Publications by authors named "Ellen Crushell"

49 Publications

Low excretor glutaric aciduria type 1 of insidious onset with dystonia and atypical clinical features, a diagnostic dilemma.

JIMD Rep 2021 Mar 16;58(1):12-20. Epub 2020 Nov 16.

Department of Paediatric Neurology Cork University Hospital Cork Republic of Ireland.

A 4-year-old girl was referred for reassessment of dyskinetic cerebral palsy. Initial investigations in her country of birth, India, had not yielded a diagnosis. MRI brain in infancy revealed bilateral putamen hyperintensity. She had generalized dyskinesia predominantly bulbar and limbs. Motor and speech development were most affected with preservation of cognitive development. There was no history of acute encephalopathic crisis or status dystonicus. Initial urine organic acids and amino acids and acylcarnitine profile (ACP) were normal. A dystonia genetic panel showed compound heterozygosity with a pathogenic variant and a variant of uncertain significance in the gene. The latter is hitherto undescribed and is indicative of a potential diagnosis of glutaric aciduria type 1 (alternatively glutaric acidemia type 1) (GA-1), an autosomal recessive disorder of mitochondrial lysine/hydroxylysine and tryptophan metabolism. Repeat urine organic acids showed isolated slightly increased 3-hydroxy glutarate excretion consistent with GA-1 and characterizing the patient as a "low excretor," a diagnostic sub-group where diagnosis is more challenging but prognosis is similar. Repeat MRI Brain at age 4 showed volume loss and symmetric T2 hyperintensity in the posterior putamina bilaterally. This case highlights the diagnostic dilemma of GA-1 where differing clinical courses, genetic variants, neuroradiological findings, and biochemical excretion patterns may lead to a later diagnosis. The presence of newborn screening for GA-1 should not dull the clinician's suspicion of the possibility that GA-1 may present with a complex movement disorder. Timely diagnosis and treatment is essential, as neurological sequelae are largely irreversible.
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http://dx.doi.org/10.1002/jmd2.12187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932869PMC
March 2021

Phosphoglucomutase-1 deficiency: Early presentation, metabolic management and detection in neonatal blood spots.

Mol Genet Metab 2020 Sep - Oct;131(1-2):135-146. Epub 2020 Sep 17.

Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

Phosphoglucomutase 1 deficiency is a congenital disorder of glycosylation (CDG) with multiorgan involvement affecting carbohydrate metabolism, N-glycosylation and energy production. The metabolic management consists of dietary D-galactose supplementation that ameliorates hypoglycemia, hepatic dysfunction, endocrine anomalies and growth delay. Previous studies suggest that D-galactose administration in juvenile patients leads to more significant and long-lasting effects, stressing the urge of neonatal diagnosis (0-6 months of age). Here, we detail the early clinical presentation of PGM1-CDG in eleven infantile patients, and applied the modified Beutler test for screening of PGM1-CDG in neonatal dried blood spots (DBSs). All eleven infants presented episodic hypoglycemia and elevated transaminases, along with cleft palate and growth delay (10/11), muscle involvement (8/11), neurologic involvement (5/11), cardiac defects (2/11). Standard dietary measures for suspected lactose intolerance in four patients prior to diagnosis led to worsening of hypoglycemia, hepatic failure and recurrent diarrhea, which resolved upon D-galactose supplementation. To investigate possible differences in early vs. late clinical presentation, we performed the first systematic literature review for PGM1-CDG, which highlighted respiratory and gastrointestinal symptoms as significantly more diagnosed in neonatal age. The modified Butler-test successfully identified PGM1-CDG in DBSs from seven patients, including for the first time Guthrie cards from newborn screening, confirming the possibility of future inclusion of PGM1-CDG in neonatal screening programs. In conclusion, severe infantile morbidity of PGM1-CDG due to delayed diagnosis could be prevented by raising awareness on its early presentation and by inclusion in newborn screening programs, enabling early treatments and galactose-based metabolic management.
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http://dx.doi.org/10.1016/j.ymgme.2020.08.003DOI Listing
September 2020

Maple syrup urine disease: Clinical outcomes, metabolic control, and genotypes in a screened population after four decades of newborn bloodspot screening in the Republic of Ireland.

J Inherit Metab Dis 2020 Dec 9. Epub 2020 Dec 9.

National Centre for Inherited Metabolic Disorders, Children's Health Ireland at Temple Street, Dublin, Ireland.

Since 1972, 18 patients (10 females/8 males) have been detected by newborn bloodspot screening (NBS) with neonatal-onset maple syrup urine disease (MSUD) in Ireland. Patients were stratified into three clusters according to clinical outcome at the time of data collection, including developmental, clinical, and IQ data. A fourth cluster comprised of two early childhood deaths; a third patient died as an adult. We present neuroimaging and electroencephalography together with clinical and biochemical data. Incidence of MSUD (1972-2018) was 1 in 147 975. Overall good clinical outcomes were achieved with 15/18 patients alive and with essentially normal functioning (with only the lowest performing cluster lying beyond a single SD on their full scale intelligence quotient). Molecular genetic analysis revealed genotypes hitherto not reported, including a possible digenic inheritance state for the BCKDHA and DBT genes in one family. Treatment has been based on early implementation of emergency treatment, diet, close monitoring, and even dialysis in the setting of acute metabolic decompensation. A plasma leucine ≥400 μmol/L (outside therapeutic range) was more frequently observed in infancy or during adolescence, possibly due to infections, hormonal changes, or noncompliance. Children require careful management during metabolic decompensations in early childhood, and this represented a key risk period in our cohort. A high level of metabolic control can be achieved through diet with early implementation of a "sick day" regime and, in some cases, dialysis as a rescue therapy. The Irish cohort, despite largely classical phenotypes, achieved good outcomes in the NBS era, underlining the importance of early diagnosis and skilled multidisciplinary team management.
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http://dx.doi.org/10.1002/jimd.12337DOI Listing
December 2020

Hypoglycemia is not a defining feature of metabolic crisis in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: Further evidence of specific biochemical markers which may aid diagnosis.

JIMD Rep 2020 Sep 30;55(1):26-31. Epub 2020 Jun 30.

National Centre for Inherited Metabolic Disorders Children's Health Ireland at Temple Street Dublin Ireland.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG Co-A) synthase (mHS) deficiency is an autosomal recessive disorder of ketone body synthesis which has traditionally been associated with hypoketotic hypoglycemia, hepatomegaly and encephalopathy, presenting in early childhood following a period of fasting. We report the third case of mHS deficiency presenting in the absence of hypoglycemia, with profound biochemical abnormalities and further evidence of potential specific diagnostic biomarkers. A previously well, 20-month old, unvaccinated male, of nonconsanguineous Polish heritage, presented with encephalopathy, hepatomegaly, severe metabolic acidosis, and mild hyperammonemia following a brief intercurrent illness. The patient was reported to have taken colloidal silver prior to presentation, posing a further diagnostic challenge. Additionally, he developed features suggestive of hemophagocytic lymphohistiocytosis during treatment. While the patient was normoglycemic prior to dextrose administration, the sample was markedly lipemic, with significant hypertriglyceridemia detected. Urine organic acid analysis revealed dicarboxylic aciduria with 4-hydroxy-6-methyl-2-pyrone (4HMP) and the presence of three other previously reported putative biomarkers for mHS deficiency. Glutarate was markedly elevated in the initial chromatogram, with a mild increase in 3-hydroxyglutarate (3HG) persisting. Raised acetylcarnitine was detected on acylcarnitine profile. Molecular genetic analysis of the gene identified compound heterozygosity for known pathogenic mutations c.634G>A and c.1016+1G>A, confirming the diagnosis of mHS deficiency. This case provides further evidence that hypoglycemia is not invariably present in symptomatic mHS deficiency. We propose that elevated acetylcarnitine, triglycerides, and 3HG are additional biochemical features during acute presentations. With the expansion of novel biomarkers, further cases of this rare disorder may emerge.
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http://dx.doi.org/10.1002/jmd2.12146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463059PMC
September 2020

Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants in LARS1.

Genet Med 2020 11 23;22(11):1863-1873. Epub 2020 Jul 23.

Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings.

Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts.

Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro.

Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke.
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http://dx.doi.org/10.1038/s41436-020-0904-4DOI Listing
November 2020

The risk of malnutrition in children with autism spectrum disorder.

Arch Dis Child Educ Pract Ed 2019 Dec 2. Epub 2019 Dec 2.

National Centre of Inherited Metabolic Disease, Children's Health Ireland at Temple Street, Dublin, Ireland.

A 9-year-old boy presented with a 2-day history of vomiting, ataxia and reduced consciousness. He had vomited intermittently in the two preceding months, without headaches, visual disturbance or early morning symptoms. He had autism spectrum disorder, and restricted eating since aged 2 years, eating only corn-crisps, Rich Tea biscuits and chips (French fries), and drinking Coca-Cola (containing 10% glucose; figure 1). Recently a dietician had prescribed a multivitamin.edpract;archdischild-2019-317453v1/F1F1F1Figure 1The patient's complete daily food intake over approximately 7 years (2-3 biscuits per day).Dietary analysis revealed an extremely low protein (0.37 g/kg/day) and low fat (0.77 g/kg/day) diet for over 7 years with a caloric intake of 1200 kCal. Estimated requirements were 1512 kCal, 0.92 mg/kg/day of protein and 1.94 mg/kg of fat (based on 35% of daily calorie intake).On examination he was encephalopathic, with hepatomegaly and ascites. His height and weight were on the 0.4th-2nd and 9th centiles, respectively. Laboratory results demonstrated glucose 2.7 mmol/L, mild anaemia, raised urea (10.7 mmol/L) with normal creatinine and raised hepatic transaminases, low albumin and elevated creatinine kinase (peak 7809 IU/L). He remained encephalopathic and was intubated for poor respiratory function. Ammonia and blood pH were normal. QUESTION 1: What nutritional/metabolic test(s) would be the next best step?Vitamin B (thiamine) levelsCopper and caeruloplasmin levelsBlood spot for acylcarnitine profilePlasma amino acid profileUrine organic acids QUESTION 2: What potentially dangerous feeding issues in paediatric intensive care exist here?Electrolyte levels and supplementationFat composition of feedsAmino acid composition of feedsVitamin levels QUESTION 3: Why might this patient have had preserved vitamin E levels?Vitamin E is added to rancherosSome vitamin E is obtained from sunlightFrench fries are relatively high in vitamin EMultivitamin preparations QUESTION 4: What metabolic disorders are associated with very low carnitine levels?Organic acidaemiasFatty acid oxidation disordersMitochondrial disorders (disorders of respiratory chain)Maple syrup urine disease (MSUD) .
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http://dx.doi.org/10.1136/archdischild-2019-317453DOI Listing
December 2019

Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.

Genet Med 2020 03 25;22(3):610-621. Epub 2019 Nov 25.

Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis.

Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods.

Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH).

Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.
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http://dx.doi.org/10.1038/s41436-019-0698-4DOI Listing
March 2020

Ten-year retrospective review (2003-2013) of 56 inpatient admissions to stabilize elevated phenylalanine levels.

JIMD Rep 2019 Mar 14;46(1):70-74. Epub 2019 Mar 14.

Department of Research Temple Street Children's University Hospital Dublin Ireland.

Phenylketonuria (PKU) is an inherited metabolic disorder affecting phenylalanine metabolism. The Irish incidence is 1:4500. Currently, there are 500 patients under the care of the National Centre for Inherited Metabolic Disorders in Temple Street Children's University Hospital. Current practice is to admit PKU patients with phenylalanine (phe) levels that are consistently out of range despite an intensive multidisciplinary team input on an outpatient basis. The aim of this study was to evaluate changes in phe levels pre, during, and post admissions and to examine if there was a sustained impact post discharge. Fifty-six patients were admitted between January 2003 and December 2013. Patients were all <18 years of age. Greater than 70% (n = 39) of the reasons for admission were due to multiple issues. Average admission time was 5 days. There was a significant decrease in median phe levels from prior to the admission to during the admission. However, there was a significant increase in median phe levels from during the admission (505 μmol/L) to both the 1-6 months' and 7-12 months' time points (618 and 651 μmol/L, respectively). The results highlight that while inpatient admissions can stabilize levels within the acute setting, this is not sustained long term. The ward environment does not accurately replicate home circumstances. This study highlighted that the reasons for admission are most often multifactorial, which is less likely to be resolved during a brief admission period.
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http://dx.doi.org/10.1002/jmd2.12019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498819PMC
March 2019

Prevention and Therapeutic Innovation in the Management of Child Health.

J Pediatr 2019 May;208:300-301

European Paediatric Association-Union of National European Paediatric Societies and Associations (EPA-UNEPSA), Berlin, Germany; Royal College of Physicians of Ireland, Dublin, Ireland; School of Medicine, University College Dublin, Temple Street Children's Hospital and Our Lady's Children's Hospital, Dublin, Ireland.

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http://dx.doi.org/10.1016/j.jpeds.2019.01.056DOI Listing
May 2019

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

J Inherit Metab Dis 2019 03 17;42(2):333-352. Epub 2019 Feb 17.

Inherited Metabolic Diseases Clinic, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado.

Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry.

Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities.

Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.
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http://dx.doi.org/10.1002/jimd.12041DOI Listing
March 2019

Newborn screening for homocystinurias: Recent recommendations versus current practice.

J Inherit Metab Dis 2019 01;42(1):128-139

Austrian Newborn Screening, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.

Purpose: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations.

Methods: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres.

Results: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns.

Conclusions: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.
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http://dx.doi.org/10.1002/jimd.12034DOI Listing
January 2019

Amino Acids and Inherited Amino Acid-Related Disorders.

J Nutr Metab 2018 10;2018:5629454. Epub 2018 Sep 10.

Bonn-Rhein Sieg University of Applied Sciences, Rheinbach, Germany.

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http://dx.doi.org/10.1155/2018/5629454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6151679PMC
September 2018

Intact transferrin and total plasma glycoprofiling for diagnosis and therapy monitoring in phosphoglucomutase-I deficiency.

Transl Res 2018 09 10;199:62-76. Epub 2018 May 10.

Department of Neurology and Translational Metabolic Laboratory, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

Phosphoglucomutase 1 (PGM1) deficiency results in a mixed phenotype of a Glycogen Storage Disorder and a Congenital Disorder of Glycosylation (CDG). Screening for abnormal glycosylation has identified more than 40 patients, manifesting with a broad clinical and biochemical spectrum which complicates diagnosis. Together with the availability of D-galactose as dietary therapy, there is an urgent need for specific glycomarkers for early diagnosis and treatment monitoring. We performed glycomics profiling by high-resolution QTOF mass spectrometry in a series of 19 PGM1-CDG patients, covering a broad range of biochemical and clinical severity. Bioinformatics and statistical analysis were used to select glycomarkers for diagnostics and define glycan-indexes for treatment monitoring. Using 3 transferrin glycobiomarkers, all PGM1-CDG patients were diagnosed with 100% specificity and sensitivity. Total plasma glycoprofiling showed an increase in high mannose glycans and fucosylation, while global galactosylation and sialylation were severely decreased. For treatment monitoring, we defined 3 glycan-indexes, reflecting normal glycosylation, a lack of complete glycans (LOCGI) and of galactose residues (LOGI). These indexes showed improved glycosylation upon D-galactose treatment with a fast and near-normalization of the galactose index (LOGI) in 6 out of 8 patients and a slower normalization of the LOCGI in all patients. Total plasma glycoprofiling showed improvement of the global high mannose glycans, fucosylation, sialylation, and galactosylation status on D-galactose treatment. Our study indicates specific glycomarkers for diagnosis of mildly and severely affected PGM1-CDG patients, and to monitor the glycan-specific effects of D-galactose therapy.
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http://dx.doi.org/10.1016/j.trsl.2018.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041963PMC
September 2018

Finger Prick to Finger Tip: Use of Mobile Phone Technology to Send PKU Blood Results.

J Nutr Metab 2018 24;2018:2178346. Epub 2018 Jun 24.

National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.

The Metabolic Dietetic Team in the National Centre for Inherited Metabolic Disorders (NCIMD) in Ireland deals with approximately 120 weekly phenylalanine (Phe) levels for both adults and children. A review of 500 Phe levels highlighted that 52% of the results were within the target range. Collaboration between information and communication technologies (ICT) departments, metabolic laboratory, and metabolic dietitians enabled the development of the PKU texting system. Following a successful pilot study, the system was then offered to all PKU patients aged over 2 years. The Phe is analysed and authorised on the laboratory system. The demographics are matched with the patient mobile phone number. Text messages are then validated and sent by the dietitian via a web portal using the Defero SMS texting service. Approximately 290 patients/families currently use the texting system. In order to assess the effectiveness of this quality improvement initiative, a patient survey was carried out in 2017. This showed 87% rated the system as either very good or excellent. 94% agreed it was time saving. 84% felt there was no influence on dietary compliance. Analysis of financial implications on dietetic time over 21 months revealed savings of €3,275 and 580 hours of dietetic time. There is no evidence, two years after implementation, that the system has had an effect on either the Phe levels in terms of recommended range or frequency of sampling.
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http://dx.doi.org/10.1155/2018/2178346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035849PMC
June 2018

Consensus clinical management guidelines for Niemann-Pick disease type C.

Orphanet J Rare Dis 2018 04 6;13(1):50. Epub 2018 Apr 6.

Mayo 1290 Clinic Department of Pediatric and Adolescent Medicine, Minnesota, USA.

Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy.NPC has an estimated incidence of ~ 1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care. For these reasons, we have developed clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients. The information contained in these guidelines was obtained through a systematic review of the literature and the experiences of the authors in their care of patients with NPC. We adopted the Appraisal of Guidelines for Research & Evaluation (AGREE II) system as method of choice for the guideline development process. We made a series of conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. In addition, these guidelines have identified gaps in the knowledge that must be filled by future research. It is anticipated that the implementation of these guidelines will lead to a step change in the quality of care for patients with NPC irrespective of their geographical location.
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http://dx.doi.org/10.1186/s13023-018-0785-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889539PMC
April 2018

Clinical, biochemical, and genetic features of four patients with short-chain enoyl-CoA hydratase (ECHS1) deficiency.

Am J Med Genet A 2018 05 25;176(5):1115-1127. Epub 2018 Mar 25.

Department of Paediatric Laboratory Medicine, Temple Street Children's University Hospital, Dublin, Ireland.

Short-chain enoyl-CoA hydratase (SCEH or ECHS1) deficiency is a rare inborn error of metabolism caused by biallelic mutations in the gene ECHS1 (OMIM 602292). Clinical presentation includes infantile-onset severe developmental delay, regression, seizures, elevated lactate, and brain MRI abnormalities consistent with Leigh syndrome (LS). Characteristic abnormal biochemical findings are secondary to dysfunction of valine metabolism. We describe four patients from two consanguineous families (one Pakistani and one Irish Traveler), who presented in infancy with LS. Urine organic acid analysis by GC/MS showed increased levels of erythro-2,3-dihydroxy-2-methylbutyrate and 3-methylglutaconate (3-MGC). Increased urine excretion of methacrylyl-CoA and acryloyl-CoA related metabolites analyzed by LC-MS/MS, were suggestive of SCEH deficiency; this was confirmed in patient fibroblasts. Both families were shown to harbor homozygous pathogenic variants in the ECHS1 gene; a c.476A > G (p.Gln159Arg) ECHS1variant in the Pakistani family and a c.538A > G, p.(Thr180Ala) ECHS1 variant in the Irish Traveler family. The c.538A > G, p.(Thr180Ala) ECHS1 variant was postulated to represent a Canadian founder mutation, but we present SNP genotyping data to support Irish ancestry of this variant with a haplotype common to the previously reported Canadian patients and our Irish Traveler family. The presence of detectable erythro-2,3-dihydroxy-2-methylbutyrate is a nonspecific marker on urine organic acid analysis but this finding, together with increased excretion of 3-MGC, elevated plasma lactate, and normal acylcarnitine profile in patients with a Leigh-like presentation should prompt consideration of a diagnosis of SCEH deficiency and genetic analysis of ECHS1. ECHS1 deficiency can be added to the list of conditions with 3-MGA.
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http://dx.doi.org/10.1002/ajmg.a.38658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947294PMC
May 2018

Catalogue of inherited disorders found among the Irish Traveller population.

J Med Genet 2018 04 22;55(4):233-239. Epub 2018 Jan 22.

Academic Centre on Rare Diseases, University College Dublin, Dublin, Republic of Ireland.

Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios. To catalogue all known inherited disorders found in the Irish Traveller population. We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers. We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication. We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.
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http://dx.doi.org/10.1136/jmedgenet-2017-104974DOI Listing
April 2018

Growth Patterns in the Irish Pyridoxine Nonresponsive Homocystinuria Population and the Influence of Metabolic Control and Protein Intake.

J Nutr Metab 2017 15;2017:8570469. Epub 2017 Nov 15.

National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.

A low methionine diet is the mainstay of treatment for pyridoxine nonresponsive homocystinuria (HCU). There are various guidelines for recommended protein intakes for HCU and clinical practice varies. Poor growth has been associated with low cystine levels. This retrospective review of 48 Irish pyridoxine nonresponsive HCU patients assessed weight, height, body mass index (BMI), protein intake, and metabolic control up to 18 years at nine set time points. Patients diagnosed through newborn screening (NBS) were compared to late diagnosed (LD) patients. At 18 years the LD group ( = 12, mean age at diagnosis 5.09 years) were heavier (estimated effect +4.97 Kg, = 0.0058) and taller (estimated effect +7.97 cm = 0.0204) than the NBS group ( = 36). There was no difference in growth rate between the groups after 10 years of age. The HCU population were heavier and taller than the general population by one standard deviation with no difference in BMI. There was no association between intermittently low cystine levels and height. Three protein intake guidelines were compared; there was no difference in adult height between those who met the lowest of the guidelines (Genetic Metabolic Dietitians International) and those with a higher protein intake.
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http://dx.doi.org/10.1155/2017/8570469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705888PMC
November 2017

Diagnosing childhood-onset inborn errors of metabolism by next-generation sequencing.

Arch Dis Child 2017 11 3;102(11):1019-1029. Epub 2017 May 3.

Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester NHS Trust, Manchester Academic Health Science Centre, Manchester, UK.

Background: Inborn errors of metabolism (IEMs) underlie a substantial proportion of paediatric disease burden but their genetic diagnosis can be challenging using the traditional approaches.

Methods: We designed and validated a next-generation sequencing (NGS) panel of 226 IEM genes, created six overlapping phenotype-based subpanels and tested 102 individuals, who presented clinically with suspected childhood-onset IEMs.

Results: In 51/102 individuals, NGS fully or partially established the molecular cause or identified other actionable diagnoses. Causal mutations were identified significantly more frequently when the biochemical phenotype suggested a specific IEM or a group of IEMs (p<0.0001), demonstrating the pivotal role of prior biochemical testing in guiding NGS analysis. The NGS panel helped to avoid further invasive, hazardous, lengthy or expensive investigations in 69% individuals (p<0.0001). Additional functional testing due to novel or unexpected findings had to be undertaken in only 3% of subjects, demonstrating that the use of NGS does not significantly increase the burden of subsequent follow-up testing. Even where a molecular diagnosis could not be achieved, NGS-based approach assisted in the management and counselling by reducing the likelihood of a high-penetrant genetic cause.

Conclusion: NGS has significant clinical utility for the diagnosis of IEMs. Biochemical testing and NGS analysis play complementary roles in the diagnosis of IEMs. Incorporating NGS into the diagnostic algorithm of IEMs can improve the accuracy of diagnosis.
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http://dx.doi.org/10.1136/archdischild-2017-312738DOI Listing
November 2017

Further evidence that d-glycerate kinase (GK) deficiency is a benign disorder.

Brain Dev 2017 Jun 9;39(6):536-538. Epub 2017 Feb 9.

National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland. Electronic address:

d-Glyceric aciduria is caused by deficiency in d-glycerate kinase (GK) due to recessive mutations in the GLYCTK gene. GK catalyzes the conversion of d-glycerate to 2-phosphoglycerate which is an intermediary reaction in the catabolism of serine and fructose. Deficiency of GK leads to accumulation of d-glycerate, which may be detected in urine organic acid analysis. Debate exists as to whether this is a benign or disease-causing disorder as the reported phenotypes vary significantly. We report two siblings from a consanguineous Pakistani family. The index case is a 5year old boy with severe autism and global developmental delay. His urine organic acid analysis showed markedly increased excretion of glycerate, determined as d-form by enantioselective gas chromatography. There was no oxalic aciduria. His younger sister (3years old) is asymptomatic and developmentally normal (already bilingual). Her urine showed similar amounts of d-glycerate. Both children are homozygous for the novel mutation c.767C>G in exon 5 of the GLYCTK gene, predicted to affect the enzyme by replacing the evolutionarily conserved Proline with Arginine (P256R). Both parents are heterozygous carriers. These cases support the view that d-glycerate kinase deficiency is a benign disorder. Long term follow-up studies with a greater number of individuals may be required for further confirmation.
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http://dx.doi.org/10.1016/j.braindev.2017.01.005DOI Listing
June 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

Beaulieu-Boycott-Innes syndrome: an intellectual disability syndrome with characteristic facies.

Clin Dysmorphol 2016 Oct;25(4):146-51

aDepartment of Clinical Genetics bNational Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital cUCD Academic Centre on Rare Diseases, School of Medicine and Medical Sciences, University College Dublin dDepartment of Clinical Genetics, Our Lady's Children's Hospital, Dublin eNorthern Ireland Regional Genetics Service, Belfast City Hospital, Belfast, UK.

We report a female child from an Irish Traveller family presenting with severe intellectual disability, dysmorphic features, renal anomalies, dental caries and cyclical vomiting. Current health issues include global developmental delay, mild concentric left ventricular hypertrophy, dental malocclusion and caries and a single duplex left kidney. The proband and her mother also have multiple epiphyseal dysplasia. Whole-exome sequencing was performed to identify the underlying genetic cause. DNA from the proband was enriched with the Agilent Sure Select v5 Exon array and sequenced on an Illumina HiSeq. Rare homozygous variants were prioritized. Whole-exome sequencing identified three linked homozygous missense variants in THOC6 (c.298T>A, p.Trp100Arg; c.700G>C, p.Val234Leu; c.824G>A, p.Gly275Asp) as the likely cause of this child's intellectual disability syndrome, resulting in a molecular diagnosis of Beaulieu-Boycott-Innes syndrome (BBIS). This is the first report of BBIS in Europe. BBIS has been reported previously in two Hutterite families and one Saudi family. A review of all patients to date shows a relatively homogenous phenotype. Core clinical features include low birth weight with subsequent growth failure, short stature, intellectual disability with language delay, characteristic facies, renal anomalies and dental malocclusion with caries. Some patients also have cardiac defects. All patients show characteristic dysmorphic facial features including a tall forehead with high anterior hairline and deep-set eyes with upslanting palpebral fissures. The coexistence of intellectual disability together with these characteristic facies should provide a diagnostic clue for BBIS during patient evaluation.
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http://dx.doi.org/10.1097/MCD.0000000000000134DOI Listing
October 2016

ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation.

Nat Commun 2016 05 27;7:11600. Epub 2016 May 27.

Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.

The V-ATPase is the main regulator of intra-organellar acidification. Assembly of this complex has extensively been studied in yeast, while limited knowledge exists for man. We identified 11 male patients with hemizygous missense mutations in ATP6AP1, encoding accessory protein Ac45 of the V-ATPase. Homology detection at the level of sequence profiles indicated Ac45 as the long-sought human homologue of yeast V-ATPase assembly factor Voa1. Processed wild-type Ac45, but not its disease mutants, restored V-ATPase-dependent growth in Voa1 mutant yeast. Patients display an immunodeficiency phenotype associated with hypogammaglobulinemia, hepatopathy and a spectrum of neurocognitive abnormalities. Ac45 in human brain is present as the common, processed ∼40-kDa form, while liver shows a 62-kDa intact protein, and B-cells a 50-kDa isoform. Our work unmasks Ac45 as the functional ortholog of yeast V-ATPase assembly factor Voa1 and reveals a novel link of tissue-specific V-ATPase assembly with immunoglobulin production and cognitive function.
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http://dx.doi.org/10.1038/ncomms11600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894975PMC
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

Periventricular Calcification, Abnormal Pterins and Dry Thickened Skin: Expanding the Clinical Spectrum of RMND1?

JIMD Rep 2016 4;26:13-9. Epub 2015 Aug 4.

Genetics Department, Temple Street Children's University Hospital, Dublin 1, Ireland.

Background: We report a consanguineous Sudanese family whose two affected sons presented with a lethal disorder characterised by severe neonatal lactic acidosis, hypertonia, microcephaly and intractable seizures. One child had additional unique features of periventricular calcification, abnormal pterins and dry thickened skin.

Methods: Exome enrichment was performed on pooled genomic libraries from the two affected children and sequenced on an Illumina HiSeq2000. After quality control and variant identification, rare homozygous variants were prioritised. Respiratory chain complex activities were measured and normalised to citrate synthase activity in cultured patient fibroblasts. RMND1 protein levels were analysed by standard Western blotting.

Results: Exome sequencing identified a previously reported homozygous missense variant in RMND1 (c.1250G>A; p.Arg417Gln), the gene associated with combined oxidation phosphorylation deficiency 11 (COXPD11), as the most likely cause of this disorder. This finding suggests the presence of a mutation hotspot at cDNA position 1250. Patient fibroblasts showed a severe decrease in mitochondrial respiratory chain complex I, III and IV activities and protein expression, albeit with normal RMND1 levels, supporting a generalised disorder of mitochondrial translation caused by loss of function.

Conclusions: The current study implicates RMND1 in the development of calcification and dermatological abnormalities, likely due to defective ATP-dependent processes in vascular smooth muscle cells and skin. Review of reported patients with RMND1 mutations shows intra-familial variability and evidence of an evolving phenotype, which may account for the clinical variability. We suggest that COXPD11 should be considered in the differential for patients with calcification and evidence of a mitochondrial disorder.
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http://dx.doi.org/10.1007/8904_2015_479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580737PMC
May 2016

Friedreich Ataxia in Classical Galactosaemia.

JIMD Rep 2016 29;26:1-5. Epub 2015 Jul 29.

National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.

Movement disorders such as ataxia are a recognized complication of classical galactosaemia, even in diet-compliant patients. Here, we report the coexistence of classical galactosaemia and Friedreich ataxia (FRDA) in nine children from seven Irish Traveller families. These two autosomal recessive disorders, the loci for which are located on either side of the centromere of chromosome 9, appear to be in linkage disequilibrium in this subgroup. Both conditions are known to occur with increased frequency amongst the Irish Traveller population.Each member of our cohort had been diagnosed with galactosaemia in the neonatal period, and all are homozygous for the common Q188R mutation in the GALT gene. Eight of the nine patients later presented with progressive ataxia, between the ages of 5-13 years. Another child presented in cardiac failure secondary to dilated cardiomyopathy at 7 years of age. He was not ataxic at presentation and, one year from diagnosis, his neurological examination remains normal. The diagnosis of FRDA was confirmed by detecting the common pathogenic GAA expansion in both alleles of the frataxin gene (FXN) in each patient.Neurological symptoms are easily attributed to an underlying diagnosis of galactosaemia. It is important to consider a diagnosis of Friedreich ataxia in a child from the Irish Traveller population with galactosaemia who presents with ataxia or cardiomyopathy.
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http://dx.doi.org/10.1007/8904_2015_477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864715PMC
May 2016

A Long-term Retrospective Evaluation of Functional and Radiographic Outcomes of Pediatric Hip Surgery in Hurler Syndrome.

J Pediatr Orthop 2016 Jan;36(1):25-8

Departments of *Orthopaedics †Haematology/Oncology §Metabolic Disease, Our Lady's Children's Hospital, Crumlin ‡Mater Misericordiae Hospital, Dublin, Ireland.

Background: After successful hematopoietic stem cell transplantation, maintaining function and mobility have become key goals in the management of patients with Hurler syndrome, (mucopolysaccharoidosis type 1H). The aim of this study was to establish the functional and radiologic outcomes after hip surgery in patients with this condition who had reached skeletal maturity.

Methods: We prospectively followed 13 mucopolysaccharoidosis type 1H patients with closed triradiate cartilages who had undergone hip surgery in a single institution (Our Lady's Children's Hospital, Crumlin) in early childhood, after successful hematopoietic stem cell transplantation. Functional assessment was performed using the Harris Hip Score. Acetabular and femoral head morphology were defined using a pelvic radiograph.

Results: The average age at follow-up was 18.6 years (range, 13.2 to 23.8 y). The average length of follow-up from surgical intervention was 14.6 years (range, 10.3 to 21.6 y). The average Harris Hip Score at follow-up was 61.0 (range, 19 to 91). At follow-up, 4 patients were either wheelchair bound or required a walking frame to mobilize in the community. At follow-up, all hips were in-joint with an average center edge angle of 37.7 degrees (range, 0 to 63 degrees). All hips displayed characteristic medial flattening of the femoral head. Ten hips (of 26 hips) showed radiologic degenerative changes with loss of joint space <2 mm.

Conclusions: Despite the surgical provision of stable well-covered hips, active intervention did not prevent the development of radiologic deterioration and clinically significant hip arthritis. We recommend that pediatric hip surgery in Hurler syndrome be designed with the possibility of early hip replacement in mind.

Level Of Evidence: Level III.
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http://dx.doi.org/10.1097/BPO.0000000000000385DOI Listing
January 2016

Effects of temporary low-dose galactose supplements in children aged 5-12 y with classical galactosemia: a pilot study.

Pediatr Res 2015 Sep 8;78(3):272-9. Epub 2015 Jun 8.

National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.

Background: Classical galactosemia is caused by severe galactose-1-phosphate uridyltransferase deficiency. Despite life-long galactose-restriction, many patients experience long-term complications. Intoxication by galactose and its metabolites as well as over-restriction of galactose may contribute to the pathophysiology. We provided temporary low-dose galactose supplements to patients. We assessed tolerance and potential beneficial effects with clinical monitoring and measurement of biochemical, endocrine, and IgG N-glycosylation profiles.

Methods: We enrolled 26 patients (8.6 ± 1.9 y). Thirteen were provided with 300 mg of galactose/day followed by 500 mg for 2 wk each (13 patient controls).

Results: We observed no clinical changes with the intervention. Temporary mild increase in galactose-1-phosphate occurred, but renal, liver, and bone biochemistry remained normal. Patients in the supplementation group had slightly higher leptin levels at the end of the study than controls. We identified six individuals as "responders" with an improved glycosylation pattern (decreased G0/G2 ratio, P < 0.05). There was a negative relationship between G0/G2 ratio and leptin receptor sOb-R in the supplementation group (P < 0.05).

Conclusion: Temporary low-dose galactose supplementation in children over 5 y is well tolerated in the clinical setting. It leads to changes in glycosylation in "responders". We consider IgG N-glycan monitoring to be useful for determining individual optimum galactose intake.
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http://dx.doi.org/10.1038/pr.2015.107DOI Listing
September 2015

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS.

J Inherit Metab Dis 2015 Nov 28;38(6):1085-92. Epub 2015 Apr 28.

UCD Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Belfield, Dublin 4, Ireland.

Background: Recessive LARS mutations were recently reported to cause a novel syndrome, infantile liver failure syndrome type 1 (ILFS1), in six Irish Travellers. We have since identified four additional patients, including one of Ashkenazi origin, representing the largest ILFS1 cohort to date. Our study aims to define the ILFS1 clinical phenotype to help guide diagnosis and patient management.

Methods: We clinically evaluated and reviewed the medical records of ten ILFS1 patients. Clinical features, histopathology and natural histories were compared and patient management strategies reviewed.

Results: Early failure to thrive, recurrent liver dysfunction, anemia, hypoalbuminemia and seizures were present in all patients. Most patients (90 %) had developmental delay. Encephalopathic episodes triggered by febrile illness have occurred in 80 % and were fatal in two children. Two patients are currently >28 years old and clinically well. Leucine supplementation had no appreciable impact on patient well-being. However, we suggest that the traditional management of reducing/stopping protein intake in patients with metabolic hepatopathies may not be appropriate for ILFS1. We currently recommend ensuring sufficient natural protein intake when unwell.

Conclusions: We report the first non-Irish ILFS1 patient, suggesting ILFS1 may be more extensive than anticipated. Low birth weight, early failure to thrive, anemia and hypoalbuminemia are amongst the first presenting features, with liver dysfunction before age 1. Episodic hepatic dysfunction is typically triggered by febrile illness, and becomes less severe with increasing age. While difficult to anticipate, two patients are currently >28 years old, suggesting that survival beyond childhood may be associated with a favourable long-term prognosis.
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http://dx.doi.org/10.1007/s10545-015-9849-1DOI Listing
November 2015