shanti balasubramaniam - Academia.edu (original) (raw)

Papers by shanti balasubramaniam

Research paper thumbnail of Barth syndrome with severe dilated cardiomyopathy and growth hormone resistance: a case report

Journal of Pediatric Endocrinology and Metabolism

Objectives To describe the metabolic and endocrine features of a patient with Barth syndrome who ... more Objectives To describe the metabolic and endocrine features of a patient with Barth syndrome who showed evidence of growth hormone resistance. Case presentation A male proband deteriorated rapidly with lactic acidosis after a circumcision at age three weeks and was found to have severe dilated cardiomyopathy. A cardiomyopathy gene panel led to the diagnosis of TAZ-deficiency Barth syndrome. He subsequently experienced hypotonia and gross motor delay, feeding difficulties for the first four years, constitutional growth delay and one episode of ketotic hypoglycaemia. Cardiomyopathy resolved on oral anti-failure therapy by age three years. He had a hormonal pattern of growth hormone resistance, and growth hormone treatment was considered, however height velocity improved spontaneously after age 3½ years. He also had biochemical primary hypothyroidism. Conclusions With careful metabolic management with l-arginine supplementation, overnight corn starch, and a prescribed exercise program,...

Research paper thumbnail of Faculty Opinions recommendation of Genomics and newborn screening: perspectives of public health programs

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Research paper thumbnail of Multi-omics approach characterises CRLS1 deficiency, a novel mitochondrial disorder

Research paper thumbnail of COX16 deficiency causes a novel mitochondrial disorder with lethal infantile presentation and complex IV deficiency

Research paper thumbnail of Teaching NeuroImage: Bilateral Nucleus Tractus Solitarius Lesions in Neurogenic Respiratory Failure

Neurology, 2021

The authors report no targeted funding Disclosures: B.Parayil Sankaran reports receipt of the cli... more The authors report no targeted funding Disclosures: B.Parayil Sankaran reports receipt of the clinical research fellowship from Mito Foundation Australia. S.B Wortmann reports no disclosures relevant to the manuscript.M.A Willemsen reports no disclosures relevant to the manuscript. S.Balalsubramaniam reports no disclosures relevant to the manuscript.

Research paper thumbnail of Functional consequences of bi-allelic PNPT1 variants associated with multisystemic disease

European Journal of Human Genetics, 2019

Research paper thumbnail of Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning

International Journal of Neonatal Screening, 2021

Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenas... more Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT genes result in enzyme deficiency. We report the case of a female infant who presented with mild gross motor delay at 4 months, and seizures with hypoglycaemia at 5 months. Newborn screening returned total leucine/isoleucine at the 99.5th centile of the population; however, as second-tier testing reported minimal alloisoleucine, the results were considered inconsistent with MSUD. Plasma amino acid and urine organic acid analyses at 5 months were, however, consistent with a diagnosis of MSUD. A brain MRI showed bilateral symmetrical T2 hyperintense signal abnormalities involving white matter, globus pallidus, thalamus, brainstem, and dentate nuclei with restricted diffusion. A repeat MRI 10 months post-dietary-intervention showed the resolution of these changes and pr...

Research paper thumbnail of The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease

Genetics in Medicine, 2020

The utility of genome sequencing (GS) in the diagnosis of suspected pediatric mitochondrial disea... more The utility of genome sequencing (GS) in the diagnosis of suspected pediatric mitochondrial disease (MD) was investigated. Methods: An Australian cohort of 40 pediatric patients with clinical features suggestive of MD were classified using the modified Nijmegen mitochondrial disease severity scoring into definite (17), probable (17), and possible (6) MD groups. Trio GS was performed using DNA extracted from patient and parent blood. Data were analyzed for single-nucleotide variants, indels, mitochondrial DNA variants, and structural variants. Results: A definitive MD gene molecular diagnosis was made in 15 cases and a likely MD molecular diagnosis in a further five cases. Causative mitochondrial DNA (mtDNA) variants were identified in four of these cases. Three potential novel MD genes were identified. In seven cases, causative variants were identified in known disease genes with no previous evidence of causing a primary MD. Diagnostic rates were higher in patients classified as having definite MD. Conclusion: GS efficiently identifies variants in MD genes of both nuclear and mitochondrial origin. A likely molecular diagnosis was identified in 67% of cases and a definitive molecular diagnosis achieved in 55% of cases. This study highlights the value of GS for a phenotypically and genetically heterogeneous disorder like MD.

Research paper thumbnail of Faculty Opinions recommendation of EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, 2017

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations... more Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities.

Research paper thumbnail of F1000Prime recommendation of Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

F1000 - Post-publication peer review of the biomedical literature, 2020

Research paper thumbnail of F1000Prime recommendation of The diagnosis of inborn errors of metabolism by an integrative "multi-omics" approach: A perspective encompassing genomics, transcriptomics, and proteomics

F1000 - Post-publication peer review of the biomedical literature, 2019

Research paper thumbnail of Ketogenic diet, a potentially valuable therapeutic option for the management of refractory epilepsy in classical neonatal nonketotic hyperglycinemia: a case report

European Journal of Clinical Nutrition, 2018

Nonketotic hyperglycinemia (NKH) is a devastating inborn error of glycine metabolism caused by de... more Nonketotic hyperglycinemia (NKH) is a devastating inborn error of glycine metabolism caused by deficient activity of the glycine cleavage enzyme. Classically, patients present with lethargy, hypotonia, myoclonic jerks, transient respiratory depression in the first week of life and often progress to death. Surviving infants have profound psychomotor retardation, refractory epilepsy and poor quality of life. Currently, no effective therapeutic avenues exist for severe NKH. Ketogenic diet (KD) has been trialled only in a small group of patients with neonatal NKH and early myoclonic encephalopathy, in whom significant improvements in seizure control were reported. We describe an infant with classical neonatal NKH who presented on the third day of life with hypotonia, poor feeding, respiratory insufficiency resulting in ventilatory support and seizures with burst-suppression pattern on electroencephalogram (EEG). KD initiated at age 6 months for intractable seizures, lead to a dramatic decrease in seizure frequency, EEG improvements, normalisation of plasma glycine levels, reduced spasticity and improved quality of life. KD may be a valuable treatment modality for refractory seizure control in classical NKH.

Research paper thumbnail of Faculty of 1000 evaluation for Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

F1000 - Post-publication peer review of the biomedical literature, 2016

Research paper thumbnail of Faculty of 1000 evaluation for Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia

F1000 - Post-publication peer review of the biomedical literature, 2015

Research paper thumbnail of Biochemical evaluation of an infant with hypoglycemia resulting from a novel de novo mutation of the GLUD1 gene and hyperinsulinism-hyperammonemia syndrome

Journal of Pediatric Endocrinology and Metabolism, 2011

Hyperinsulinism-hyperammonemia syndrome (HI/HA) (OMIM 606762), the second most common form of con... more Hyperinsulinism-hyperammonemia syndrome (HI/HA) (OMIM 606762), the second most common form of congenital hyperinsulinism (CHI) is associated with activating missense mutations in the GLUD1 gene, which encodes the mitochondrial matrix enzyme, glutamate dehydrogenase (GDH). Patients present with recurrent symptomatic postprandial hypoglycemia following protein-rich meals (leucine-sensitive hypoglycemia) as well as fasting hypoglycemia accompanied by asymptomatic elevations of plasma ammonia. In contrast to other forms of CHI, the phenotype is reported to be milder thus escaping recognition for the first few months of life. Early diagnosis and appropriate management are essential to avoid the neurodevelopmental consequences including epilepsy and learning disabilities which are prevalent in this disorder. We report an infant presenting with afebrile seizures secondary to hyperinsulinemic hypoglycemia resulting from a novel de novo mutation of the GLUD1 gene.

Research paper thumbnail of Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5′-phosphate availability

Journal of Inherited Metabolic Disease, 2010

We describe two neonates presenting with perinatal hypophosphatasia and severe epileptic encephal... more We describe two neonates presenting with perinatal hypophosphatasia and severe epileptic encephalopathy resulting in death. Both had increased levels of urinary vanillactate, indicating functional deficiency of aromatic amino acid decarboxylase, a pyridoxal-5-phosphate (PLP)-dependent enzyme required for dopamine and serotonin biosynthesis. Clinical findings and results of subsequent metabolic investigations were consistent with secondary pyridoxine-deficient encephalopathy. These patients highlight the importance of tissue non-specific alkaline phosphatase in the neuronal PLP-dependent metabolism of neurotransmitters. In addition, the disturbance of PLP metabolism appears to underlie the predominant neurological presentation in our patients. We recommend the measurement of serum alkaline phosphatase (ALP) during the assessment of perinatal seizures.

Research paper thumbnail of Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management

Journal of Inherited Metabolic Disease, 2012

Research paper thumbnail of Treatment of Lesch–Nyhan disease with S-adenosylmethionine: Experience with five young Malaysians, including a girl

Brain and Development, 2014

Research paper thumbnail of Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function

The American Journal of Human Genetics, 2011

Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfe... more Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.

Research paper thumbnail of Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease

Human Molecular Genetics, 2022

Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical ... more Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical presentations. Here, we report four individuals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected individuals had a similar infantile presentation comprising progressive encephalopathy, bull’s eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected individual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibrob...

Research paper thumbnail of Barth syndrome with severe dilated cardiomyopathy and growth hormone resistance: a case report

Journal of Pediatric Endocrinology and Metabolism

Objectives To describe the metabolic and endocrine features of a patient with Barth syndrome who ... more Objectives To describe the metabolic and endocrine features of a patient with Barth syndrome who showed evidence of growth hormone resistance. Case presentation A male proband deteriorated rapidly with lactic acidosis after a circumcision at age three weeks and was found to have severe dilated cardiomyopathy. A cardiomyopathy gene panel led to the diagnosis of TAZ-deficiency Barth syndrome. He subsequently experienced hypotonia and gross motor delay, feeding difficulties for the first four years, constitutional growth delay and one episode of ketotic hypoglycaemia. Cardiomyopathy resolved on oral anti-failure therapy by age three years. He had a hormonal pattern of growth hormone resistance, and growth hormone treatment was considered, however height velocity improved spontaneously after age 3½ years. He also had biochemical primary hypothyroidism. Conclusions With careful metabolic management with l-arginine supplementation, overnight corn starch, and a prescribed exercise program,...

Research paper thumbnail of Faculty Opinions recommendation of Genomics and newborn screening: perspectives of public health programs

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

Research paper thumbnail of Multi-omics approach characterises CRLS1 deficiency, a novel mitochondrial disorder

Research paper thumbnail of COX16 deficiency causes a novel mitochondrial disorder with lethal infantile presentation and complex IV deficiency

Research paper thumbnail of Teaching NeuroImage: Bilateral Nucleus Tractus Solitarius Lesions in Neurogenic Respiratory Failure

Neurology, 2021

The authors report no targeted funding Disclosures: B.Parayil Sankaran reports receipt of the cli... more The authors report no targeted funding Disclosures: B.Parayil Sankaran reports receipt of the clinical research fellowship from Mito Foundation Australia. S.B Wortmann reports no disclosures relevant to the manuscript.M.A Willemsen reports no disclosures relevant to the manuscript. S.Balalsubramaniam reports no disclosures relevant to the manuscript.

Research paper thumbnail of Functional consequences of bi-allelic PNPT1 variants associated with multisystemic disease

European Journal of Human Genetics, 2019

Research paper thumbnail of Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning

International Journal of Neonatal Screening, 2021

Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenas... more Maple syrup urine disease is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase, responsible for degradation of leucine, isoleucine, and valine. Biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT genes result in enzyme deficiency. We report the case of a female infant who presented with mild gross motor delay at 4 months, and seizures with hypoglycaemia at 5 months. Newborn screening returned total leucine/isoleucine at the 99.5th centile of the population; however, as second-tier testing reported minimal alloisoleucine, the results were considered inconsistent with MSUD. Plasma amino acid and urine organic acid analyses at 5 months were, however, consistent with a diagnosis of MSUD. A brain MRI showed bilateral symmetrical T2 hyperintense signal abnormalities involving white matter, globus pallidus, thalamus, brainstem, and dentate nuclei with restricted diffusion. A repeat MRI 10 months post-dietary-intervention showed the resolution of these changes and pr...

Research paper thumbnail of The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease

Genetics in Medicine, 2020

The utility of genome sequencing (GS) in the diagnosis of suspected pediatric mitochondrial disea... more The utility of genome sequencing (GS) in the diagnosis of suspected pediatric mitochondrial disease (MD) was investigated. Methods: An Australian cohort of 40 pediatric patients with clinical features suggestive of MD were classified using the modified Nijmegen mitochondrial disease severity scoring into definite (17), probable (17), and possible (6) MD groups. Trio GS was performed using DNA extracted from patient and parent blood. Data were analyzed for single-nucleotide variants, indels, mitochondrial DNA variants, and structural variants. Results: A definitive MD gene molecular diagnosis was made in 15 cases and a likely MD molecular diagnosis in a further five cases. Causative mitochondrial DNA (mtDNA) variants were identified in four of these cases. Three potential novel MD genes were identified. In seven cases, causative variants were identified in known disease genes with no previous evidence of causing a primary MD. Diagnostic rates were higher in patients classified as having definite MD. Conclusion: GS efficiently identifies variants in MD genes of both nuclear and mitochondrial origin. A likely molecular diagnosis was identified in 67% of cases and a definitive molecular diagnosis achieved in 55% of cases. This study highlights the value of GS for a phenotypically and genetically heterogeneous disorder like MD.

Research paper thumbnail of Faculty Opinions recommendation of EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature, 2017

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations... more Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities.

Research paper thumbnail of F1000Prime recommendation of Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians

F1000 - Post-publication peer review of the biomedical literature, 2020

Research paper thumbnail of F1000Prime recommendation of The diagnosis of inborn errors of metabolism by an integrative "multi-omics" approach: A perspective encompassing genomics, transcriptomics, and proteomics

F1000 - Post-publication peer review of the biomedical literature, 2019

Research paper thumbnail of Ketogenic diet, a potentially valuable therapeutic option for the management of refractory epilepsy in classical neonatal nonketotic hyperglycinemia: a case report

European Journal of Clinical Nutrition, 2018

Nonketotic hyperglycinemia (NKH) is a devastating inborn error of glycine metabolism caused by de... more Nonketotic hyperglycinemia (NKH) is a devastating inborn error of glycine metabolism caused by deficient activity of the glycine cleavage enzyme. Classically, patients present with lethargy, hypotonia, myoclonic jerks, transient respiratory depression in the first week of life and often progress to death. Surviving infants have profound psychomotor retardation, refractory epilepsy and poor quality of life. Currently, no effective therapeutic avenues exist for severe NKH. Ketogenic diet (KD) has been trialled only in a small group of patients with neonatal NKH and early myoclonic encephalopathy, in whom significant improvements in seizure control were reported. We describe an infant with classical neonatal NKH who presented on the third day of life with hypotonia, poor feeding, respiratory insufficiency resulting in ventilatory support and seizures with burst-suppression pattern on electroencephalogram (EEG). KD initiated at age 6 months for intractable seizures, lead to a dramatic decrease in seizure frequency, EEG improvements, normalisation of plasma glycine levels, reduced spasticity and improved quality of life. KD may be a valuable treatment modality for refractory seizure control in classical NKH.

Research paper thumbnail of Faculty of 1000 evaluation for Adenosine kinase deficiency: expanding the clinical spectrum and evaluating therapeutic options

F1000 - Post-publication peer review of the biomedical literature, 2016

Research paper thumbnail of Faculty of 1000 evaluation for Mutation in mitochondrial ribosomal protein S7 (MRPS7) causes congenital sensorineural deafness, progressive hepatic and renal failure and lactic acidemia

F1000 - Post-publication peer review of the biomedical literature, 2015

Research paper thumbnail of Biochemical evaluation of an infant with hypoglycemia resulting from a novel de novo mutation of the GLUD1 gene and hyperinsulinism-hyperammonemia syndrome

Journal of Pediatric Endocrinology and Metabolism, 2011

Hyperinsulinism-hyperammonemia syndrome (HI/HA) (OMIM 606762), the second most common form of con... more Hyperinsulinism-hyperammonemia syndrome (HI/HA) (OMIM 606762), the second most common form of congenital hyperinsulinism (CHI) is associated with activating missense mutations in the GLUD1 gene, which encodes the mitochondrial matrix enzyme, glutamate dehydrogenase (GDH). Patients present with recurrent symptomatic postprandial hypoglycemia following protein-rich meals (leucine-sensitive hypoglycemia) as well as fasting hypoglycemia accompanied by asymptomatic elevations of plasma ammonia. In contrast to other forms of CHI, the phenotype is reported to be milder thus escaping recognition for the first few months of life. Early diagnosis and appropriate management are essential to avoid the neurodevelopmental consequences including epilepsy and learning disabilities which are prevalent in this disorder. We report an infant presenting with afebrile seizures secondary to hyperinsulinemic hypoglycemia resulting from a novel de novo mutation of the GLUD1 gene.

Research paper thumbnail of Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5′-phosphate availability

Journal of Inherited Metabolic Disease, 2010

We describe two neonates presenting with perinatal hypophosphatasia and severe epileptic encephal... more We describe two neonates presenting with perinatal hypophosphatasia and severe epileptic encephalopathy resulting in death. Both had increased levels of urinary vanillactate, indicating functional deficiency of aromatic amino acid decarboxylase, a pyridoxal-5-phosphate (PLP)-dependent enzyme required for dopamine and serotonin biosynthesis. Clinical findings and results of subsequent metabolic investigations were consistent with secondary pyridoxine-deficient encephalopathy. These patients highlight the importance of tissue non-specific alkaline phosphatase in the neuronal PLP-dependent metabolism of neurotransmitters. In addition, the disturbance of PLP metabolism appears to underlie the predominant neurological presentation in our patients. We recommend the measurement of serum alkaline phosphatase (ALP) during the assessment of perinatal seizures.

Research paper thumbnail of Hyperinsulinaemic hypoglycaemia: genetic mechanisms, diagnosis and management

Journal of Inherited Metabolic Disease, 2012

Research paper thumbnail of Treatment of Lesch–Nyhan disease with S-adenosylmethionine: Experience with five young Malaysians, including a girl

Brain and Development, 2014

Research paper thumbnail of Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function

The American Journal of Human Genetics, 2011

Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfe... more Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (AdoMet), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.

Research paper thumbnail of Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease

Human Molecular Genetics, 2022

Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical ... more Mitochondrial diseases are a group of inherited diseases with highly varied and complex clinical presentations. Here, we report four individuals, including two siblings, affected by a progressive mitochondrial encephalopathy with biallelic variants in the cardiolipin biosynthesis gene CRLS1. Three affected individuals had a similar infantile presentation comprising progressive encephalopathy, bull’s eye maculopathy, auditory neuropathy, diabetes insipidus, autonomic instability, cardiac defects and early death. The fourth affected individual presented with chronic encephalopathy with neurodevelopmental regression, congenital nystagmus with decreased vision, sensorineural hearing loss, failure to thrive and acquired microcephaly. Using patient-derived fibroblasts, we characterized cardiolipin synthase 1 (CRLS1) dysfunction that impaired mitochondrial morphology and biogenesis, providing functional evidence that the CRLS1 variants cause mitochondrial disease. Lipid profiling in fibrob...