Impact of citrulline substitution on clinical outcome after liver transplantation in carbamoyl phosphate synthetase 1 and ornithine transcarbamylase deficiency.

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.

Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource.

Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disorder caused by pathogenic variants in GBE1 which results in reduced or deficient glycogen branching enzyme activity. Consequently, glycogen synthesis is impaired and leads to accumulation of poorly branched glycogen known as polyglucosan. GSD IV is characterized by a remarkable degree of phenotypic heterogeneity with presentations in utero, during infancy, early childhood, adolescence, or middle to late adulthood. The clinical continuum encompasses hepatic, cardiac, muscular, and neurologic manifestations that range in severity. The adult-onset form of GSD IV, referred to as adult polyglucosan body disease (APBD), is a neurodegenerative disease characterized by neurogenic bladder, spastic paraparesis, and peripheral neuropathy. There are currently no consensus guidelines for the diagnosis and management of these patients, resulting in high rates of misdiagnosis, delayed diagnosis, and lack of standardized clinical care. To address this, a group of experts from the United States developed a set of recommendations for the diagnosis and management of all clinical phenotypes of GSD IV, including APBD, to support clinicians and caregivers who provide long-term care for individuals with GSD IV. The educational resource includes practical steps to confirm a GSD IV diagnosis and best practices for medical management, including (a) imaging of the liver, heart, skeletal muscle, brain, and spine, (b) functional and neuromusculoskeletal assessments, (c) laboratory investigations, (d) liver and heart transplantation, and (e) long-term follow-up care. Remaining knowledge gaps are detailed to emphasize areas for improvement and future research.

Menorrhagia in patients with type I glycogen storage disease.

OBJECTIVE: To evaluate menorrhagia in a cohort of women with glycogen storage disease type I because it appears to be an under-recognized problem in females of reproductive age. METHODS: A retrospective chart review was performed on 13 menstruating patients with glycogen storage disease type I (age 23-48 years) for a diagnosis of menorrhagia. RESULTS: Nine (69%) (confidence interval 0.39-0.91) women had development of menorrhagia. Median hemoglobin values in these patients were generally low (range 9.5-12.85 g/dL) but not different from those of the nonmenorrhagia group (hemoglobin range 9.55-11.0 g/dL) with glycogen storage disease type I. Four patients with menorrhagia required hospitalization or emergency department visits for treatment of menorrhagia. Two of the four patients hospitalized required blood transfusion, with an additional patient requiring a transfusion during pregnancy. Eight patients (89%) either were recommended to have or required medical or surgical treatment of their menorrhagia. CONCLUSION: Glycogen storage disease type I is associated with menorrhagia. The evaluation should include assessment of coagulation functions and referral to a gynecologist, hematologist, or both, because bleeding diathesis and polycystic ovary syndrome are common in patients with glycogen storage disease type I.

Elevation of guanidinoacetate in newborn dried blood spots and impact of early treatment in GAMT deficiency.

Guanidinoacetate methyltransferase (GAMT) deficiency is a good candidate disorder for newborn screening because early treatment appears to improve outcomes. We report elevation of guanidinoacetate in archived newborn dried blood spots for 3 cases (2 families) of GAMT deficiency compared with an unaffected carrier and controls. We also report a new case of a patient treated from birth with normal developmental outcome at the age of 42 months.

An individually, modified approach to desensitize infants and young children with Pompe disease, and significant reactions to alglucosidase alfa infusions.

PURPOSE: Pompe disease (PD) is a progressive metabolic myopathy for which the only available treatment is alglucosidase alfa (Myozyme®). Enzyme replacement therapy (ERT) has improved ventilator-free survival, and cardiac and motor functions in patients with infantile PD. However, for an adequate response to occur, a large amount of enzymes must be infused. In some patients, this may be problematic due to infusion-associated reactions (IARs) occurring in approximately 50% of patients receiving alglucosidase alfa infusions. Whilst the majority of these reactions are mild, life threatening hypersensitivity reactions may occur in some patients. In these patients desensitization is indicated to enable continued ERT safely. Infants and young children with PD and significant infusion reactions pose unique management challenges because of their young age, limited communication skills, variable presentation and underlying cardiomyopathy. METHODS/SUBJECTS: In 2 patients with PD who experienced significant ERT-related reactions: an infant (IgE positive) and a young child (IgE negative), we implemented a desensitization protocol, that started by administering a reduced dose of alglucosidase alfa (10 mg/kg weekly) instead of the standard (20 mg/kg bi-weekly) using serial micro-dilutions that were individually prepared and delivered in a highly regulated manner based on patients' clinical manifestations and tolerance. RESULTS: Successful desensitization was achieved in both patients, allowing them to eventually continue to receive the full dose of ERT safely. CONCLUSION: Therapeutic demands in infants and young children with PD need to be tailored according to the patient presentation, and underlying cardiac and fluid-volume status. Desensitization allowed both patients to continue alglucosidase alfa treatment at the recommended dose without prolonged interruption of therapy, or further reactions.

Expanding the clinical spectrum of late-onset Pompe disease: dilated arteriopathy involving the thoracic aorta, a novel vascular phenotype uncovered.

PURPOSE: Cerebro-vascular arteriopathy has been reported in late-onset Pompe disease (LOPD). Evidence of increased aortic stiffness in some patients and smooth muscle involvement in LOPD raises the possibility of aortic involvement. Our aim was to determine if aortic arteriopathy may be a complication of LOPD. METHODS: One patient with LOPD was diagnosed with aortic dilatation at Duke Metabolic clinic, 4 others were diagnosed at University of Mainz, Germany, where chest X-ray and echocardiography are routinely done for patients. Other causes of aortic vascular disease were assessed. RESULTS: We report evidence of dilated arteriopathy involving primarily the ascending thoracic aorta in 5 females with late-onset Pompe disease. One patient had a bicuspid aortic valve and developed dissection. Another patient with juvenile onset disease had both thoracic and basilar artery aneurysms. CONCLUSIONS: Aneurysmal dilatation of the thoracic aorta is an underreported vascular complication of LOPD, probably due to the same pathological process that occurs in the brain. Chest X-ray together with echocardiography should be incorporated as initial screening tools for aortic aneurysms in patients with LOPD. When ectasia is suspected, or the ascending aorta is not visualized, contrast- mediated thoracic CT or MRA may be necessary. Large-scale studies are warranted to determine the prevalence and extent of aortic vascular involvement.

Follow-up of a child with pyruvate dehydrogenase deficiency on a less restrictive ketogenic diet.

A male child with X-linked pyruvate dehydrogenase deficiency presented with severe neonatal lactic acidosis. Poor compliance following initiation of the ketogenic diet justified modification to a less restrictive form which improved compliance. One year after starting the modified diet, he remained clinically stable, showing developmental progress.

Severe cleidocranial dysplasia and hypophosphatasia in a child with microdeletion of the C-terminal region of RUNX2.

Cleidocranial dysplasia (CCD) is a rare autosomal dominant skeletal dysplasia due to mutations causing haploinsufficiency of RUNX2, an osteoblast transcription factor specific for bone and cartilage. The classic form of CCD is characterized by delayed closure of the fontanels, hypoplastic or aplastic clavicles and dental anomalies. Clinical reports suggest that a subset of patients with CCD have skeletal changes which mimic hypophosphatasia (HPP). Mutations in RUNX2 are detected in approximately 65% of cases of CCD, and microdeletions occur in 13%. We present clinical and radiological features in a 6-year-old child with severe CCD manifested by absence of the clavicles marked calvarial hypomineralization, osteoporosis and progressive kyphoscoliosis. HPP features included Bowdler spurs, severe osteopenia, and low alkaline phosphatase. Following negative mutation analysis of RUNX2, comparative genomic hybridization (CGH) microarray was performed. The result revealed a microdeletion in RUNX2, disrupting the C-terminal part of the gene.

Serum brain-derived neurotrophic factor concentrations in lean and overweight children and adolescents.

CONTEXT: Brain-derived neurotrophic factor (BDNF) and its receptor appear to be important components of the leptin-signaling cascade involved in energy homeostasis, and mice with BDNF or TrkB gene haploinsufficiency have excessive adiposity. Little is known about the relationship between adiposity and BDNF, particularly in children. OBJECTIVE: The objective of the study was to study the association of serum BDNF with measures of adiposity in children. DESIGN/SETTING/PATIENTS: BDNF was determined by a sandwich-type ELISA after an overnight fast in convenience sample of 328 subjects, aged 3-19 yr enriched for extreme obesity. In 43, BDNF was also measured before, and again 1 h after, consuming a high-energy content (787 kcal) milkshake. MAIN OUTCOME MEASURES: Measures included associations between BDNF and measures of adiposity. RESULTS: There were no significant univariate associations between log BDNF and adiposity measured by body mass index (BMI), BMI-Z score, or fat mass. However, in an analysis of covariance accounting for age, sex, race, pubertal status, and platelet count, BDNF was lower in overweight children (mean +/- sd, 39.8 +/- 24.8 vs. 47.0 +/- 25.4 ng/dl, P = 0.03); in multiple regression analyses with log BDNF as the dependent variable, BMI (P = 0.03), BMI-Z (P = 0.01), and body fat (P < 0.02) were all negatively associated with BDNF once age, pubertal status, and platelet count were included in the model. Ingestion of a meal did not significantly alter serum BDNF 1 h later (P = 0.26). CONCLUSIONS: Serum BDNF is lower in extremely overweight children and adolescents than those of normal weight. It remains to be determined whether obese individuals with low serum BDNF for age and platelet count have mutations that alter BDNF function.

Gender-specific correlates of leptin with hypertension-related phenotypes in African Americans.

Leptin may be a link in the relationship of obesity with hypertension. We evaluated associations of leptin with blood pressure (BP) in 54 normotensive and 114 hypertensive African American individuals. Plasma leptin was higher (P <.03) in hypertensive women than in normotensive women, although body mass index did not differ (30.5 +/- 0.5 v 30.2 +/- 0.8 kg/m(2)). After adjusting for obesity and insulin resistance, there were no significant relationships between leptin and BP; however, leptin independently predicted 28% of the variability of heart rate in hypertensive men (P <.01) and 18% of the variability of lithium clearance in hypertensive women (P <.01). Thus, in these obese hypertensive African American women, there is no direct or independent association of leptin with BP. However, leptin may contribute to hypertension in these women by increasing renal tubular sodium reabsorption.