Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.

BACKGROUND: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C. METHODS: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo. RESULTS: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred. CONCLUSIONS: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).

Inborn errors of the malate aspartate shuttle - Update on patients and cellular models.

The malate aspartate shuttle (MAS) plays a pivotal role in transporting cytosolic reducing equivalents - electrons - into the mitochondria for energy conversion at the electron transport chain (ETC) and in the process of oxidative phosphorylation. The MAS consists of two pairs of cytosolic and mitochondrial isoenzymes (malate dehydrogenases 1 and 2; and glutamate oxaloacetate transaminases 1 and 2) and two transporters (malate-2-oxoglutarate carrier and aspartate glutamate carrier (AGC), the latter of which has two tissue-dependent isoforms AGC1 and AGC2). While the inner mitochondrial membrane is impermeable to NADH, the MAS forms one of the main routes for mitochondrial electron uptake by promoting uptake of malate. Inherited bi-allelic pathogenic variants in five of the seven components of the MAS have been described hitherto and cause a wide spectrum of symptoms including early-onset epileptic encephalopathy. This review provides an overview of reported patients suffering from MAS deficiencies. In addition, we give an overview of diagnostic procedures and research performed on patient-derived cellular models and tissues. Current cellular models are briefly discussed and novel ways to achieve a better understanding of MAS deficiencies are highlighted.

Empagliflozin for treating neutropenia and neutrophil dysfunction in 21 infants with glycogen storage disease 1b.

Empagliflozin has been successfully repurposed for treating neutropenia and neutrophil dysfunction in patients with glycogen storage disease type 1b (GSD 1b), however, data in infants are missing. We report on efficacy and safety of empagliflozin in infants with GSD 1b. This is an international retrospective case series on 21 GSD 1b infants treated with empagliflozin (total treatment time 20.6 years). Before starting empagliflozin (at a median age of 8.1 months with a median dose of 0.3 mg/kg/day) 12 patients had clinical signs and symptoms of neutrophil dysfunction. Six of these previously symptomatic patients had no further neutropenia/neutrophil dysfunction-associated findings on empagliflozin. Eight patients had no signs and symptoms of neutropenia/neutrophil dysfunction before start and during empagliflozin treatment. One previously asymptomatic individual with a horseshoe kidney developed a central line infection with pyelonephritis and urosepsis during empagliflozin treatment. Of the 10 patients who were treated with G-CSF before starting empagliflozin, this was stopped in four and decreased in another four. Eleven individuals were never treated with G-CSF. While in 17 patients glucose homeostasis remained stable on empagliflozin, four showed glucose homeostasis instability in the introductory phase. In 17 patients, no other side effects were reported, while genital (n = 2) or oral (n = 1) candidiasis and skin infection (n = 1) were reported in the remaining four. Empagliflozin had a good effect on neutropenia/neutrophil dysfunction-related signs and symptoms and a favourable safety profile in infants with GSD 1b and therefore qualifies for further exploration as first line treatment.

Nocturnal vestibular stimulation using a rocking bed improves a severe sleep disorder in a patient with mitochondrial disease.

Mitochondrial diseases are rare genetic disorders often accompanied by severe sleep disorders. We present the case of a 12-year-old boy diagnosed with a severe primary mitochondrial disease, exhibiting ataxia, spasticity, progressive external ophthalmoplegia, cardiomyopathy and severely disrupted sleep, but no cognitive impairment. Interestingly, his parents reported improved sleep during night train rides. Based on this observation, we installed a rocking bed in the patient's bedroom and performed different interventions, including immersive multimodal vestibular, kinesthetic and auditory stimuli, reminiscent of the sensory experiences encountered during train rides. Over a 5-month period, we conducted four 2-week nocturnal interventions, separated by 1-week washout phases, to determine the subjectively best-perceived stimulation parameters, followed by a final 4-week intervention using the optimal parameters. We assessed sleep duration and quality using the Mini Sleep Questionnaire, monitored pulse rate changes and used videography to document nocturnal interactions between the patient and caregivers. Patient-reported outcome measures, clinical examinations and personal outcomes of specific interests were used to document daytime sleepiness, restlessness, anxiety, fatigue, cognitive performance and physical posture. In the final 4-week intervention, sleep duration increased by 25%, required caregiver interactions reduced by 75%, and caregiving time decreased by 40%. Subjective fatigue, assessed by the Checklist Individual Strength, decreased by 40%, falling below the threshold of severe fatigue. Our study suggests that rocking beds could provide a promising treatment regime for selected patients with persistent severe sleep disorders. Further research is required to validate these findings in larger patient populations with sleep disorders and other conditions.

Impact of the SARS-CoV-2 pandemic on the health of individuals with intoxication-type metabolic diseases-Data from the E-IMD consortium.

The SARS-CoV-2 pandemic challenges healthcare systems worldwide. Within inherited metabolic disorders (IMDs) the vulnerable subgroup of intoxication-type IMDs such as organic acidurias (OA) and urea cycle disorders (UCD) show risk for infection-induced morbidity and mortality. This study (observation period February 2020 to December 2021) evaluates impact on medical health care as well as disease course and outcome of SARS-CoV-2 infections in patients with intoxication-type IMDs managed by participants of the European Registry and Network for intoxication type metabolic diseases Consortium (E-IMD). Survey's respondents managing 792 patients (n = 479 pediatric; n = 313 adult) with intoxication-type IMDs (n = 454 OA; n = 338 UCD) in 14 countries reported on 59 (OA: n = 36; UCD: n = 23), SARS-CoV-2 infections (7.4%). Medical services were increasingly requested (95%), mostly alleviated by remote technologies (86%). Problems with medical supply were scarce (5%). Regular follow-up visits were reduced in 41% (range 10%-50%). Most infected individuals (49/59; 83%) showed mild clinical symptoms, while 10 patients (17%; n = 6 OA including four transplanted MMA patients; n = 4 UCD) were hospitalized (metabolic decompensation in 30%). ICU treatment was not reported. Hospitalization rate did not differ for diagnosis or age group (p = 0.778). Survival rate was 100%. Full recovery was reported for 100% in outpatient care and 90% of hospitalized individuals. SARS-CoV-2 impacts health care of individuals with intoxication-type IMDs worldwide. Most infected individuals, however, showed mild symptoms and did not require hospitalization. SARS-CoV-2-induced metabolic decompensations were usually mild without increased risk for ICU treatment. Overall prognosis of infected individuals is very promising and IMD-specific or COVID-19-related complications have not been observed.

Untargeted plasma metabolomics identifies broad metabolic perturbations in glycogen storage disease type I.

BACKGROUND: The metabolic defect in glycogen storage disease type I (GSDI) results in fasting hypoglycemia and typical secondary metabolic abnormalities (eg, hypertriglyceridemia, hyperlactatemia, hyperuricemia). The aim of this study was to assess further perturbations of the metabolic network in GSDI patients under ongoing treatment. METHODS: In this prospective observational study, plasma samples of 14 adult patients (11 GSDIa, 3 GSDIb. Mean age 26.4 years, range 16-46 years) on standard treatment were compared to a cohort of 31 healthy controls utilizing ultra-high performance liquid chromatography (UHPLC) in combination with high resolution tandem mass spectrometry (HR-MS/MS) and subsequent statistical multivariate analysis. In addition, plasma fatty acid profiling was performed by GC/EI-MS. RESULTS: The metabolomic profile showed alterations of metabolites in different areas of the metabolic network in both GSD subtypes, including pathways of fuel metabolism and energy generation, lipids and fatty acids, amino acid and methyl-group metabolism, the urea cycle, and purine/pyrimidine metabolism. These alterations were present despite adequate dietary treatment, did not correlate with plasma triglycerides or lactate, both parameters typically used to assess the quality of metabolic control in clinical practice, and were not related to the presence or absence of complications (ie, nephropathy or liver adenomas). CONCLUSION: The metabolic defect of GSDI has profound effects on a variety of metabolic pathways in addition to the known typical abnormalities. These alterations are present despite optimized dietary treatment, which may contribute to the risk of developing long-term complications, an inherent problem of GSDI which appears to be only partly modified by current therapy.

Galactokinase deficiency: lessons from the GalNet registry.

PURPOSE: Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype. METHODS: Observational study collecting medical data of 53 not previously reported GALK1 deficient patients from 17 centers in 11 countries from December 2014 to April 2020. RESULTS: Neonatal or childhood cataract was reported in 15 and 4 patients respectively. The occurrence of neonatal hypoglycemia and infection were comparable with the general population, whereas bleeding diathesis (8.1% versus 2.17-5.9%) and encephalopathy (3.9% versus 0.3%) were reported more often. Elevated transaminases were seen in 25.5%. Cognitive delay was reported in 5 patients. Urinary galactitol was elevated in all patients at diagnosis; five showed unexpected Gal-1-P increase. Most patients showed enzyme activities ≤1%. Eleven different genotypes were described, including six unpublished variants. The majority was homozygous for NM_000154.1:c.82C>A (p.Pro28Thr). Thirty-five patients were diagnosed following newborn screening, which was clearly beneficial. CONCLUSION: The phenotype of GALK1 deficiency may include neonatal elevation of transaminases, bleeding diathesis, and encephalopathy in addition to cataract. Potential complications beyond the neonatal period are not systematically surveyed and a better delineation is needed.

Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment.

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency.

PURPOSE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking. METHODS: A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients. RESULTS: Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%). CONCLUSION: The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients.

Glycemic control and complications in glycogen storage disease type I: Results from the Swiss registry.

BACKGROUND: Regular carbohydrate intake to avoid hypoglycemia is the mainstay of dietary treatment in glycogen storage disease type I (GSDI). The aim of this study was to evaluate the quality of dietary treatment and glycemic control in a cohort of GSDI patients, in relation to the presence of typical long-term complications. METHODS: Data of 25 patients (22 GSD subtype Ia and 3 GSDIb, median age 20y) from the Swiss hepatic glycogen storage disease registry was analyzed cross-sectionally. Frequency and type of hypoglycemia symptoms were assessed prospectively using a structured questionnaire. Diagnostic continuous glucose monitoring (CGM) was performed as part of usual clinical care to assess glycemic control in 14 patients, usually once per year with a mean duration of 6.2 ±â€¯1.1 consecutive days per patient per measurement. RESULTS: Although maintenance of euglycemia is the primary goal of dietary treatment, few patients (n = 3, 13%) performed capillary blood glucose measurements regularly. Symptoms possibly associated with hypoglycemia were present in 13 patients (57%), but CGM revealed periods of low glucose (<4 mmol/l) in all patients, irrespective of the presence of symptoms. GSDIa patients with liver adenomas (n = 9, 41%) showed a higher frequency and area under the curve (AUC) of low blood glucose than patients without adenomas (frequency 2.7 ±â€¯0.8 vs. 1.5 ±â€¯0.7 per day, AUC 0.11 ±â€¯0.08 vs. 0.03 ±â€¯0.02 mmol/l/d; p < 0.05). Similarly, the presence of microalbuminuria was also associated with the frequency of low blood glucose. Z-Scores of bone density correlated negatively with lactate levels. CONCLUSION: The quality of glucose control is related to the presence of typical long-term complications in GSDI. Many patients experience episodes of asymptomatic low blood glucose. Regular assessment of glucose control is an essential element to evaluate the quality of treatment, and increasing the frequency of glucose self-monitoring remains an important goal of patient education and motivation. CGM devices may support patients to optimize dietary therapy in everyday life.

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

AIM: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry. RESULTS: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities. CONCLUSION: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.

Disturbed sphingolipid metabolism with elevated 1-deoxysphingolipids in glycogen storage disease type I - A link to metabolic control.

BACKGROUND: 1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids. They are formed during sphingolipid de novo synthesis by the enzyme serine palmitoyltransferase, due to the alternate use of alanine over its canonical substrate serine. Pathologically elevated 1-deoxySL are involved in several neurological and metabolic disorders. The objective of this study was to investigate the role of 1-deoxySL in glycogen storage disease type I (GSDI). METHODS: In this prospective, longitudinal observational study (median follow-up 1.8y), the plasma 1-deoxySL profile was analyzed in 15 adult GSDI patients (12 GSDIa, 3 GSDIb), and 31 healthy controls, along with standard parameters for monitoring GSDI. RESULTS: 1-Deoxysphinganine (1-deoxySA) concentrations were elevated in GSDI compared to controls (191 ±â€¯129 vs 35 ±â€¯14 nmol/l, p < 0.0001). Concordant with the mechanism of 1-deoxySL synthesis, plasma alanine was higher (625 ±â€¯182 vs 398 ±â€¯90 µmol/l, p < 0.0001), while serine was lower in GSDI than in controls (88 ±â€¯22 vs 110 ±â€¯18 µmol/l. p < 0.001). Accordingly, serine, alanine and triglycerides were determinants of 1-deoxySA in the longitudinal analysis of GSDIa. 1-deoxySA concentrations correlated with the occurrence of low blood glucose (area under the curve below 4 mmol/l) in continuous glucose monitoring. The 1-deoxySL profile in GSDIb was distinct from GSDIa, with a different ratio of saturated to unsaturated 1-deoxySL. CONCLUSION: In addition to the known abnormalities of lipoproteins, GSDI patients also have a disturbed sphingolipid metabolism with elevated plasma 1-deoxySL concentrations. 1-DeoxySA relates to the occurrence of low blood glucose, and may constitute a potential new biomarker for assessing metabolic control. GSDIa and Ib have distinct 1-deoxySL profiles indicating that both GSD subtypes have diverse phenotypes regarding lipid metabolism.

Epidemiology of mucopolysaccharidoses.

The aim of this study was to obtain data about the epidemiology of the different types of mucopolysaccharidoses in Japan and Switzerland and to compare with similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1.7 and 1.3%, respectively. A retrospective epidemiological data collection was performed in Switzerland between 1975 and 2008 (34years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12, 24, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3 and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS is also reported to be higher in these countries. Birth prevalence of MPS II in Switzerland and other European countries is comparatively lower. The birth prevalence of MPS III and IV in Switzerland is higher than in Japan but comparable to that in most other European countries. Moreover, the birth prevalence of MPS VI and VII was very low in both, Switzerland and Japan. Overall, the frequency of MPS varies for each population due to differences in ethnic backgrounds and/or founder effects that affect the birth prevalence of each type of MPS, as seen for other rare genetic diseases. Methods for identification of MPS patients are not uniform across all countries, and consequently, if patients are not identified, recorded prevalence rates will be aberrantly low.

International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up.

Classical galactosemia (CG) is an inborn error of galactose metabolism. Evidence-based guidelines for the treatment and follow-up of CG are currently lacking, and treatment and follow-up have been demonstrated to vary worldwide. To provide patients around the world the same state-of-the-art in care, members of The Galactosemia Network (GalNet) developed an evidence-based and internationally applicable guideline for the diagnosis, treatment, and follow-up of CG. The guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. A systematic review of the literature was performed, after key questions were formulated during an initial GalNet meeting. The first author and one of the working group experts conducted data-extraction. All experts were involved in data-extraction. Quality of the body of evidence was evaluated and recommendations were formulated. Whenever possible recommendations were evidence-based, if not they were based on expert opinion. Consensus was reached by multiple conference calls, consensus rounds via e-mail and a final consensus meeting. Recommendations addressing diagnosis, dietary treatment, biochemical monitoring, and follow-up of clinical complications were formulated. For all recommendations but one, full consensus was reached. A 93 % consensus was reached on the recommendation addressing age at start of bone density screening. During the development of this guideline, gaps of knowledge were identified in most fields of interest, foremost in the fields of treatment and follow-up.

Further Concerns About Glutamine: A Case Report on Hyperammonemic Encephalopathy.

OBJECTIVE: We report a case of a woman with hyperammonemic encephalopathy following glutamine supplementation. DESIGN: Case report. INTERVENTIONS: Plasma amino acid analysis suggestive of a urea cycle defect and initiation of a treatment with lactulose and the two ammonia scavenger drugs sodium benzoate and phenylacetate. Together with a restricted protein intake ammonia and glutamine plasma levels decreased with subsequent improvement of the neurological status. MEASUREMENTS AND MAIN RESULTS: Massive catabolism and exogenous glutamine administration may have contributed to hyperammonemia and hyperglutaminemia in this patient. CONCLUSION: This case adds further concerns regarding glutamine administration to critically ill patients and implies the importance of monitoring ammonia and glutamine serum levels in such patients.

Fatal hyperammonemia and carbamoyl phosphate synthetase 1 (CPS1) deficiency following high-dose chemotherapy and autologous hematopoietic stem cell transplantation.

Fatal hyperammonemia secondary to chemotherapy for hematological malignancies or following bone marrow transplantation has been described in few patients so far. In these, the pathogenesis of hyperammonemia remained unclear and was suggested to be multifactorial. We observed severe hyperammonemia (maximum 475 µmol/L) in a 2-year-old male patient, who underwent high-dose chemotherapy with carboplatin, etoposide and melphalan, and autologous hematopoietic stem cell transplantation for a neuroblastoma stage IV. Despite intensive care treatment, hyperammonemia persisted and the patient died due to cerebral edema. The biochemical profile with elevations of ammonia and glutamine (maximum 1757 µmol/L) suggested urea cycle dysfunction. In liver homogenates, enzymatic activity and protein expression of the urea cycle enzyme carbamoyl phosphate synthetase 1 (CPS1) were virtually absent. However, no mutation was found in CPS1 cDNA from liver and CPS1 mRNA expression was only slightly decreased. We therefore hypothesized that the acute onset of hyperammonemia was due to an acquired, chemotherapy-induced (posttranscriptional) CPS1 deficiency. This was further supported by in vitro experiments in HepG2 cells treated with carboplatin and etoposide showing a dose-dependent decrease in CPS1 protein expression. Due to severe hyperlactatemia, we analysed oxidative phosphorylation complexes in liver tissue and found reduced activities of complexes I and V, which suggested a more general mitochondrial dysfunction. This study adds to the understanding of chemotherapy-induced hyperammonemia as drug-induced CPS1 deficiency is suggested. Moreover, we highlight the need for urgent diagnostic and therapeutic strategies addressing a possible secondary urea cycle failure in future patients with hyperammonemia during chemotherapy and stem cell transplantation.

Highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy.

BACKGROUND: Multiple acyl-CoA dehydrogenase deficiency- (MADD-), also called glutaric aciduria type 2, associated leukodystrophy may be severe and progressive despite conventional treatment with protein- and fat-restricted diet, carnitine, riboflavin, and coenzyme Q10. Administration of ketone bodies was described as a promising adjunct, but has only been documented once. METHODS: We describe a Portuguese boy of consanguineous parents who developed progressive muscle weakness at 2.5 y of age, followed by severe metabolic decompensation with hypoglycaemia and coma triggered by a viral infection. Magnetic resonance (MR) imaging showed diffuse leukodystrophy. MADD was diagnosed by biochemical and molecular analyses. Clinical deterioration continued despite conventional treatment. Enteral sodium D,L-3-hydroxybutyrate (NaHB) was progressively introduced and maintained at 600 mg/kg BW/d (≈ 3% caloric need). Follow up was 3 y and included regular clinical examinations, biochemical studies, and imaging. RESULTS: During follow up, the initial GMFC-MLD (motor function classification system, 0 = normal, 6 = maximum impairment) level of 5-6 gradually improved to 1 after 5 mo. Social functioning and quality of life recovered remarkably. We found considerable improvement of MR imaging and spectroscopy during follow up, with a certain lag behind clinical recovery. There was some persistent residual developmental delay. CONCLUSION: NaHB is a highly effective and safe treatment that needs further controlled studies.

Reversal of cardiomyopathy in propionic acidemia after liver transplantation: a 10-year follow-up.

Cardiomyopathy is a frequent complication in propionic acidemia. It is mostly rapidly fatal and independent of the metabolic control or medical intervention. Here, we present the reversal of a severe cardiomyopathy after liver transplantation in a patient with propionic acidemia and the long-term stability after ten years. Liver transplantation in patients with propionic acidemia may be considered a valid and long-lasting treatment when cardiomyopathy is progressive and unresponsive to medical therapy.

Mutations in SDHD lead to autosomal recessive encephalomyopathy and isolated mitochondrial complex II deficiency.

BACKGROUND: Defects of the mitochondrial respiratory chain complex II (succinate dehydrogenase (SDH) complex) are extremely rare. Of the four nuclear encoded proteins composing complex II, only mutations in the 70 kDa flavoprotein (SDHA) and the recently identified complex II assembly factor (SDHAF1) have been found to be causative for mitochondrial respiratory chain diseases. Mutations in the other three subunits (SDHB, SDHC, SDHD) and the second assembly factor (SDHAF2) have so far only been associated with hereditary paragangliomas and phaeochromocytomas. Recessive germline mutations in SDHB have recently been associated with complex II deficiency and leukodystrophy in one patient. METHODS AND RESULTS: We present the clinical and molecular investigations of the first patient with biochemical evidence of a severe isolated complex II deficiency due to compound heterozygous SDHD gene mutations. The patient presented with early progressive encephalomyopathy due to compound heterozygous p.E69 K and p.*164Lext*3 SDHD mutations. Native polyacrylamide gel electrophoresis and western blotting demonstrated an impaired complex II assembly. Complementation of a patient cell line additionally supported the pathogenicity of the novel identified mutations in SDHD. CONCLUSIONS: This report describes the first case of isolated complex II deficiency due to recessive SDHD germline mutations. We therefore recommend screening for all SDH genes in isolated complex II deficiencies. It further emphasises the importance of appropriate genetic counselling to the family with regard to SDHD mutations and their role in tumorigenesis.

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders.

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial.