While the presence of hyperlipidaemia in glycogen storage disease (GSD) type Ia and Ib is generally accepted, few investigators have adequately assessed lipid profiles of GSD III in children, in whom the presence of hyperlipidaemia may be most prominent. We analysed the lipid profiles in 44 GSD III patients from 6 months to 30 years of age. Hypertriglyceridaemia and hypercholesterolaemia were common in children younger than 3 years of age. Hypertriglyceridaemia correlated negatively with age, and may reflect increased severity of hypoglycaemia in this younger population. The presence of hyperlipidaemia during childhood in these patients identifies another GSD population that could be at risk for early cardiovascular disease (CVD). Consequently, the outcome of clinical trials investigating the vascular effect of hyperlipidaemia in GSD applies to types other than GSD I.
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.
Glycogen storage disease type III (GSD III) is caused by a deficiency in debranching enzyme, which leads to an accumulation of abnormal glycogen called limit dextrin in affected tissues. Muscle and liver involvement is present in GSD type IIIa, while the defect is limited to the liver only in GSD type IIIb. Besides skeletal muscle involvement, a cardiomyopathy resembling idiopathic hypertrophic cardiomyopathy is seen. Management consists of maintaining normoglycaemia by supplementation with cornstarch therapy and/or protein. While studies are lacking regarding the best treatment for skeletal muscle disease, a high-protein diet was previously reported to be beneficial. No cases of improvement in cardiomyopathy have been reported. Our patient presented in infancy with hypoglycaemia and hepatomegaly. His prescribed management consisted of cornstarch supplementation and a high-protein diet providing 20% of his total energy needs. At 16 years of age, he developed a severe cardiomyopathy with a left ventricular mass index of 209 g/m2. The cardiomyopathy remained stable on a protein intake of 20–25% of total energy. At age 22 years, the diet was changed to increase his protein intake to 30% of total energy and minimize his cornstarch therapy to only what was required to maintain normoglycaemia. Dramatic improvement in the cardiomyopathy occurred. Over one year, his left ventricular mass index decreased from 159.7 g/m2 to 78 g/m2 (normal 50–86 g/m2) and the creatine kinase levels decreased from 455 U/L to 282 U/L. Avoidance of overtreatment with carbohydrate and a high-protein diet can reverse and may prevent cardiomyopathy.
Patients with type Ia glycogen storage disease (GSD) have been surviving well into adulthood since continuous glucose therapy was introduced in the 1970s, and there have been many documented successful pregnancies in women with this condition. Historically, few individuals with type Ib GSD, however, survived into adulthood prior to the introduction of granulocyte colony stimulating factor (G-CSF) in the late 1980s. There are no previously published reports of pregnancies in GSD type Ib. In this case report we describe the course and management of five successful pregnancies in three patients with GSD type Ib. Patient 1 experienced an increase in glucose requirement in all three of her pregnancies, starting from the second trimester onwards. There were no major complications related to neutropenia except for oral ulcers. The infants did well, except for respiratory distress in two of them at birth. Patient 2 used cornstarch to maintain euglycemia, but precise dosing was not part of her regimen, and, hence, an increase in metabolic demands was difficult to demonstrate. She developed a renal calculus and urinary tract infection during her pregnancy and had chronic iron deficiency anemia but no neutropenia. The neonate did well after delivery. Patient 3 had poor follow-up during pregnancy. Increasing glucose requirements, worsening lipid profile, neutropenia associated with multiple infections, and anemia were noted. The newborn infant did well after delivery. In addition to the case reports, the challenges of the usage of G-CSF, the treatment of enterocolitis, and comparisons with the management of GSD Ia are discussed.
Pulmonary arterial hypertension (PAH) and hepatopulmonary syndrome (HPS) are rare pulmonary vascular complications of type 1 Gaucher disease (GD1). We examined GBA1 genotype, spleen status, Severity Score Index (SSI), and other patient characteristics as determinants of GD/PAH-HPS phenotype. We also examined the long-term outcomes of imiglucerase enzyme replacement therapy (ERT) +/− adjuvant therapies in 14 consecutive patients. We hypothesized a role of BMPR2 and ALK1 as genetic modifiers underlying GD/PAH-HPS phenotype. Median age at diagnosis of GD1 was 5 yrs (2–22); PAH was diagnosed at median 36 yrs (22–63). There was a preponderance of females (ratio 5:2). ERT was commenced at median 36.5 yrs (16–53) and adjuvant therapy at 36 yrs (24–57). GBA1 genotype was N370S homozygous in two patients, N370S heteroallelic in 12. Median SSI was 15 (7–20). All patients had undergone splenectomy at median age 12 yrs (2–30). In three patients, HPS was the initial presentation, and PAH developed after its resolution; in these three, HPS responded dramatically to ERT. In seven patients, sequencing of the coding regions of BMPR2 and ALK1 was undertaken: 3/7 were heterozygous for BMPR2 polymorphisms; none harbored ALK1 variants. With ERT (± adjuvant therapy), 5/14 improved dramatically, five remained stable, two worsened, and two died prematurely. In this largest series of GD/PAH-HPS patients, there is preponderance of females and N370S heteroallelic GBA1 genotype. Splenectomy appears essential to development of this phenotype. In some patients, HPS precedes PAH. BMPR2 and ALK1 appear not be modifier genes for this rare phenotype of GD. ERT +/− adjuvant therapy improves prognosis of this devastating GD phenotype.
Glycosphingolipid storage diseases are a group of inherited metabolic diseases in which glycosphingolipids accumulate due to their impaired lysosomal breakdown. Splenic B cells isolated from NPC1, Sandhoff, GM1-gangliosidosis and Fabry disease mouse models showed large (20- to 30-fold) increases in disease specific glycosphingoli-pids and up to a 4-fold increase in cholesterol. The magnitude of glycosphingolipid storage was in the order NPC1 > Sandhoff, ~ GM1 gangliosidosis > Fabry. Except for Fabry disease, glycosphingolipid storage led to an increase in the lysosomal compartment and altered glycosphingolipid trafficking. In order to investigate the consequences of storage on B cell function, the levels of surface expression of B cell IgM receptor and its associated components were quantitated in Sandhoff B cells, since they are all raft-associated on activation. Both the B cell receptor, CD21 and CD19 had decreased cell surface expression. In contrast, CD40 and MHC II, surface receptors that do not associate with lipid rafts, were unchanged. Using a pulse chase biotinylation procedure, surface B cell receptors on a Sandhoff lymphoblast cell line were found to have a significantly decreased half-life. Increased co-localization of fluorescently conjugated cholera toxin and lysosomes was also observed in Sandhoff B cells. Glycosphingolipid storage leads to the enhanced formation of lysosomal lipid rafts, altered endocytic trafficking and increased degradation of the B cell receptor.
Propionic acidemia (PA) is an autosomal recessive disease that results from deficiency of propionyl-CoA carboxylase (PCC). In virtually all reported cases of PA, the phenotype includes metabolic acidosis and/or neurological deficits. We report on a 14-year-old Asian male with PA who presented with isolated cardiomyopathy without any episodes of metabolic acidosis or evidence of any neurocognitive deficits. On routine metabolic screening, the patient was found to have urine organic acids suggestive of PA. Biochemical and genetic characterization confirmed a PCC deficiency with two novel mutations in PCCB: IVS7+2 T>G (c.763+2 T>G) and p.R410Q (c.1229 G>A). Residual enzyme activity likely explains our patient’s mild phenotype. Splicing mutations tend to result in a milder phenotype as these mutations may still produce small amounts of normal enzyme. In addition, the similar p.R410W mutation has been shown to have partial residual activity.
Moreover, this case illustrates the important but under-recognized manifestation of isolated cardiomyopathy as the sole clinical presentation in PA. A thorough metabolic evaluation should be performed in all pediatric patients with cardiomyopathy. Such an evaluation has important implications for clinical management and genetic counseling.
Smith-Lemli-Opitz syndrome (SLOS) is caused by a genetic deficiency in 7-dehydrocholesterol (7-DHC) reductase (EC 220.127.116.11), the last enzyme of the cholesterol synthetic pathway. In SLOS, plasma cholesterol concentration is reduced and immediate precursor concentration (7-DHC) is elevated. Surprisingly, total sterol synthesis is reduced but HMG-CoA reductase activity, a rate-limiting enzyme in cholesterol synthesis is unaltered as judged by normal urinary excretion of mevalonic acid (MVA) (Pappu, 2002). These findings raise the possibility of increased diversion of MVA into the MVA shunt pathway away from sterol synthesis, by activation of the shunt pathway enzymes. To test this hypothesis, we measured the urinary excretion of 3-methylglutaconic acid (U-3MGC), a by-product of the shunt pathway, in 19 mild-to-moderately severely affected SLOS subjects (10 males, 9 females) receiving either a cholesterol-free or a high cholesterol diet, and in 20 age- and sex-matched controls. U-3MGC was similar in SLOS and controls, and was unaffected by dietary cholesterol intake. Further, no change in U-3MGC was observed in a subset of SLOS subjects (n=9) receiving simvastatin. In contrast, U-MVA was reduced by cholesterol supplementation (~54%, p<0.05) and by simvastatin (~50%, p<0.04). There was no correlation between U-3MGC and either plasma sterol concentrations, urinary isoprenoids, or the subjects’ clinical severity score. However U-3MGC was inversely correlated with age (p<0.04) and body weight (p<0.02), and higher in females than in males (~65%, p<0.025). The data show that DHCR7 deficiency does not result in 3MGC accumulation in SLOS and suggest that the MVA shunt pathway is not activated in patients with the condition.
The urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular 1H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate–nitric oxide–cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.
Gaucher disease is caused by a deficiency of the lysosomal enzyme glucocerebrosidase (acid β-glucosidase), with consequent cellular accumulation of glucosylceramide (GL-1). The disease is managed by intravenous administrations of recombinant glucocerebrosidase (imiglucerase), although symptomatic patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy (ERT) is not an option may also be treated by substrate reduction therapy (SRT) with miglustat. To determine whether the sequential use of both ERT and SRT may provide additional benefits, we compared the relative pharmacodynamic efficacies of separate and sequential therapies in a murine model of Gaucher disease (D409V/null). As expected, ERT with recombinant glucocerebrosidase was effective in reducing the burden of GL-1 storage in the liver, spleen, and lung of 3-month-old Gaucher mice. SRT using a novel inhibitor of glucosylceramide synthase (Genz-112638) was also effective, albeit to a lesser degree than ERT. Animals administered recombinant glucocerebrosidase and then Genz-112638 showed the lowest levels of GL-1 in all the visceral organs and a reduced number of Gaucher cells in the liver. This was likely because the additional deployment of SRT following enzyme therapy slowed the rate of reaccumulation of GL-1 in the affected organs. Hence, in patients whose disease has been stabilized by intravenously administered recombinant glucocerebrosidase, orally administered SRT with Genz-112638 could potentially be used as a convenient maintenance therapy. In patients naïve to treatment, ERT followed by SRT could potentially accelerate clearance of the offending substrate.
Although coronary artery pathology is a prominent feature of mucopolysaccharidosis (MPS), it may be underestimated by coronary angiography because of its diffuse nature. It is also generally assumed that cardiovascular risk is increased in MPS and reduced following hematopoietic stem cell transplantation (HSCT) or enzyme replacement therapy (ERT), but this has never been formally evaluated. Non-invasive methods of assessing vascular endothelial function may provide a measure of cardiovascular risk in MPS. We evaluated endothelial function, using digital reactive hyperemia, in youth with MPS and in healthy controls.
Digital reactive hyperemic index (RHI) was measured in 12 children and adolescents (age 10.3 ± 3.9 years old; 11 boys) with treated MPS and nine age- and gender-matched (11.4 ± 4.0; 8 boys) healthy controls. An independent t-test was used to compare RHI between individuals with MPS and controls.
Children and adolescents with MPS (MPS type II: N = 5; type I: N = 4; type VI: N = 3) whether treated by HSCT (N = 4) or ERT (N = 8) had significantly lower RHI compared to controls (MPS 1.22 ± 0.19 vs. controls 1.46 ± 0.32, p<0.05).
These preliminary findings suggest that children and adolescents with treated MPS have significantly poorer endothelial function when compared to healthy controls. Further investigation into the utility of endothelial function for risk stratification and the long term implications of reduced endothelial function in MPS is warranted.
Endothelial Function; Mucopolysaccharidosis; Children; Adolescents
We sought to determine the activation status and proliferative capacities of splenic lymphocyte populations from a mevalonate kinase-deficient mouse model of hyper-IgD syndrome (HIDS). We previously reported that murine mevalonate kinase gene ablation was embryonic lethal for homozygous mutants while heterozygotes (Mvk+/−) demonstrated several phenotypic features of human HIDS including increased serum levels of IgD, IgA, and TNFα, temperature dysregulation, hematological abnormalities, and splenomegaly.
Methods and results
Flow cytometric analysis of cell surface activation markers on T and B lymphocytes, and macrophage populations, demonstrated aberrant expression of B7 glycoproteins in all splenic cell types studied. Differences in expression levels between Mvk+/− and Mvk+/+ littermate controls were observed in both the basal state (unstimulated) and after Concanavalin A (Con-A) stimulation in vitro of whole splenocyte cultures. In Mvk+/− CD4 and CD8 T cells, alterations in expression of CD25, CD80, CD152, and CD28 were observed. Mvk+/− splenic macrophages expressed altered levels of CD80, CD86, CD40, and CD11c while Mvk+/− B lymphocytes had differential expression of CD40, CD80, and CD86. Mvk+/− splenocyte subpopulations also exhibited altered proliferative capacities in response to in vitro stimulation.
We postulate that imbalances in the expression of cell surface proteins necessary for activation, proliferation, and regulation of the intensity and duration of an immune response may result in defective T cell activation, proliferation, and effector functions in our model and potentially in human HIDS.
Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood. Symptoms typically present at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. Studies on sex differences in JNCL have yielded mixed results, but parent anecdotes suggest that females experience a more precipitous disease course. Therefore, we sought to determine if sex-based differences exist in JNCL. We used data from the Unified Batten Disease Rating Scale (UBDRS), the Batten Disease Support and Research Association (BDSRA) database, and the PedsQL quality of life (QoL) survey to evaluate sex-based differences in functional independence and time from symptom onset to death. On average, females had JNCL symptom onset one year later and death one year earlier than did males. Despite a later age at onset, females had lower functional capability, earlier loss of independent function, and lower physical QoL. Future research in sex differences in JNCL may help to further understand the biological mechanisms underpinning the disease course and may point to targeted therapies.
Individuals with phenylketonuria (PKU) must follow a lifelong low-phenylalanine (Phe) diet to prevent neurological impairment. Compliance with the low-Phe diet is often poor owing to restriction in natural foods and the requirement for consumption of a Phe-free amino acid formula or medical food. Glycomacropeptide (GMP), a natural protein produced during cheese-making, is uniquely suited to a low-Phe diet because when isolated from cheese whey it contains minimal Phe (2.5–5 mg Phe/g protein). This paper reviews progress in evaluating the safety, acceptability and efficacy of GMP in the nutritional management of PKU. A variety of foods and beverages can be made with GMP to improve the taste, variety and convenience of the PKU diet. Sensory studies in individuals with PKU demonstrate that GMP foods are acceptable alternatives to amino acid medical foods. Studies in the PKU mouse model demonstrate that GMP supplemented with limiting indispensable amino acids provides a nutritionally adequate source of protein and improves the metabolic phenotype by reducing concentrations of Phe in plasma and brain. A case report in an adult with classical PKU who followed the GMP diet for 10 weeks at home indicates safety, acceptability of GMP food products, a 13–14% reduction in blood Phe levels (p<0.05) and improved distribution of dietary protein throughout the day compared with the amino acid diet. In summary, food products made with GMP that is supplemented with limiting indispensable amino acids provide a palatable alternative source of protein that may improve dietary compliance and metabolic control of PKU.
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is a rare inherited metabolic disorder of ketone metabolism, characterized by ketoacidotic episodes and often permanent ketosis. To date there are ∼20 disease-associated alleles on the OXCT1 gene that encodes the mitochondrial enzyme SCOT. SCOT catalyzes the first, rate-limiting step of ketone body utilization in peripheral tissues, by transferring a CoA moiety from succinyl-CoA to form acetoacetyl-CoA, for entry into the tricarboxylic acid cycle for energy production. We have determined the crystal structure of human SCOT, providing a molecular understanding of the reported mutations based on their potential structural effects. An interactive version of this manuscript (which may contain additional mutations appended after acceptance of this manuscript) may be found on the web address: http://www.thesgc.org/jimd/SCOT.
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Nearly all children with MPS IVA develop skeletal deformities affecting the spine. At the atlanto-axial spine, odontoid hypoplasia occurs. GAG deposition around the dens, leads to peri-odontoid infiltration. Transverse/alar ligament incompetence causes instability. Atlanto-axial instability is associated with cord compression and myelopathy, leading to major morbidity and mortality. Intervention is often required. Does the presence of widened bullet shaped vertebra in platyspondily encroach on the spinal canal and cause spinal stenosis in MPS IVA? So far, there have been no standardised morphometric measurements of the paediatric MPS IVA cervical spine to evaluate whether there is pre-existing spinal stenosis predisposing to compressive myelopathy or whether this is purely an acquired process secondary to instability and compression. This study provides the first radiological quantitative analysis of the cervical spine and spinal cord in a series of affected children. MRI morphometry indicates that the MPS IVA spine is narrower at C1–2 level giving an inverted funnel shape. There is no evidence of a reduction in the Torg ratio (canal-body ratio) in the cervical spine. The spinal canal does not exceed 11 mm at any level, significantly smaller than normal historical cohorts (14 mm). The sagittal diameter and axial surface area of both spinal canal and cord are reduced. C1–2 level cord compression was evident in the canal-cord ratio but the Torg ratio was not predictive of cord compression. In MPS IVA the reduction in the space available for the cord (SAC) is multifactorial rather than due to congenital spinal stenosis.
Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio-Brailsford or Morquio A syndrome, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetyl-galactosamine-6-sulphate sulphatase (GALNS). MPS IVA is multisystemic but manifests primarily as a progressive skeletal dysplasia. Spinal involvement is a major cause of morbidity and mortality in MPS IVA. Early diagnosis and timely treatment of problems involving the spine are critical in preventing or arresting neurological deterioration and loss of function. This review details the spinal manifestations of MPS IVA and describes the tools used to diagnose and monitor spinal involvement. The relative utility of radiography, computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of cervical spine instability, stenosis, and cord compression is discussed. Surgical interventions, anaesthetic considerations, and the use of neurophysiological monitoring during procedures performed under general anaesthesia are reviewed. Recommendations for regular radiological imaging and neurologic assessments are presented, and the need for a more standardized approach for evaluating and managing spinal involvement in MPS IVA is addressed.
Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an autosomal recessive lysosomal storage disorder resulting from a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Diagnosis can be challenging and requires agreement of clinical, radiographic, and laboratory findings. A group of biochemical genetics laboratory directors and clinicians involved in the diagnosis of MPS IVA, convened by BioMarin Pharmaceutical Inc., met to develop recommendations for diagnosis. The following conclusions were reached. Due to the wide variation and subtleties of radiographic findings, imaging of multiple body regions is recommended. Urinary glycosaminoglycan analysis is particularly problematic for MPS IVA and it is strongly recommended to proceed to enzyme activity testing even if urine appears normal when there is clinical suspicion of MPS IVA. Enzyme activity testing of GALNS is essential in diagnosing MPS IVA. Additional analyses to confirm sample integrity and rule out MPS IVB, multiple sulfatase deficiency, and mucolipidoses types II/III are critical as part of enzyme activity testing. Leukocytes or cultured dermal fibroblasts are strongly recommended for enzyme activity testing to confirm screening results. Molecular testing may also be used to confirm the diagnosis in many patients. However, two known or probable causative mutations may not be identified in all cases of MPS IVA. A diagnostic testing algorithm is presented which attempts to streamline this complex testing process.
Barth syndrome (BTHS) is an X-linked mitochondrial defect characterised by dilated cardiomyopathy, neutropaenia and 3-methylglutaconic aciduria (3-MGCA). We report on two affected brothers with c.646G > A (p.G216R) TAZ gene mutations. The pathogenicity of the mutation, as indicated by the structure-based functional analyses, was further confirmed by abnormal monolysocardiolipin/cardiolipin ratio in dry blood spots of the patients as well as the occurrence of this mutation in another reported BTHS proband. In both brothers, 2D-echocardiography revealed some features of left ventricular noncompaction (LVNC) despite marked differences in the course of the disease; the eldest child presented with isolated cardiomyopathy from late infancy, whereas the youngest showed severe lactic acidosis without 3-MGCA during the neonatal period. An examination of the patients’ fibroblast cultures revealed that extremely low mitochondrial membrane potentials (mtΔΨ about 50 % of the control value) dominated other unspecific mitochondrial changes detected (respiratory chain dysfunction, abnormal ROS production and depressed antioxidant defense). 1) Our studies confirm generalised mitochondrial dysfunction in the skeletal muscle and the fibroblasts of BTHS patients, especially a severe impairment in the mtΔΨ and the inhibition of complex V activity. It can be hypothesised that impaired mtΔΨ and mitochondrial ATP synthase activity may contribute to episodes of cardiac arrhythmia that occurred unexpectedly in BTHS patients. 2) Severe lactic acidosis without 3-methylglutaconic aciduria in male neonates as well as an asymptomatic mild left ventricular noncompaction may characterise the ranges of natural history of Barth syndrome.
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Combined methylmalonic acidemia and homocystinuria, cblC type, is stated to be the most common inborn error of intracellular cobalamin metabolism. The disorder can display a wide spectrum of clinical manifestations, spanning the prenatal period through late adulthood. While increased homocysteine concentrations and impaired methyl group metabolism may contribute to disease-related complications, the characteristic macular and retinal degeneration seen in many affected patients appears to be unique to cblC disease. The early detection of cblC disease by newborn screening mandates a careful assessment of therapeutic approaches and provides a new opportunity to improve the outcome of affected patients. The following article reviews the current knowledge on the complications, pathophysiology, and outcome of cblC disease in an effort to better guide clinical practice and future therapeutic trials.
This paper provides a detailed overview and discussion of anaesthesia in patients with mucopolysaccharidosis (MPS), the evaluation of risk factors in these patients and their anaesthetic management, including emergency airway issues. MPS represents a group of rare lysosomal storage disorders associated with an array of clinical manifestations. The high prevalence of airway obstruction and restrictive pulmonary disease in combination with cardiovascular manifestations poses a high anaesthetic risk to these patients. Typical anaesthetic problems include airway obstruction after induction or extubation, intubation difficulties or failure [can’t intubate, can’t ventilate (CICV)], possible emergency tracheostomy and cardiovascular and cervical spine issues. Because of the high anaesthetic risk, the benefits of a procedure in patients with MPS should always be balanced against the associated risks. Therefore, careful evaluation of anaesthetic risk factors should be made before the procedure, involving evaluation of airways and cardiorespiratory and cervical spine problems. In addition, information on the specific type of MPS, prior history of anaesthesia, presence of cervical instability and range of motion of the temporomandibular joint are important and may be pivotal to prevent complications during anaesthesia. Knowledge of these risk factors allows the anaesthetist to anticipate potential problems that may arise during or after the procedure. Anaesthesia in MPS patients should be preferably done by an experienced (paediatric) anaesthetist, supported by a multidisciplinary team (ear, nose, throat surgeon and intensive care team), with access to all necessary equipment and support.
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MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This accumulation can lead to the progressive development of a variety of clinical manifestations. Ear, nose, throat (ENT) and respiratory problems are very common in patients with MPS and are often among the first symptoms to appear. Typical features of MPS include upper and lower airway obstruction and restrictive pulmonary disease, which can lead to chronic rhinosinusitis or chronic ear infections, recurrent upper and lower respiratory tract infections, obstructive sleep apnoea, impaired exercise tolerance, and respiratory failure. This review provides a detailed overview of the ENT and respiratory manifestations that can occur in patients with MPS and discusses the issues related to their evaluation and management.
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Cobalamin C (cblC), a combined form of methylmalonic acidaemia and hyperhomocysteinaemia, is recognized as the most frequent inborn error of intracellular cobalamin metabolism. This condition can be detected by expanded newborn screening and can have an acute neonatal presentation that is life-threatening if not suspected and promptly treated. Intramuscular (IM) hydroxocobalamin (OHCbl) is the main treatment for patients with cblC, but formal dosing guidelines do not exist. A clinical improvement and a decrease of plasma methylmalonic acid (MMA) and total homocysteine (tHcy) levels, and an increase in methionine are typically observed after its initiation. It is well recognized that despite treatment, long-term complications such as developmental delay and progressive visual loss, may still develop. We describe the biochemical response of a 13-year-old boy with worsening metabolic parameters despite strict adherence to a conventional treatment regimen. We progressively increased the OHCbl dose from 1 to 20 mg IM per day and observed a dose-dependent response with an 80% reduction of plasma MMA (25 to 5.14 μmol/L; normal range <0.27 μmol/L), a 55% reduction of tHcy (112 to 50 μmol/L; normal range: 0–13 μmol/L) and a greater than twofold increase in methionine (17 to 36 μmol/L; normal range: 7–47 μmol/L). This suggests that higher OHCbl doses might be required to achieve an optimal biochemical response in cblC patients, but it is unknown whether it may slow or eliminate other complications. Future clinical trials to determine the benefits of higher-dose OHCbl therapy in patients with cblC and other disorders of intracellular cobalamin metabolism should be planned.
Juvenile neuronal ceroid lipofuscinosis (JNCL; CLN3 disease; Batten disease) is an autosomal recessive neurodegenerative disease of childhood that typically presents at school age with vision loss followed by progressive cognitive decline, motor dysfunction, seizures, and behavior problems. No therapy has been shown to slow the progression of disease in JNCL patients, and all current treatments are symptomatic. Flupirtine has been shown in vitro to reduce apoptosis in CLN3 lymphocytes. Based on that preclinical study, several children with JNCL were given flupirtine by their parents. The purpose of this study was to determine if there was evidence of attenuated disease progression in any JNCL symptom domain. We administered a survey to parents of JNCL children to qualitatively assess flupirtine efficacy. We used the Unified Batten Disease Rating Scale (UBDRS) to determine specific aspects of disease progression and investigated three age-related factors: loss of independent ambulation, loss of intelligible speech, and loss of ability to perform independent activities of daily living. The median scores for the UBDRS physical, behavior, and capability subscales were determined in flupirtine-exposed subjects and compared to age-, sex-, and genotype-matched subjects who had never taken flupirtine. Twenty-one percent of survey responders reported administering flupirtine to their JNCL child, and 56% of these families perceived beneficial changes that they attributed to flupirtine. However, our quantitative, prospectively obtained data did not show any change in JNCL disease progression that could be attributed to flupirtine. This study highlights the need for prospective experimental therapeutic research.