Sarah Grünert - Academia.edu (original) (raw)

Papers by Sarah Grünert

Research paper thumbnail of A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome

Genes

Vertebral, Cardiac, Renal and Limb Defect Syndrome (VCRL), is a very rare congenital malformation... more Vertebral, Cardiac, Renal and Limb Defect Syndrome (VCRL), is a very rare congenital malformation syndrome. Pathogenic variants in HAAO (3-Hydroxyanthranilate 3,4-dioxygenase), NADSYN1 (NAD+ Synthetase-1) and KYNU (Kynureninase) have been identified in a handful of affected individuals. All three genes encode for enzymes essential for the NAD+ de novo synthesis pathway. Using Trio-Exome analysis and CGH array analysis in combination with long range PCR, we have identified a novel homozygous copy number variant (CNV) encompassing exon 5 of KYNU in an individual presenting with overlapping features of VCRL and Catel–Manzke Syndrome. Interestingly, only the mother, not the father carried the small deletion in a heterozygous state. High-resolution SNP array analysis subsequently delineated a maternal isodisomy of chromosome 2 (UPD2). Increased xanthurenic acid excretion in the urine confirmed the genetic diagnosis. Our findings confirm the clinical, genetic and metabolic phenotype of VC...

Research paper thumbnail of Additional file 1 of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: one disease - many faces

Additional file 1: Table S1. Publications included in this literature review for the analysis of ... more Additional file 1: Table S1. Publications included in this literature review for the analysis of clinical, biochemical and genetic data.

Research paper thumbnail of Additional file 2 of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: one disease - many faces

Additional file 2: Table S2. Publications that were additionally included for the overview on all... more Additional file 2: Table S2. Publications that were additionally included for the overview on all known mutations in HMGCL.

Research paper thumbnail of Neugeborenes mit Trinkschwäche und Somnolenz am 2. Lebenstag

Monatsschrift Kinderheilkunde

Research paper thumbnail of Mitochondrial damage in renal epithelial cells is potentiated by protein exposure in propionic aciduria

Propionic aciduria (PA) is caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxy... more Propionic aciduria (PA) is caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). Due to inefficient propionate catabolism patients are endangered by life-threatening ketoacidotic crisis. Protein and amino acid restriction are major therapeutic pillars. However, long-term complications like neurological deterioration and cardiac abnormalities cannot be prevented. Chronic kidney disease (CKD), which is a well-known characteristic of methylmalonic aciduria two enzymatic steps down-stream from PCC, has been recognized as a novel late-onset complication in PA. The pathophysiology of CKD in PA is unclear. We investigated mitochondrial structure and metabolism in human renal tubular cells of healthy controls and PA patients. The cells were exposed to either standard cell culture conditions (NT), high protein (HP) or high concentrations of isoleucine and valine (I/V). Mitochondrial morphology changed to condensed, fractured morphology in PA cells irrespective of ...

Research paper thumbnail of Disorders of Ketone Body Metabolism

Ketone body utilisation is of special importance in times of fasting/starvation or increased ener... more Ketone body utilisation is of special importance in times of fasting/starvation or increased energy demand. However, both formation and utilisation of ketone bodies (ketogenesis and ketolysis) can be impeded by inborn errors of metabolism. In case of genetic deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (mHMGS) or of 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HMGL), the formation of ketone bodies is impaired. If one of the enzymes of ketolysis is affected, namely, succinyl-CoA:3-oxoacid CoA transferase (SCOT) or methylacetoacetyl-CoA thiolase (MAT, “β-ketothiolase”), ketones accumulate and a life-threatening ketoacidosis may result. Since treatment options allow to minimise the risk for metabolic decompensations, awareness of those diseases is important, as is information on how to treat and to prevent clinical manifestations.

Research paper thumbnail of Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder ca... more BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder caused by deficiency of electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase. The clinical picture of late-onset forms is highly variable with symptoms ranging from acute metabolic decompensations to chronic, mainly muscular problems or even asymptomatic cases.MethodsAll 350 cases of late-onset MADD reported in the literature to date have been analyzed and evaluated with respect to age at presentation, diagnostic delay, biochemical features and diagnostic parameters as well as response to treatment.ResultsMean age at onset was 19.2 years. The mean delay between onset of symptoms and diagnosis was 3.9 years. Chronic muscular symptoms were more than twice as common as acute metabolic decompensations (85% versus 33% of patients, respectively). 20% had both acute and chronic symptoms. 5% of patients had died at a mean age of 5.8 years, while 3% of patients have remain...

Research paper thumbnail of The Biochemical High Excreter Phenotype Is the Major Risk Factor for Cognitive Impairment in Early Diagnosed Individuals with Glutaric Aciduria Type 1

Abstracts of the 46th Annual Meeting of the Society for Neuropediatrics

Research paper thumbnail of Glycogen Storage Disease Type Ia: Current Management Options, Burden and Unmet Needs

Nutrients

Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzy... more Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not preve...

Research paper thumbnail of The spectrum of peripheral neuropathy in disorders of the mitochondrial trifunctional protein

Journal of Inherited Metabolic Disease

Research paper thumbnail of Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

International Journal of Molecular Sciences

Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid... more Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid oxidation disorders (lc-FAOD) characterized by impaired β-oxidation. Here, we performed lipidomic and proteomic analysis in fibroblasts from patients with very long-chain acyl-CoA dehydrogenase (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) deficiencies after incubation with heptanoate (C7) and octanoate (C8). Defects of β-oxidation induced striking proteomic alterations, whereas the effect of treatment with mc-FAs was minor. However, mc-FAs induced a remodeling of complex lipids. Especially C7 appeared to act protectively by restoring sphingolipid biosynthesis flux and improving the observed dysregulation of protein homeostasis in LCHADD under control conditions.

Research paper thumbnail of Different Lipid Signature in Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

Cells

Long-chain fatty acid oxidation disorders (lc-FAOD) are a group of diseases affecting the degrada... more Long-chain fatty acid oxidation disorders (lc-FAOD) are a group of diseases affecting the degradation of long-chain fatty acids. In order to investigate the disease specific alterations of the cellular lipidome, we performed undirected lipidomics in fibroblasts from patients with carnitine palmitoyltransferase II, very long-chain acyl-CoA dehydrogenase, and long-chain 3-hydroxyacyl-CoA dehydrogenase. We demonstrate a deep remodeling of mitochondrial cardiolipins. The aberrant phosphatidylcholine/phosphatidylethanolamine ratio and the increased content of plasmalogens and of lysophospholipids support the theory of an inflammatory phenotype in lc-FAOD. Moreover, we describe increased ratios of sphingomyelin/ceramide and sphingomyelin/hexosylceramide in LCHAD deficiency which may contribute to the neuropathic phenotype of LCHADD/mitochondrial trifunctional protein deficiency.

Research paper thumbnail of Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

Journal of Inherited Metabolic Disease

Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic ... more Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic diseases. Six years ago, a detailed evaluation of the available evidence on diagnosis and management of these disorders has been published for the first time. The article received considerable attention, illustrating the importance of an expert panel to evaluate and compile recommendations to guide rare disease patient care. Since that time, a growing body of evidence on transplant outcomes in MMA and PA patients and use of precursor free amino acid mixtures allows for updates of the guidelines. In this article, we aim to incorporate this newly published knowledge and provide a revised version of the guidelines. The analysis was performed by a panel of multidisciplinary health care experts, who followed an updated guideline development methodology (GRADE). Hence, the full body of evidence up until autumn 2019 was re‐evaluated, analysed and graded. As a result, 21 updated recommendations were compiled in a more concise paper with a focus on the existing evidence to enable well‐informed decisions in the context of MMA and PA patient care.

Research paper thumbnail of Primary carnitine deficiency – diagnosis after heart transplantation: better late than never!

Orphanet Journal of Rare Diseases

Background Primary carnitine deficiency due to mutations in the SLC22A5 gene is a rare but well-t... more Background Primary carnitine deficiency due to mutations in the SLC22A5 gene is a rare but well-treatable metabolic disorder that puts patients at risk for metabolic decompensations, skeletal and cardiac myopathy and sudden cardiac death. Results We report on a 7-year-old boy diagnosed with primary carnitine deficiency 2 years after successful heart transplantation thanks his younger sister’s having been identified via expanded newborn screening during a pilot study evaluating an extension of the German newborn screening panel. Conclusion As L-carnitine supplementation can prevent and mostly reverse clinical symptoms of primary carnitine deficiency, all patients with cardiomyopathy should be investigated for primary carnitine deficiency even if newborn screening results were unremarkable.

Research paper thumbnail of Thiamine Treatment and Favorable Outcome in an Infant with Biallelic TPK1 Variants

Neuropediatrics

Episodic encephalopathy due to mutations in the thiamine pyrophosphokinase 1 (TPK1) gene is a rar... more Episodic encephalopathy due to mutations in the thiamine pyrophosphokinase 1 (TPK1) gene is a rare autosomal recessive metabolic disorder. Patients reported so far have onset in early childhood of acute encephalopathic episodes, which result in a progressive neurologic dysfunction including ataxia, dystonia, and spasticity. Here, we report the case of an infant with TPK1 deficiency (compound heterozygosity for two previously described pathogenic variants) presenting with two encephalopathic episodes and clinical stabilization under oral thiamine and biotin supplementation. In contrast to other reported cases, our patient showed an almost normal psychomotor development, which might be due to an early diagnosis and subsequent therapy.

Research paper thumbnail of Genotype and residual enzyme activity in medium‐chain acyl‐CoA dehydrogenase ( MCAD ) deficiency: Are predictions possible?

Journal of Inherited Metabolic Disease

Research paper thumbnail of Improved inflammatory bowel disease, wound healing and normal oxidative burst under treatment with empagliflozin in glycogen storage disease type Ib

Orphanet Journal of Rare Diseases

Background Glycogen storage disease type Ib (GSD Ib) is a rare inborn error of glycogen metabolis... more Background Glycogen storage disease type Ib (GSD Ib) is a rare inborn error of glycogen metabolism due to mutations in SLC37A4. Besides a severe form of fasting intolerance, the disorder is usually associated with neutropenia and neutrophil dysfunction causing serious infections, inflammatory bowel disease, oral, urogenital and perianal lesions as well as impaired wound healing. Recently, SGLT2 inhibitors such as empagliflozin that reduce the plasma levels of 1,5-anhydroglucitol have been described as a new treatment option for the neutropenia and neutrophil dysfunction in patients with GSD Ib. Results We report on a 35-year-old female patient with GSD Ib who had been treated with G-CSF for neutropenia since the age of 9. She had a large chronic abdominal wound as a consequence of recurrent operations due to complications of her inflammatory bowel disease. Treatment with 20 mg empagliflozin per day resulted in normalisation of the neutrophil count and neutrophil function even after ...

Research paper thumbnail of Three Successful Pregnancies in a Patient With Glycogen Storage Disease Type 0

BackgroundGlycogen storage disease type 0 (GSD 0) is a rare inborn error of metabolism due to def... more BackgroundGlycogen storage disease type 0 (GSD 0) is a rare inborn error of metabolism due to deficiency of the enzyme glycogen synthase (EC 2.4.1.11). Patients with this disorder are unable to store glucose as glycogen in the liver. GSD 0 is therefore characterized by ketotic fasting hypoglycemia in combination with postprandial hyperglycemia and hyperlactatemia. So far, only one pregnancy has been described in a woman with GSD 0. Case presentationWe herein report a 32 year-old patient GSD 0 with three successful pregnancies. The diagnosis of GSD 0 was made in early childhood due to characteristic symptoms. The patient had two healthy children at the time of her first visit in our metabolic centre. The diet was optimised prior to her third pregnancy with a protein-rich diet including cornstarch and protein supplements. Pregnancy was confirmed at week 6 of gestation. Dietary management was difficult during pregnancy, especially in the first trimester due to severe nausea. Labour was...

Research paper thumbnail of Impact of interventional and non‐interventional variables on anthropometric long‐term development in glutaric aciduria type 1: A national prospective multi‐centre study

Journal of Inherited Metabolic Disease

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency ... more Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency of glutaryl‐CoA dehydrogenase, mostly affecting the brain. Early identification by newborn screening (NBS) significantly improves neurologic outcome. It has remained unclear whether recommended therapy, particular low lysine diet, is safe or negatively affects anthropometric long‐term outcome. This national prospective, observational, multi‐centre study included 79 patients identified by NBS and investigated effects of interventional and non‐interventional parameters on body weight, body length, body mass index (BMI) and head circumference as well as neurological parameters. Adherence to recommended maintenance and emergency treatment (ET) had a positive impact on neurologic outcome and allowed normal anthropometric development until adulthood. In contrast, non‐adherence to ET, resulting in increased risk of dystonia, had a negative impact on body weight (mean SDS −1.07; P = .023) and body length (mean SDS −1.34; P = −.016). Consistently, longitudinal analysis showed a negative influence of severe dystonia on weight and length development over time (P < .001). Macrocephaly was more often found in female (mean SDS 0.56) than in male patients (mean SDS −0.20; P = .049), and also in individuals with high excreter phenotype (mean SDS 0.44) compared to low excreter patients (mean SDS −0.68; P = .016). In GA1, recommended long‐term treatment is effective and allows for normal anthropometric long‐term development up to adolescence, with gender‐ and excreter type‐specific variations. Delayed ET and severe movement disorder result in poor anthropometric outcome.

Research paper thumbnail of A newborn screening approach to diagnose 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency

JIMD Reports

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessively i... more 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessively inherited metabolic disorder. Patients suffer from avoidable neurologically devastating metabolic decompensations and thus would benefit from newborn screening (NBS). The diagnosis is currently made by measuring dry blood spot acylcarnitines (C5OH and C6DC) followed by urinary organic acid profiling for the differential diagnosis from several other disorders. Using untargeted metabolomics (reversed-phase UHPLC coupled to an Orbitrap Elite hybrid mass spectrometer) of plasma samples from 5 HMGCLD patients and 19 age-matched controls, we found 3-methylglutaconic acid and 3-hydroxy-3-methylglutaric acid, together with 3-hydroxyisovalerylcarnitine as

Research paper thumbnail of A Homozygous Deletion of Exon 5 of KYNU Resulting from a Maternal Chromosome 2 Isodisomy (UPD2) Causes Catel-Manzke-Syndrome/VCRL Syndrome

Genes

Vertebral, Cardiac, Renal and Limb Defect Syndrome (VCRL), is a very rare congenital malformation... more Vertebral, Cardiac, Renal and Limb Defect Syndrome (VCRL), is a very rare congenital malformation syndrome. Pathogenic variants in HAAO (3-Hydroxyanthranilate 3,4-dioxygenase), NADSYN1 (NAD+ Synthetase-1) and KYNU (Kynureninase) have been identified in a handful of affected individuals. All three genes encode for enzymes essential for the NAD+ de novo synthesis pathway. Using Trio-Exome analysis and CGH array analysis in combination with long range PCR, we have identified a novel homozygous copy number variant (CNV) encompassing exon 5 of KYNU in an individual presenting with overlapping features of VCRL and Catel–Manzke Syndrome. Interestingly, only the mother, not the father carried the small deletion in a heterozygous state. High-resolution SNP array analysis subsequently delineated a maternal isodisomy of chromosome 2 (UPD2). Increased xanthurenic acid excretion in the urine confirmed the genetic diagnosis. Our findings confirm the clinical, genetic and metabolic phenotype of VC...

Research paper thumbnail of Additional file 1 of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: one disease - many faces

Additional file 1: Table S1. Publications included in this literature review for the analysis of ... more Additional file 1: Table S1. Publications included in this literature review for the analysis of clinical, biochemical and genetic data.

Research paper thumbnail of Additional file 2 of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: one disease - many faces

Additional file 2: Table S2. Publications that were additionally included for the overview on all... more Additional file 2: Table S2. Publications that were additionally included for the overview on all known mutations in HMGCL.

Research paper thumbnail of Neugeborenes mit Trinkschwäche und Somnolenz am 2. Lebenstag

Monatsschrift Kinderheilkunde

Research paper thumbnail of Mitochondrial damage in renal epithelial cells is potentiated by protein exposure in propionic aciduria

Propionic aciduria (PA) is caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxy... more Propionic aciduria (PA) is caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). Due to inefficient propionate catabolism patients are endangered by life-threatening ketoacidotic crisis. Protein and amino acid restriction are major therapeutic pillars. However, long-term complications like neurological deterioration and cardiac abnormalities cannot be prevented. Chronic kidney disease (CKD), which is a well-known characteristic of methylmalonic aciduria two enzymatic steps down-stream from PCC, has been recognized as a novel late-onset complication in PA. The pathophysiology of CKD in PA is unclear. We investigated mitochondrial structure and metabolism in human renal tubular cells of healthy controls and PA patients. The cells were exposed to either standard cell culture conditions (NT), high protein (HP) or high concentrations of isoleucine and valine (I/V). Mitochondrial morphology changed to condensed, fractured morphology in PA cells irrespective of ...

Research paper thumbnail of Disorders of Ketone Body Metabolism

Ketone body utilisation is of special importance in times of fasting/starvation or increased ener... more Ketone body utilisation is of special importance in times of fasting/starvation or increased energy demand. However, both formation and utilisation of ketone bodies (ketogenesis and ketolysis) can be impeded by inborn errors of metabolism. In case of genetic deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (mHMGS) or of 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HMGL), the formation of ketone bodies is impaired. If one of the enzymes of ketolysis is affected, namely, succinyl-CoA:3-oxoacid CoA transferase (SCOT) or methylacetoacetyl-CoA thiolase (MAT, “β-ketothiolase”), ketones accumulate and a life-threatening ketoacidosis may result. Since treatment options allow to minimise the risk for metabolic decompensations, awareness of those diseases is important, as is information on how to treat and to prevent clinical manifestations.

Research paper thumbnail of Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency

BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder ca... more BackgroundMultiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder caused by deficiency of electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase. The clinical picture of late-onset forms is highly variable with symptoms ranging from acute metabolic decompensations to chronic, mainly muscular problems or even asymptomatic cases.MethodsAll 350 cases of late-onset MADD reported in the literature to date have been analyzed and evaluated with respect to age at presentation, diagnostic delay, biochemical features and diagnostic parameters as well as response to treatment.ResultsMean age at onset was 19.2 years. The mean delay between onset of symptoms and diagnosis was 3.9 years. Chronic muscular symptoms were more than twice as common as acute metabolic decompensations (85% versus 33% of patients, respectively). 20% had both acute and chronic symptoms. 5% of patients had died at a mean age of 5.8 years, while 3% of patients have remain...

Research paper thumbnail of The Biochemical High Excreter Phenotype Is the Major Risk Factor for Cognitive Impairment in Early Diagnosed Individuals with Glutaric Aciduria Type 1

Abstracts of the 46th Annual Meeting of the Society for Neuropediatrics

Research paper thumbnail of Glycogen Storage Disease Type Ia: Current Management Options, Burden and Unmet Needs

Nutrients

Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzy... more Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not preve...

Research paper thumbnail of The spectrum of peripheral neuropathy in disorders of the mitochondrial trifunctional protein

Journal of Inherited Metabolic Disease

Research paper thumbnail of Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

International Journal of Molecular Sciences

Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid... more Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid oxidation disorders (lc-FAOD) characterized by impaired β-oxidation. Here, we performed lipidomic and proteomic analysis in fibroblasts from patients with very long-chain acyl-CoA dehydrogenase (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) deficiencies after incubation with heptanoate (C7) and octanoate (C8). Defects of β-oxidation induced striking proteomic alterations, whereas the effect of treatment with mc-FAs was minor. However, mc-FAs induced a remodeling of complex lipids. Especially C7 appeared to act protectively by restoring sphingolipid biosynthesis flux and improving the observed dysregulation of protein homeostasis in LCHADD under control conditions.

Research paper thumbnail of Different Lipid Signature in Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

Cells

Long-chain fatty acid oxidation disorders (lc-FAOD) are a group of diseases affecting the degrada... more Long-chain fatty acid oxidation disorders (lc-FAOD) are a group of diseases affecting the degradation of long-chain fatty acids. In order to investigate the disease specific alterations of the cellular lipidome, we performed undirected lipidomics in fibroblasts from patients with carnitine palmitoyltransferase II, very long-chain acyl-CoA dehydrogenase, and long-chain 3-hydroxyacyl-CoA dehydrogenase. We demonstrate a deep remodeling of mitochondrial cardiolipins. The aberrant phosphatidylcholine/phosphatidylethanolamine ratio and the increased content of plasmalogens and of lysophospholipids support the theory of an inflammatory phenotype in lc-FAOD. Moreover, we describe increased ratios of sphingomyelin/ceramide and sphingomyelin/hexosylceramide in LCHAD deficiency which may contribute to the neuropathic phenotype of LCHADD/mitochondrial trifunctional protein deficiency.

Research paper thumbnail of Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

Journal of Inherited Metabolic Disease

Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic ... more Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic diseases. Six years ago, a detailed evaluation of the available evidence on diagnosis and management of these disorders has been published for the first time. The article received considerable attention, illustrating the importance of an expert panel to evaluate and compile recommendations to guide rare disease patient care. Since that time, a growing body of evidence on transplant outcomes in MMA and PA patients and use of precursor free amino acid mixtures allows for updates of the guidelines. In this article, we aim to incorporate this newly published knowledge and provide a revised version of the guidelines. The analysis was performed by a panel of multidisciplinary health care experts, who followed an updated guideline development methodology (GRADE). Hence, the full body of evidence up until autumn 2019 was re‐evaluated, analysed and graded. As a result, 21 updated recommendations were compiled in a more concise paper with a focus on the existing evidence to enable well‐informed decisions in the context of MMA and PA patient care.

Research paper thumbnail of Primary carnitine deficiency – diagnosis after heart transplantation: better late than never!

Orphanet Journal of Rare Diseases

Background Primary carnitine deficiency due to mutations in the SLC22A5 gene is a rare but well-t... more Background Primary carnitine deficiency due to mutations in the SLC22A5 gene is a rare but well-treatable metabolic disorder that puts patients at risk for metabolic decompensations, skeletal and cardiac myopathy and sudden cardiac death. Results We report on a 7-year-old boy diagnosed with primary carnitine deficiency 2 years after successful heart transplantation thanks his younger sister’s having been identified via expanded newborn screening during a pilot study evaluating an extension of the German newborn screening panel. Conclusion As L-carnitine supplementation can prevent and mostly reverse clinical symptoms of primary carnitine deficiency, all patients with cardiomyopathy should be investigated for primary carnitine deficiency even if newborn screening results were unremarkable.

Research paper thumbnail of Thiamine Treatment and Favorable Outcome in an Infant with Biallelic TPK1 Variants

Neuropediatrics

Episodic encephalopathy due to mutations in the thiamine pyrophosphokinase 1 (TPK1) gene is a rar... more Episodic encephalopathy due to mutations in the thiamine pyrophosphokinase 1 (TPK1) gene is a rare autosomal recessive metabolic disorder. Patients reported so far have onset in early childhood of acute encephalopathic episodes, which result in a progressive neurologic dysfunction including ataxia, dystonia, and spasticity. Here, we report the case of an infant with TPK1 deficiency (compound heterozygosity for two previously described pathogenic variants) presenting with two encephalopathic episodes and clinical stabilization under oral thiamine and biotin supplementation. In contrast to other reported cases, our patient showed an almost normal psychomotor development, which might be due to an early diagnosis and subsequent therapy.

Research paper thumbnail of Genotype and residual enzyme activity in medium‐chain acyl‐CoA dehydrogenase ( MCAD ) deficiency: Are predictions possible?

Journal of Inherited Metabolic Disease

Research paper thumbnail of Improved inflammatory bowel disease, wound healing and normal oxidative burst under treatment with empagliflozin in glycogen storage disease type Ib

Orphanet Journal of Rare Diseases

Background Glycogen storage disease type Ib (GSD Ib) is a rare inborn error of glycogen metabolis... more Background Glycogen storage disease type Ib (GSD Ib) is a rare inborn error of glycogen metabolism due to mutations in SLC37A4. Besides a severe form of fasting intolerance, the disorder is usually associated with neutropenia and neutrophil dysfunction causing serious infections, inflammatory bowel disease, oral, urogenital and perianal lesions as well as impaired wound healing. Recently, SGLT2 inhibitors such as empagliflozin that reduce the plasma levels of 1,5-anhydroglucitol have been described as a new treatment option for the neutropenia and neutrophil dysfunction in patients with GSD Ib. Results We report on a 35-year-old female patient with GSD Ib who had been treated with G-CSF for neutropenia since the age of 9. She had a large chronic abdominal wound as a consequence of recurrent operations due to complications of her inflammatory bowel disease. Treatment with 20 mg empagliflozin per day resulted in normalisation of the neutrophil count and neutrophil function even after ...

Research paper thumbnail of Three Successful Pregnancies in a Patient With Glycogen Storage Disease Type 0

BackgroundGlycogen storage disease type 0 (GSD 0) is a rare inborn error of metabolism due to def... more BackgroundGlycogen storage disease type 0 (GSD 0) is a rare inborn error of metabolism due to deficiency of the enzyme glycogen synthase (EC 2.4.1.11). Patients with this disorder are unable to store glucose as glycogen in the liver. GSD 0 is therefore characterized by ketotic fasting hypoglycemia in combination with postprandial hyperglycemia and hyperlactatemia. So far, only one pregnancy has been described in a woman with GSD 0. Case presentationWe herein report a 32 year-old patient GSD 0 with three successful pregnancies. The diagnosis of GSD 0 was made in early childhood due to characteristic symptoms. The patient had two healthy children at the time of her first visit in our metabolic centre. The diet was optimised prior to her third pregnancy with a protein-rich diet including cornstarch and protein supplements. Pregnancy was confirmed at week 6 of gestation. Dietary management was difficult during pregnancy, especially in the first trimester due to severe nausea. Labour was...

Research paper thumbnail of Impact of interventional and non‐interventional variables on anthropometric long‐term development in glutaric aciduria type 1: A national prospective multi‐centre study

Journal of Inherited Metabolic Disease

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency ... more Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder, caused by inherited deficiency of glutaryl‐CoA dehydrogenase, mostly affecting the brain. Early identification by newborn screening (NBS) significantly improves neurologic outcome. It has remained unclear whether recommended therapy, particular low lysine diet, is safe or negatively affects anthropometric long‐term outcome. This national prospective, observational, multi‐centre study included 79 patients identified by NBS and investigated effects of interventional and non‐interventional parameters on body weight, body length, body mass index (BMI) and head circumference as well as neurological parameters. Adherence to recommended maintenance and emergency treatment (ET) had a positive impact on neurologic outcome and allowed normal anthropometric development until adulthood. In contrast, non‐adherence to ET, resulting in increased risk of dystonia, had a negative impact on body weight (mean SDS −1.07; P = .023) and body length (mean SDS −1.34; P = −.016). Consistently, longitudinal analysis showed a negative influence of severe dystonia on weight and length development over time (P < .001). Macrocephaly was more often found in female (mean SDS 0.56) than in male patients (mean SDS −0.20; P = .049), and also in individuals with high excreter phenotype (mean SDS 0.44) compared to low excreter patients (mean SDS −0.68; P = .016). In GA1, recommended long‐term treatment is effective and allows for normal anthropometric long‐term development up to adolescence, with gender‐ and excreter type‐specific variations. Delayed ET and severe movement disorder result in poor anthropometric outcome.

Research paper thumbnail of A newborn screening approach to diagnose 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency

JIMD Reports

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessively i... more 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessively inherited metabolic disorder. Patients suffer from avoidable neurologically devastating metabolic decompensations and thus would benefit from newborn screening (NBS). The diagnosis is currently made by measuring dry blood spot acylcarnitines (C5OH and C6DC) followed by urinary organic acid profiling for the differential diagnosis from several other disorders. Using untargeted metabolomics (reversed-phase UHPLC coupled to an Orbitrap Elite hybrid mass spectrometer) of plasma samples from 5 HMGCLD patients and 19 age-matched controls, we found 3-methylglutaconic acid and 3-hydroxy-3-methylglutaric acid, together with 3-hydroxyisovalerylcarnitine as