Mitochondrial respiratory chain disorders (MRC) are amongst the most common group of inborn errors of metabolism. MRC, of which complex I deficiency accounts for approximately a quarter, are very ...diverse, causing a wide range of clinical problems and can be difficult to diagnose. We report an illustrative MRC case whose diagnosis was elusive. Clinical signs included failure to thrive caused by recurrent vomiting, hypotonia and progressive loss of motor milestones. Initial brain imaging suggested Leigh syndrome but without expected diffusion restriction. Muscle respiratory chain enzymology was unremarkable. Whole‐genome sequencing identified a maternally inherited NDUFV1 missense variant NM_007103.4 (NDUFV1):c.1157G > A; p.(Arg386His) and a paternally inherited synonymous variant NM_007103.4 (NDUFV1):c.1080G > A; (p.Ser360=). RNA sequencing demonstrated aberrant splicing. This case emphasizes the diagnostic odyssey of a patient in whom a confirmed diagnosis was elusive because of atypical features and normal muscle respiratory chain enzyme (RCE) activities, along with a synonymous variant, which are often filtered out from genomic analyses. It also illustrates the following points: (1) complete resolution of magnetic resonance imaging changes may be part of the picture in mitochondrial disease; (2) analysis for synonymous variants is important for undiagnosed patients; and (3) RNA‐seq is a powerful tool to demonstrate pathogenicity of putative splicing variants.
Aim
Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare neurodegenerative disorder presenting in children aged 2–4 years with seizures and loss of motor and language skills, ...followed by blindness and death in late childhood. Initial presenting features are similar to a range of common epilepsies. We aim to highlight typical clinical and radiological features that may prompt diagnosis of CLN2 disease in early disease stages.
Methods
We present a series of 13 Australian patients with CLN2 disease, describing clinical features, disease evolution, neuroimaging, electroencephalogram, biochemical and genetic results. Expert neuroradiological magnetic resonance imaging (MRI) analysis was retrospectively performed on 10 cases.
Results
Twelve patients presented with seizures, with initial seizures being focal (n = 4), generalised tonic–clonic (n = 3), absence (n = 3) and febrile (n = 2). Eleven patients (85%) had a language delay before the onset of seizures. Cerebellar or cerebral atrophy was noted in all patients on centralised MRI review, with abnormalities of the brain‐stem, ventricles, corpus callosum and hippocampi.
Conclusions
Early language delay with the onset of seizures at 2–4 years of age is the hallmark of CLN2 disease. MRI findings of early subtle atrophy in the cerebellum or posterior cortical regions should hasten testing for CLN2 disease to enable early initiation of enzyme replacement therapy.
Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a ...rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this diagnosis was excluded by HIBCH sequencing and normal enzyme activity. In contrast to HIBCH deficiency, the excretion of 3-hydroxyisobutyryl-carnitine was normal in the children, suggesting deficiency of short-chain enoyl-CoA hydratase (ECHS1 gene). This mitochondrial enzyme is active in several metabolic pathways involving fatty acids and amino acids, including valine, and is immediately upstream of HIBCH in the valine pathway. Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1. ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity. The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders. Deficiency of ECHS1 or HIBCH should be considered in children with Leigh disease. Urine metabolite testing can detect and distinguish between these two disorders.
Congenital disorders of glycosylation (CDG) are a clinically and biochemically heterogeneous subgroup of inherited metabolic disorders. Most CDG with abnormal N‐glycosylation can be detected by ...transferrin screening, however, MOGS‐CDG escapes this routine screening. Combined with the clinical heterogeneity of reported cases, diagnosing MOGS‐CDG can be challenging. Here, we clinically characterize ten MOGS‐CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia. Glycomics confirmed accumulation of a Glc3Man7GlcNAc2 glycan in plasma. For quantification of the diagnostic Glcα1‐3Glcα1‐3Glcα1‐2Man tetrasaccharide in urine, we developed and validated a liquid chromatography‐mass spectrometry method of 2‐aminobenzoic acid (2AA) labeled urinary glycans. As an internal standard, isotopically labeled 13C6‐2AA Glc3Man was used, while labeling efficiency was controlled by use of 12C6‐2AA and 13C6‐2AA labeled laminaritetraose. Recovery, linearity, intra‐ and interassay coefficients of variability of these labeled compounds were determined. Furthermore, Glc3Man was specifically identified by retention time matching against authentic MOGS‐CDG urine and compared with Pompe urine. Glc3Man was increased in all six analyzed cases, ranging from 34.1 to 618.0 μmol/mmol creatinine (reference <5 μmol). In short, MOGS‐CDG has a broad manifestation of symptoms but can be diagnosed with the use of a quantitative method for analysis of urinary Glc3Man excretion.
Summary
Objectives and aims: To document the incidence of difficult airway management and difficult intubation in the era of replacement therapy for Australian children with mucopolysaccharidosis ...(MPS).
Background: Medical treatment for MPS has developed significantly since 1980’s with a large number of patients now being offered either bone marrow transplant or enzyme replacement. The impact of these therapies on the incidence of difficult airway management has not been adequately documented. Similarly, anesthesia techniques and airway devices have been developed, which are thought to have greatly increased the safety of managing these patients under anesthesia but their role in children with MPS has not been systematically described.
Methods: A retrospective chart review of 17 patients with MPS who had received anesthetics at the Royal Children’s Hospital during the time frame January 1998–January 2011. The primary outcome was the incidence of difficult or failed intubation. Secondary outcomes were the relationship between the incidence of difficult intubation and treatment with enzyme replacement therapy (ERT) or bone marrow transplantation.
Results: Seventeen patients received 141 anesthetics for 214 procedures. Difficult face mask ventilation occurred in 20 anesthetics (14.2%). Difficult intubation occurred in 40 anesthetics (25%). Failed intubation occurred in two cases (1.6%).The incidence of difficult intubation was 12% in MPS I, 35% MPS II, 86.7% in MPS VI, and 0% in MPS III and IV.
Conclusions: Hematopoietic stem cell transplantation prior to 2 years of age reduces the incidence of difficult mask ventilation and difficult intubation in children with MPS I. ERT was initiated late in the clinical course of MPS II and VI and induced improvements in upper airway patency but did not reduce the incidence of difficult airway management.
Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase (HMCS2) deficiency results in episodes of hypoglycemia and increases in fatty acid metabolites. Metabolite abnormalities described to date in ...HMCS2 deficiency are nonspecific and overlap with other inborn errors of metabolism, making the biochemical diagnosis of HMCS2 deficiency difficult. Urinary organic acid profiles from periods of metabolic decompensation were studied in detail in HMCS2-deficient patients from four families. An additional six unrelated patients were identified from clinical presentation and/or qualitative identification of abnormal organic acids. The diagnosis was confirmed by sequencing and deletion/duplication analysis of the
HMGCS2
gene. Seven related novel organic acids were identified in urine profiles. Five of them (3,5-dihydroxyhexanoic 1,5 lactone;
trans
-5-hydroxyhex-2-enoate; 4-hydroxy-6-methyl-2-pyrone; 5-hydroxy-3-ketohexanoate; 3,5-dihydroxyhexanoate) were identified by comparison with synthesized or commercial authentic compounds. We provisionally identified
trans
-3-hydroxyhex-4-enoate and 3-hydroxy-5-ketohexanoate by their mass spectral characteristics. These metabolites were found in samples taken during periods of decompensation and normalized when patients recovered. When cutoffs of adipic >200 and 4-hydroxy-6-methyl-2-pyrone >20 μmol/mmol creatinine were applied, all eight samples taken from five HMCS2-deficient patients during episodes of decompensation were flagged with a positive predictive value of 80 % (95 % confidence interval 35–100 %). Some ketotic patients had increased 4-hydroxy-6-methyl-2-pyrone. Molecular studies identified a total of 12 novel mutations, including a large deletion of
HMGCS2
exon 1 in two families, highlighting the need to perform quantitative gene analyses. There are now 26 known
HMGCS2
mutations, which are reviewed in the text. 4-Hydroxy-6-methyl-2-pyrone and related metabolites are markers for HMCS2 deficiency. Detection of these metabolites will streamline the biochemical diagnosis of this disorder.
Familial chylomicronemia syndrome (FCS) is a rare disorder of triglyceride (TG) metabolism caused by loss of function variants in one of five known canonical genes involved in chylomicron lipolysis ...and clearance—LPL, APOC2, APOA5, LMF1, and GPIHBP1. Pathogenic variants in LPL, which encodes the hydrolytic enzyme lipoprotein lipase, account for over 80%–90% of cases. FCS may present in infancy with hypertriglyceridemia‐induced acute pancreatitis and is challenging to manage both acutely and in the long‐term. Here, we report our experience managing two unrelated infants consecutively diagnosed with hypertriglyceridemia‐induced acute pancreatitis caused by LPL deficiency. Both had elevated TGs at presentation (205 and 30 mmol/L, respectively) and molecular genetic testing confirmed each infant carried a different homozygous pathogenic variant in the LPL gene, specifically, c.987C>A (p.Tyr329Ter) and c.632C>A (p.Thr211Lys). The more severely affected infant had cutaneous xanthomata, lipemia retinalis and lipemic plasma at presentation, and required management in an intensive care setting. Acute stabilisation was achieved using insulin and heparin infusions together with the iterative implementation of a fat‐restricted diet, low in long chain triglycerides (LCT) and supplemented with medium chain triglycerides (MCT). In both cases, provision of adequate caloric intake (~110–120 kcal/kg/day) was also found to be important for a sustained TG reduction during the acute phase of management. In summary, a high index of suspicion is required to diagnose FCS in infants with hypertriglyceridemia‐induced acute pancreatitis, management of which can be challenging, highlighting the need for more evidence‐based recommendations.
Abstract
Contiguous
ABCD1
/
DXS1357E
deletion syndrome (CADDS) is a rare deletion syndrome involving two contiguous genes on Xq28,
ABCD1
and
BCAP31
(formerly known as
DXS1357E
). Only nine ...individuals with this diagnosis have been reported in the medical literature to date. Intragenic loss‐of‐function variants in
BCAP31
cause the deafness, dystonia, and cerebral hypomyelination syndrome (DDCH). Isolated pathogenic intragenic variants in
ABCD1
are associated with the most common peroxisomal disorder, X‐linked adrenoleukodystrophy (X‐ALD), a single transporter deficiency, which in its more severe cerebral form is characterised by childhood‐onset neurodegeneration and high levels of very‐long‐chain fatty acids (VLCFA). While increased VLCFA levels also feature in CADDS, the few patients described to date all presented as neonates with a severe phenotype. Here we report a tenth individual with CADDS, a male infant with dysmorphic facial features who was diagnosed through ultra‐rapid whole genome sequencing (WGS) in the setting of persistent cholestatic liver disease, sensorineural hearing loss, hypotonia and growth failure and developmental delay. Biochemical studies showed elevated VLCFA and mildly reduced plasmalogens. He died at 7 months having developed pancreatic exocrine deficiency and interstitial lung disease, two features we propose to be possible extensions to the CADDS phenotype. We also review the genetic, phenotypic, and biochemical features in previously reported individuals with CADDS.
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