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Due to the majority of currently available genome data deriving from individuals of European ancestry, the clinical interpretation of genomic variants in individuals from diverse ethnic backgrounds remains a major diagnostic challenge. Here, we investigated the genetic cause of a complex neurodevelopmental phenotype in two Palestinian siblings. Whole exome sequencing identified a homozygous missense TECPR2 variant (Chr14(GRCh38):g.102425085G>A; NM_014844.5:c.745G>A, p.(Gly249Arg)) absent in gnomAD, segregating appropriately with the inheritance pattern in the family. Variant assessment with in silico pathogenicity prediction and protein modeling tools alongside population database frequencies led to classification as a variant of uncertain significance. As pathogenic TECPR2 variants are associated with hereditary sensory and autonomic neuropathy with intellectual disability, we reviewed previously published candidate TECPR2 missense variants to clarify clinical outcomes and variant classification using current approved guidelines, classifying a number of published variants as of uncertain significance. This work highlights genomic healthcare inequalities and the challenges in interpreting rare genetic variants in populations underrepresented in genomic databases. It also improves understanding of the clinical and genetic spectrum of TECPR2-related neuropathy and contributes to addressing genomic data disparity and inequalities of the genomic architecture in Palestinian populations.
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Secuenciación del Exoma , Neuropatías Hereditarias Sensoriales y Autónomas , Mutación Missense , Linaje , Hermanos , Humanos , Masculino , Femenino , Mutación Missense/genética , Neuropatías Hereditarias Sensoriales y Autónomas/genética , Neuropatías Hereditarias Sensoriales y Autónomas/patología , Neuropatías Hereditarias Sensoriales y Autónomas/diagnóstico , Fenotipo , Niño , Árabes/genética , Predisposición Genética a la Enfermedad , HomocigotoRESUMEN
SLC4A10 is a plasma-membrane bound transporter that utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of CSF. Using next generation sequencing on samples from five unrelated families encompassing nine affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorder including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioural abnormalities including delayed habituation and alterations in the two-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggest an important role of SLC4A10 in the production of the CSF. However, it is notable that despite diverse roles of the CSF in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies, which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties.
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Convulsiones , Simportadores de Sodio-Bicarbonato , Niño , Ratones , Humanos , Animales , Simportadores de Sodio-Bicarbonato/genética , Simportadores de Sodio-Bicarbonato/metabolismo , Convulsiones/genética , Mutación/genética , Neurotransmisores , Ácido gamma-Aminobutírico/genética , Mamíferos/metabolismo , Antiportadores de Cloruro-Bicarbonato/genética , Antiportadores de Cloruro-Bicarbonato/metabolismoRESUMEN
Introduction: and importance: Hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome (OMIM 238970) seems to be an autosomal recessive disorder caused by a mitochondrial ornithine transporter 1 deficiency, which results in urea cycle dysfunction. HHH is the most uncommon of the urea cycle diseases, with less than 100 cases recorded. Case presentation: A previously healthy 29 year old male presented to the emergency department complaining of decreased level of consciousness. CT scan, Cerebro-spinal-fluid analysis and toxicology screen were non-significant. Extended serum analysis showed elevated levels of ammonia. Urgent amino acid level analysis showed elevated ornithine. Follow up genetic testing showed that the patient is homozygous for the mutation c.44delG in exon 3 of SLC25A15 gene. Clinical discussion: In this case, HHH syndrome presented as a late-onset metabolic encephalopathy. For diagnosis; elevated levels of ammonia, ornithine accompanied by the abovementioned genetic mutation confirms the diagnosis. Treatment focuses on reduction of the ammonia levels using sodium benzoat, citrulline or arginine, and low protein diet. Conclusions: HHH syndrome, which is a urea cycle disorder, can present as a late-onset metabolic encephalopathy. High suspicion for genetic causes of metabolic encephalopathy should be maintained even for older patients without prior diagnosis in childhood/adolescence.
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Background: Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome, is a rare autosomal recessive disorder characterized by impaired ornithine transport across the inner mitochondrial membrane. HHH is caused by biallelic disease-causing variants in the SLC25A15 gene. The clinical presentation of HHH is highly variable ranging from severe neonatal encephalopathy and hepatic failure to a milder form with corresponding learning difficulties. Methods: In this study, data from thirteen patients with HHH syndrome, diagnosed between the age of 1 week-29 years at two tertiary care centers in Palestine, is presented. The clinical, biochemical, and molecular data are reviewed. Results: Analysis of the SLC25A15 gene sequence revealed a novel homozygous frameshift deletion in exon 5, NM_014252.4:c.552-555delTTTC; p (Phe185SerfsTer8) in nine patients. The remaining four patients had a recurrent homozygous frameshift variant; NM_014252.4:c.446delG, (p.Ser149ThrfsTer45). The major acute clinical presentation found was encephalopathy and liver dysfunction. Nervous system involvement was common, progressive, and presented with signs of upper motor neuron disease as well as variable degrees of cognitive impairment. One patient had an initial presentation in adulthood with acute encephalopathy that responded well to treatment. There was no clear genotype-phenotype correlation. Conclusion: Our results confirm the marked clinical heterogeneity of HHH including severe neonatal presentation, hepatic failure, and progressive pyramidal tract dysfunction in all age groups. The disease progression was variable, even in patients with the same genetic variant, and in patients with severe neonatal-onset hepatic encephalopathy. We report a novel pathogenic variant in the SLC25A15 gene, further expanding the molecular spectrum of the disease.
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BACKGROUND: Recessive forms of megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM 604004) is a rare early-onset leukodystrophy that presents with macrocephaly, seizures, slowly progressive gross motor deterioration, and MRI evidence of diffuse symmetric white matter swelling and subcortical cysts in the anterior temporal and frontoparietal regions. Later in the disease course, significant spasticity and ataxia develop, which may be accompanied by intellectual deterioration. This disease is caused mostly by biallelic pathogenic variants in the MLC1 gene. METHODS: In this study, we analysed the clinical and molecular architecture of 6 individuals, belonging to 4 unrelated consanguineous Palestinian families, presenting with consistent MLC features. We sequenced the entire coding and flanking intronic regions of the MLC1 gene. RESULTS: In all recruited individuals, we detected one recurrent homozygous splice donor mutation NM_015166.4: c.423 + 1G > A. All parents were heterozygous carriers. The mutation abolishes a highly conserved splice site in humans and other species. In silico splice predictors suggested the loss of a canonical splice donor site (CADD score 33.0. SpliceAI: 0.980). The c.423 + 1G > A variant is rare; it was detected in only 4 heterozygous carriers in gnomAD. CONCLUSION: In this study, we identified a recurrent MLC1 variant (c.423 + 1G > A) as the cause of MLC among a group of Palestinian patients originating from a particular region of the country. Cost-effective studies should be performed to evaluate the implementation of carrier screening in adults originating from this region. Our findings have the potential to contribute to improved genetic diagnosis and carrier testing for individuals within this population and the wider community.
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Quistes , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias , Proteínas de la Membrana , Árabes/genética , Consanguinidad , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico por imagen , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Humanos , Proteínas de la Membrana/genética , MutaciónRESUMEN
CONTEXT: The hyperinsulinism/hyperammonemia (HI/HA) syndrome, the second-most common form of congenital hyperinsulinism, has been associated with dominant mutations in GLUD1, coding for the mitochondrial enzyme glutamate dehydrogenase, that increase enzyme activity by reducing its sensitivity to allosteric inhibition by GTP. OBJECTIVE: To identify the underlying genetic etiology in 2 siblings who presented with the biochemical features of HI/HA syndrome but did not carry pathogenic variants in GLUD1, and to determine the functional impact of the newly identified mutation. METHODS: The patients were investigated by whole exome sequencing. Yeast complementation studies and biochemical assays on the recombinant mutated protein were performed. The consequences of stable slc25a36 silencing in HeLa cells were also investigated. RESULTS: A homozygous splice site variant was identified in solute carrier family 25, member 36 (SLC25A36), encoding the pyrimidine nucleotide carrier 2 (PNC2), a mitochondrial nucleotide carrier that transports pyrimidine as well as guanine nucleotides across the inner mitochondrial membrane. The mutation leads to a 26-aa in-frame deletion in the first repeat domain of the protein, which abolishes transport activity. Furthermore, knockdown of slc25a36 expression in HeLa cells caused a marked reduction in the mitochondrial GTP content, which likely leads to a hyperactivation of glutamate dehydrogenase in our patients. CONCLUSION: We report for the first time a mutation in PNC2/SLC25A36 leading to HI/HA and provide functional evidence of the molecular mechanism responsible for this phenotype. Our findings underscore the importance of mitochondrial nucleotide metabolism and expand the role of mitochondrial transporters in insulin secretion.
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Hiperinsulinismo Congénito , Hiperamonemia , Hiperinsulinismo , Hiperinsulinismo Congénito/genética , Glutamato Deshidrogenasa/genética , Guanosina Trifosfato/metabolismo , Células HeLa , Humanos , Hiperamonemia/genética , Hiperinsulinismo/genética , Hipoglucemia , Mutación , NucleótidosRESUMEN
BACKGROUND: Niemann-Pick disease type C (NPC) is an autosomal recessive, neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of tissue-specific lipids in lysosomes. METHODS: We described sixteen patients with NPC diagnosed between the age of 1 month and 30 years at two tertiary care centers in Palestine. The clinical phenotype, brain magnetic resonance imaging (MRI), and molecular genetic analysis data were reviewed. RESULTS: The diagnosis was confirmed by molecular analysis in all patients. Fourteen out of sixteen patients were homozygous for the NPC1 p.G992W variant. Among them, most were categorized as having the late-infantile neurological form of disease onset. They predominantly manifested with early-onset visceral manifestations in the form of hepatosplenomegaly and prolonged neonatal jaundice, and late-onset neuropsychiatric manifestations in the form of vertical supranuclear gaze palsy (VSGP), ataxia, cognitive impairment and seizures. Brain MRI in 6 patients was normal in 5 or consistent with cerebellar hemisphere atrophy in 1 of them. Two other mutations were identified in the NPC1 gene, of which p.V845Cfs*24 was novel. CONCLUSIONS: Our results revealed phenotypic heterogeneity of NPC even within the same genotype, and add to the increasingly recognized evidence that cholestatic jaundice and hepatosplenomegaly during infancy, should alert the physician for the possibility of NPC. We reported a novel mutation in the NPC1 gene further expanding its genotype.
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Enfermedad de Niemann-Pick Tipo CRESUMEN
BACKGROUND: Tyrosinemia type 1 (hepatorenal tyrosinemia, HT1) is a rare autosomal recessive inborn error of tyrosine metabolism caused by deficiency of the last enzyme in the tyrosine catabolic pathway, fumarylacetoacetate hydrolase (FAH) leading to severe hepatic, renal and peripheral nerve damage if left untreated. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. MATERIAL AND METHODS: A retrospective single center study was carried out based on the clinical and biochemical presentation, therapy and outcome of 25 Palestinian patients with HT1 diagnosed during the last 25 years. RESULTS: HT1 is not included in newborn screening program in Palestine. The mean age at diagnosis was 8 months and the main clinical manifestations were coagulopathy, hepatomegaly, splenomegaly and renal tubular dysfunction. The main biochemical abnormalities were elevated plasma tyrosine, serum transaminases and prothrombin time, and low serum phosphorous with elevated alkaline phosphatase compatible with hypophosphatemic rickets secondary to renal tubular dysfunction. All patients were treated with nitisinone. The mean duration of nitisinone treatment was 74 months and the mean dosage was 0.89 mg/kg/day. None developed HCC or neurological crisis. CONCLUSIONS: Most patients present with liver failure and renal tubular dysfunction. Nitisinone treatment was effective therapy in all patients and improved both short- and long-term prognosis of HT1. Renal tubular dysfunction improved in all patients within the first week of starting nitisinone. Early diagnosis is necessary because delay in the treatment increases the risk of progressive liver failure HCC, progressive renal disease and neuropathy.
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OBJECTIVE: To identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy. METHODS: Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients' cells and in yeast. RESULTS: Two brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (PITRM1) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. PITRM1 is a mitochondrial matrix enzyme that degrades 10-65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides ≥40 amino acids. CONCLUSION: PITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity.
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Enfermedades Cerebelosas/genética , Cerebelo/patología , Mutación con Pérdida de Función , Metaloendopeptidasas/genética , Adolescente , Edad de Inicio , Árabes/genética , Atrofia , Enfermedades Cerebelosas/enzimología , Cerebelo/enzimología , Niño , Humanos , Masculino , Mitocondrias/enzimología , Proteínas Mitocondriales/genética , Linaje , Secuenciación del Exoma , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
INTRODUCTION: Glycine encephalopathy (GE), also known as non-ketotic hyperglycinemia (NKH), is a rare inborn error of glycine metabolism caused by a defect in glycine cleavage system, a multi-enzyme complex located in mitochondrial membrane. This defect results in elevated glycine concentration in plasma and cerebrospinal fluid (CSF). Clinical manifestations vary from severe lethargy, hypoactivity and apneic episodes in the neonatal form, mild or moderate psychomotor delay and seizures in the infantile form, and abnormal behaviors, ataxia and choreoathetoid movements in late onset form. More than 50 GLDC mutations were found, reflecting large heterogeneity of the gene. METHODS: We describe the clinical, biochemical and molecular characteristics of three Palestinian siblings who have distinct clinical phenotypes. Molecular study was performed utilizing standard Polymerase Chain Reaction (PCR) amplification then direct DNA sequencing for the affected family members. RESULTS: Their phenotypes included severe symptoms in neonatal period, infantile onset of seizure and psychomotor delay and a mild late-onset form with speech delay at age 20months. All siblings were homozygous for a novel mutation Y164H in exon 4 of GLDC gene. The described novel homozygous variant in our study is predicted deleterious and pathogenic. CONCLUSIONS: This article further expands the genetic spectrum of glycine encephalopathy and adds an evidence of the clinical heterogeneity of glycine encephalopathy even in siblings with identical mutation.
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Glicina-Deshidrogenasa (Descarboxilante)/genética , Glicina-Deshidrogenasa (Descarboxilante)/metabolismo , Hiperglicinemia no Cetósica/genética , Hiperglicinemia no Cetósica/metabolismo , Mutación , Árabes , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , HermanosRESUMEN
BACKGROUND: Fanconi-Bickel syndrome (FBS, OMIM 227810) is a rare autosomal recessive disease caused by a deficiency of glucose transporter 2 (GLUT2), a member of the facilitative glucose transporter family (Santer et al. J Inherit Metab Dis 21:191-194, 1998). The typical clinical picture is characterized by hepatorenal glycogen accumulation resulting in hepato- and nephromegaly, impaired utilization of glucose and galactose, proximal renal tubular dysfunction, rickets and severe short stature. CASE PRESENTATION: We report 2 Palestinian patients from 2 families who were homozygous for the mutation p.R301X (C>T) in exon 7of GLUT2 gene. Patient 1 showed clinical and laboratory improvement with age characterized by normal growth and resolution of rickets. Patient 2 had severe phenotype characterized by progressive weight loss, persistent metabolic acidosis, marked polyuria and clinical and laboratory findings of rickets progressing to death at age 10 months. CONCLUSION: This report further expands the clinical spectrum of FBS even with identical mutations. Other yet unknown genetic, environmental or stochastic factors may be responsible for phenotypic variability.
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Síndrome de Fanconi/genética , Síndrome de Fanconi/patología , Mutación/genética , Niño , Resultado Fatal , Femenino , Hospitalización , Humanos , Lactante , Recién Nacido , Medio Oriente , FenotipoRESUMEN
We report the first Palestinian child manifesting with 3-methylglutaconic aciduria psychomotor delay, muscle hypotonia, sensori-neural deafness, and Leigh-like lesions on brain magnetic resonance imaging (MRI), a clinical phenotype that is characteristic of MEGDEL syndrome. MEGDEL syndrome was recently found to be caused by mutations in SERAC1, encoding a protein essential for mitochondrial function, phospholipid remodeling, and intracellular cholesterol trafficking. We identified a novel homozygous mutation in SERAC1 gene (c.1018delT) that generates frame shift and premature termination of protein translation. Plasma and cerebrospinal fluid lactate, plasma alanine, and respiratory chain complexes in fresh muscle were normal. This report further expands the genetic spectrum of MEGDEL syndrome and adds to the evidence that it is associated with variable patterns of respiratory chain abnormalities.
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Hidrolasas de Éster Carboxílico/genética , Pérdida Auditiva Sensorineural/genética , Enfermedad de Leigh/genética , Trastornos de la Destreza Motora/genética , Hipotonía Muscular/genética , Mutación/genética , Árabes , Consanguinidad , Pérdida Auditiva Sensorineural/complicaciones , Humanos , Lactante , Enfermedad de Leigh/complicaciones , Imagen por Resonancia Magnética , Masculino , Trastornos de la Destreza Motora/complicaciones , Hipotonía Muscular/complicacionesRESUMEN
BACKGROUND: Celiac disease (CD) is a complex autoimmune disorder that can lead to an inflammatory small intestinal villous atrophy and malabsorption. Hartnup disease is an autosomal recessive disorder caused by increased urinary excretion of neutral amino acids. Co-occurrence of Hartnup disease and CD is extremely rare with only a single case reported. CASE PRESENTATION: We report a 3-year girl with chronic diarrhea, Hypoalbuminemia and exfoliative erythema. She was diagnosed with celiac disease, which did not improve on gluten free diet. Hartnup disease was suspected and was confirmed by neutral aminoaciduria. Niacin was started and followed by dramatic improvement. CONCLUSION: Presence of Celiac and Hartnup disease in single individual is very rare. Complete nutritional assessment of refractory celiac patient can reveal underlying nutritional deficiency.
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Enfermedad Celíaca/complicaciones , Dermatitis Exfoliativa/etiología , Diarrea/etiología , Enfermedad de Hartnup/complicaciones , Hipoalbuminemia/etiología , Preescolar , Enfermedad Crónica , Eritema/etiología , Femenino , Humanos , Niacina/deficiencia , Niacina/uso terapéutico , Complejo Vitamínico B/uso terapéuticoRESUMEN
Leukoencephalopathy refers to any disease of the white matter including hereditary as well as acquired and toxic causes. Inherited leukodystrophies are diseases of myelin including abnormal myelin development, hypomyelination, or degeneration of myelin. We report a 6-year old female who presented with absence seizure at the age of 4 years. Cerebral magnetic resonance imaging (MRI) of the brain showed bilateral periventricular confluent high signal intensity. The seizure responded to anticonvulsant therapy, and the clinical course was characterized by normal development and neurological examination.
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Ethylmalonic encephalopathy (EE) is a rare autosomal recessive disorder caused by mutations in the ETHE1 gene and characterized by chronic diarrhea, encephalopathy, relapsing petechiae and acrocyanosis. Nephrotic syndrome has been described in an infant with EE but the renal histology findings were not described in previous reports. We report a Palestinian girl with EE who presented with chronic diarrhea, encephalopathy, petechial rash and acrocyanosis. Subsequently, she developed progressive deterioration of renal function caused by rapidly progressive glomerulonephritis resulting in death within few days. This is, to our knowledge, the first reported occurrence of rapidly progressive glomerulonephritis in a child with ethylmalonic encephalopathy. Its presence is a serious complication associated with poor prognosis and may be explained by the diffuse vascular damage.
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Encefalopatías Metabólicas Innatas/complicaciones , Encefalopatías Metabólicas Innatas/metabolismo , Glomerulonefritis/complicaciones , Glomerulonefritis/metabolismo , Malonatos/metabolismo , Púrpura/complicaciones , Púrpura/metabolismo , Encefalopatías Metabólicas Innatas/patología , Consanguinidad , Exantema/etiología , Resultado Fatal , Femenino , Glomerulonefritis/patología , Humanos , Lactante , Riñón/patología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/metabolismo , Mutación/genética , Mutación/fisiología , Síndrome Nefrótico/complicaciones , Linaje , Proteinuria/etiología , Proteinuria/metabolismo , Púrpura/patologíaRESUMEN
A 7-month old girl with GM1 gangliosidosis type 1 manifested with diffuse ecchymosis and Mongolian spots. The cutaneous lesions were present at birth before the appearance of the other features of the disease. We postulate that dermal pigmentation may be recognized as an early sign of GM1 gangliosidosis.
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Propionic acidemia manifesting with hyperglycemia is rare. Few cases have been reported mainly of the neonatal-onset form associated with high mortality. We report a 9-month-old Palestinian boy who manifested with coma, severe hyperglycemia and ketoacidosis mimicking diabetic ketoacidosis. Family history of unexplained infant deaths was helpful in reaching the correct diagnosis. In response to therapy, the patient regained consciousness without neurologic deficits and had normal examination. This is, to our knowledge, the first case report of late-onset propionic acidemia that had this presentation and survived.
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Cetoacidosis Diabética/diagnóstico , Acidemia Propiónica/diagnóstico , Cetoacidosis Diabética/fisiopatología , Dieta , Humanos , Lactante , Masculino , Linaje , Acidemia Propiónica/dietoterapia , Acidemia Propiónica/fisiopatologíaRESUMEN
Ethylmalonic encephalopathy is caused by mutations in ETHE1, a mitochondrial matrix sulfur dioxygenase, leading to failure to detoxify sulfide, a product of intestinal anaerobes and, in trace amounts, tissues. Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantially prolonged the lifespan of Ethe1-deficient mice, with the combined treatment being additive. The same dual treatment caused marked clinical improvement in five affected children, with hardly any adverse or side effects.
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Acetilcisteína/administración & dosificación , Encefalopatías Metabólicas Innatas/tratamiento farmacológico , Metronidazol/administración & dosificación , Acetilcisteína/efectos adversos , Administración Oral , Animales , Antiinfecciosos/administración & dosificación , Antiinfecciosos/efectos adversos , Encefalopatías Metabólicas Innatas/genética , Encefalopatías Metabólicas Innatas/metabolismo , Encefalopatías Metabólicas Innatas/mortalidad , Preescolar , Dioxigenasas/genética , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Lactante , Masculino , Malonatos/metabolismo , Metronidazol/efectos adversos , Ratones , Ratones Noqueados , Proteínas Mitocondriales/genética , Resultado del TratamientoRESUMEN
We report on a female infant with congenital iron storage disease, facial dysmorphism, intractable diarrhea, and hair abnormalities. The intractable diarrhea failed to resolve despite total parenteral nutrition and complete bowel rest for more than 3 weeks. The patient also had elevated liver enzymes and failure to thrive. Histopathologic examination of the liver revealed marked iron deposits in hepatocytes with portal edema, fibrosis, and septal formation. No metabolic abnormalities could be detected. She died at the age of 10 months. We suggest that this case could have a specific iron storage syndrome that is similar to the two sibs reported by Stankler et al. [1982; Arch Dis Child 57:212-216] and Verloes et al. [1997; Am J Med Genet 68:391-395]. The condition was called the tricho-hepato-enteric (THE) syndrome.
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Anomalías Múltiples/patología , Diarrea Infantil/patología , Cabello/anomalías , Hepatopatías/patología , Anomalías Múltiples/genética , Diagnóstico Diferencial , Cara/anomalías , Resultado Fatal , Femenino , Hemocromatosis/patología , Humanos , Lactante , Hierro/metabolismo , Cariotipificación , Hepatopatías/metabolismo , SíndromeRESUMEN
Glutaric aciduria type 1 (GA1) is a rare cerebral organic aciduria which typically manifests as an acute encephalopathic crisis followed by profound long-term neurological handicap. We report the diagnosis of 12 new patients from a single laboratory in Israel during a 5-year period. Eleven of the 12 were of Palestinian origin, and only two were related. One patient was asymptomatic whilst one was mildly, one moderately and nine severely affected, two of whom had unusual MRI findings. Two patients had normal glutaric acid excretion and normal blood glutarylcarnitine levels yet glutarylcarnitine excretion was increased, indicating its utility as a diagnostic marker. Four novel GCDH mutations (Thr193_Arg194insHis, Asn329Ser, Thr341Pro, Met405Val) and five previously reported mutations (Ser119Leu, Leu283Pro, Ala293Thr, Gly390Arg and Thr416Ile) were identified. Severely and mildly affected or even asymptomatic patients shared the same genotypes (Thr416Ile/Thre416Ile and Aal293Thr/Thr193_Arg194insHis). Knowledge of the responsible mutation enabled successful prenatal diagnosis on chorionic villous DNA in three families. In conclusion, GA1 is genetically heterogeneous and has a relatively high incidence in the Palestinian population, reflecting the historical tradition of marriages within extended kindreds, particularly in isolated villages. Additional genetic and/or environmental factors must account for the phenotypic heterogeneity in patients with the same genotype. The diagnosis was not suspected in the majority of cases despite typical clinical and/or neuroimaging features, suggesting that glutaric aciduria may be under-diagnosed. Greater awareness of glutaric aciduria amongst pediatricians, neonatologists and radiologists is the key to identifying the disorder in the presymptomatic phase and preventing its catastrophic consequences.