Efrat ben-shalom - Academia.edu (original) (raw)

Papers by Efrat ben-shalom

Pediatric Nephrology, 2015

Infections are an important cause of morbidity and mortality in solid organ transplant recipients... more Infections are an important cause of morbidity and mortality in solid organ transplant recipients. Neutrophils play a crucial role in the initial host defense against bacterial pathogens. Neutropenia is not uncommon after renal transplantation in adults; however, there are scarce published data in children. We conducted a historical cohort study to evaluate the incidence, clinical course, and management of severe neutropenia after renal transplantation in children. In a single-center study, we collected clinical and laboratory data on all children (<20 years) who underwent renal transplantation from January 2005 to March 2014. All post-transplantation blood counts were reviewed; the lowest absolute neutrophil count was recorded and correlated with clinical information and other laboratory findings. Of the 72 patients studied, 46 (64 %) had at least one episode of neutropenia [absolute neutrophil count (ANC) <1500/μl] during the study period, 16 of whom (22 %) had severe neutropenia (ANC < 500/μl), 2-11 months (median, 3.5) after renal transplantation. Work-up for viral infection or malignancy was performed. Initial management included dose decrease and subsequent discontinuation of antimetabolite, stopping co-trimoxazole and valganciclovir. Bone marrow aspiration in four children revealed normal marrow cellularity in all cases, with myelocyte maturational arrest in two. Eight children (11 %) were treated with granulocyte colony-stimulating factor (G-CSF) (5 mcg/kg/day) 1-4 doses (median, 2), with excellent response in all and no adverse effects. Eight children presented with fever during severe neutropenia, and were treated with empiric antibiotics. Mycophenolate/azathioprine were resumed in all patients unless contraindicated (pre-existing BK viremia -1, PTLD -1). Recurrence of neutropenia was seen in five patients, only one of whom required further treatment with G-CSF. Graft function was preserved during and after resolution of neutropenia. Post-transplant neutropenia in children is common, and mostly occurs in the first few months. Its etiology is probably primarily a result of the combination of immunosuppressive agents and prophylactic treatment of infections in the early post-transplant period. Decreasing immunosuppressive or antimicrobial medications carries the risk of acute rejection or infection. Off-label treatment with G-CSF may present a safe and effective alternative.

Pediatric Nephrology, 2014

Primary hyperoxalurias (PH) comprise a group of three distinct metabolic diseases caused by deran... more Primary hyperoxalurias (PH) comprise a group of three distinct metabolic diseases caused by derangement of glyoxylate metabolism in the liver. Recent years have seen advances in several aspects of PH research. This paper reviews current knowledge of the genetic and biochemical basis of PH, the specific epidemiology and clinical presentation of each type, and therapeutic approaches in different disease stages. Potential future specific therapies are discussed.

Pediatric Nephrology, 2014

Central venous catheters are frequently used as access for hemodialysis (HD) in children. One of ... more Central venous catheters are frequently used as access for hemodialysis (HD) in children. One of the known complications is central venous stenosis. Although this complication is not rare, it is often asymptomatic and therefore unacknowledged. Superior vena cava (SVC) stenosis is obviously suspected in the presence of upper body edema, but several other signs and symptoms are often unrecognized as being part of this syndrome. We describe four patients with various manifestations of central venous stenosis and SVC syndrome. These sometimes life- or organ-threatening conditions include obstructive sleep apnea, unresolving stridor, increased intracranial pressure, increased intraocular pressure, right-sided pleural effusion, protein-losing enteropathy and lymphadenopathy. The temporal relationship of these complications associated with the use of central venous catheters and documentation of venous stenosis, together with their resolution after alleviation of high venous pressure, points to a causal role. We suggest pathophysiological mechanisms for the formation of each of these complications. In patients with occlusion of the SVC, various unexpected clinical entities can be caused by high central venous pressure. As often the etiology is not obvious, a high index of suspicion is needed as in some cases prompt alleviation of the high pressure is mandatory.

Pediatric Nephrology, 2009

Dent&... more Dent's disease is an X-linked proximal tubulopathy. It often manifests in childhood with symptoms of Fanconi syndrome and low-molecular-weight proteinuria. We describe four boys from three unrelated families whose only presenting symptoms of Dent's disease were nephrotic-range proteinuria and histological findings of focal segmental and/or global glomerulosclerosis. In all families, a causal mutation in the CLCN5 gene, encoding a voltage-gated chloride transporter and chloride-proton exchanger, was identified. All three mutations are pathogenic: two are novel (p.Asp727fs and p.Trp122X), and one is a recurrent mutation, p.R648X. Given the atypical phenotype of these patients with Dent's disease, it is possible that this clinical entity is markedly underdiagnosed and that our report represents only the tip of the iceberg. The diagnosis of Dent's disease should be considered in all patients with nephrotic-range proteinuria without hypoalbuminemia or edema. Establishing the diagnosis of Dent's disease will prevent the administration of unnecessary immunosuppressive medications with their undesirable side effects.

Pediatric Nephrology, 2009

Congenital analbuminemia is a rare autosomal recessive disease in which albumin is not synthesize... more Congenital analbuminemia is a rare autosomal recessive disease in which albumin is not synthesized. Patients with this disorder generally have minimal symptoms despite complete absence of the most abundant serum protein. We report a family in which the proband presented with acute glomerulonephritis and was found to have underlying congenital analbuminemia. Consequently, the patient's two older sisters were diagnosed with the same condition. Sequencing of the human serum albumin gene was performed, and a homozygous mutation in exon 3 was found in all three patients. Together with these three patients of Arab ethnicity, this mutation, known as Kayseri, is the most frequently described mutation in congenital analbuminemia. This article discusses clinical features and diagnostic challenges of this disorder, particularly in this case, where concomitant renal disease was present.

Pediatric Nephrology, 2008

Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular disease, and it is prevale... more Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular disease, and it is prevalent in children with end-stage renal disease (ESRD) and after renal transplantation (RTx) on cross-sectional studies. Our aim was to compare prospectively left ventricular mass index (LVMI) in children with ESRD, before and after RTx. Thirteen patients aged 1.5-15 years underwent echocardiogram prior to and at least 3 months after RTx, and again in the second year after transplantation. A control group consisted of children with ESRD who remained on dialysis. Systolic and diastolic blood pressure index decreased significantly over the study period only in the children who had undergone RTx. Mean LVMI in children with ESRD decreased from 45.4±12.6 g/m 2.7 to 34.9±10.4 g/m 2.7 after RTx (P=0.001), but it remained unchanged in patients who remained on dialysis. The prevalence of LVH decreased from 54% to 8% (P=0.03) after RTx. Systolic and diastolic blood pressure index were correlated with LVMI. Mean body mass index increased during the study period from 17.3±2.5 to 20±4.6 (P=0.05); however, no correlation was found with LVMI. LVH in children with ESRD is potentially reversible after RTx, especially with good control of hypertension.

Nephrology Dialysis Transplantation, 2008

Background. Improvements in dialysis technology allow replacement therapy for even the youngest o... more Background. Improvements in dialysis technology allow replacement therapy for even the youngest of children with end stage renal disease. Nevertheless, the cumulative experience in this age group is limited. Methods. We compared the outcome of 20 children who initiated chronic dialysis before the age of 1 year (weight 4.9 ± 2 kg, Group 1), with a particular focus on those under the age of 1 month (eight children, weight 2.9 ± 0.34), to that of 14 patients, aged 1.1-3 years when starting dialysis (weight 10.1 ± 1.7, Group 2). Results. The outcome was poor in the youngest age group; only 3/8 survived to 3 years. Of those who started dialysis between the ages of 0.3 and 3 years, 84% underwent kidney transplantation. The survival of 1-, 3-, 5-and 8-year-old patients was 96%, 88%, 84% and 84% respectively. Severe co-morbidities were present in almost half of those who died. Hospital stay was 3.5 times longer in Group 1 than in Group 2 during the first 3 months of dialysis. Permanent central venous catheters inserted under ultrasound guidance resulted in a 4.4-fold increase in catheter survival compared to non-cuffed catheters. Marked blood loss at beginning of haemodialysis (HD) is attributable to residual volume in the dialysis system (15.7 mL/kg/month) and frequent blood tests (12.1 ± 5.9 mL/kg/month). These values decreased 2-fold after 8 months of treatment. Conclusions. The main factors determining the poor outcome of infants on dialysis are extremely young age at initiation and severe co-morbidities. Despite some disadvantages, HD may be successfully implemented in infants and toddlers, in highly specialized centres with a well-trained nursing staff.

Molecular Genetics and Metabolism, 2002

In an infant who suffered from prolonged icterus and hepatocellular dysfunction we detected an in... more In an infant who suffered from prolonged icterus and hepatocellular dysfunction we detected an increase of citrulline and dibasic amino acids in plasma and urine. The amino acid levels along with all the abnormal liver tests normalized upon replacing breastmilk by formula feeding; there was no relapse after human milk was tentatively reintroduced. A novel mutation, a $9.5-kb genomic duplication, was identified in the citrin gene (SLC25A13) resulting in the insertion of exon 15. No mutation was detected in the CAT2A specific exon of the SLC7A2 gene which encodes for the liver transporter of cationic amino acids. This is the first report of infantile citrin deficiency in non-Asian patients.

Bioorganic & Medicinal Chemistry, 2007

Selective and effective TK2 inhibitors can be obtained by introduction of bulky lipophilic chains... more Selective and effective TK2 inhibitors can be obtained by introduction of bulky lipophilic chains (acyl or alkyl entities) at the 2' position of araT and BVaraU, nucleoside analogues naturally endowed with a low TK2 affinity. These derivatives showed a competitive inhibitory activity against TK2 in micromolar range. BVaraU nucleoside analogues, modified on the 2'-O-acyl chain with a terminal N-Boc amino-group, conserved or increased the inhibitory activity against TK2 (7l and 7m IC(50): 6.4 and 3.8 microM, respectively). The substitution of an ester for a carboxamide moiety at the 2' position of araT afforded a consistent reduction of the inhibitory activity (25, IC(50): 480 microM). On the contrary, modifications at 2'-OH position of araC and araG, have provided inactive derivatives against TK2 and dGK, respectively. The biological activity of a representative compound, 2'-O-decanoyl-BVaraU, was also investigated in normal human fibroblasts and was found to impair mitochondrial function due to TK2 inhibition.

Biochemical and Biophysical Research Communications, 2003

Deficiency of mitochondrial thymidine kinase (TK2) is associated with mitochondrial DNA (mtDNA) d... more Deficiency of mitochondrial thymidine kinase (TK2) is associated with mitochondrial DNA (mtDNA) depletion and manifests by severe skeletal myopathy in infancy. In order to elucidate the pathophysiology of this condition, mitochondrial deoxyribonucleoside triphosphate (dNTP) pools were determined in patients' fibroblasts. Despite normal mtDNA content and cytochrome c oxidase (COX) activity, mitochondrial dNTP pools were imbalanced. Specifically, deoxythymidine triphosphate (dTTP) content was markedly decreased, resulting in reduced dTTP:deoxycytidine triphosphate ratio. These findings underline the importance of balanced mitochondrial dNTP pools for mtDNA synthesis and may serve as the basis for future therapeutic interventions.

Annals of Neurology, 2004

The mitochondrial respiratory chain comprises 85 subunits, 13 of which are mitochondrial encoded.... more The mitochondrial respiratory chain comprises 85 subunits, 13 of which are mitochondrial encoded. The synthesis of these 13 proteins requires many nuclear-encoded proteins that participate in mitochondrial DNA replication, transcript production, and a distinctive mitochondrial translation apparatus. We report a patient with agenesis of corpus callosum, dysmorphism, and fatal neonatal lactic acidosis with markedly decreased complex I and IV activity in muscle and liver and a generalized mitochondrial translation defect identified in pulse-label experiments. The defect was associated with marked reduction of the 12S rRNA transcript level likely attributed to a nonsense mutation in the MRPS16 gene. A new group of mitochondrial respiratory chain disorders is proposed, resulting from mutations in nuclear encoded components of the mitochondrial translation apparatus.

Annals of Neurology, 2002

Carbamylphosphate synthase is the first enzymatic reaction of the urea cycle. Its activator, N-ac... more Carbamylphosphate synthase is the first enzymatic reaction of the urea cycle. Its activator, N-acetylglutamate, is synthesized from acetyl-CoA and glutamate in a reaction catalyzed by N-acetylglutamate synthase (NAGS). We have identified the putative human NAGS gene and report the first mutation in this gene in a family with carbamylglutamate responsive hyperammonemia and normal activity of the urea cycle enzymes. Mutation analysis has a higher diagnostic specificity than the enzymatic assay in NAGS deficiency. A therapeutic trial with carbamylglutamate is recommended whenever hyperammonemia without an organic aciduria, increased orotate excretion, or diagnostic amino acidemia/uria is detected.

The American Journal of Human Genetics, 2011

The American Journal of Human Genetics, 2010

Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis cha... more Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respectively). To determine the etiology of an as yet uncharacterized type of PH, we selected a cohort of 15 non-PH I/PH II patients from eight unrelated families with calcium oxalate nephrolithiasis for high-density SNP microarray analysis. We determined that mutations in an uncharacterized gene, DHDPSL, on chromosome 10 cause a third type of PH (PH III). To overcome the difficulties in data analysis attributed to a state of compound heterozygosity, we developed a strategy of "heterozygosity mapping"-a search for long heterozygous patterns unique to all patients in a given family and overlapping between families, followed by reconstruction of haplotypes. This approach enabled us to determine an allelic fragment shared by all patients of Ashkenazi Jewish descent and bearing a 3 bp deletion in DHDPSL. Overall, six mutations were detected: four missense mutations, one in-frame deletion, and one splice-site mutation. Our assumption is that DHDPSL is the gene encoding 4-hydroxy-2-oxoglutarate aldolase, catalyzing the final step in the metabolic pathway of hydroxyproline.

Pediatric Nephrology, 2015

Infections are an important cause of morbidity and mortality in solid organ transplant recipients... more Infections are an important cause of morbidity and mortality in solid organ transplant recipients. Neutrophils play a crucial role in the initial host defense against bacterial pathogens. Neutropenia is not uncommon after renal transplantation in adults; however, there are scarce published data in children. We conducted a historical cohort study to evaluate the incidence, clinical course, and management of severe neutropenia after renal transplantation in children. In a single-center study, we collected clinical and laboratory data on all children (<20 years) who underwent renal transplantation from January 2005 to March 2014. All post-transplantation blood counts were reviewed; the lowest absolute neutrophil count was recorded and correlated with clinical information and other laboratory findings. Of the 72 patients studied, 46 (64 %) had at least one episode of neutropenia [absolute neutrophil count (ANC) <1500/μl] during the study period, 16 of whom (22 %) had severe neutropenia (ANC < 500/μl), 2-11 months (median, 3.5) after renal transplantation. Work-up for viral infection or malignancy was performed. Initial management included dose decrease and subsequent discontinuation of antimetabolite, stopping co-trimoxazole and valganciclovir. Bone marrow aspiration in four children revealed normal marrow cellularity in all cases, with myelocyte maturational arrest in two. Eight children (11 %) were treated with granulocyte colony-stimulating factor (G-CSF) (5 mcg/kg/day) 1-4 doses (median, 2), with excellent response in all and no adverse effects. Eight children presented with fever during severe neutropenia, and were treated with empiric antibiotics. Mycophenolate/azathioprine were resumed in all patients unless contraindicated (pre-existing BK viremia -1, PTLD -1). Recurrence of neutropenia was seen in five patients, only one of whom required further treatment with G-CSF. Graft function was preserved during and after resolution of neutropenia. Post-transplant neutropenia in children is common, and mostly occurs in the first few months. Its etiology is probably primarily a result of the combination of immunosuppressive agents and prophylactic treatment of infections in the early post-transplant period. Decreasing immunosuppressive or antimicrobial medications carries the risk of acute rejection or infection. Off-label treatment with G-CSF may present a safe and effective alternative.

Pediatric Nephrology, 2014

Primary hyperoxalurias (PH) comprise a group of three distinct metabolic diseases caused by deran... more Primary hyperoxalurias (PH) comprise a group of three distinct metabolic diseases caused by derangement of glyoxylate metabolism in the liver. Recent years have seen advances in several aspects of PH research. This paper reviews current knowledge of the genetic and biochemical basis of PH, the specific epidemiology and clinical presentation of each type, and therapeutic approaches in different disease stages. Potential future specific therapies are discussed.

Pediatric Nephrology, 2014

Central venous catheters are frequently used as access for hemodialysis (HD) in children. One of ... more Central venous catheters are frequently used as access for hemodialysis (HD) in children. One of the known complications is central venous stenosis. Although this complication is not rare, it is often asymptomatic and therefore unacknowledged. Superior vena cava (SVC) stenosis is obviously suspected in the presence of upper body edema, but several other signs and symptoms are often unrecognized as being part of this syndrome. We describe four patients with various manifestations of central venous stenosis and SVC syndrome. These sometimes life- or organ-threatening conditions include obstructive sleep apnea, unresolving stridor, increased intracranial pressure, increased intraocular pressure, right-sided pleural effusion, protein-losing enteropathy and lymphadenopathy. The temporal relationship of these complications associated with the use of central venous catheters and documentation of venous stenosis, together with their resolution after alleviation of high venous pressure, points to a causal role. We suggest pathophysiological mechanisms for the formation of each of these complications. In patients with occlusion of the SVC, various unexpected clinical entities can be caused by high central venous pressure. As often the etiology is not obvious, a high index of suspicion is needed as in some cases prompt alleviation of the high pressure is mandatory.

Pediatric Nephrology, 2009

Dent&... more Dent's disease is an X-linked proximal tubulopathy. It often manifests in childhood with symptoms of Fanconi syndrome and low-molecular-weight proteinuria. We describe four boys from three unrelated families whose only presenting symptoms of Dent's disease were nephrotic-range proteinuria and histological findings of focal segmental and/or global glomerulosclerosis. In all families, a causal mutation in the CLCN5 gene, encoding a voltage-gated chloride transporter and chloride-proton exchanger, was identified. All three mutations are pathogenic: two are novel (p.Asp727fs and p.Trp122X), and one is a recurrent mutation, p.R648X. Given the atypical phenotype of these patients with Dent's disease, it is possible that this clinical entity is markedly underdiagnosed and that our report represents only the tip of the iceberg. The diagnosis of Dent's disease should be considered in all patients with nephrotic-range proteinuria without hypoalbuminemia or edema. Establishing the diagnosis of Dent's disease will prevent the administration of unnecessary immunosuppressive medications with their undesirable side effects.

Pediatric Nephrology, 2009

Congenital analbuminemia is a rare autosomal recessive disease in which albumin is not synthesize... more Congenital analbuminemia is a rare autosomal recessive disease in which albumin is not synthesized. Patients with this disorder generally have minimal symptoms despite complete absence of the most abundant serum protein. We report a family in which the proband presented with acute glomerulonephritis and was found to have underlying congenital analbuminemia. Consequently, the patient's two older sisters were diagnosed with the same condition. Sequencing of the human serum albumin gene was performed, and a homozygous mutation in exon 3 was found in all three patients. Together with these three patients of Arab ethnicity, this mutation, known as Kayseri, is the most frequently described mutation in congenital analbuminemia. This article discusses clinical features and diagnostic challenges of this disorder, particularly in this case, where concomitant renal disease was present.

Pediatric Nephrology, 2008

Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular disease, and it is prevale... more Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular disease, and it is prevalent in children with end-stage renal disease (ESRD) and after renal transplantation (RTx) on cross-sectional studies. Our aim was to compare prospectively left ventricular mass index (LVMI) in children with ESRD, before and after RTx. Thirteen patients aged 1.5-15 years underwent echocardiogram prior to and at least 3 months after RTx, and again in the second year after transplantation. A control group consisted of children with ESRD who remained on dialysis. Systolic and diastolic blood pressure index decreased significantly over the study period only in the children who had undergone RTx. Mean LVMI in children with ESRD decreased from 45.4±12.6 g/m 2.7 to 34.9±10.4 g/m 2.7 after RTx (P=0.001), but it remained unchanged in patients who remained on dialysis. The prevalence of LVH decreased from 54% to 8% (P=0.03) after RTx. Systolic and diastolic blood pressure index were correlated with LVMI. Mean body mass index increased during the study period from 17.3±2.5 to 20±4.6 (P=0.05); however, no correlation was found with LVMI. LVH in children with ESRD is potentially reversible after RTx, especially with good control of hypertension.

Nephrology Dialysis Transplantation, 2008

Background. Improvements in dialysis technology allow replacement therapy for even the youngest o... more Background. Improvements in dialysis technology allow replacement therapy for even the youngest of children with end stage renal disease. Nevertheless, the cumulative experience in this age group is limited. Methods. We compared the outcome of 20 children who initiated chronic dialysis before the age of 1 year (weight 4.9 ± 2 kg, Group 1), with a particular focus on those under the age of 1 month (eight children, weight 2.9 ± 0.34), to that of 14 patients, aged 1.1-3 years when starting dialysis (weight 10.1 ± 1.7, Group 2). Results. The outcome was poor in the youngest age group; only 3/8 survived to 3 years. Of those who started dialysis between the ages of 0.3 and 3 years, 84% underwent kidney transplantation. The survival of 1-, 3-, 5-and 8-year-old patients was 96%, 88%, 84% and 84% respectively. Severe co-morbidities were present in almost half of those who died. Hospital stay was 3.5 times longer in Group 1 than in Group 2 during the first 3 months of dialysis. Permanent central venous catheters inserted under ultrasound guidance resulted in a 4.4-fold increase in catheter survival compared to non-cuffed catheters. Marked blood loss at beginning of haemodialysis (HD) is attributable to residual volume in the dialysis system (15.7 mL/kg/month) and frequent blood tests (12.1 ± 5.9 mL/kg/month). These values decreased 2-fold after 8 months of treatment. Conclusions. The main factors determining the poor outcome of infants on dialysis are extremely young age at initiation and severe co-morbidities. Despite some disadvantages, HD may be successfully implemented in infants and toddlers, in highly specialized centres with a well-trained nursing staff.

Molecular Genetics and Metabolism, 2002

In an infant who suffered from prolonged icterus and hepatocellular dysfunction we detected an in... more In an infant who suffered from prolonged icterus and hepatocellular dysfunction we detected an increase of citrulline and dibasic amino acids in plasma and urine. The amino acid levels along with all the abnormal liver tests normalized upon replacing breastmilk by formula feeding; there was no relapse after human milk was tentatively reintroduced. A novel mutation, a $9.5-kb genomic duplication, was identified in the citrin gene (SLC25A13) resulting in the insertion of exon 15. No mutation was detected in the CAT2A specific exon of the SLC7A2 gene which encodes for the liver transporter of cationic amino acids. This is the first report of infantile citrin deficiency in non-Asian patients.

Bioorganic & Medicinal Chemistry, 2007

Selective and effective TK2 inhibitors can be obtained by introduction of bulky lipophilic chains... more Selective and effective TK2 inhibitors can be obtained by introduction of bulky lipophilic chains (acyl or alkyl entities) at the 2' position of araT and BVaraU, nucleoside analogues naturally endowed with a low TK2 affinity. These derivatives showed a competitive inhibitory activity against TK2 in micromolar range. BVaraU nucleoside analogues, modified on the 2'-O-acyl chain with a terminal N-Boc amino-group, conserved or increased the inhibitory activity against TK2 (7l and 7m IC(50): 6.4 and 3.8 microM, respectively). The substitution of an ester for a carboxamide moiety at the 2' position of araT afforded a consistent reduction of the inhibitory activity (25, IC(50): 480 microM). On the contrary, modifications at 2'-OH position of araC and araG, have provided inactive derivatives against TK2 and dGK, respectively. The biological activity of a representative compound, 2'-O-decanoyl-BVaraU, was also investigated in normal human fibroblasts and was found to impair mitochondrial function due to TK2 inhibition.

Biochemical and Biophysical Research Communications, 2003

Deficiency of mitochondrial thymidine kinase (TK2) is associated with mitochondrial DNA (mtDNA) d... more Deficiency of mitochondrial thymidine kinase (TK2) is associated with mitochondrial DNA (mtDNA) depletion and manifests by severe skeletal myopathy in infancy. In order to elucidate the pathophysiology of this condition, mitochondrial deoxyribonucleoside triphosphate (dNTP) pools were determined in patients' fibroblasts. Despite normal mtDNA content and cytochrome c oxidase (COX) activity, mitochondrial dNTP pools were imbalanced. Specifically, deoxythymidine triphosphate (dTTP) content was markedly decreased, resulting in reduced dTTP:deoxycytidine triphosphate ratio. These findings underline the importance of balanced mitochondrial dNTP pools for mtDNA synthesis and may serve as the basis for future therapeutic interventions.

Annals of Neurology, 2004

The mitochondrial respiratory chain comprises 85 subunits, 13 of which are mitochondrial encoded.... more The mitochondrial respiratory chain comprises 85 subunits, 13 of which are mitochondrial encoded. The synthesis of these 13 proteins requires many nuclear-encoded proteins that participate in mitochondrial DNA replication, transcript production, and a distinctive mitochondrial translation apparatus. We report a patient with agenesis of corpus callosum, dysmorphism, and fatal neonatal lactic acidosis with markedly decreased complex I and IV activity in muscle and liver and a generalized mitochondrial translation defect identified in pulse-label experiments. The defect was associated with marked reduction of the 12S rRNA transcript level likely attributed to a nonsense mutation in the MRPS16 gene. A new group of mitochondrial respiratory chain disorders is proposed, resulting from mutations in nuclear encoded components of the mitochondrial translation apparatus.

Annals of Neurology, 2002

Carbamylphosphate synthase is the first enzymatic reaction of the urea cycle. Its activator, N-ac... more Carbamylphosphate synthase is the first enzymatic reaction of the urea cycle. Its activator, N-acetylglutamate, is synthesized from acetyl-CoA and glutamate in a reaction catalyzed by N-acetylglutamate synthase (NAGS). We have identified the putative human NAGS gene and report the first mutation in this gene in a family with carbamylglutamate responsive hyperammonemia and normal activity of the urea cycle enzymes. Mutation analysis has a higher diagnostic specificity than the enzymatic assay in NAGS deficiency. A therapeutic trial with carbamylglutamate is recommended whenever hyperammonemia without an organic aciduria, increased orotate excretion, or diagnostic amino acidemia/uria is detected.

The American Journal of Human Genetics, 2011

The American Journal of Human Genetics, 2010

Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis cha... more Primary hyperoxaluria (PH) is an autosomal-recessive disorder of endogenous oxalate synthesis characterized by accumulation of calcium oxalate primarily in the kidney. Deficiencies of alanine-glyoxylate aminotransferase (AGT) or glyoxylate reductase (GRHPR) are the two known causes of the disease (PH I and II, respectively). To determine the etiology of an as yet uncharacterized type of PH, we selected a cohort of 15 non-PH I/PH II patients from eight unrelated families with calcium oxalate nephrolithiasis for high-density SNP microarray analysis. We determined that mutations in an uncharacterized gene, DHDPSL, on chromosome 10 cause a third type of PH (PH III). To overcome the difficulties in data analysis attributed to a state of compound heterozygosity, we developed a strategy of "heterozygosity mapping"-a search for long heterozygous patterns unique to all patients in a given family and overlapping between families, followed by reconstruction of haplotypes. This approach enabled us to determine an allelic fragment shared by all patients of Ashkenazi Jewish descent and bearing a 3 bp deletion in DHDPSL. Overall, six mutations were detected: four missense mutations, one in-frame deletion, and one splice-site mutation. Our assumption is that DHDPSL is the gene encoding 4-hydroxy-2-oxoglutarate aldolase, catalyzing the final step in the metabolic pathway of hydroxyproline.