Publications by authors named "Andrew A M Morris"

25 Publications

  • Page 1 of 1

Cystathionine β-synthase deficiency in the E-HOD registry-part I: pyridoxine responsiveness as a determinant of biochemical and clinical phenotype at diagnosis.

J Inherit Metab Dis 2021 May 28;44(3):677-692. Epub 2020 Dec 28.

Division of Metabolism and Children's Research Center, University Children's Hospital, Zurich, Switzerland.

Cystathionine β-synthase (CBS) deficiency has a wide clinical spectrum, ranging from neurodevelopmental problems, lens dislocation and marfanoid features in early childhood to adult onset disease with predominantly thromboembolic complications. We have analysed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry. We developed comprehensive criteria to classify patients into four groups of pyridoxine responsivity: non-responders (NR), partial, full and extreme responders (PR, FR and ER, respectively). All groups showed overlapping concentrations of plasma total homocysteine while pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The FR and ER groups had a later age of onset and diagnosis and a longer diagnostic delay than NR and PR patients. Lens dislocation was common in all groups except ER but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the NR group while no ER patient had cognitive impairment. Thromboembolism was the commonest presenting feature in ER patients, whereas it was least likely at presentation in the NR group. This probably is due to the differences in ages at presentation: all groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Therefore, a standardised pyridoxine-responsiveness test in newly diagnosed patients and a critical review of previous assessments is indispensable to ensure adequate therapy and to prevent or reduce long-term complications.
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http://dx.doi.org/10.1002/jimd.12338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247016PMC
May 2021

Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients.

Orphanet J Rare Dis 2019 12 4;14(1):285. Epub 2019 Dec 4.

Beatrix Children's Hospital, Groningen, Division of Metabolic Diseases, University of Groningen, University Medical Center Groningen, CA33, PO box 30.001, 9700 RB, Groningen, Netherlands.

Background: Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) and dietary phenylalanine and tyrosine restriction improves physical health and life expectancy in Tyrosinemia type 1 (TT1). However, neurocognitive outcome is suboptimal. This study aimed to investigate behavior problems and health-related quality of life (HR-QoL) in NTBC-dietary-treated TT1 and to relate this to phenylalanine and tyrosine concentrations.

Results: Thirty-one TT1 patients (19 males; mean age 13.9 ± 5.3 years) were included in this study. Emotional and behavioral problems, as measured by the Achenbach System of Empirically Based Assessment, were present in almost all domains. Attention and thought problems were particularly evident. HR-QoL was assessed by the TNO AZL Children's and Adults QoL questionnaires. Poorer HR-QoL as compared to reference populations was observed for the domains: independent daily functioning, cognitive functioning and school performance, social contacts, motor functioning, and vitality. Both internalizing and externalizing behavior problems were associated with low phenylalanine (and associated lower tyrosine) concentrations during the first year of life. In contrast, high tyrosine (and associated higher phenylalanine) concentrations during life and specifically the last year before testing were associated with more internalizing behavior and/or HR-QoL problems.

Conclusions: TT1 patients showed several behavior problems and a lower HR-QoL. Associations with metabolic control differed for different age periods. This suggests the need for continuous fine-tuning and monitoring of dietary treatment to keep phenylalanine and tyrosine concentrations within target ranges in NTBC-treated TT1 patients.
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http://dx.doi.org/10.1186/s13023-019-1259-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894144PMC
December 2019

Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy.

Hum Mol Genet 2019 01;28(2):258-268

Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.

Recessively inherited variants in AARS2 (NM_020745.2) encoding mitochondrial alanyl-tRNA synthetase (mt-AlaRS) were first described in patients presenting with fatal infantile cardiomyopathy and multiple oxidative phosphorylation defects. To date, all described patients with AARS2-related fatal infantile cardiomyopathy are united by either a homozygous or compound heterozygous c.1774C>T (p.Arg592Trp) missense founder mutation that is absent in patients with other AARS2-related phenotypes. We describe the clinical, biochemical and molecular investigations of two unrelated boys presenting with fatal infantile cardiomyopathy, lactic acidosis and respiratory failure. Oxidative histochemistry showed cytochrome c oxidase-deficient fibres in skeletal and cardiac muscle. Biochemical studies showed markedly decreased activities of mitochondrial respiratory chain complexes I and IV with a mild decrease of complex III activity in skeletal and cardiac muscle. Using next-generation sequencing, we identified a c.1738C>T (p.Arg580Trp) AARS2 variant shared by both patients that was in trans with a loss-of-function heterozygous AARS2 variant; a c.1008dupT (p.Asp337*) nonsense variant or an intragenic deletion encompassing AARS2 exons 5-7. Interestingly, our patients did not harbour the p.Arg592Trp AARS2 founder mutation. In silico modelling of the p.Arg580Trp substitution suggested a deleterious impact on protein stability and folding. We confirmed markedly decreased mt-AlaRS protein levels in patient fibroblasts, skeletal and cardiac muscle, although mitochondrial protein synthesis defects were confined to skeletal and cardiac muscle. In vitro data showed that the p.Arg580Trp variant had a minimal effect on activation, aminoacylation or misaminoacylation activities relative to wild-type mt-AlaRS, demonstrating that instability of mt-AlaRS is the biological mechanism underlying the fatal cardiomyopathy phenotype in our patients.
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http://dx.doi.org/10.1093/hmg/ddy294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321959PMC
January 2019

Novel GFM2 variants associated with early-onset neurological presentations of mitochondrial disease and impaired expression of OXPHOS subunits.

Neurogenetics 2017 Dec 26;18(4):227-235. Epub 2017 Oct 26.

Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G>A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A>C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case. Both patients presented similarly in early childhood with global developmental delay, raised CSF lactate and abnormalities on cranial MRI. Sanger sequencing of familial samples confirmed the segregation of bi-allelic GFM2 variants with disease, while investigations into steady-state mitochondrial protein levels revealed respiratory chain subunit defects and loss of mtEFG2 protein in muscle. These data demonstrate the effects of defective mtEFG2 function, caused by previously unreported variants, confirming pathogenicity and expanding the clinical phenotypes associated with GFM2 variants.
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http://dx.doi.org/10.1007/s10048-017-0526-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705740PMC
December 2017

Phenotypic Heterogeneity in a Congenital Disorder of Glycosylation Caused by Mutations in STT3A.

J Child Neurol 2017 05 16;32(6):560-565. Epub 2017 Mar 16.

3 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

STT3A encodes the catalytic subunit of the oligosaccharyltransferase complex. A congenital disorder of glycosylation caused by mutations in STT3A has only been reported in one family to date, associated with a Type I congenital disorder of glycosylation pattern of transferrin glycoforms. The authors describe a further 5 related individuals with a likely pathogenic variant in STT3A, 2 of whom also had variants in TUSC3. Common phenotypic features in all symptomatic individuals include developmental delay, intellectual disability, with absent speech and seizures. Two individuals also developed episodic hypothermia and altered consciousness. The family were investigated by autozygosity mapping, which revealed both a homozygous region containing STT3A and, in addition, a homozygous deletion of TUSC3 in one child. A likely pathogenic variant in STT3A was confirmed on Sanger sequencing of all affected individuals: the authors discuss the molecular findings in detail and further delineate the clinical phenotype of this rare disorder.
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http://dx.doi.org/10.1177/0883073817696816DOI Listing
May 2017

Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency.

J Inherit Metab Dis 2017 01 24;40(1):49-74. Epub 2016 Oct 24.

Division of Genetic and Metabolism, Children's National Health System, Washington, DC, USA.

Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 μmol/L. Nevertheless, we recommend keeping the concentration below 100 μmol/L because levels fluctuate and the complications associated with high levels are so serious.
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http://dx.doi.org/10.1007/s10545-016-9979-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203861PMC
January 2017

Recessive Mutations in TRMT10C Cause Defects in Mitochondrial RNA Processing and Multiple Respiratory Chain Deficiencies.

Am J Hum Genet 2016 May 28;98(5):993-1000. Epub 2016 Apr 28.

Institute of Neuroscience, Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address:

Mitochondrial disorders are clinically and genetically diverse, with mutations in mitochondrial or nuclear genes able to cause defects in mitochondrial gene expression. Recently, mutations in several genes encoding factors involved in mt-tRNA processing have been identified to cause mitochondrial disease. Using whole-exome sequencing, we identified mutations in TRMT10C (encoding the mitochondrial RNase P protein 1 [MRPP1]) in two unrelated individuals who presented at birth with lactic acidosis, hypotonia, feeding difficulties, and deafness. Both individuals died at 5 months after respiratory failure. MRPP1, along with MRPP2 and MRPP3, form the mitochondrial ribonuclease P (mt-RNase P) complex that cleaves the 5' ends of mt-tRNAs from polycistronic precursor transcripts. Additionally, a stable complex of MRPP1 and MRPP2 has m(1)R9 methyltransferase activity, which methylates mt-tRNAs at position 9 and is vital for folding mt-tRNAs into their correct tertiary structures. Analyses of fibroblasts from affected individuals harboring TRMT10C missense variants revealed decreased protein levels of MRPP1 and an increase in mt-RNA precursors indicative of impaired mt-RNA processing and defective mitochondrial protein synthesis. The pathogenicity of the detected variants-compound heterozygous c.542G>T (p.Arg181Leu) and c.814A>G (p.Thr272Ala) changes in subject 1 and a homozygous c.542G>T (p.Arg181Leu) variant in subject 2-was validated by the functional rescue of mt-RNA processing and mitochondrial protein synthesis defects after lentiviral transduction of wild-type TRMT10C. Our study suggests that these variants affect MRPP1 protein stability and mt-tRNA processing without affecting m(1)R9 methyltransferase activity, identifying mutations in TRMT10C as a cause of mitochondrial disease and highlighting the importance of RNA processing for correct mitochondrial function.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863561PMC
May 2016

A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype.

J Med Genet 2016 09 18;53(9):634-41. Epub 2016 Apr 18.

Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.

Background: Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis.

Methods: Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed.

Results: We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (<9th centile) and similar facial features including a prominent forehead, smooth philtrum and deep-set eyes associated with a recurrent homozygous c.64T>C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly.

Conclusions: Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features-particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry-should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations.
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http://dx.doi.org/10.1136/jmedgenet-2015-103576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013090PMC
September 2016

When to Suspect and How to Diagnose Mitochondrial Disorders?

Indian J Pediatr 2016 Oct 13;83(10):1157-63. Epub 2016 Jan 13.

Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, NHS Foundation Trust, Saint Mary's Hospital, Oxford Road, Manchester, M13 9WL, UK.

Disorders of the mitochondrial respiratory chain are an exceedingly diverse group. The clinical features can affect any tissue or organ and occur at any age, with any mode of inheritance. The diagnosis of mitochondrial disorders requires knowledge of the clinical phenotypes and access to a wide range of laboratory techniques. A few syndromes are associated with a specific genetic defect and in these cases it is appropriate to proceed directly to an appropriate test of blood or urine. In most cases, however, the best strategy starts with biochemical and histochemical studies on a muscle biopsy. Appropriate molecular genetic studies can then be chosen, based on these results and the clinical picture. Unfortunately, there is currently limited availability of respiratory chain studies in India. Exome sequencing is undertaken increasingly often; without preceding mitochondrial studies, this can lead to misleading results.
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http://dx.doi.org/10.1007/s12098-015-1932-yDOI Listing
October 2016

Recognition, assessment and management of hypoglycaemia in childhood.

Arch Dis Child 2016 06 30;101(6):575-580. Epub 2015 Dec 30.

Paediatric Inherited Metabolic Disease, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester, UK.

Hypoglycaemia is frequent in children and prompt management is required to prevent brain injury. In this article we will consider hypoglycaemia in children after the neonatal period. The most common causes are diabetes mellitus and idiopathic ketotic hypoglycaemia (IKH) but a number of endocrine disorders and inborn errors of metabolism (IEMs) need to be excluded. Elucidation of the diagnosis relies primarily on investigations during a hypoglycaemic episode but may also involve biochemical tests between episodes, dynamic endocrine tests and molecular genetics. Specific treatment such as cortisol replacement and pancreatic surgery may be required for endocrine causes of hypoglycaemia, such as adrenal insufficiency and congenital hyperinsulinism. In contrast, in IKH and most IEMs, hypoglycaemia is prevented by limiting the duration of fasting and maintaining a high glucose intake during illnesses.
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http://dx.doi.org/10.1136/archdischild-2015-308337DOI Listing
June 2016

LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population.

Brain 2015 Dec 27;138(Pt 12):3503-19. Epub 2015 Oct 27.

1 Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

Mitochondrial Complex IV [cytochrome c oxidase (COX)] deficiency is one of the most common respiratory chain defects in humans. The clinical phenotypes associated with COX deficiency include liver disease, cardiomyopathy and Leigh syndrome, a neurodegenerative disorder characterized by bilateral high signal lesions in the brainstem and basal ganglia. COX deficiency can result from mutations affecting many different mitochondrial proteins. The French-Canadian variant of COX-deficient Leigh syndrome is unique to the Saguenay-Lac-Saint-Jean region of Québec and is caused by a founder mutation in the LRPPRC gene. This encodes the leucine-rich pentatricopeptide repeat domain protein (LRPPRC), which is involved in post-transcriptional regulation of mitochondrial gene expression. Here, we present the clinical and molecular characterization of novel, recessive LRPPRC gene mutations, identified using whole exome and candidate gene sequencing. The 10 patients come from seven unrelated families of UK-Caucasian, UK-Pakistani, UK-Indian, Turkish and Iraqi origin. They resemble the French-Canadian Leigh syndrome patients in having intermittent severe lactic acidosis and early-onset neurodevelopmental problems with episodes of deterioration. In addition, many of our patients have had neonatal cardiomyopathy or congenital malformations, most commonly affecting the heart and the brain. All patients who were tested had isolated COX deficiency in skeletal muscle. Functional characterization of patients' fibroblasts and skeletal muscle homogenates showed decreased levels of mutant LRPPRC protein and impaired Complex IV enzyme activity, associated with abnormal COX assembly and reduced steady-state levels of numerous oxidative phosphorylation subunits. We also identified a Complex I assembly defect in skeletal muscle, indicating different roles for LRPPRC in post-transcriptional regulation of mitochondrial mRNAs between tissues. Patient fibroblasts showed decreased steady-state levels of mitochondrial mRNAs, although the length of poly(A) tails of mitochondrial transcripts were unaffected. Our study identifies LRPPRC as an important disease-causing gene in an early-onset, multisystem and neurological mitochondrial disease, which should be considered as a cause of COX deficiency even in patients originating outside of the French-Canadian population.
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http://dx.doi.org/10.1093/brain/awv291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655343PMC
December 2015

Expanding the clinical and molecular spectrum of thiamine pyrophosphokinase deficiency: a treatable neurological disorder caused by TPK1 mutations.

Mol Genet Metab 2014 Dec 5;113(4):301-6. Epub 2014 Oct 5.

Department of Paediatrics, Paracelsus Medical University, Salzburg, Austria.

Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate, a cofactor for a number of enzymes, including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. Episodic encephalopathy type thiamine metabolism dysfunction (OMIM 614458) due to TPK1 mutations is a recently described rare disorder. The mechanism of the disease, its phenotype and treatment are not entirely clear. We present two patients with novel homozygous TPK1 mutations (Patient 1 with p.Ser160Leu and Patient 2 with p.Asp222His). Unlike the previously described phenotype, Patient 2 presented with a Leigh syndrome like non-episodic early-onset global developmental delay, thus extending the phenotypic spectrum of the disorder. We, therefore, propose that TPK deficiency may be a better name for the condition. The two cases help to further refine the neuroradiological features of TPK deficiency and show that MRI changes can be either fleeting or progressive and can affect either white or gray matter. We also show that in some cases lactic acidosis can be absent and 2-ketoglutaric aciduria may be the only biochemical marker. Furthermore, we have established the assays for TPK enzyme activity measurement and thiamine pyrophosphate quantification in frozen muscle and blood. These tests will help to diagnose or confirm the diagnosis of TPK deficiency in a clinical setting. Early thiamine supplementation prevented encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. We present evidence suggesting that thiamine supplementation may rescue TPK enzyme activity. Lastly, in silico protein structural analysis shows that the p.Ser160Leu mutation is predicted to interfere with TPK dimerization, which may be a novel mechanism for the disease.
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http://dx.doi.org/10.1016/j.ymgme.2014.09.010DOI Listing
December 2014

Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies.

JAMA 2014 Jul;312(1):68-77

Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England.

Importance: Mitochondrial disorders have emerged as a common cause of inherited disease, but their diagnosis remains challenging. Multiple respiratory chain complex defects are particularly difficult to diagnose at the molecular level because of the massive number of nuclear genes potentially involved in intramitochondrial protein synthesis, with many not yet linked to human disease.

Objective: To determine the molecular basis of multiple respiratory chain complex deficiencies.

Design, Setting, And Participants: We studied 53 patients referred to 2 national centers in the United Kingdom and Germany between 2005 and 2012. All had biochemical evidence of multiple respiratory chain complex defects but no primary pathogenic mitochondrial DNA mutation. Whole-exome sequencing was performed using 62-Mb exome enrichment, followed by variant prioritization using bioinformatic prediction tools, variant validation by Sanger sequencing, and segregation of the variant with the disease phenotype in the family.

Results: Presumptive causal variants were identified in 28 patients (53%; 95% CI, 39%-67%) and possible causal variants were identified in 4 (8%; 95% CI, 2%-18%). Together these accounted for 32 patients (60% 95% CI, 46%-74%) and involved 18 different genes. These included recurrent mutations in RMND1, AARS2, and MTO1, each on a haplotype background consistent with a shared founder allele, and potential novel mutations in 4 possible mitochondrial disease genes (VARS2, GARS, FLAD1, and PTCD1). Distinguishing clinical features included deafness and renal involvement associated with RMND1 and cardiomyopathy with AARS2 and MTO1. However, atypical clinical features were present in some patients, including normal liver function and Leigh syndrome (subacute necrotizing encephalomyelopathy) seen in association with TRMU mutations and no cardiomyopathy with founder SCO2 mutations. It was not possible to confidently identify the underlying genetic basis in 21 patients (40%; 95% CI, 26%-54%).

Conclusions And Relevance: Exome sequencing enhances the ability to identify potential nuclear gene mutations in patients with biochemically defined defects affecting multiple mitochondrial respiratory chain complexes. Additional study is required in independent patient populations to determine the utility of this approach in comparison with traditional diagnostic methods.
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http://dx.doi.org/10.1001/jama.2014.7184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558267PMC
July 2014

SURF1 deficiency: a multi-centre natural history study.

Orphanet J Rare Dis 2013 Jul 5;8:96. Epub 2013 Jul 5.

Background: SURF1 deficiency, a monogenic mitochondrial disorder, is the most frequent cause of cytochrome c oxidase (COX) deficient Leigh syndrome (LS). We report the first natural history study of SURF1 deficiency.

Methods: We conducted a multi-centre case notes review of 44 SURF1-deficient patients from ten different UK centres and two Australian centres. Survival data for LRPPRC-deficient LS and nuclear-encoded complex I-deficient LS patients were obtained from previous publications. The survival of SURF1-deficient patients was compared with these two groups using Kaplan-Meier survival analysis and logrank test.

Results: The majority of patients (32/44, 73%) presented in infancy (median 9.5 months). Frequent symptoms were poor weight gain (95%, median age 10 months), hypotonia (93%, median age 14 months), poor feeding/vomiting (89%, median age 10 months), developmental delay (88%, median age 14 months), developmental regression (71%, median age 19 months), movement disorder (52%, median age 24 months), oculomotor involvement (52%, median age 29 months) and central respiratory failure (78%, median age 31 months). Hypertrichosis (41%), optic atrophy (23%), encephalopathy (20%), seizures (14%) and cardiomyopathy (2%) were observed less frequently.

Conclusions: SURF1-deficient patients have a homogeneous clinical and biochemical phenotype. Early recognition is essential to expedite diagnosis and enable prenatal diagnosis.
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http://dx.doi.org/10.1186/1750-1172-8-96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706230PMC
July 2013

Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes.

J Inherit Metab Dis 2012 Nov 27;35(6):1037-49. Epub 2012 Mar 27.

Department of Human Genetics, Emory University School of Medicine, Rm. 325.2 Whitehead Bldg, 615 Michael St, Atlanta, GA 30322, USA.

Without intervention, classic galactosemia is a potentially fatal disorder in infancy. With the benefit of early diagnosis and dietary restriction of galactose, the acute sequelae of classic galactosemia can be prevented or reversed. However, despite early and lifelong dietary treatment, many galactosemic patients go on to experience serious long-term complications including cognitive disability, speech problems, neurological and/or movement disorders and, in girls and women, ovarian dysfunction. Further, there remains uncertainty surrounding what constitutes a 'best practice' for treating this disorder. To explore the extent and implications of this uncertainty, we conducted a small but global survey of healthcare providers who follow patients with classic galactosemia, seeking to compare established protocols for diagnosis, intervention, and follow-up, as well as the outcomes and outcome frequencies seen in the patient populations cared for by these providers. We received 13 survey responses representing five continents and 11 countries. Respondents underscored disparities in approaches to diagnosis, management and follow-up care. Notably, we saw no clear relationship between differing approaches to care and long-term outcomes in the populations studied. Negative outcomes occurred in the majority of cases regardless of when treatment was initiated, how tightly galactose intake was restricted, or how closely patients were monitored. We document here what is, to our knowledge, the first global comparison of healthcare approaches to classic galactosemia. These data reinforce the idea that there is currently no one best practice for treating patients with classic galactosemia, and underscore the need for more extensive and statistically powerful comparative studies to reveal potential positive or negative impacts of differing approaches.
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http://dx.doi.org/10.1007/s10545-012-9477-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774053PMC
November 2012

Peritoneal dialysis for chronic renal failure in a patient with methylmalonic acidaemia.

Pediatr Nephrol 2009 May 2;24(5):1085-7. Epub 2008 Dec 2.

Department of Nephrology, Royal Liverpool Children's Hospital, Liverpool, UK.

Chronic renal failure is a common complication of methylmalonic acidaemia (MMA). It is usually managed with haemodialysis and renal transplantation. We report the use of continuous cycling peritoneal dialysis (CCPD) for 20 months in a paediatric patient with chronic renal failure due to MMA. This procedure resulted in the elimination of 950 micromol methylmalonate (MM) per day and a fall in the plasma MM concentration from 3.9 to 0.74 mmol/l. As a result of this treatment, the frequency at which this patient was hospitalised was markedly reduced prior to a successful renal transplantation.
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http://dx.doi.org/10.1007/s00467-008-1068-7DOI Listing
May 2009

Analysis of mutant DNA polymerase gamma in patients with mitochondrial DNA depletion.

Hum Mutat 2009 Feb;30(2):248-54

Department of Clinical Neurosciences, Institute of Neurology, University College London, London, United Kingdom.

We studied six unrelated children with depletion of mitochondrial DNA (mtDNA). They presented with Leigh syndrome, infantile hepatocerebral mtDNA depletion syndrome, or Alpers-Huttenlocher syndrome. Several genes have been implicated in mtDNA depletion. Screening of candidate genes indicated that all six patients were compound heterozygous for missense mutations in the gene for the catalytic subunit of DNA polymerase gamma (POLG). Three of the identified mutations, c.3328C>T (p.H1110Y), c.3401A>G (p.H1134R), and c.3406G>A (p.E1136K), have not been reported earlier. To investigate the functional consequences of the mutations, we carried out a series of biochemical assays in cultured fibroblasts. These studies revealed that fibroblast cultures from the patients with infantile hepatocerebral mtDNA depletion syndrome progressively lost their mtDNA during culturing, whereas fibroblast cultures from patients presenting with Leigh syndrome or Alpers-Huttenlocher syndrome had reduced but stable levels of mtDNA. DNA polymerase gamma activity was below the normal range in all patient cultures, except for one; however, this culture showed low levels of the heterodimeric enzyme and poor DNA polymerase gamma processivity. Parental fibroblast cultures had normal catalytic efficiency of DNA polymerase gamma, consistent with the observation that all carriers are asymptomatic. Thus, we report the first patient with Leigh syndrome caused by POLG mutations. The cell culture experiments established the pathogenicity of the identified POLG mutations and helped to define the molecular mechanisms responsible for mtDNA depletion in the patients' tissues. The assays may facilitate the identification of those patients in whom screening for POLG mutations would be most appropriate.
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http://dx.doi.org/10.1002/humu.20852DOI Listing
February 2009

ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.

Brain 2007 Aug 20;130(Pt 8):2045-54. Epub 2007 Jun 20.

The Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Skejby Sygehus, Aarhus, Denmark.

Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.
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http://dx.doi.org/10.1093/brain/awm135DOI Listing
August 2007

Diagnosis and early management of inborn errors of metabolism presenting around the time of birth.

Acta Paediatr 2006 Jan;95(1):6-14

Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, London, UK.

Unlabelled: Inherited metabolic diseases often present around the time of birth. They are responsible for some cases of hydrops fetalis and a number of dysmorphic syndromes. Patients with inborn errors may also present at (or shortly after) birth with seizures or severe hypotonia. Most affected babies, however, appear normal at birth and subsequently deteriorate, with hypoglycaemia, acidosis, neurological or cardiac problems, or liver disease. Treatment often involves measures to reduce catabolism and to remove toxic metabolites. It should not be delayed for a definitive diagnosis.

Conclusion: In the newborn period, inborn errors can easily be misdiagnosed as sepsis or birth asphyxia; prompt detection requires vigilance and the early measurement of biochemical markers, such as plasma ammonia.
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http://dx.doi.org/10.1080/08035250500349413DOI Listing
January 2006

A novel point mutation in the mitochondrial tRNA(Trp) gene produces a neurogastrointestinal syndrome.

Eur J Hum Genet 2004 Jun;12(6):509-12

Mitochondrial Research Group, School of Neurology, Neurobiology and Psychiatry, The Medical School, University of Newcastle upon Tyne, UK.

We report a novel, heteroplasmic point mutation in the mitochondrial tRNA for tryptophan at position 5532. The mutation was present in all the tissues studied and segregated with the biochemical defect, with higher levels of mutation present in cytochrome c oxidase-deficient muscle fibres. The patient manifested a neurogastrointestinal syndrome with features including failure to thrive, psychomotor retardation, ophthalmoplegia, sensorineural deafness and encephalopathy together with vomiting, diarrhoea and colitis.
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http://dx.doi.org/10.1038/sj.ejhg.5201185DOI Listing
June 2004

Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome.

Nat Genet 2004 Apr 28;36(4):400-4. Epub 2004 Mar 28.

Section of Medical and Molecular Genetics, University of Birmingham, and Liver Unit, Birmingham Children's Hospital, UK.

ARC syndrome (OMIM 208085) is an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity. Platelet dysfunction is common. Affected infants do not thrive and usually die in the first year of life. To elucidate the molecular basis of ARC, we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC. VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion.
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http://dx.doi.org/10.1038/ng1325DOI Listing
April 2004

Leigh disease associated with a novel mitochondrial DNA ND5 mutation.

Eur J Hum Genet 2002 Feb;10(2):141-4

Department of Neurology, The Medical School, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.

Leigh disease is a genetically heterogeneous, neurodegenerative disorder of childhood that is caused by defects of either the nuclear or mitochondrial genome. Here, we report the molecular genetic findings in a patient with neuropathological hallmarks of Leigh disease and complex I deficiency. Direct sequencing of the seven mitochondrial DNA (mtDNA)-encoded complex I (ND) genes revealed a novel missense mutation (T12706C) in the mitochondrial ND5 gene. The mutation is predicted to change an invariant amino acid in a highly conserved transmembrane helix of the mature polypeptide and was heteroplasmic in both skeletal muscle and cultured skin fibroblasts. The association of the T12706C ND5 mutation with a specific biochemical defect involving complex I is highly suggestive of a pathogenic role for this mutation.
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http://dx.doi.org/10.1038/sj.ejhg.5200773DOI Listing
February 2002

Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation.

Nat Genet 2002 Feb 22;30(2):145-6. Epub 2002 Jan 22.

Departments of Neurology, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.

Mutations of mitochondrial DNA (mtDNA) are an important cause of genetic disease. We describe a family with an unusual homoplasmic mutation that resulted in six neonatal deaths and one surviving child with Leigh syndrome. The mother is clinically normal, but a severe biochemical and molecular genetic defect was present in both a fatally affected child and the mother. This family highlights the role of homoplasmic mt-tRNA mutations in genetic disease.
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http://dx.doi.org/10.1038/ng819DOI Listing
February 2002

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients.

Pediatrics 2002 Jan;109(1):99-104

Department of Pediatrics Academic Medical Center, University of Amsterdam, the Netherlands.

Objectives: To assess the mode of presentation, biochemical abnormalities, clinical course, and effects of therapy in patients of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.

Background: LCHAD deficiency is a rare, autosomal recessive inborn error of fatty acid oxidation. Although case reports and small series of patients have been published, these may not give a true picture of the clinical and biochemical spectrum associated with this disorder. To improve the early recognition and management of this potentially lethal disorder, we have reviewed a large cohort of LCHAD-deficient patients.

Methods: A questionnaire was sent to the referring physicians of 61 unselected patients with LCHAD deficiency diagnosed in our center. The standardized questionnaire requested information about the clinical signs and symptoms at presentation, the clinical history, family history, pregnancy, biochemical parameters at presentation, treatment, and clinical outcome.

Results: Questionnaires on 50 patients (82%) were returned and included in this study. The mean age of clinical presentation was 5.8 months (range: 1 day-26 months). Seven (15%) of the patients presented in the neonatal period. Thirty-nine patients (78%) presented with hypoketotic hypoglycemia, the classical features of a fatty acid oxidation disorder. Eleven patients (22%) presented with chronic problems, consisting of failure to thrive, feeding difficulties, cholestatic liver disease, and/or hypotonia. In retrospect, most (82%) of the patients presenting with an acute metabolic derangement also suffered from a combination of chronic nonspecific symptoms before the metabolic crises. Mortality in this series was high (38%), all dying before or within 3 months after diagnosis. Morbidity in the surviving patients is also high, with recurrent metabolic crises and muscle problems despite therapy.

Conclusions: LCHAD deficiency often presents with a combination of chronic nonspecific symptoms. Early diagnosis is difficult in the absence of the classical metabolic derangement. Survival can be improved by prompt diagnosis, but morbidity remains alarmingly high despite current therapeutic regimes.
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http://dx.doi.org/10.1542/peds.109.1.99DOI Listing
January 2002
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