Publications by authors named "Irini Manoli"

49 Publications

Differentiating Moebius syndrome and other congenital facial weakness disorders with electrodiagnostic studies.

Muscle Nerve 2021 Jan 2. Epub 2021 Jan 2.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Introduction: Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW.

Methods: Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography.

Results: MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement.

Discussion: EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.
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http://dx.doi.org/10.1002/mus.27159DOI Listing
January 2021

Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry.

Brain Commun 2020 14;2(1):fcaa014. Epub 2020 Feb 14.

Quantitative Medical Imaging Section, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA.

In this study, we used a novel imaging technique, DTI (diffusion tensor imaging)-driven tensor-based morphometry, to investigate brain anatomy in subjects diagnosed with Moebius syndrome ( = 21), other congenital facial weakness disorders ( = 9) and healthy controls ( = 15). First, we selected a subgroup of subjects who satisfied the minimum diagnostic criteria for Moebius syndrome with only mild additional neurological findings. Compared to controls, in this cohort, we found a small region of highly significant volumetric reduction in the paramedian pontine reticular formation and the medial longitudinal fasciculus, important structures for the initiation and coordination of conjugate horizontal gaze. Subsequently, we tested if volume measurements from this region could help differentiate individual subjects of the different cohorts that were included in our study. We found that this region allowed discriminating Moebius syndrome subjects from congenital facial weakness disorders and healthy controls with high sensitivity (94%) and specificity (89%). Interestingly, this region was normal in congenital facial weakness subjects with oculomotor deficits of myopathic origin, who would have been classified as Moebius on the basis of purely clinical diagnostic criteria, indicating a potential role for diffusion MRI morphometry for differential diagnosis in this condition. When the entire Moebius syndrome cohort was compared to healthy controls, in addition to this 'landmark' region, other areas of significantly reduced volume in the brainstem emerged, including the location of the nuclei and fibres of cranial nerve VI (abducens nerve), and fibres of cranial nerve VII (facial nerve), and a more rostral portion of the medial longitudinal fasciculus. The high sensitivity and specificity of DTI-driven tensor-based morphometry in reliably detecting very small areas of volumetric abnormality found in this study suggest broader applications of this analysis in personalized medicine to detect hypoplasia or atrophy of small pathways and/or brainstem nuclei in other neurological disorders.
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http://dx.doi.org/10.1093/braincomms/fcaa014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158234PMC
February 2020

The first pancreatic neuroendocrine tumor in Li-Fraumeni syndrome: a case report.

BMC Cancer 2020 Mar 30;20(1):256. Epub 2020 Mar 30.

Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Building 10, Room 4-5952, Bethesda, MD, 20892, USA.

Background: Li-Fraumeni syndrome is a cancer predisposition syndrome caused by germline TP53 tumor suppressor gene mutations, with no previous association with pancreatic neuroendocrine tumors (PNETs). Here we present the first case of PNET associated with Li-Fraumeni syndrome.

Case Presentation: This is a 43-year-old female who underwent laparoscopic distal pancreatectomy at age 39 for a well-differentiated grade 2 cystic PNET. When the patient was 41 years old, her seven-year-old daughter was found to have an astrocytoma and a germline TP53 mutation. While undergoing surveillance with Gallium-DOTATATE positron emission tomography/computed tomography for her PNET, the patient was found to have a large choroid plexus papilloma in her right temporal lobe. She underwent genetic counseling and testing that identified a germline pathogenic variant in TP53, leading to the diagnosis of Li-Fraumeni syndrome. Her PNET had a hemizygous pathogenic TP53 mutation with loss of the wild-type alternate allele, consistent with loss of heterozygosity and the two-hit hypothesis. She was enrolled in a Li-Fraumeni syndrome protocol and continues surveillance screening with our service.

Conclusions: This is the first PNET reported in association with Li-Fraumeni syndrome. Pancreatic cancer risk is elevated in this syndrome, and our case highlights the need for vigilance in screening for pancreatic neoplasms in these patients.
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http://dx.doi.org/10.1186/s12885-020-06723-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106707PMC
March 2020

High-dose hydroxocobalamin achieves biochemical correction and improvement of neuropsychiatric deficits in adults with late onset cobalamin C deficiency.

JIMD Rep 2020 Jan 13;51(1):17-24. Epub 2019 Dec 13.

Department of Genetic Medicine and Pediatrics Johns Hopkins University Baltimore Maryland.

Cobalamin C () deficiency is the most common inborn error of intracellular cobalamin metabolism caused by pathogenic variant(s) in and manifests with methylmalonic acidemia, hyperhomocysteinemia, and hypomethioninemia with a variable age of presentation. Individuals with late-onset may be asymptomatic until manifesting neuropsychiatric symptoms, thromboembolic events, and renal disease. Although hydroxocobalamin provides a foundation for therapy, optimal dose regimen for adult patients has not been systematically evaluated. We report three adult siblings with late-onset disease, and their biochemical and clinical responses to high-dose hydroxocobalamin. The 28-year-old proband presented with severe psychosis, progressive neurological deterioration, and deep venous thrombosis complicated by a pulmonary embolism. MRI studies identified lesions in the spinal cord, periventricular white matter, and basal ganglia. Serum homocysteine and methylmalonic acid levels were markedly elevated. Hydroxocobalamin at standard dose (1 mg/day) initially resulted in partial metabolic correction. A regimen of high-dose hydroxocobalamin (25 mg/day) together with betaine and folic acid resulted in rapid and sustainable biochemical correction, resolution of psychosis, improvement of neurological functions, and amelioration of brain and spinal cord lesions. Two siblings who did not manifest neuropsychiatric symptoms or thromboembolism achieved a satisfactory metabolic control with the same high-dose regimen. Hydroxocobalamin injection was then spaced out to 25 mg weekly with good and sustainable metabolic control. All three patients are compound heterozygotes for c.271dupA p.Arg91LysfsX14 and c.389A > G p.Tyr130Cys. This study highlights the importance of evaluating intracellular cobalamin metabolism in adults with neuropsychiatric manifestations and/or thromboembolic events, and demonstrates that high-dose hydroxocobalamin achieves rapid and sustainable metabolic control and improvement in neuropsychiatric outcomes in adults with late-onset disease.
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http://dx.doi.org/10.1002/jmd2.12087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012733PMC
January 2020

Epstein-Barr virus NK and T cell lymphoproliferative disease: report of a 2018 international meeting.

Leuk Lymphoma 2020 04 13;61(4):808-819. Epub 2019 Dec 13.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Epstein-Barr virus (EBV) normally infects B cells, but in some persons the virus infects T or NK cells. Infection of B cells can result in infectious mononucleosis, and the virus is associated with several B cell malignancies including Hodgkin lymphoma, Burkitt lymphoma, and diffuse large B cell lymphoma. Infection of T or NK cells with EBV is associated with extranodal NK/T cell lymphoma, aggressive NK-cell leukemia, systemic EBV-associated T-cell lymphoma, and chronic active EBV disease, which in some cases can include hydroa vacciniforme-like lymphoproliferative disease and severe mosquito bite allergy. While NK and T cell lymphoproliferative disease is more common in Asia and Latin America, increasing numbers of cases are being reported from the United States and Europe. This review focuses on classification, clinical findings, pathogenesis, and recent genetic advances in NK and T cell lymphoproliferative diseases associated with EBV.
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http://dx.doi.org/10.1080/10428194.2019.1699080DOI Listing
April 2020

Noninvasive monitoring of chronic kidney disease using pH and perfusion imaging.

Sci Adv 2019 08 14;5(8):eaaw8357. Epub 2019 Aug 14.

Division of MR Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Chronic Kidney Disease (CKD) is a cardinal feature of methylmalonic acidemia (MMA), a prototypic organic acidemia. Impaired growth, low activity, and protein restriction affect muscle mass and lower serum creatinine, which can delay diagnosis and management of renal disease. We have designed an alternative strategy for monitoring renal function based on administration of a pH sensitive MRI agent and assessed this in a mouse model. This protocol produced three metrics: kidney contrast, ~4% for severe renal disease mice compared to ~13% and ~25% for moderate renal disease and healthy controls, filtration fraction (FF), ~15% for severe renal disease mice compared to ~79% and 100% for moderate renal disease and healthy controls, and variation in pH, ~0.45 units for severe disease mice compared to 0.06 and 0.01 for moderate disease and healthy controls. Our results demonstrate that MRI can be used for early detection and monitoring of CKD.
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http://dx.doi.org/10.1126/sciadv.aaw8357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693904PMC
August 2019

Comparison of Three-Dimensional Surface Imaging Systems Using Landmark Analysis.

J Craniofac Surg 2019 Sep;30(6):1869-1872

National Institute of Dental and Craniofacial Research, National Institutes of Health.

Numerous 3d imaging systems are now available commercially for the capture of facial shape data via landmarking or surface shape comparisons but it is not known whether these systems produce data of comparable quality. This study investigates the error associated with landmark coordinate data collected on facial surface images taken using three 3d imaging systems: the 3dMDface system (3dMD, Atlanta, GA), the Planmeca ProFace system (Planmeca, Roselle, IL), and the Vectra H1 handheld system (Canfield Scientific, Parsippany, NJ). This was a retrospective study involving 3d imaging data that used geometric morphometric analysis to assess overall shape differences as well as landmark-specific differences among the systems. Ten individuals evaluated at the NIDCR dental clinic on various protocols were imaged on all 3 systems. The subject pool consisted of syndromic and unaffected subjects, as disease status was irrelevant to the question of reproducibility and variability. Variation in landmark placement across systems was assessed by ANOVA, covariance matrix, and summary statistics. No overall shape or size differences were found among the systems. However, there was some landmark-specific variation and the 3dMD and Vectra systems were generally more similar to each other than either was to the Planmeca system. The data acquired by these 3 systems are comparable, although landmarks on the eyes and ears are noisy and most different among systems.
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http://dx.doi.org/10.1097/SCS.0000000000005795DOI Listing
September 2019

Chronic kidney disease in propionic acidemia.

Genet Med 2019 12 28;21(12):2830-2835. Epub 2019 Jun 28.

National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Purpose: Propionic acidemia (PA) is a severe metabolic disorder characterized by multiorgan pathology, including renal disease. The prevalence of chronic kidney disease (CKD) in PA patients and factors associated with CKD in PA are not known.

Methods: Thirty-one subjects diagnosed with PA underwent laboratory and clinical evaluations through a dedicated natural history study at the National Institutes of Health (ClinicalTrials.gov identifier: NCT02890342).

Results: Cross-sectional analysis of the creatinine-based estimated glomerular filtration rate (eGFR) in subjects with native kidneys revealed an age-dependent decline in renal function (P < 0.002). Among adults with PA, 4/8 (50%) had eGFR <60 mL/min/1.73 m. There was a significant discrepancy between eGFRs calculated using estimating equations based on serum creatinine compared with serum cystatin C (P < 0.0001). The tubular injury marker, plasma lipocalin-2, and plasma uric acid were strongly associated with CKD (P < 0.0001). The measured 24-hour creatinine excretion was below normal, even after adjusting for age, height, and sex.

Conclusion: CKD is common in adults with PA and is associated with age. The poor predictive performance of standard eGFR estimating equations, likely due to reduced creatine synthesis in kidney and liver, could delay the recognition of CKD and management of ensuing complications in this population.
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http://dx.doi.org/10.1038/s41436-019-0593-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045176PMC
December 2019

Hydroa vacciniforme-like lymphoproliferative disorder: an EBV disease with a low risk of systemic illness in whites.

Blood 2019 06 7;133(26):2753-2764. Epub 2019 May 7.

Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Patients with classic hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) typically have high levels of Epstein-Barr virus (EBV) DNA in T cells and/or natural killer (NK) cells in blood and skin lesions induced by sun exposure that are infiltrated with EBV-infected lymphocytes. HVLPD is very rare in the United States and Europe but more common in Asia and South America. The disease can progress to a systemic form that may result in fatal lymphoma. We report our 11-year experience with 16 HVLPD patients from the United States and England and found that whites were less likely to develop systemic EBV disease (1/10) than nonwhites (5/6). All (10/10) of the white patients were generally in good health at last follow-up, while two-thirds (4/6) of the nonwhite patients required hematopoietic stem cell transplantation. Nonwhite patients had later age of onset of HVLPD than white patients (median age, 8 vs 5 years) and higher levels of EBV DNA (median, 1 515 000 vs 250 000 copies/ml) and more often had low numbers of NK cells (83% vs 50% of patients) and T-cell clones in the blood (83% vs 30% of patients). RNA-sequencing analysis of an HVLPD skin lesion in a white patient compared with his normal skin showed increased expression of interferon-γ and chemokines that attract T cells and NK cells. Thus, white patients with HVLPD were less likely to have systemic disease with EBV and had a much better prognosis than nonwhite patients. This trial was registered at www.clinicaltrials.gov as #NCT00369421 and #NCT00032513.
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http://dx.doi.org/10.1182/blood.2018893750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598378PMC
June 2019

FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia.

JCI Insight 2018 12 6;3(23). Epub 2018 Dec 6.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.
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http://dx.doi.org/10.1172/jci.insight.124351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328030PMC
December 2018

Effects of medical food leucine content in the management of methylmalonic and propionic acidemias.

Curr Opin Clin Nutr Metab Care 2018 Jan;21(1):42-48

Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose Of Review: The current review highlights the varied effects of medical foods high in leucine (Leu) and devoid of valine (Val) and isoleucine (Ile) in the management of methylmalonic acidemia (MMA) and propionic acidemia and cobalamin C (cblC) deficiency, aiming to advance dietary practices.

Recent Findings: Leu is a key metabolic regulator with a multitude of effects on different organ systems. Recent observational studies have demonstrated that these effects can have unintended consequences in patients with MMA as a result of liberal use of medical foods. The combination of protein restriction and medical food use in MMA and propionic acidemia results in an imbalanced branched-chain amino acid (BCAA) dietary content with a high Leu-to-Val and/or Ile ratio. This leads to decreased plasma levels of Val and Ile and predicts impaired brain uptake of multiple essential amino acids. Decreased transport of methionine (Met) across the blood-brain barrier due to high circulating Leu levels is of particular concern in cblC deficiency in which endogenous Met synthesis is impaired.

Summary: Investigations into the optimal composition of medical foods for MMA and propionic acidemia, and potential scenarios in which Leu supplementation may be beneficial are needed. Until then, MMA/propionic acidemia medical foods should be used judiciously in the dietary management of these patients and avoided altogether in cblC deficiency.
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http://dx.doi.org/10.1097/MCO.0000000000000428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815322PMC
January 2018

Recurrent scarring papulovesicular lesions on sun-exposed skin in a 22-year-old man.

J Am Acad Dermatol 2018 03 28;78(3):637-642. Epub 2017 Sep 28.

Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

KEY TEACHING POINTS.
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http://dx.doi.org/10.1016/j.jaad.2017.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815928PMC
March 2018

Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.

Am J Med Genet A 2017 Oct 4;173(10):2763-2771. Epub 2017 Aug 4.

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Horstick et al. (2013) previously reported a homozygous p.Trp284Ser variant in STAC3 as the cause of Native American myopathy (NAM) in 5 Lumbee Native American families with congenital hypotonia and weakness, cleft palate, short stature, ptosis, kyphoscoliosis, talipes deformities, and susceptibility to malignant hyperthermia (MH). Here we present two non-Native American families, who were found to have STAC3 pathogenic variants. The first proband and her affected older sister are from a consanguineous Qatari family with a suspected clinical diagnosis of Carey-Fineman-Ziter syndrome (CFZS) based on features of hypotonia, myopathic facies with generalized weakness, ptosis, normal extraocular movements, cleft palate, growth delay, and kyphoscoliosis. We identified the homozygous c.851G>C;p.Trp284Ser variant in STAC3 in both sisters. The second proband and his affected sister are from a non-consanguineous, Puerto Rican family who was evaluated for a possible diagnosis of Moebius syndrome (MBS). His features included facial and generalized weakness, minimal limitation of horizontal gaze, cleft palate, and hypotonia, and he has a history of MH. The siblings were identified to be compound heterozygous for STAC3 variants c.851G>C;p.Trp284Ser and c.763_766delCTCT;p.Leu255IlefsX58. Given the phenotypic overlap of individuals with CFZS, MBS, and NAM, we screened STAC3 in 12 individuals diagnosed with CFZS and in 50 individuals diagnosed with MBS or a congenital facial weakness disorder. We did not identify any rare coding variants in STAC3. NAM should be considered in patients presenting with facial and generalized weakness, normal or mildly abnormal extraocular movement, hypotonia, cleft palate, and scoliosis, particularly if there is a history of MH.
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http://dx.doi.org/10.1002/ajmg.a.38375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843189PMC
October 2017

A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome.

Nat Commun 2017 07 6;8:16077. Epub 2017 Jul 6.

Department of Neurology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.
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http://dx.doi.org/10.1038/ncomms16077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504296PMC
July 2017

Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism.

Mol Metab 2016 Oct 6;5(10):926-936. Epub 2016 Aug 6.

Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA. Electronic address:

Objective: Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear.

Methods: To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis.

Results: Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding.

Conclusions: Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5034611PMC
http://dx.doi.org/10.1016/j.molmet.2016.08.001DOI Listing
October 2016

Response to Cunningham et al.

Genet Med 2016 Apr 10;18(4):414-5. Epub 2016 Mar 10.

Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1038/gim.2016.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586539PMC
April 2016

Ophthalmic Manifestations and Long-Term Visual Outcomes in Patients with Cobalamin C Deficiency.

Ophthalmology 2016 Mar 26;123(3):571-82. Epub 2016 Jan 26.

National Human Genome Research Institute, Genetics and Molecular Biology Branch, National Institutes of Health, Bethesda, Maryland.

Purpose: To explore the ocular manifestations of cobalamin C (cblC) deficiency, an inborn error of intracellular vitamin B12 metabolism.

Design: Retrospective, observational case series.

Participants: Twenty-five cblC patients underwent clinical and ophthalmic examination at the National Institutes of Health between August 2004 and September 2012. Patient ages ranged from 2 to 27 years at last ophthalmic visit, and follow-up ranged from 0 to 83 months (median, 37 months; range, 13-83 months) over a total of 69 visits.

Methods: Best-corrected visual acuity, slit-lamp biomicroscopy, dilated fundus examination, wide-field photography, fundus autofluorescence imaging, sedated electroretinography, optical coherence tomography, genetics and metabolite assessment.

Main Outcome Measures: Visual acuity and presence and degree of retinal degeneration and optic nerve pallor.

Results: Nystagmus (64%), strabismus (52%), macular degeneration (72%), optic nerve pallor (68%), and vascular changes (64%) were present. c.271dupA (p.R91KfsX14) homozygous patients (n = 14) showed early and extensive macular degeneration. Electroretinography showed that scotopic and photopic responses were reduced and delayed, but were preserved remarkably in some patients despite severe degeneration. Optical coherence tomography images through the central macular lesion of a patient with severe retinal degeneration showed extreme thinning, some preservation of retinal lamination, and nearly complete loss of the outer nuclear layer. Despite hyperhomocysteinemia, no patients exhibited lens dislocation.

Conclusions: This longitudinal study reports ocular outcomes in the largest group of patients with cblC deficiency systematically examined at a single center over an extended period. Differences in progression and severity of macular degeneration, optic nerve pallor, and vascular attenuation between homozygous c.271dupA (p.R91KfsX14) patients and compound heterozygotes were noted. The pace and chronicity of ophthalmic manifestations lacked strict correlation to metabolic status as measured during visits. Prenatal or early treatment, or both, may have mitigated ocular disease, leading to better functional acuity, but patients still progressed to severe macular degeneration. The effects of prenatal or early treatment, or both, in siblings; the manifestation of severe disease in infancy; the presence of comorbid developmental abnormalities; and the possible laminar structural defect noted in many patients are findings showing that cblC deficiency displays a developmental as well as a degenerative ocular phenotype.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065014PMC
http://dx.doi.org/10.1016/j.ophtha.2015.10.041DOI Listing
March 2016

Neutralizing Antibodies Against Adeno-Associated Viral Capsids in Patients with mut Methylmalonic Acidemia.

Hum Gene Ther 2016 May 22;27(5):345-53. Epub 2016 Mar 22.

1 Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Isolated methylmalonic acidemia (MMA), a group of autosomal recessive inborn errors of metabolism, is most commonly caused by complete (mut(0)) or partial (mut(-)) deficiency of the enzyme methylmalonyl-CoA mutase (MUT). The severe metabolic instability and increased mortality experienced by many affected individuals, especially those with mut(0) MMA, has led centers to use elective liver transplantation as a treatment for these patients. We have previously demonstrated the efficacy of systemic adeno-associated viral (AAV) gene delivery as a treatment for MMA in a murine model and therefore sought to survey AAV antibody titers against serotypes 2, 8, and 9 in a group of well-characterized MMA patients, accrued via a dedicated natural history study ( clinicaltrials.gov ID: NCT00078078). Plasma samples provided by 42 patients (8 mut(-) and 34 mut(0); 10 had received organ transplantation), who ranged in age between 2 and 31 years, were analyzed to examine AAV2 (n = 35), AAV8 (n = 41), and AAV9 (n = 42) antibody titers. In total, the seroprevalence of antibodies against AAV2, AAV8, or AAV9 was 20%, 22%, and 24%, respectively. We observed a lower-than-expected seropositivity rate (titers ≥1:20) in the pediatric MMA patients (2-18 years) for both AAV2 (p < 0.05) and AAV8 (p < 0.01) neutralizing antibodies (NAbs) compared with historical controls. Those with positive NAb titers were typically older than 18 years (p < 0.05 all serotypes) or had received solid organ transplantation (p < 0.01 AAV8, AAV9). The mut(0) patients who had not been transplanted (n = 24)-that is, the subset with the greatest need for improved treatments-represented the seronegative majority, with 21 out of 24 patients lacking Abs against all AAV capsids tested. The unexpected lack of NAbs against AAV in this patient population has encouraging implications for systemic gene delivery as a treatment for mut MMA.
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http://dx.doi.org/10.1089/hum.2015.092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841085PMC
May 2016

Medical genetics and genomic medicine in Greece: achievements and challenges.

Mol Genet Genomic Med 2015 Sep 15;3(5):383-90. Epub 2015 Sep 15.

Medical Genetics, Choremio Research Laboratory, "Aghia Sophia" Children's Hospital, University of Athens - School of Medicine Athens, Greece.

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http://dx.doi.org/10.1002/mgg3.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585445PMC
September 2015

A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 2: cobalamin C deficiency.

Genet Med 2016 Apr 13;18(4):396-404. Epub 2015 Aug 13.

Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose: Cobalamin C (cblC) deficiency impairs the biosynthesis of 5'-deoxyadenosyl-adenosyl- and methyl-cobalamin, resulting in methylmalonic acidemia combined with hyperhomocysteinemia and hypomethioninemia. However, some patients with cblC deficiency are treated with medical foods, devoid of methionine and high in leucine content, that are formulated for patients with isolated propionate oxidative defects. We examined the effects of imbalanced branched-chain amino acid intake on growth outcomes in cblC-deficient patients.

Methods: Dietary intake was correlated with biochemical, anthropometric, and body composition measurements and other disease parameters in a cohort of 28 patients with early-onset cblC deficiency.

Results: Protein-restricted diets were followed by 21% of the patients, whereas 32% received medical foods. Patients on protein-restricted diets had lower height-for-age z-score (P = 0.034), whereas patients consuming medical foods had lower head circumference Z-scores (P = 0.037), plasma methionine concentrations (P = 0.001), and predicted methionine influx through the blood-brain barrier Z-score (-1.29 vs. -0.0617; P = 0.007). The combination of age at diagnosis, a history of seizures, and the leucine-to-valine dietary intake ratio best predicted head circumference Z-score based on multiple regression modeling (R(2) = 0.945).

Conclusions: Patients with cblC deficiency treated with medical foods designed for isolated methylmalonic acidemia are at risk for iatrogenic methionine deficiency that could adversely affect brain growth and development.Genet Med 18 4, 396-404.
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http://dx.doi.org/10.1038/gim.2015.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752912PMC
April 2016

A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias.

Genet Med 2016 Apr 13;18(4):386-95. Epub 2015 Aug 13.

Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose: Medical foods for methylmalonic acidemias (MMAs) and propionic acidemias contain minimal valine, isoleucine, methionine, and threonine but have been formulated with increased leucine. We aimed to assess the effects of imbalanced branched-chain amino acid intake on metabolic and growth parameters in a cohort of patients with MMA ascertained via a natural history study.

Methods: Cross-sectional anthropometric and body-composition measurements were correlated with diet content and disease-related biomarkers in 61 patients with isolated MMA (46 mut, 9 cblA, and 6 cblB).

Results: Patients with MMA tolerated close to the recommended daily allowance (RDA) of complete protein (mut(0): 99.45 ± 32.05% RDA). However, 85% received medical foods, in which the protein equivalent often exceeded complete protein intake (35%). Medical food consumption resulted in low plasma valine and isoleucine concentrations, prompting paradoxical supplementation with these propiogenic amino acids. Weight- and height-for-age z-scores correlated negatively with the leucine-to-valine intake ratio (r = -0.453; P = 0.014; R(2) = 0.209 and r = -0.341; P = 0.05; R(2) = 0.123, respectively).

Conclusion: Increased leucine intake in patients with MMA resulted in iatrogenic amino acid deficiencies and was associated with adverse growth outcomes. Medical foods for propionate oxidation disorders need to be redesigned and studied prospectively to ensure efficacy and safety.Genet Med 18 4, 386-395.
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http://dx.doi.org/10.1038/gim.2015.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752925PMC
April 2016

Propofol administration in patients with methylmalonic acidemia and intracellular cobalamin metabolism disorders: a review of theoretical concerns and clinical experiences in 28 patients.

J Inherit Metab Dis 2015 Sep 19;38(5):847-53. Epub 2015 May 19.

Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Building 49, Room 4A18, Bethesda, MD, USA.

Background: Methylmalonic acidemia and intracellular cobalamin metabolism disorders represent a heterogeneous group of inborn errors of metabolism. Most patients will require diagnostic and/or therapeutic procedures frequently requiring sedation or anesthetic management due to neurological and neurocognitive impairments. It has been stated that propofol is contraindicated in this population. We report our experience with propofol administration in a large series of patients.

Methods: Twenty eight patients (14 mut, seven cblC, three cblA, three cblB, one cblG) aged 2-35.6 years enrolled in a natural history study (ClinicalTrials.gov identifier: NCT00078078) and required anesthetics for 39 diagnostic or therapeutic procedures. Data were collected on the anesthetic technique, perianesthetic course, and adverse events related to propofol.

Results: Propofol was used as the sole induction agent in most cases (36/39) and as the primary maintenance agent in all cases. Infusion rates were 100-400 mcg kg(-1) min(-1) (mean = 214). Infusion duration was 60-325 min (mean = 158) and total doses ranged between 270-3610 mg (mean = 1217). Adverse events were recorded in two cases; neither appeared to be related to propofol administration.

Conclusions: Propofol is an effective, safe induction and maintenance agent for elective short procedures requiring anesthesia in patients with MMA and cobalamin metabolism disorders. Despite multiple comorbidities and propensity toward instability, those affected can receive anesthesia with an acceptable safety profile, if metabolically and hemodynamically stabilized prior to the event.

Synopsis: A review of the perianesthetic records of 28 patients with isolated MMA and intracellular cobalamin metabolism disorders suggests that propofol anesthesia can be administered safely to these patients, in the setting of metabolic stability.
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http://dx.doi.org/10.1007/s10545-015-9816-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577977PMC
September 2015

Delineating the spectrum of impairments, disabilities, and rehabilitation needs in methylmalonic acidemia (MMA).

Am J Med Genet A 2015 Sep 10;167A(9):2075-84. Epub 2015 May 10.

Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

Methylmalonic acidemia patients have complex rehabilitation needs that can be targeted to optimize societal independence and quality of life. Thirty-seven individuals with isolated MMA (28 mut, 5 cblA, 4 cblB), aged 2-33 years, were enrolled in a natural history study, and underwent age-appropriate clinical assessments to characterize impairments and disabilities. Neurological examination and brain imaging studies were used to document movement disorders and the presence of basal ganglia injury. A range of impairments and disabilities were identified by a team of physical medicine experts. Movement disorders, such as chorea and tremor, were common (n = 31, 83%), even among patients without evidence of basal ganglia injury. Joint hypermobility (n = 24, 69%) and pes planus (n = 22, 60%) were frequent and, in many cases, under-recognized. 23 (62%) patients required gastrostomy feedings. 18/31 patients >4 years old (58%) had difficulties with bathing and dressing. 16 of 23 school-aged patients received various forms of educational support. Five of the 10 adult patients were employed or in college; three lived independently. Unmet needs were identified in access to rehabilitation services, such as physical therapy (unavailable to 14/31), and orthotics (unavailable to 15/22). We conclude that patients with MMA are challenged by a number of functional limitations in essential activities of mobility, self-care, and learning, in great part caused by movement disorders and ligamentous laxity. Early assessment, referral, and implementation of age-appropriate rehabilitation services should significantly improve independence and quality of life.
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http://dx.doi.org/10.1002/ajmg.a.37127DOI Listing
September 2015

Liver or combined liver-kidney transplantation for patients with isolated methylmalonic acidemia: who and when?

J Pediatr 2015 Jun 14;166(6):1346-50. Epub 2015 Apr 14.

Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2015.03.026DOI Listing
June 2015

Methylmalonic acidemia (MMA) in pregnancy: a case series and literature review.

J Inherit Metab Dis 2015 Sep 8;38(5):839-46. Epub 2015 Jan 8.

Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.

Introduction: Women with inherited metabolic disorders, including those with previously life-limiting conditions such as MMA, are reaching child-bearing age more often due to advances in early diagnosis and improved pediatric care. Information surrounding maternal and fetal complications associated with the underlying disorders remains largely unexplored.

Methods: Pregnancies affected by maternal MMA were ascertained through study 04-HG-0127 "Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders" (clinicaltrials.gov identifier: NCT00078078) and via literature review. Prenatal and delivery records in study participants were reviewed.

Results: Seventeen pregnancies were identified in women with isolated MMA, including three abortions, one termination, and 13 completed pregnancies [three cases with cblA (four pregnancies), four cases of mut- (one cobalamin responsive, three non-responsive), five cases with unknown type of MMA]. Seventeen percent (3/17) of the pregnancies resulted in a first trimester abortion, while 38.5% (5/13) of the completed pregnancies resulted in preterm deliveries. A cesarean delivery rate of 53.8% (7/13) was noted among the cohort. Fetal distress or nonreassuring fetal status was the indication for 57% (4/7) cesarean deliveries. One patient was reported to have metabolic crisis as well as episodes of mild hyperammonemia. Malformations or adverse outcomes in the progeny were not observed.

Conclusion: Although there have been a small number of pregnancies identified in women with MMA, the cumulative results suggest that the majority of pregnancies can be complicated by cesarean delivery and increased risk of prematurity. A pregnancy registry could clarify perinatal complications and define management approaches needed to ensure optimal maternal and fetal outcomes in this growing patient population.
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http://dx.doi.org/10.1007/s10545-014-9802-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496322PMC
September 2015

An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1.

Am J Hum Genet 2013 Sep;93(3):506-14

Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

Derivatives of vitamin B12 (cobalamin) are essential cofactors for enzymes required in intermediary metabolism. Defects in cobalamin metabolism lead to disorders characterized by the accumulation of methylmalonic acid and/or homocysteine in blood and urine. The most common inborn error of cobalamin metabolism, combined methylmalonic acidemia and hyperhomocysteinemia, cblC type, is caused by mutations in MMACHC. However, several individuals with presumed cblC based on cellular and biochemical analysis do not have mutations in MMACHC. We used exome sequencing to identify the genetic basis of an X-linked form of combined methylmalonic acidemia and hyperhomocysteinemia, designated cblX. A missense mutation in a global transcriptional coregulator, HCFC1, was identified in the index case. Additional male subjects were ascertained through two international diagnostic laboratories, and 13/17 had one of five distinct missense mutations affecting three highly conserved amino acids within the HCFC1 kelch domain. A common phenotype of severe neurological symptoms including intractable epilepsy and profound neurocognitive impairment, along with variable biochemical manifestations, was observed in all affected subjects compared to individuals with early-onset cblC. The severe reduction in MMACHC mRNA and protein within subject fibroblast lines suggested a role for HCFC1 in transcriptional regulation of MMACHC, which was further supported by the identification of consensus HCFC1 binding sites in MMACHC. Furthermore, siRNA-mediated knockdown of HCFC1 expression resulted in the coordinate downregulation of MMACHC mRNA. This X-linked disorder demonstrates a distinct disease mechanism by which transcriptional dysregulation leads to an inborn error of metabolism with a complex clinical phenotype.
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http://dx.doi.org/10.1016/j.ajhg.2013.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769968PMC
September 2013

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia.

Proc Natl Acad Sci U S A 2013 Aug 29;110(33):13552-7. Epub 2013 Jul 29.

Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.

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. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. 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.
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http://dx.doi.org/10.1073/pnas.1302764110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746875PMC
August 2013

Renal growth in isolated methylmalonic acidemia.

Genet Med 2013 Dec 2;15(12):990-6. Epub 2013 May 2.

Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.

Purpose: We sought to predict renal growth based on clinical and metabolic parameters in patients with isolated methylmalonic acidemia, a group of disorders associated with chronic kidney disease.

Methods: Fifty patients with methylmalonic acidemia, followed from 2004 to 2011, were classified by molecular genetics and studied using a combined cross-sectional and longitudinal design that included renal ultrasound examinations, anthropometric measurements, and metabolic phenotyping. Renal length was compared with that of healthy controls and modeled to other clinical parameters using multiple-regression analyses.

Results: Comparisons with age-matched controls showed that renal length in subjects with methylmalonic acidemia was significantly decreased (P < 0.05). Stepwise regression modeling found that combinations of height, serum cystatin C, and serum methymalonic acid concentrations best predicted kidney size. The regression equations used to generate methylmalonic acidemia kidney nomograms were renal length (cm) = 6.79 + 0.22 × age for the controls and 6.80 + 0.09 × age for the methylmalonic acidemia cohort (P < 0.001; constant and slope).

Conclusion: Renal length, reflective of kidney growth, significantly decreased in patients with methylmalonic acidemia over time as compared with controls and was predictable with select clinical parameters. Cystatin C and serum methylmalonic acid concentrations were highly correlated with smaller kidneys and decreased renal function in this patient population.
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http://dx.doi.org/10.1038/gim.2013.42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149057PMC
December 2013