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.

Clinical insights from Wolman disease: Evaluating infantile hepatosplenomegaly.

There is a broad differential diagnosis of infantile hepatosplenomegaly, with some etiologies being debilitating and treatable. A structured approach to history, examination, and laboratory and radiographic findings is important in diagnosis. Herein, we present a case of Wolman disease presenting as hepatosplenomegaly in an infant. This case details important learning points to help distinguish the diagnosis of Wolman disease from other conditions with overlapping clinical features, such as hemophagocytic lymphohistiocytosis (HLH). The advent of enzyme replacement therapy has dramatically changed the natural history of Wolman disease, and this child showed remarkable improvement with treatment. This child was later found to have extensive adenopathy with retroperitoneal lymph node biopsy demonstrating diffuse infiltration by lipid-laden macrophages, fatty deposits, cholesterol crystals, and calcifications. Similar to the collection of characteristic cells in other lysosomal storage disorders, we postulate that this is characteristic of underlying Wolman disease. We conclude with a summary of learning points from this presentation on infantile hepatosplenomegaly, pertinent to the geneticist, pediatrician, and pediatric subspecialists.

The diagnosis and management of Gaucher disease in pediatric patients: Where do we go from here?

Gaucher disease (GD) is an autosomal recessive inherited lysosomal storage disease that often presents in early childhood and is associated with damage to multiple organ systems. Many challenges associated with GD diagnosis and management arise from the considerable heterogeneity of disease presentations and natural history. Phenotypic classification has traditionally been based on the absence (in type 1 GD) or presence (in types 2 and 3 GD) of neurological involvement of varying severity. However, patient management and prediction of prognosis may be best served by a dynamic, evolving definition of individual phenotype rather than by a rigid system of classification. Patients may experience considerable delays in diagnosis, which can potentially be reduced by effective screening programs; however, program implementation can involve ethical and practical challenges. Variation in the clinical course of GD and an uncertain prognosis also complicate decisions concerning treatment initiation, with differing stakeholder perspectives around efficacy and acceptable cost/benefit ratio. We review the challenges faced by physicians in the diagnosis and management of GD in pediatric patients. We also consider future directions and goals, including acceleration of accurate diagnosis, improvements in the understanding of disease heterogeneity (natural history, response to treatment, and prognosis), the need for new treatments to address unmet needs for all forms of GD, and refinement of the tools for monitoring disease progression and treatment efficacy, such as specific biomarkers.

CNTNAP1-Related Congenital Hypomyelinating Neuropathy.

BACKGROUND: Congenital hypomyelinating neuropathy is a rare form of hereditary peripheral neuropathy characterized by nonprogressive weakness, areflexia, hypotonia, severely reduced nerve conduction velocities, and hypomyelination. Mutations in contactin-associated protein 1 (CNTNAP1) were recently described as a cause of congenital hypomyelinating neuropathy. CNTNAP1-associated congenital hypomyelinating neuropathy is characterized by severe hypotonia, multiple distal joint contractures, and high mortality in the first few months of life. METHODS: Whole-exome sequencing was performed in two siblings with congenital hypotonia. Detailed phenotyping data were compared with previously reported cases. RESULTS: A novel, heterozygous compound mutation of CNTNAP1 was identified in both siblings. We also reviewed 17 patients harboring 10 distinct mutations from previously published studies. All patients presented with severe hypotonia, respiratory distress, and multiple cranial nerve palsies at birth. Six of 19 patients survived beyond infancy and required chronic mechanical ventilation. Seizures were common in the surviving patients. CONCLUSIONS: These findings suggest that CNTNAP1-related congenital hypomyelinating neuropathy is a distinct form of hereditary neuropathy that affects both the central and peripheral nervous systems with no clear phenotype-genotype correlation. Our findings also indicate that arthrogryposis multiplex congenita and early lethality are not universal outcomes for patients with congenital hypomyelinating neuropathy.

Squalene Synthase Deficiency: Clinical, Biochemical, and Molecular Characterization of a Defect in Cholesterol Biosynthesis.

Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect. The metabolite profile in plasma and urine suggested that their defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial splicing defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady state.

Correlating liver stiffness with disease severity scoring system (DS3) values in Gaucher disease type 1 (GD1) patients.

Gaucher disease (GD) is an autosomal-recessive lysosomal storage disease caused by a deficiency of the enzyme, glucocerebrocidase, resulting in accumulation of lipid-laden storage cells in multiple organs such as bone marrow, liver, spleen, and lungs. Type 1 Gaucher disease is the most common form of this condition in which the brain and spinal cord (the central nervous system) are not affected. The Gaucher disease severity scoring system (GD-DS3) is typically used to assess disease severity accounting for skeletal, hematologic, and visceral disease. In addition to being time consuming for the clinician to calculate the scores, some of the assessments are subjective and may falsely increase or decrease disease severity. The purpose of this study was to determine if there is a correlation between liver stiffness values obtained from MR elastography (MRE) and the GD-DS3 score. An IRB approved, HIPAA compliant retrospective study was performed. All patients with type 1 GD imaged with MRE between 2011 and 2016 were included in this study. Clinical and imaging data was collected. Two pediatric radiologists analyzed MR images from abdomen and thigh studies independently to determine bone marrow involvement using a semi-quantitative scoring system with one reviewer analyzing a subset of studies to determine inter-observer reliability. The collected data was used to calculate a GD-DS3 score for all patients. GD-DS3 scores were compared with liver MRE stiffness values. Clinical MRE scores were plotted against GD-DS3 severity scores for 31 patients (15 males, 16 females; median age 27years, age range: 4-67years). The median GD-DS3 score was 4 (range: 1-10.1) and median MRE value was 2.43kPa (range: 1.30-5.20kPa). A significant positive correlation was found between MRE and GD-DS3 scores; Pearson's correlation coefficient value of r=0.47, p<0.001 for all scores, r=0.68, p<0.001 for complete scores and r=0.46, p<0.07 for incomplete scores. The inter-observer variation of bone marrow burden showed only fair agreement with a Kappa coefficient of 0.26. There is a significant positive correlation between increasing liver stiffness and increasing composite GD-DS3 scores. This supports the use of MRE, a non-invasive reproducible quantitative test, as both an additional assessment and independent marker for monitoring disease severity and progression in GD.

Widespread Vasculopathy in a Patient with Morquio A Syndrome.

Morquio A syndrome (mucopolysaccharidosis IV type A), an autosomal recessive lysosomal storage disorder caused by a defective N-acetylgalactosamine 6-sulfatase gene, leads to lysosomal accumulation of keratan sulfate and chondroitin 6-sulfate. This accumulation affects multiple systems and causes notable cardiovascular manifestations, such as thickening of the left-sided valves, ventricular hypertrophy, and intimal stenosis of the coronary arteries. There have been few reports of vasculopathy in this population. We present the case of a 58-year-old woman with Morquio A syndrome who was found to have aortic dilation on a routine screening echocardiogram. Magnetic resonance images revealed multiple tortuous, dilated arteries in her head, neck, and abdomen. The diffuse vasculopathy seen in this patient should prompt further study to determine whether this is an underreported phenomenon of clinical significance or an unusual finding in this rare disorder.

Home infusion of intravenous velaglucerase alfa: Experience from pooled clinical studies in 104 patients with type 1 Gaucher disease.

The introduction of a home therapy option during clinical trials of velaglucerase alfa in patients with type 1 Gaucher disease marked the first time that home infusions have been permitted during a clinical trial for an investigational drug for Gaucher disease. Home infusions were an available option in 4 open-label velaglucerase alfa clinical studies to eligible patients who received their initial infusions at a clinic. Patients who participated in the home therapy option and received at least 10% of their infusions at home (n=100) received a range of 11.6%-100% of their scheduled infusions at home (median 87.5%), excluding infusions received at the clinic during protocol-mandated visits. The length of time over which individual patients received home therapy ranged from 13days to 4.56years (median 0.57years). During the time that home therapy was available, 2904 of 3572 (81.3%) infusions were administered at home. Ten patients experienced 62 infusion-related adverse events (IRAEs) during 38 home infusions, with malaise, pain, hypertension, fatigue, and headache being reported most frequently. No notable differences were found between the type and severity of IRAEs experienced at home and those experienced at the clinic. Home infusions administered by trained and qualified medical personnel were successfully introduced into the velaglucerase alfa clinical development program, and fewer than 10% of patients experienced IRAEs in the home setting. Local labeling and practice guidelines should be consulted for administration of velaglucerase alfa infusions at home.

Stability is maintained in adults with Gaucher disease type 1 switched from velaglucerase alfa to eliglustat or imiglucerase: A sub-analysis of the eliglustat ENCORE trial.

Gaucher disease type 1 is an autosomal recessive disorder caused by deficient activity of the lysosomal enzyme acid ß-glucosidase resulting in accumulation of glucosylceramide and clinical manifestations of anemia, thrombocytopenia, hepatosplenomegaly, and skeletal disease. The historic standard of care is intravenous recombinant enzyme therapy with imiglucerase. Eliglustat, an oral substrate reduction therapy, is a first-line treatment for adults with Gaucher disease type 1 who have a compatible CYP2D6-metabolizer phenotype (≈ 95% of patients). The 12-month ENCORE trial (NCT00943111) found eliglustat non-inferior to imiglucerase in maintaining stability in adult Gaucher patients previously stabilized after ≥ 3 years of enzyme therapy (imiglucerase or velaglucerase alfa). This post-hoc analysis examined safety and efficacy in the 30 ENCORE patients who were receiving velaglucerase alfa at study entry and were randomized to eliglustat (n = 22) or imiglucerase (n = 8). Efficacy and safety in velaglucerase alfa-transitioned patients were consistent with the full ENCORE trial population; 90% of patients switched to eliglustat and 88% of patients switched to imiglucerase met the composite endpoint (stable hemoglobin concentration, platelet count, spleen volume, and liver volume). Clinical stability was maintained for 12 months in Gaucher disease type 1 patients in the ENCORE trial who switched from velaglucerase alfa to either eliglustat or imiglucerase.

A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency.

BACKGROUND: Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. RESULTS: Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment. CONCLUSIONS: Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.).

A Novel Catastrophic Presentation of X-Linked Adrenoleukodystrophy.

OBJECTIVE: We report a novel presentation of childhood cerebral X-linked adrenoleukodystrophy: status epilepticus followed by abrupt and catastrophic neurologic deterioration. METHODS: A description of the clinical presentation, laboratory evaluation, and imaging findings leading to a diagnosis of X-linked adrenoleukodystrophy. RESULTS: A 3-year-old male with prior history of autism presented with fever, diarrhea, and status epilepticus requiring a pentobarbital coma. Admission labs were notable only for a glucose level of 22 mg/dL, which stabilized after correction. The child never returned to his prior neurologic baseline, with complete loss of gross motor, fine motor, and speech skills. Serial brain magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) was notable for progressive diffuse cortical signal changes with swelling, diffusion restriction, and ultimately laminar necrosis. Nine months after presentation, CSF (cerebrospinal fluid) protein and MRS lactate were persistently elevated, concerning for a neurodegenerative disorder. This led to testing for mitochondrial disease, followed by lysosomal and peroxisomal disorders. Very long-chain fatty acids were elevated. Identification of a pathogenic ABCD1 mutation confirmed the diagnosis of X-linked adrenoleukodystrophy. CONCLUSIONS: Boys with childhood cerebral X-linked adrenoleukodystrophy typically present with gradual behavioral changes. Rare reports of boys presenting with transient altered mental status or status epilepticus describe a recovery to their pre-presentation baseline. To our knowledge this is the first X-ALD patient to present with status epilepticus with abrupt and catastrophic loss of neurologic function. X-linked adrenoleukodystrophy should be suspected in young males presenting with seizures, acute decline in neurologic function, with persistently elevated CSF protein and MRS lactate.

Intelligent drug-delivery devices based on micro- and nano-technologies.

This review focuses on the current drug-delivery modalities in R&D, as well as commercially available. Intelligent drug-delivery systems are described as novel technological innovations and clinical approaches to improve conventional treatments. These systems differ in methodology of therapeutic administration, intricacy, materials and patient compliance to address numerous clinical conditions that require various pharmacological therapies. These systems have been primarily described as active and passive microelectrical mechanical system devices, injectors and nanoparticle-based therapies, optimized to tailor specific pharmacokinetic profiles. The most critical considerations for the design of these intelligent delivery systems include the controlled release, target specificity, on-demand dosage adjustment, mass transfer and stability of the pharmacological agents. Drug-delivery systems continue to be developed and enhanced to provide better and more sophisticated treatments, promising an improvement in quality of life and extension of life expectancy.

Recurrent pancreatitis in ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) deficiency is a urea cycle defect with varying frequency and severity of episodes of hyperammonemia. We report three patients with OTC deficiency with recurrent pancreatitis. The pathogenesis of acute pancreatitis in this patient population requires further elucidation. Pancreatitis significantly affected dietary/metabolic management and increased frequency of hospitalizations.

Cardiac disease in methylmalonic acidemia.

Methylmalonic acidemia (MMA) is a heterogeneous disorder, with onset from infancy to adulthood and varying degrees of organ involvement and severity. Cardiac disease is a known lethal complication of other organic acidemias, but has not been associated with MMA. We identified 3 patients with MMA and cardiac disease.

Predictive validity of a non-induced mouse model of compulsive-like behavior.

A key to advancing the understanding of obsessive-compulsive disorder (OCD)-like symptoms is the development of spontaneous animal models. Over 55 generations of bidirectional selection for nest-building behavior in house mice, Mus musculus, resulted in a 40-fold difference in the amount of cotton used for a nest in high (BIG) and low (SMALL) selected lines. The nesting behavior of BIG mice appears to be compulsive-like and has initial face validity as an animal model for OCD in humans. Compulsive-like digging behavior was assessed; BIG male mice buried about three times as many marbles as SMALL male mice, strengthening face validity. Using the open field and elevated plus maze, SMALL male mice showed higher levels of anxiety/fear-like behavior than BIG male mice, indicating that compulsive-like and not anxiety-like behavior was measured. To establish predictive validity, chronic (4 weeks) oral administration of fluoxetine (30, 50 and 100mg/kg/day) and clomipramine (80 mg/kg/day), both effective in treating OCD, significantly reduced compulsive-like nest-building behavior in BIG male mice. Compulsive-like digging behavior was also significantly reduced by chronic oral fluoxetine (30 and 80 mg/kg/day) treatment in BIG male mice. General locomotor activity was not affected by chronic oral fluoxetine (30 and 80 mg/kg/day) treatment; chronic oral treatment with desipramine (30 mg/kg/day), an antidepressant not effective in treating OCD, had no effect on nesting behavior of BIG male mice, strengthening predictive validity. Together, the results indicate that these mice have good face and predictive validity as a non-induced mouse model of compulsive-like behavior relevant to OCD.