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Posted by Myles at AM. Older Posts Home. Subscribe to: Posts Atom. Patients with upper respiratory infections generally recovered slowly, while cases of dietary non-adherence resolved more quickly. The response of individual patients may vary depending on clinical status and triggering factors. Mitochondrial disorders are an increasingly recognized cause of heart dysfunction, with the primary manifestations being cardiomyopathy and conduction defects. This review focuses on the complex genetics of mitochondrial disease and recently discovered conditions that affect mitochondrial function.

Next-generation sequencing techniques, especially whole-exome sequencing, have led to the discovery of a number of conditions that cause mitochondrial dysfunction and subsequent cardiac abnormalities. Nuclear DNA defects are the main cause of mitochondrial disease in children, with disease pathogenesis being related to either abnormalities in specific mitochondrial electron transport chain subunits or in proteins related to subunit or mitochondrial DNA maintenance, mitochondrial protein translation, lipid bilayer structure, or other aspects of mitochondrial function.

Currently, symptomatic therapy using standard medications targeting relief of complications is the primary approach to treatment. There are no US Food and Drug Administration-approved therapies for the specific treatment of mitochondrial disease. However, on the basis of recent advances in understanding of the pathophysiology of these complex disorders, various novel approaches are either in clinical trials or in development. To evaluate the association between newborn acylcarnitine profiles and the subsequent development of necrotizing enterocolitis NEC with the use of routinely collected newborn screening data in infants born preterm.

A retrospective cohort study was conducted with the use of discharge records for infants born preterm admitted to neonatal intensive care units in California from to who had linked state newborn screening results. A model-development cohort of 94 preterm births from to was used to develop a risk-stratification model that was then applied to a validation cohort of 22 births from Fourteen acylcarnitine levels and acylcarnitine ratios were associated with increased risk of developing NEC.

Six acylcarnitine levels, along with birth weight and total parenteral nutrition, identified Abnormal fatty acid metabolism was associated with prematurity and the development of NEC. Metabolic profiling through newborn screening may serve as an objective biologic surrogate of risk for the development of disease and thus facilitate disease-prevention strategies. The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease.

This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability.

Variants were assessed for their effect on CAMK2 function and on neuronal migration. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Hawkinsinuria is a rare disorder of tyrosine metabolism that can manifest with metabolic acidosis and growth arrest around the time of weaning off breast milk, typically followed by spontaneous resolution of symptoms around 1 year of age. The urinary metabolites hawkinsin, quinolacetic acid, and pyroglutamic acid can aid in identifying this condition, although their relationship to the clinical manifestations is not known.

Herein we describe clinical and laboratory findings in two fraternal twins with hawkinsinuria who presented with failure to thrive and metabolic acidosis. Close clinical follow-up and laboratory testing revealed previously unrecognized hypoglycemia, hypophosphatemia, combined hyperlipidemia, and anemia, along with the characteristic urinary metabolites, including massive pyroglutamic aciduria.

Treatment with N-acetyl-L-cysteine NAC restored normal growth and normalized or improved most biochemical parameters. The dramatic response to NAC therapy supports the idea that glutathione depletion plays a key role in the pathogenesis of hawkinsinuria. Long-chain fatty acid oxidation disorders LC-FAOD can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment.

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Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy was treated with triheptanoin under emergency treatment or compassionate use protocols.

Case reports from 10 patients 8 infants with moderate or severe cardiomyopathy associated with LC-FAOD are summarized. The majority of these patients were detected by newborn screening, with follow up confirmatory testing, including mutation analysis; all patients were managed with standard treatment, including medium chain triglyceride MCT oil. While on this regimen, they presented with acute heart failure requiring hospitalization and cardiac support ventilation, ECMO, vasopressors and, in some cases, resuscitation.

The patients discontinued MCT oil and began treatment with triheptanoin, an investigational drug. Triheptanoin is expected to provide anaplerotic metabolites, to replace deficient TCA cycle intermediates and improve effective energy metabolism. Cardiac function was measured by echocardiography and ejection fraction EF was assessed. Continued treatment was associated with longer-term stabilization of clinical signs of cardiomyopathy.

The most common adverse event observed was gastrointestinal distress. Of the 10 patients, 7 have continued on treatment, 1 elected to discontinue due to tolerability issues, and 2 patients died from other causes. Overall, the presented cases suggest a therapeutic effect of triheptanoin in the management of acute cardiomyopathy associated with LC-FAOD. In December , a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders PMD and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners.

Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials RCTs has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape.

As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1 defining the disease, 2 clinical trial design, 3 biomarker selection, 4 mechanistic approaches, 5 challenges in using dietary supplements, 6 standards of clinical care, and 7 collaboration issues.

Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.

Also known as Mi2, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c. ArgGln , c. TrpLeu , c.

ArgLeu , and c. Previous studies in yeast showed the equivalent Arg and Trp residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p. ArgGln and p. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the roleof CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.

An understanding of health related quality of life HRQoL in children and families affected by methylmalonic acidemia MMA is important in planning counseling and therapeutic intervention. Liver transplantation LT is used as a treatment for MMA; however, its risks and benefits continue to be investigated. Scores for children with MMA were lowest in school and social functioning and scores for families were lowest in worry and activity impairment. Inborn metabolic diseases of the liver can be life-threatening disorders that cause debilitating and permanent neurological damage.

Symptoms may manifest as early as the neonatal period.

Gregory Enns, MD

Liver transplant replaces the enzymatically deficient liver, allowing for metabolism of toxic metabolites. Patient and graft survival is comparable to that of the United States, where most of the studies are based on deceased donors. No living donor complications were observed, suggesting that LDLT is as safe and effective as deceased donor transplants performed in the USA. Increased utilization of living donors in the USA will allow for early transplantation to prevent permanent neurological damage in those with severe disease.

Pediatric transplant centers should consider utilizing living donors when feasible for children with metabolic disorders of the liver. Early medical and dietary interventions can result in significantly better outcomes and improved quality of life for patients with GA-I. We describe a novel case with the known pathogenic MV variant and a novel VL variant, and present updated and previously unreported clinical, biochemical, functional and molecular data on eight other patients all sharing the MV allele. Three of the nine patients are of African American ancestry, with two as siblings. Binder phenotype, or maxillonasal dysostosis, is a distinctive pattern of facial development characterized by a short nose with a flat nasal bridge, an acute nasolabial angle, a short columella, a convex upper lip, and class III malocclusion.

We report 3 cases of prenatally diagnosed Binder phenotype associated with perinatal respiratory impairment. Mutations in GNAO1 have been described in 11 patients to date. Although most of these individuals had epileptic encephalopathy, four patients had a severe movement disorder as the prominent feature. We describe the largest series of patients with de novoGNAO1 mutations who have severe chorea, developmental delay, and hypotonia in the absence of epilepsy.

Six patients with recurrent missense mutations in GNAO1 as detected by whole exome sequencing were identified at three institutions. We describe the presentation, clinical course, and response to treatment of these patients. All six patients exhibited global developmental delay and hypotonia from infancy. Chorea developed by age fouryears in all but one patient, who developed chorea at 14years. Treatments with neuroleptics and tetrabenazine were most effective in the baseline management of chorea.

Gregory Enns - Stanford Children's Health

The chorea became gradually progressive and marked by episodes of severe, refractory ballismus requiring intensive care unit admissions in four of six patients. Exacerbations indirectly led to the death of two patients. Patients with GNAO1 mutations can present with a severe, progressive movement disorder in the absence of epilepsy. Exacerbations may be refractory to treatment and can result in life-threatening secondary complications. Early and aggressive treatment of these exacerbations with direct admission to intensive care units for treatment with anesthetic drips may prevent some secondary complications.

However the chorea and ballismus can be refractory to maximum medical therapy. Whole-exome sequencing of 13 individuals with developmental delay commonly accompanied by abnormal muscle tone and seizures identified de novo missense mutations enriched within a sub-region of GNB1, a gene encoding the guanine nucleotide-binding proteinsubunit beta-1, G. These 13 individuals were identified among a base of 5, individuals recruited for various undiagnosed genetic disorders.

The majority of these 13 mutations affect known G binding sites, which suggests that a likely disease mechanism is through the disruption of the protein interface required for G-G interaction resulting in a constitutively active G or through the disruption of residues relevant for interaction between G and certain downstream effectors resulting in reduced interaction with the effectors. Strikingly, 8 of the 13 individuals recruited here for a neurodevelopmental disorder have a germline de novo GNB1 mutation that overlaps a set of five recurrent somatic tumor mutations for which recent functional studies demonstrated a gain-of-function effect due to constitutive activation of G protein downstream signaling cascades for some of the affected residues.

The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency LALD in infancy. Investigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure GF.

Kaplan-Meier survival analyses were conducted for the overall population and for treated and untreated patients. Records for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3. Among patients with early GF, median age at death was 3. These data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.

Genet Med 18 5, This spectral region was chosen due to the strong NH3 absorption strength and lack of spectral interference from H2O and CO2 for laser-based sensing applications.

Professor of Pediatrics (Genetics) at the Lucile Salter Packard Children's Hospital

Spectroscopic parameters were determined by multi-line fitting using Voigt lineshapes of absorption spectra measured with two quantum cascade lasers in thermodynamically-controlled optical cells. The temperature dependence of broadening was measured over a range of temperatures between and K. These measurements aid the development of mid-infrared NH3 sensors for a broad range of gas mixtures and at elevated temperatures.

The aim of this study was to characterize key clinical manifestations of lysosomal acid lipase deficiency LAL D in children and adults. Investigators reviewed medical records of LAL D patients ages 5 years, extracted historical data, and obtained prospective laboratory and imaging data on living patients to develop a longitudinal dataset.

A total of 49 patients were enrolled; 48 had confirmed LAL D. Mean age at first disease-related abnormality was 9. Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 AHDC1. The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors.

Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development.

Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype. N-Glycanase 1, encoded by NGLY1, catalyzes the deglycosylation of misfolded N-linked glycoproteins retrotranslocated into the cytosol. We identified nine cases with mutations in NGLY1. The patients show developmental delay, seizures, peripheral neuropathy, abnormal liver function and alacrima absence of tears.

The mutations in NGLY1 resulted in the absence of N-glycanase 1 protein in patient-derived fibroblasts.


Applying a recently established cellular deglycosylation-dependent Venus fluorescence assay, we found that patient fibroblasts had dramatically reduced fluorescence, indicating a pronounced reduction in N-glycanase enzymatic activity. Using this assay, we could find no evidence of other related activities. Similar safety and efficacy data were observed for children View details for DOI Leigh syndrome is a progressive neurodegenerative disorder with usual onset of symptoms during the first year of life.

The disorder has been associated with mutations in over 30 genes. This difficulty with genetic heterogeneity makes whole exome sequencing a more cost-effective approach for investigation of etiology. We describe an individual with typical Leigh syndrome who was found to have compound heterozygous mutations in the gene HIBCH 3-hydroxyisobutyryl coenzyme A hydrolase , an enzyme involved in the catabolism of valine.

She exhibited significant clinical improvement after a valine-restricted diet. A subset of patients with uncharacterized Leigh syndrome present with specific biochemical abnormalities. This report highpoints the challenges and restrictions of routine metabolic testing and features the recognition of inborn errors of metabolism as potential treatable causes of Leigh syndrome.

Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals.

Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa.

Of samples tested to date, no anti-drug antibodies have been detected. Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. Methylmalonic acidemia MMA is one of the most frequently encountered forms of branched-chain organic acidemias. Biochemical abnormalities seen in some MMA patients, such as lactic acidemia and increased tricarboxylic acid cycle intermediate excretion, suggest mitochondrial dysfunction.

In order to investigate the possibility of mitochondrial involvement in MMA, we examined liver tissue for evidence of mitochondrial ultrastructural abnormalities. Five explanted livers obtained from MMA mut 0 patients undergoing liver transplantation were biopsied. All patients had previous episodes of metabolic acidosis, lactic acidemia, ketonuria, and hyperammonemia. All biopsies revealed a striking mitochondriopathy by electron microscopy. Mitochondria were markedly variable in size, shape, and conformation of cristae. The inner matrix appeared to be greatly expanded and the cristae were diminutive and disconnected.

No crystalloid inclusions were noted. This series clearly documents extensive mitochondrial ultrastructure abnormalities in liver samples from MMA patients undergoing transplantation, providing pathological evidence for mitochondrial dysfunction in the pathophysiology of MMA mut 0. Considering the trend to abnormally large mitochondria, the metabolic effects of MMA may restrict mitochondrial fission or promote fusion.

The correlation between mitochondrial dysfunction and morphological abnormalities in MMA may provide insights for better understanding and monitoring of optimized or novel therapeutic strategies. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain i current success rates for causal gene detection in a clinical setting; ii if there are insurance authorization issues; and iii if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing.

Methods:We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers. Results:A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage.

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Only three Conclusion:Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost. Genet Med advance online publication 13 February Genetics in Medicine ; doi Although mitochondrial disorders are among the most common inherited conditions that cause neurologic impairment, there are currently no U.

Food and Drug Administration FDA -approved medications designed to treat primary mitochondrial disease. This is in part related to the lack of biomarkers to monitor disease status or response to treatment and the paucity of randomized, controlled clinical trials focused on mitochondrial disease therapies.

Despite this discouraging historical precedent, a number of new approaches to mitochondrial disease therapy are on the horizon. By studying metabolites central to redox chemistry, investigators are gaining new insights into potential noninvasive biomarkers. Controlled clinical trials designed to study the effects of novel redox-modulating therapies, such as EPI, in patients with inherited mitochondrial disease are also underway.

Furthermore, several new compounds with potential effects on inner mitochondrial membrane function and mitochondrial biogenesis are in development. Such advances are providing the foundation for a new era in mitochondrial disease therapeutics. Mitochondrial next generation sequencing NGS panels offer single-step analysis of the numerous nuclear genes involved in the structure, function, and maintenance of mitochondria.

However, the complexities of mitochondrial biology and genetics raise points for consideration in clinical use of these tests. To understand the current status of mitochondrial genetic testing, we assessed the gene offerings and consent forms of mitochondrial NGS panels available from seven US-based clinical laboratories. None of the consent documents reviewed had options for patient preference regarding receipt of incidental findings. These findings raise points of discussion applicable to mitochondrial diagnostics, but also to the larger arenas of exome and genome sequencing, including the need to consider the boundaries between clinical and research testing, the necessity of appropriate informed consent, and the responsibilities of clinical laboratories and clinicians.

Based on these findings, we recommend careful evaluation by laboratories of the genes offered on NGS panels, clear communication of the predicted phenotypes, and revised consent forms to allow patients to make choices about receiving incidental findings. We hope that our analysis and recommendations will help to maximize the considerable clinical utility of NGS panels for the diagnosis of mitochondrial disease. Whole-genome sequencing WGS is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.

To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. A multidisciplinary team reviewed all potentially reportable genetic findings.

Five physicians proposed initial clinical follow-up based on the genetic findings. Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.

Curation of 90 to genetic variants in each participant required a median of 54 minutes range, minutes per genetic variant, resulted in moderate classification agreement between professionals Gross , 0. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer.

Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up Fleiss , 0. The pathophysiology of succinic semialdehyde dehydrogenase SSADH deficiency is not completely understood. Oxidative stress, mitochondrial pathology, and low reduced glutathione levels have been demonstrated in mice, but no studies have been reported in humans.

Thus, targeting the oxidative stress axis may be a potential therapeutic approach if our findings are confirmed in other patients. Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience.

The Mitochondrial Medicine Society MMS assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care. Clinicians have limited evidence-based guidelines on which to formulate clinical decisions regarding diagnosis, treatment and management for patients with mitochondrial disorders.

The Mitochondrial Medicine Society MMS assessed the current state of clinical practice including diagnosis, preventive care and treatment, as provided by various mitochondrial disease providers in North America. In this second of two reports, we present data related to clinical practice that highlight the challenges clinicians face in the routine care of patients with established mitochondrial disease. Concerning variability in treatment and preventative care approaches were noted.

We hope that sharing this information will be a first step toward formulating a set of consensus criteria and establishing standards of care. Clinically, MDSs are mainly categorized as myopathic, encephalomyopathic, hepatocerebral, or multi-systemic forms. To date, the myopathic form of MDS is mainly caused by mutations in the TK2 gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides.

We analyzed 9 unrelated families with 11 affected subjects exhibiting the myopathic form of MDS, by sequencing the TK2 gene. Twelve mutations including 4 novel mutations were detected in 9 families. Skeletal muscle specimens were available from 7 out of 11 subjects. Respiratory chain enzymatic activities in skeletal muscle were measured in 6 subjects, and enzymatic activities were reduced in 3 subjects. Quantitative analysis of mtDNA content in skeletal muscle was performed in 5 subjects, and marked mtDNA content reduction was observed in each.

In addition, we outline the molecular and clinical characteristics of this syndrome in a total of 52 patients including those previously reported, and a total of 36 TK2 mutations are summarized. Clinically, hypotonia and proximal muscle weakness are the major phenotypes present in all subjects. In summary, our study expands the molecular and clinical spectrum associated with TK2 deficiency. Cholesteryl ester storage disease CESD , an inherited deficiency of lysosomal acid lipase LAL , is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly.

To assess the clinical effects and safety of the recombinant human LAL, sebelipase alfa, nine patients received four once-weekly infusions 0. Sebelipase alfa was well tolerated, with mostly mild adverse events unrelated to sebelipase alfa. No antidrug antibodies were detected. Conclusion: These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with CESD is well tolerated, rapidly decreases serum transaminases, and that these improvements are sustained with long-term dosing and are accompanied by improvements in serum lipid profile.

Isolated methylmalonic acidemia MMA , caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase MUT , is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. Renal biopsies and biomarker analysis from a large and diverse patient cohort ClinicalTrials. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.

A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism NDSI-IEM , was launched in to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism IEM that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous dietary or endogenous protein, carbohydrate, or fat.

For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM.

Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers. Genetically defined Leigh syndrome LS is a rare, fatal inherited neurodegenerative disorder that predominantly affects children. Although mitochondrial dysfunction has clearly been associated with oxidative stress, few studies have specifically examined Leigh syndrome patients' blood glutathione levels. In this study, we analyzed the balance between oxidized and reduced glutathione in lymphocytes of 10 patients with genetically confirmed LS and monitored the effects of glutathione status following 6 months of treatment with EPI, a novel redox therapeutic.

Lymphocytes were obtained from blood samples of 10 children with a genetically confirmed diagnosis of LS and in 20 healthy subjects. Total, reduced, oxidized and protein-bound glutathione levels were determined by HPLC analysis. Erythrocyte superoxide dismutase and glutathione peroxidase enzyme activities were measured by spectrophotometric assays. Plasma total thiols, carbonyl contents and malondialdehyde were assessed by spectrophotometric and fluorometric assays.

These findings negatively correlated with the glutathione peroxidase activity, which underwent a significant decrease in patients. The data presented here strongly support glutathione as a "redox blood signature" in mitochondrial disorders and its use as a clinical trial endpoint in the development of mitochondrial disease therapies.

Purpose:The application of massively parallel sequencing technology to the analysis of the mitochondrial genome has demonstrated great improvement in the molecular diagnosis of mitochondrial DNA-related disorders. The objective of this study was to investigate the performance characteristics and to gain new insights into the analysis of the mitochondrial genome.

Methods:The entire mitochondrial genome was analyzed as a single amplicon using a long-range PCR-based enrichment approach coupled with massively parallel sequencing. The interference of the nuclear mitochondrial DNA homologs was distinguished from the actual mitochondrial DNA sequences by comparison with the results obtained from conventional PCR-based Sanger sequencing using multiple pairs of primers. Results:Our results demonstrated the uniform coverage of the entire mitochondrial genome.

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This single amplicon massively parallel sequencing strategy provides an accurate quantification of mutation heteroplasmy as well as the detection and mapping of mitochondrial DNA deletions. Conclusion:The ability to quantitatively and qualitatively evaluate every single base of the entire mitochondrial genome is indispensible to the accurate molecular diagnosis and genetic counseling of mitochondrial DNA-related disorders.

This new approach may be considered as first-line testing for comprehensive analysis of the mitochondrial genome. Genet Med 5 Mutations in several known or putative glycosyltransferases cause glycosylation defects in -dystroglycan -DG , an integral component of the dystrophin glycoprotein complex. The hypoglycosylation reduces the ability of -DG to bind laminin and other extracellular matrix ligands and is responsible for the pathogenesis of an inherited subset of muscular dystrophies known as the dystroglycanopathies.

By exome and Sanger sequencing we identified two individuals affected by a dystroglycanopathy with mutations in -1,3-N-acetylgalactosaminyltransferase 2 B3GALNT2. A subsequent study of a separate cohort of individuals identified recessive mutations in four additional cases that were all affected by dystroglycanopathy with structural brain involvement. We show that functional dystroglycan glycosylation was reduced in the fibroblasts and muscle when available of these individuals via flow cytometry, immunoblotting, and immunocytochemistry.

B3GALNT2 localized to the endoplasmic reticulum, and this localization was perturbed by some of the missense mutations identified. Moreover, knockdown of b3galnt2 in zebrafish recapitulated the human congenital muscular dystrophy phenotype with reduced motility, brain abnormalities, and disordered muscle fibers with evidence of damage to both the myosepta and the sarcolemma.

Functional dystroglycan glycosylation was also reduced in the b3galnt2 knockdown zebrafish embryos. LT has emerged as a surgical treatment for UCDs. We hypothesize that LT can be safely and broadly utilized in the pediatric population to effectively prevent hyperammonemic crises and potentially improve neurocognitive outcomes. Amyoplasia congenita is a distinct form of arthrogryposis with characteristic features including internally rotated and adducted shoulders, extended elbows, flexion, and ulnar deviation of the wrists, and adducted thumbs.

Fetal hypokinesia, secondary to a variety of genetic conditions, neuromuscular disorders, and environmental agents, is associated with contractures. In order to increase our understanding of the phenotypic spectrum associated with SURF 1 deficiency, a common cause of mitochondrial respiratory chain complex IV deficiency and Leigh syndrome, we describe a now 6-year-old boy who presented in the neonatal period with amyoplasia congenita.

His development was normal until age Following the onset of neurological symptoms, he gradually developed severe kyphosis and lower limb contractures. Blood and cerebrospinal fluid lactate levels were elevated and head imaging showed characteristic features of Leigh syndrome. He was found to harbor two pathogenic heterozygous mutations in the SURF 1 gene. In this case, mitochondrial dysfunction and the resultant energy deficiency may have played a role in causing abnormal neuronal development during embryogenesis, causing arthrogryposis. A variety of mitochondrial respiratory chain complex deficiencies have been associated with contractures of varying severity.

Therefore, mitochondrial disorders should be considered in the differential diagnosis of neonatal arthrogryposis, especially if other characteristic findings such as lactic acidemia or basal ganglia abnormalities are present. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases.

A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis. There was a strong inverse correlation between initial C5OH level and residual enzyme activity. Developmental outcome included several children with mental retardation including one with Down syndrome and one with schizencephaly and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity.

Free carnitine deficiency was relatively common. Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms poor feeding, hypoglycemia, fasting intolerance, etc.

Genitopatellar syndrome GPS is a skeletal dysplasia with cerebral and genital anomalies for which the molecular basis has not yet been determined. The mutant transcripts do not undergo nonsense-mediated decay in cells from subjects with GPS. In addition, human pathological analyses and mouse expression studies point to systemic roles of KAT6B in controlling organismal growth and development. Myst4 the mouse orthologous gene is expressed in mouse tissues corresponding to those affected by GPS.

Phenotypic differences and similarities between GPS, the Say-Barber-Biesecker variant of Ohdo syndrome caused by different mutations of KAT6B , and Rubinstein-Taybi syndrome caused by mutations in other histone acetyltransferases are discussed. Together, the data support an epigenetic dysregulation of the limb, brain, and genital developmental programs. Propionic acidemia is an organic acidemia that can lead to metabolic acidosis, coma and death, if not treated appropriately in the acute setting. Recent advancements in treatment have allowed patients with propionic acidemia to live beyond the neonatal period and acute presentation.

The natural history of the disease is just beginning to be elucidated as individuals reach older ages. However, as of yet no clear genotype-phenotype correlations are known. As patients age, the natural progression of propionic acidemia illuminates intellectual difficulties, increased risk for neurological complications, including stroke-like episodes, cardiac complications, and gastrointestinal difficulties, as well as a number of other complications.

This article reviews the available literature for the natural history of propionic acidemia. Here we report a novel missense mutation found in the HSD17B10 gene, namely c. The affected boy, who possesses mutant HSD10 p. V65A , has a neurological syndrome with metabolic derangements, choreoathetosis, refractory epilepsy and learning disability.

He has no history of acute decompensation or metabolic acidosis whereas his urine organic acid profile, showing elevated levels of 2-methylhydroxybutyrate and tiglylglycine, is characteristic of HSD10 deficiency. His HSD10 activity was much lower than the normal control level, with normal -ketothiolase activity. The c. The patient's mother is an asymptomatic carrier, and has a mixed ancestry Hawaiian, Japanese and Chinese.

This demonstrates that HSD10 deficiency patients are not confined to a particular ethnicity although previously reported cases were either Spanish or German descendants. This study evaluated the question whether length of in utero exposure to selective serotonin reuptake inhibitor SSRI antidepressants might affect neonatal outcome and psychomotor development in infancy. Birth outcome was determined in the offspring of 55 women with major depressive disorder who used SSRI medication for different durations during their pregnancies.

Duration of in utero exposure to SSRIs was negatively associated with total Apgar scores, specifically the activity subscale. Odds ratios for a low score View details for DOI We report that -tocotrienol quinone ATQ3 is a metabolite of -tocotrienol, and that ATQ3 is a potent cellular protectant against oxidative stress and aging.

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ATQ3 is orally bioavailable, crosses the blood-brain barrier, and has demonstrated clinical response in inherited mitochondrial disease in open label studies. ATQ3 activity is dependent upon reversible 2e-redox-cycling. ATQ3 may represent a broader class of unappreciated dietary-derived phytomolecular redox motifs that digitally encode biochemical data using redox state as a means to sense and transfer information essential for cellular function.

The panel involved in the development of this consensus statement acknowledged the lack of data regarding the potential for more subtle suboptimal outcomes and the need for further research into treatment options. In subsequent years, the approval of new treatment options for PKU and outcome data for patients treated from the newborn period by dietary therapy alone have become available.

We hypothesized that a review of the PKU literature since would provide further evidence related to neurocognitive, psychosocial, and physical outcomes that could serve as a basis for reassessment of the NIH Consensus Statement. A systematic review of literature residing in PubMed, Scopus and PsychInfo was performed in order to assess the outcome data over the last decade in diet-alone early-treated PKU patients to assess the need for new recommendations and validity of older recommendations in light of new evidence.

Despite the remarkable success of public health programs that have instituted newborn screening and early introduction of dietary therapy for PKU, there is a growing body of evidence that suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, bone pathology and maternal PKU outcomes are suboptimal.

The time may be right for revisiting the NIH Consensus Statement in order to address a number of important issues related to PKU management, including treatment advancements for metabolic control in PKU, blood Phe variability, neurocognitive and psychological assessments, routine screening measures for nutritional biomarkers, and bone pathology. In order to determine long-term outcome, including survival, growth and development, following liver transplantation in children with metabolic disorders, we retrospectively reviewed charts of 54 children with metabolic disorders evaluated from for presenting symptoms, transplantation timing and indications, survival, metabolic parameters, growth, and development.

Thirty-three patients underwent liver transplantation 12 received combined liver-kidney transplants at a median age of 21 months. At a median follow-up of 3. For the group as a whole, weight Z scores improved and body mass index at follow-up was in the normal range. Two yr post-transplantation, psychomotor development improved significantly p View details for DOI Although the protocol that most experienced metabolic centers in the United States follow for treating acute hyperammonemia in urea cycle disorders UCDs is similar to that proposed by Brusilow and Batshaw in the early s, over the years a steady evolution has taken place.

Continued developments in intensive care, surgical and hemodialysis techniques, fluid and electrolyte management, cardiovascular support, and emergency transport have contributed to improved management of acute hyperammonemia. Compared to historical data, survival of urea cycle patients has also improved following treatment with alternative pathway therapy, in addition to appropriate supportive care, including the provision of adequate calories to prevent catabolism and promote anabolism and hemodialysis if needed.

However, overall neurological outcomes have been suboptimal. There are currently a number of exciting prospective new therapies on the horizon, including novel medications or cell-based treatments. Nevertheless, the therapeutic expertise that is currently in place at centers specializing in management of metabolic emergencies already has the potential to improve survival and outcome in these children significantly.

The early identification of UCD patients so that transport to a metabolic treatment center may be carried out without delay continues to be a major area of focus and challenge. Phenylketonuria PKU was the first inherited metabolic disease in which treatment was found to prevent clinical features of the disorder; dietary management was established almost 60 years ago. The institution of a low-phenylalanine Phe diet in the first few weeks of life was made possible by Guthrie neonatal screening, which further increased effectiveness of therapy.

Indeed, neonatal diagnosis of PKU followed by institution of a low-Phe diet has been a remarkable success in preventing the devastating brain damage associated with untreated PKU. Nevertheless, significant difficulties exist in caring for PKU patients, including problems with adhering to the prescribed dietary regimen and the presence of neurocognitive deficits despite therapy.

During the past few years, several ideas for new treatment strategies have emerged. This review aims to address these treatment strategies based on theoretical considerations of the biochemistry and pathogenesis of PKU. Recent times have seen the introduction of a wide array of novel treatments currently in clinical use, including more palatable medical foods, glycomacropeptide, large neutral amino acids, and tetrahydrobiopterin.

Gregory Enns

Human trials are underway using an enzymatic therapeutic approach, while preclinical work continues in the fields of gene and cellular therapy. These therapeutic strategies propose to treat PKU at various levels, including nutritional intake, gut, liver, and blood-brain barrier, and have the potential to further improve outcome in PKU. Hypoplastic glomerulocystic kidney disease is an autosomal dominant disorder caused by mutations in hepatocyte nuclear factor-1beta. Hepatoblastoma is a sporadic occurring tumor of embryonal origin that has been associated with the several overgrowth syndromes.

We report a case of concomitant hypoplastic glomerulocystic kidney disease and hepatoblastoma. Review of the literature identified 4 other patients with a similar association. We propose that hypoplastic glomerulocystic kidney disease and hepatoblastoma represent a possible association, and we excluded mutations in hepatocyte nuclear factor-1beta in our patient as causative of this putative association. To describe 3 patients with the cblD disorder, a rare inborn error of cobalamin metabolism caused by mutations in the MMADHC gene that can result in isolated homocystinuria, isolated methylmalonic aciduria, or combined homocystinuria and methylmalonic aciduria.