Publications by authors named "Mohammed Almannai"

30 Publications

  • Page 1 of 1

Hyperammonemia, Lactic Acidosis, and Arrhythmia in a Newborn.

Clin Chem 2021 Jan;67(1):327-330

The Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.

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http://dx.doi.org/10.1093/clinchem/hvaa151DOI Listing
January 2021

Clinical trials in mitochondrial disorders, an update.

Mol Genet Metab 2020 Sep - Oct;131(1-2):1-13. Epub 2020 Oct 6.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, Shatin, Hong Kong. Electronic address:

Mitochondrial disorders comprise a molecular and clinically diverse group of diseases that are associated with mitochondrial dysfunction leading to multi-organ disease. With recent advances in molecular technologies, the understanding of the pathomechanisms of a growing list of mitochondrial disorders has been greatly expanded. However, the therapeutic approaches for mitochondrial disorders have lagged behind with treatment options limited mainly to symptom specific therapies and supportive measures. There is an increasing number of clinical trials in mitochondrial disorders aiming for more specific and effective therapies. This review will cover different treatment modalities currently used in mitochondrial disorders, focusing on recent and ongoing clinical trials.
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http://dx.doi.org/10.1016/j.ymgme.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537630PMC
October 2020

Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort.

Genet Med 2020 Dec 3;22(12):2071-2080. Epub 2020 Aug 3.

Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.

Purpose: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD.

Methods: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia.

Results: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively.

Conclusion: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.
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http://dx.doi.org/10.1038/s41436-020-0919-xDOI Listing
December 2020

Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy.

Genet Med 2020 Oct 28;22(10):1598-1605. Epub 2020 May 28.

Genome Dynamics and Function Program, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.

Purpose: Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy.

Methods: Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype.

Results: We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype.

Conclusions: We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy.
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http://dx.doi.org/10.1038/s41436-020-0833-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521996PMC
October 2020

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy.

Ann Clin Transl Neurol 2020 05 14;7(5):610-627. Epub 2020 Apr 14.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.

Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.

Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory.

Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood.

Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.
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http://dx.doi.org/10.1002/acn3.51003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261753PMC
May 2020

Further delineation of METTL23-associated intellectual disability.

Am J Med Genet A 2020 04 18;182(4):785-791. Epub 2020 Feb 18.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

METTL23 belongs to a family of methyltransferase like proteins (METTL) that transfer methyl group to various substrates. Recently, pathogenic homozygous variants in METTL23 were identified in patients from three families who presented with intellectual disability (ID) and variable dysmorphic features. In this report, we present unpublished phenotypic data from the original family as well as six new subjects from four families who also presented with mild to moderate ID and dysmorphic features, and were found to harbor four previously unpublished homozygous or compound heterozygous variants in METTL23. Our report further supports the role of this gene in autosomal recessive ID and emphasizes the mild but consistent facial features.
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http://dx.doi.org/10.1002/ajmg.a.61503DOI Listing
April 2020

Carnitine Inborn Errors of Metabolism.

Molecules 2019 Sep 6;24(18). Epub 2019 Sep 6.

Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, UAE.

Carnitine plays essential roles in intermediary metabolism. In non-vegetarians, most of carnitine sources (~75%) are obtained from diet whereas endogenous synthesis accounts for around 25%. Renal carnitine reabsorption along with dietary intake and endogenous production maintain carnitine homeostasis. The precursors for carnitine biosynthesis are lysine and methionine. The biosynthetic pathway involves four enzymes: 6--trimethyllysine dioxygenase (TMLD), 3-hydroxy-6--trimethyllysine aldolase (HTMLA), 4--trimethylaminobutyraldehyde dehydrogenase (TMABADH), and γ-butyrobetaine dioxygenase (BBD). OCTN2 (organic cation/carnitine transporter novel type 2) transports carnitine into the cells. One of the major functions of carnitine is shuttling long-chain fatty acids across the mitochondrial membrane from the cytosol into the mitochondrial matrix for β-oxidation. This transport is achieved by mitochondrial carnitine-acylcarnitine cycle, which consists of three enzymes: carnitine palmitoyltransferase I (CPT I), carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPT II). Carnitine inborn errors of metabolism could result from defects in carnitine biosynthesis, carnitine transport, or mitochondrial carnitine-acylcarnitine cycle. The presentation of these disorders is variable but common findings include hypoketotic hypoglycemia, cardio(myopathy), and liver disease. In this review, the metabolism and homeostasis of carnitine are discussed. Then we present details of different inborn errors of carnitine metabolism, including clinical presentation, diagnosis, and treatment options. At the end, we discuss some of the causes of secondary carnitine deficiency.
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http://dx.doi.org/10.3390/molecules24183251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766900PMC
September 2019

6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects.

Pediatr Neurol 2019 07 18;96:40-47. Epub 2019 Feb 18.

Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (MNGHA), Riyadh, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia; College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. Electronic address:

Background: Tetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders.

Method: We conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency.

Results: Similar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?).

Conclusion: The deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.02.008DOI Listing
July 2019

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Hum Mutat 2019 07 24;40(7):908-925. Epub 2019 Apr 24.

Metabolic Unit, Great Ormond Street Hospital NHS Trust, Institute for Child Health UCL, London, UK.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.
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http://dx.doi.org/10.1002/humu.23731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661012PMC
July 2019

Mitochondrial dynamics: Biological roles, molecular machinery, and related diseases.

Mol Genet Metab 2018 12 16;125(4):315-321. Epub 2018 Oct 16.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, ShaTin, Hong Kong Special Administrative Region. Electronic address:

Mitochondria are dynamic organelles that undergo fusion, fission, movement, and mitophagy. These processes are essential to maintain the normal mitochondrial morphology, distribution, and function. Mitochondrial fusion allows the exchange of intramitochondrial material, whereas the fission process is required to replicate the mitochondria during cell division, facilitate the transport and distribution of mitochondria, and allow the isolation of damaged organelles. Mitochondrial mobility is essential for mitochondrial distribution depending on the cellular metabolic demands. Mitophagy is needed for the elimination of dysfunctional and damaged mitochondria to maintain a healthy mitochondrial population. The mitochondrial dynamic processes are mediated by a number of nuclear-encoded proteins that function in mitochondrial transport, fusion, fission, and mitophagy. Disorders of mitochondrial dynamics are caused by pathogenic variants in the genes encoding these proteins. These diseases have a high clinical variability, and range in severity from isolated optic atrophy to lethal encephalopathy. These disorders include defects in mitochondrial fusion (caused by pathogenic variants in MFN2, OPA1, YME1L1, MSTO1, and FBXL4), mitochondrial fission (caused by pathogenic variants in DNM1L and MFF), and mitochondrial autophagy (caused by pathogenic variants in PINK1 and PRKN). In this review, the molecular machinery and biological roles of mitochondrial dynamic processes are discussed. Subsequently, the currently known diseases related to mitochondrial dynamic defects are presented.
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http://dx.doi.org/10.1016/j.ymgme.2018.10.003DOI Listing
December 2018

FARS2 deficiency; new cases, review of clinical, biochemical, and molecular spectra, and variants interpretation based on structural, functional, and evolutionary significance.

Mol Genet Metab 2018 11 29;125(3):281-291. Epub 2018 Jul 29.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Electronic address:

An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.
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http://dx.doi.org/10.1016/j.ymgme.2018.07.014DOI Listing
November 2018

Megaloblastic Anemia Progressing to Severe Thrombotic Microangiopathy in Patients with Disordered Vitamin B Metabolism: Case Reports and Literature Review.

J Pediatr 2018 11 26;202:315-319.e2. Epub 2018 Jul 26.

Baylor College of Medicine, Department of Pediatrics, Section of Hematology/Oncology, Texas Children's Hospital, Houston, TX.

We describe 2 children with cobalamin G disease, a disorder of vitamin B metabolism with normal serum B levels. They presented with megaloblastic anemia progressing rapidly to severe thrombotic microangiopathy. In infants presenting with acute thrombotic microangiopathy, cobalamin disorders should be considered early as diagnosis and targeted treatment can be lifesaving.
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http://dx.doi.org/10.1016/j.jpeds.2018.06.054DOI Listing
November 2018

Mitochondrial DNA replication: clinical syndromes.

Essays Biochem 2018 07 20;62(3):297-308. Epub 2018 Jul 20.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, U.S.A.

Each nucleated cell contains several hundreds of mitochondria, which are unique organelles in being under dual genome control. The mitochondria contain their own DNA, the mtDNA, but most of mitochondrial proteins are encoded by nuclear genes, including all the proteins required for replication, transcription, and repair of mtDNA. MtDNA replication is a continuous process that requires coordinated action of several enzymes that are part of the mtDNA replisome. It also requires constant supply of deoxyribonucleotide triphosphates(dNTPs) and interaction with other mitochondria for mixing and unifying the mitochondrial compartment. MtDNA maintenance defects are a growing list of disorders caused by defects in nuclear genes involved in different aspects of mtDNA replication. As a result of defects in these genes, mtDNA depletion and/or multiple mtDNA deletions develop in affected tissues resulting in variable manifestations that range from adult-onset mild disease to lethal presentation early in life.
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http://dx.doi.org/10.1042/EBC20170101DOI Listing
July 2018

Newborn Screening: History, Current Status, and Future Directions.

Pediatr Clin North Am 2018 04 28;65(2):389-405. Epub 2017 Dec 28.

Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children's Hospital, One Baylor Plaza, Houston, TX 77030, USA. Electronic address:

Newborn screening programs aim to achieve presymptomatic diagnosis of treatable disorders allowing for early initiation of medical care to prevent or reduce significant morbidity and mortality. Many of the conditions included in the newborn screening panels are inborn errors of metabolism; however, screening for endocrine, hematologic, immunologic, and cardiovascular diseases, and hearing loss is also included in many panels. Newborn screening tests are not diagnostic and therefore diagnostic testing is needed to confirm or exclude the suspected diagnosis. Further advancement in technology is expected to allow continuous expansion of newborn screening.
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http://dx.doi.org/10.1016/j.pcl.2017.11.013DOI Listing
April 2018

Inborn Errors of Metabolism with Seizures: Defects of Glycine and Serine Metabolism and Cofactor-Related Disorders.

Pediatr Clin North Am 2018 04 28;65(2):279-299. Epub 2017 Dec 28.

Division of Clinical Genetics and Metabolic Disorders, Pediatrics Department, Tawam Hospital, Tawam Roundabout, Al-Ain 15258, United Arab Emirates. Electronic address:

Inborn errors of metabolism (IEM) are relatively uncommon causes for seizures in children; however, they should be considered in the differential diagnosis because several IEM are potentially treatable and seizures can be resolved if appropriate treatment is initiated. Clues from clinical presentation, physical examination, laboratory tests, and brain imaging can raise the possibility of IEM. Several IEM can present with seizures, either as the main presenting finding or as a part of a more complex phenotype. These include cofactor-related disorders, glycine and serine metabolism defects, and other disorders.
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http://dx.doi.org/10.1016/j.pcl.2017.11.007DOI Listing
April 2018

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects.

Hum Mutat 2018 04 13;39(4):461-470. Epub 2018 Jan 13.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis.
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http://dx.doi.org/10.1002/humu.23387DOI Listing
April 2018

Therapies for mitochondrial diseases and current clinical trials.

Mol Genet Metab 2017 11 18;122(3):1-9. Epub 2017 Sep 18.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA. Electronic address:

Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders that result from dysfunction of the mitochondrial oxidative phosphorylation due to molecular defects in genes encoding mitochondrial proteins. Despite the advances in molecular and biochemical methodologies leading to better understanding of the etiology and mechanism of these diseases, there are still no satisfactory therapies available for mitochondrial disorders. Treatment for mitochondrial diseases remains largely symptomatic and does not significantly alter the course of the disease. Based on limited number of clinical trials, several agents aiming at enhancing mitochondrial function or treating the consequences of mitochondrial dysfunction have been used. Several agents are currently being evaluated for mitochondrial diseases. Therapeutic strategies for mitochondrial diseases include the use of agents enhancing electron transfer chain function (coenzyme Q, idebenone, riboflavin, dichloroacetate, and thiamine), agents acting as energy buffer (creatine), antioxidants (vitamin C, vitamin E, lipoic acid, cysteine donors, and EPI-743), amino acids restoring nitric oxide production (arginine and citrulline), cardiolipin protector (elamipretide), agents enhancing mitochondrial biogenesis (bezafibrate, epicatechin, and RTA 408), nucleotide bypass therapy, liver transplantation, and gene therapy. Although, there is a lack of curative therapies for mitochondrial disorders at the current time, the increased number of clinical research evaluating agents that target different aspects of mitochondrial dysfunction is promising and is expected to generate more therapeutic options for these diseases in the future.
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http://dx.doi.org/10.1016/j.ymgme.2017.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773113PMC
November 2017

Molecular and clinical spectra of FBXL4 deficiency.

Hum Mutat 2017 12 6;38(12):1649-1659. Epub 2017 Oct 6.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies.
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http://dx.doi.org/10.1002/humu.23341DOI Listing
December 2017

Quantitation of phenylbutyrate metabolites by UPLC-MS/MS demonstrates inverse correlation of phenylacetate:phenylacetylglutamine ratio with plasma glutamine levels.

Mol Genet Metab 2017 11 31;122(3):39-45. Epub 2017 Aug 31.

Division of Biochemical Genetics, Baylor Genetics Laboratories, Houston, TX, United States; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States. Electronic address:

Urea cycle disorders (UCDs) are genetic conditions characterized by nitrogen accumulation in the form of ammonia and caused by defects in the enzymes required to convert ammonia to urea for excretion. UCDs include a spectrum of enzyme deficiencies, namely n-acetylglutamate synthase deficiency (NAGS), carbamoyl phosphate synthetase I deficiency (CPS1), ornithine transcarbamylase deficiency (OTC), argininosuccinate lyase deficiency (ASL), citrullinemia type I (ASS1), and argininemia (ARG). Currently, sodium phenylbutyrate and glycerol phenylbutyrate are primary medications used to treat patients with UCDs, and long-term monitoring of these compounds is critical for preventing drug toxic levels. Therefore, a fast and simple ultra-performance liquid chromatography (UPLC-MS/MS) method was developed and validated for quantification of phenylbutyrate (PB), phenylacetate (PA), and phenylacetylglutamine (PAG) in plasma and urine. The separation of all three analytes was achieved in 2min, and the limits of detection were <0.04μg/ml. Intra-precision and inter-precision were <8.5% and 4% at two quality control concentrations, respectively. Average recoveries for all compounds ranged from 100% to 106%. With the developed assay, a strong correlation between PA and the PA/PAG ratio and an inverse correlation between PA/PAG ratio and plasma glutamine were observed in 35 patients with confirmed UCDs. Moreover, all individuals with a ratio ≥0.6 had plasma glutamine levels<1000μmol/l. Our data suggest that a PA/PAG ratio in the range of 0.6-1.5 will result in a plasma glutamine level<1000μmol/l without reaching toxic levels of PA.
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http://dx.doi.org/10.1016/j.ymgme.2017.08.011DOI Listing
November 2017

Arginine and citrulline for the treatment of MELAS syndrome.

J Inborn Errors Metab Screen 2017 Jan 24;5. Epub 2017 Mar 24.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome is a maternally inherited mitochondrial disease with a broad spectrum of manifestations. In addition to impaired energy production, nitric oxide (NO) deficiency occurs in MELAS syndrome and leads to impaired blood perfusion in microvasculature that can contribute to several complications including stroke-like episodes, myopathy, and lactic acidosis. The supplementation of NO precursors, L-arginine and L-citrulline, increases NO production and hence can potentially have therapeutic utility in MELAS syndrome. L-citrulline raises NO production to a greater extent than L-arginine; therefore, L-citrulline may have a better therapeutic effect. The clinical effect of L-citrulline has not yet been studied and clinical studies on L-arginine, which are limited, only evaluated the stroke-like episodes aspect of the disease. Controlled studies are still needed to assess the clinical effects of L-arginine and L-citrulline on different aspects of MELAS syndrome.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519148PMC
http://dx.doi.org/10.1177/2326409817697399DOI Listing
January 2017

Milder clinical and biochemical phenotypes associated with the c.482G>A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening.

Mol Genet Metab 2017 09 29;122(1-2):60-66. Epub 2017 Jun 29.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Texas Children's Hospital, Houston, TX, USA. Electronic address:

Introduction: Cobalamin C disease is a multisystemic disease with variable manifestations and age of onset. Genotype-phenotype correlations are well-recognized in this disorder. Here, we present a large cohort of individuals with cobalamin C disease, several of whom are heterozygous for the c.482G>A pathogenic variant (p.Arg161Gln). We compared clinical characteristics of individuals with this pathogenic variant to those who do not have this variant. To our knowledge, this study represents the largest single cohort of individuals with the c.482G>A (p.Arg161Gln) pathogenic variant.

Methods: A retrospective chart review of 27 individuals from 21 families with cobalamin C disease who are followed at our facility was conducted.

Results: 13 individuals (48%) are compound heterozygous with the c.482G>A (p.Arg161Gln) on one allele and a second pathogenic variant on the other allele. Individuals with the c.482G>A (p.Arg161Gln) pathogenic variant had later onset of symptoms and easier metabolic control. Moreover, they had milder biochemical abnormalities at presentation which likely contributed to the observation that 4 individuals (31%) in this group were missed by newborn screening.

Conclusion: The c.482G>A (p.Arg161Gln) pathogenic variant is associated with milder disease. These individuals may not receive a timely diagnosis as they may not be identified on newborn screening or because of unrecognized, late onset symptoms. Despite the milder presentation, significant complications can occur, especially if treatment is delayed.
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http://dx.doi.org/10.1016/j.ymgme.2017.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612879PMC
September 2017

Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.

Am J Hum Genet 2017 Jan 8;100(1):91-104. Epub 2016 Dec 8.

Rosalind & Morris Goodman Cancer Research Center and Department of Medicine, McGill University, Montreal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University and McGill University Health Center, Montreal, QC H3A 1A3, Canada. Electronic address:

Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.
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http://dx.doi.org/10.1016/j.ajhg.2016.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223032PMC
January 2017

Corner fracture type spondylometaphyseal dysplasia: Overlap with type II collagenopathies.

Am J Med Genet A 2017 Mar 26;173(3):733-739. Epub 2016 Nov 26.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Spondylometaphyseal dysplasia (SMD) corner fracture type (also known as SMD "Sutcliffe" type, MIM 184255) is a rare skeletal dysplasia that presents with mild to moderate short stature, developmental coxa vara, mild platyspondyly, corner fracture-like lesions, and metaphyseal abnormalities with sparing of the epiphyses. The molecular basis for this disorder has yet to be clarified. We describe two patients with SMD corner fracture type and heterozygous pathogenic variants in COL2A1. These two cases together with a third case of SMD corner fracture type with a heterozygous COL2A1 pathogenic variant previously described suggest that this disorder overlaps with type II collagenopathies. The finding of one of the pathogenic variants in a previously reported case of spondyloepimetaphyseal dysplasia (SEMD) Strudwick type and the significant clinical similarity suggest an overlap between SMD corner fracture and SEMD Strudwick types. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315610PMC
March 2017

Newborn screening: a review of history, recent advancements, and future perspectives in the era of next generation sequencing.

Curr Opin Pediatr 2016 12;28(6):694-699

Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA.

Purpose Of Review: The purpose of this review is to summarize the development and recent advancements of newborn screening.

Recent Findings: Early initiation of medical care has modified the outcome for many disorders that were previously associated with high morbidity (such as cystic fibrosis, primary immune deficiencies, and inborn errors of metabolism) or with significant neurodevelopmental disabilities (such as phenylketonuria and congenital hypothyroidism). The new era of mass spectrometry and next generation sequencing enables the expansion of the newborn screen panel, and will help to address technical issues such as turnaround time, and decreasing false-positive and false-negative rates for the testing.

Summary: The newborn screening program is a successful public health initiative that facilitates early diagnosis of treatable disorders to reduce long-term morbidity and mortality.
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http://dx.doi.org/10.1097/MOP.0000000000000414DOI Listing
December 2016

Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation.

Mol Genet Metab 2016 Apr 27;117(4):407-12. Epub 2016 Jan 27.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA. Electronic address:

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders. The pathogenesis of this syndrome is not fully understood and believed to result from several interacting mechanisms including impaired mitochondrial energy production, microvasculature angiopathy, and nitric oxide (NO) deficiency. NO deficiency in MELAS syndrome is likely to be multifactorial in origin with the decreased availability of the NO precursors, arginine and citrulline, playing a major role. In this study we used stable isotope infusion techniques to assess NO production in children with MELAS syndrome and healthy pediatric controls. We also assessed the effect of oral arginine and citrulline supplementations on NO production in children with MELAS syndrome. When compared to control subjects, children with MELAS syndrome were found to have lower NO production, arginine flux, plasma arginine, and citrulline flux. In children with MELAS syndrome, arginine supplementation resulted in increased NO production, arginine flux, and arginine concentration. Citrulline supplementation resulted in a greater increase of these parameters. Additionally, citrulline supplementation was associated with a robust increase in citrulline concentration and flux and de novo arginine synthesis rate. The greater effect of citrulline in increasing NO production is due to its greater ability to increase arginine availability particularly in the intracellular compartment in which NO synthesis takes place. This study, which is the first one to assess NO metabolism in children with mitochondrial diseases, adds more evidence to the notion that NO deficiency occurs in MELAS syndrome, suggests a better effect for citrulline because of its greater role as NO precursor, and indicates that impaired NO production occurs in children as well as adults with MELAS syndrome. Thus, the initiation of treatment with NO precursors may be beneficial earlier in life. Controlled clinical trials to assess the therapeutic effects of arginine and citrulline on clinical complications of MELAS syndrome are needed.
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http://dx.doi.org/10.1016/j.ymgme.2016.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818739PMC
April 2016

Successful treatment of rhino-orbital mucormycosis with posaconazole and hyperbaric oxygen therapy.

Pediatr Hematol Oncol 2013 Apr 27;30(3):184-6. Epub 2013 Feb 27.

Department of Pediatrics, University of South Alabama, Children's & Women's Hospital, Mobile, AL 36604, USA.

Mucormycosis is a rare, but invasive infection caused by ubiquitous molds. Amphotericin B and surgery have been known to help improve the outcome. Sporadic case reports support the use of posaconazole in adults. We report a toddler with acute lymphoblastic leukemia who acquired rhino-orbital mucormycosis caused by Rhizopus species at the end of induction chemotherapy. She was successfully treated with multiple surgical debridements, amphotericin B, posaconazole and hyperbaric oxygen therapy. In conclusion, mucormycosis is a serious infection that requires aggressive surgical and medical therapy. To the best of our knowledge the use of posaconazole combined with hyperbaric oxygen therapy has not been reported in a toddler with leukemia and invasive Rhizopus sp. infection. This approach was found to be safe and effective in our patient.
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http://dx.doi.org/10.3109/08880018.2013.770587DOI Listing
April 2013