transferrin isoform pattern, and, in most cases, the disease was confirmed by determining PMM2 activity in fibroblasts and/or lymphocytes. Residual PMM2 activity in fibroblasts ranged from not detectable to 60% of the mean controls. DNA and RNA were isolated from fresh blood or fibroblasts from patients to perform molecular studies of the PMM2 gene, resulting in the identification of 30 different mutations, four of them newly reported here (p.Y102C, p.T118S, p.P184T, and p.D209G). From these 30 mutations, 15 have only been identified among Iberian PMM2-CDG patients. As in other Caucasian populations, p.R141H was the most frequent mutation (24 alleles, prevalence 20.6%), but less than in other European series in which this mutation represents 35-43% of the disease alleles. The next frequent mutations were p.D65Y (12 alleles, prevalence 10.3%) and p.T237M (9 alleles, prevalence 7.6%), while p.F119L and p.E139K, the most frequent changes in Scandinavian and French populations, respectively, were not found in our patients. The most common genotype was [p.R141H] + [p.T237M], and four homozygous patients for p.Y64C, p.D65Y, p.P113L, and p.T237M were detected. The broad mutational spectrum and the diversity of phenotypes found in the Iberian populations hamper genotype-phenotype correlation.

Déficit de succínico semialdehído deshidrogenasa. Disminución de los niveles de 4 OH butírico con dosis bajas de vigabatrina / Succinic semialdehyde dehydrogenase deficiency: Decrease in 4-OH-butyric acid levels with low doses of vigabatrin

La deficiencia de succínico semialdehído deshidrogenasa o aciduria gammahidroxibutírica (GHB) es una rara enfermedad autosómica recesiva por alteración en el metabolismo del neurotransmisor inhibidor del ácido gammaaminobutírico. Debido a la deficiencia de esta enzima, se produce acúmulo del metabolito ácido GHB. El espectro clínico es heterogéneo con distintas manifestaciones neurológicas. El tratamiento más utilizado es la vigabatrina, aunque se discute su eficacia. Presentamos el caso de una familia con 2 hijos afectados. El mayor presenta retraso en la adquisición de hitos motores, marcha liberada a los 2 años, dificultad en la psicomotricidad fina, hipotonía axial, normorreflexia y retraso en el lenguaje tanto comprensivo como expresivo. Se evalúa al menor por hipotonía axial. Estudio metabólico: aumento de ácido GHB en orina y en plasma. El diagnóstico se confirma mediante el análisis de mutaciones del gen ALDH5A1. Se trata con vigabatrina en dosis bajas, lo que conduce a una disminución de los niveles de GHB en plasma en más de dos tercios y una evolución clínica favorable (AU)

Succinic semialdehyde dehydrogenase deficiency (gamma-hydroxybutyric aciduria) is a rare neurometabolic disease caused by a deficiency in gamma-aminobutyric degradation, resulting in an increase in gamma-hydroxybutyric acid in biological fluids. The clinical spectrum is heterogeneous, including a variety of neurological manifestations and psychiatric symptoms. The treatment usually used is vigabatrin, but its clinical efficacy is under discussion. We present two affected siblings. The older brother was examined when he was 2.5 years old due to psychomotor and developmental delay, disturbances in motor coordination, axial hypotonia and language disability. His younger brother had mild axial hypotonia when 5 months old. Metabolic studies demonstrated a high plasma and urine concentration of gamma-hydroxybutyric acid. Mutation analysis of the gene ALDH5A1 confirmed the disease. After 1 year of treatment with low-doses of vigabatrin of the older patient, a decrease in gamma-hydroxybutyric acid plasma levels and a slow clinical improvement were observed (AU)

[Succinic semialdehyde dehydrogenase deficiency: decrease in 4-OH-butyric acid levels with low doses of vigabatrin]. / Déficit de succínico semialdehído deshidrogenasa. Disminución de los niveles de 4 OH butírico con dosis bajas de vigabatrina.

Succinic semialdehyde dehydrogenase deficiency (gamma-hydroxybutyric aciduria) is a rare neurometabolic disease caused by a deficiency in gamma-aminobutyric degradation, resulting in an increase in gamma-hydroxybutyric acid in biological fluids. The clinical spectrum is heterogeneous, including a variety of neurological manifestations and psychiatric symptoms. The treatment usually used is vigabatrin, but its clinical efficacy is under discussion. We present two affected siblings. The older brother was examined when he was 2.5 years old due to psychomotor and developmental delay, disturbances in motor coordination, axial hypotonia and language disability. His younger brother had mild axial hypotonia when 5 months old. Metabolic studies demonstrated a high plasma and urine concentration of gamma-hydroxybutyric acid. Mutation analysis of the gene ALDH5A1 confirmed the disease. After 1 year of treatment with low-doses of vigabatrin of the older patient, a decrease in gamma-hydroxybutyric acid plasma levels and a slow clinical improvement were observed.