Mucopolysaccharidosis III is a rare genetic disease characterized by progressive cognitive decline and severe hyperactivity that does not respond to stimulants. Somatic features are relatively mild. ...Patients are often initially misdiagnosed as having idiopathic developmental delay, attention deficit/hyperactivity disorder and/or autism spectrum disorders, putting them at risk for unnecessary testing and treatments.
Conclusion
Children with developmental or speech delay, especially those with a characteristic somatic feature or behavioural abnormalities, should be screened for MPS III.
Niemann‐Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the ...heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12‐month, prospective, randomised, double‐blind, placebo‐controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2‐18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5‐domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5‐domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of −1.40 (95% confidence interval: −2.76, −0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of −2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment‐related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.
Background
Niemann Pick type C (NPC) lysosomal disorder is linked to the disruption of cholesterol transport. Recent data suggest that the molecular background of this disease is more complex. It was ...found that accumulation of cholesterol and glycolipids in the late endosomal/lysosomal compartment of NPC1 cells may affect mitochondrial functions.
Materials and Methods
In this study, primary skin fibroblasts derived from skin biopsies of two anonymous patients with NPC‐carrying mutations in the NPC1 gene, characterized by a high total cholesterol content, as well as two healthy donors were used. The presence of signaling proteins in the whole cell lysates and mitochondrial fractions were examined by Western blotting assay.
Results
In this report, we provide experimental evidence that in NPC1 cells, dysfunction of mitochondria and cellular metabolism, as reported by Wos et al in 2016, coexist with alterations in signal transduction pathways, such as the mammalian target of rapamycin, AKT, phosphoinositide‐dependent protein kinase‐1, glycogen synthase kinase‐3 β, and Jun amino‐terminal kinase, leading to abnormal cholesterol accumulation and distribution.
Conclusion
Differences in signal transduction between control and NPC1 cells may suggest that the latter cells experienced significant alterations in the complex molecular mechanisms that control cellular energy metabolism and vesicular transport.
In this report, we tested the hypothesis that the Niemann Pick type C (NPC) disease is accompanied by changes in signal transduction pathways involved in the regulation of cell metabolism. The differences in signal transduction in NPC mutant cells may suggest a complex molecular mechanism responsible for the development and sustenance of the NPC disease, involving impaired cellular energy metabolism and its regulation, which leads to perturbed cholesterol distribution in NPC mutant cells.
Objective To describe demographic, genetic, and clinical characteristics of patients with neuronopathic Gaucher disease (NGD). Methods All patients enrolled in the Neurological Outcomes Subregistry ...of the International Collaborative Gaucher Group (ICGG) Gaucher Registry as of June 2007 were identified. Results The study cohort comprised 131 patients from 17 countries who were enrolled in the Neurological Outcomes Subregistry. The onset of neurological manifestations had occurred before 2 years of age in 47% (61 out of 131 patients), 2 years of age or older in 41% (54 out of 131), and could not be ascertained in the remaining 12% (16 out of 131). The most common manifestations were inability to look to the extreme up or down (45%, 55 out of 123), abnormally slow object tracking (43%, 53 out of 123), convergent squint (36%, 44 out of 121), and ataxia (15 to 20%, 18-27 out of 117). Seizures were reported in 19 out of 122 patients (16%), and myoclonic seizures were reported in 3 out of 121 patients (2%). The most common genotypes were L444P/L444P (76 out of 108, 70%), L444P/D409H (9 out of 108, 8%), D409H/D409H (8 out of 108, 7%), and L444P/rare allele (6 out of 108, 6%); full sequencing was not performed in all patients. Conclusions Neurological manifestations of GD often begin to appear before the age of 2 years. The most common neurological signs and manifestations are brainstem abnormalities and fine motor dysfunction. The most common genotype is L444P/L444P.
Fabry disease, an inherited lysosomal storage disorder, causes multi-organ pathology resulting in substantial morbidity and a reduced life expectancy. Although Fabry disease is an X-linked disorder, ...both genders may be affected, but generally to a lesser extent in females. The disease spectrum ranges from classic early-onset disease to non-classic later-onset phenotypes, with complications occurring in multiple organs or being confined to a single organ system depending on the stage of the disease. The impact of therapy depends upon patient- and disease-specific factors and timing of initiation.
A European panel of experts collaborated to develop a set of organ-specific therapeutic goals for Fabry disease, based on evidence identified in a recent systematic literature review and consensus opinion.
A series of organ-specific treatment goals were developed. For each organ system, optimal treatment strategies accounted for inter-patient differences in disease severity, natural history, and treatment responses as well as the negative burden of therapy and the importance of multidisciplinary care. The consensus therapeutic goals and proposed patient management algorithm take into account the need for early disease-specific therapy to delay or slow the progression of disease as well as non-specific adjunctive therapies that prevent or treat the effects of organ damage on quality of life and long-term prognosis.
These consensus recommendations help advance Fabry disease management by considering the balance between anticipated clinical benefits and potential therapy-related challenges in order to facilitate individualized treatment, optimize patient care and improve quality of life.
•Therapeutic goals for Fabry patients should be individualized based on patient characteristics, disease variant and stage.•Reversal of symptoms or prevention of disease progression is the goal for most parameters associated with Fabry disease.•Disease management requires multidisciplinary input based on a comprehensive organ assessment and regular monitoring.•Early initiation of disease-specific therapy can delay progression in patients with Fabry disease.•Optimal disease management should consider anticipated clinical benefits and potential therapy-related challenges.
Adenylosuccinate lyase deficiency Jurecka, Agnieszka; Zikanova, Marie; Kmoch, Stanislav ...
Journal of inherited metabolic disease,
March 2015, Letnik:
38, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Adenylosuccinate lyase ADSL) deficiency is a defect of purine metabolism affecting purinosome assembly and reducing metabolite fluxes through purine
de novo
synthesis and purine nucleotide recycling ...pathways. Biochemically this defect manifests by the presence in the biologic fluids of two dephosphorylated substrates of ADSL enzyme: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado). More than 80 individuals with ADSL deficiency have been identified, but incidence of the disease remains unknown. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The fatal neonatal form has onset from birth and presents with fatal neonatal encephalopathy with a lack of spontaneous movement, respiratory failure, and intractable seizures resulting in early death within the first weeks of life. Patients with type I (severe form) present with a purely neurologic clinical picture characterized by severe psychomotor retardation, microcephaly, early onset of seizures, and autistic features. A more slowly progressing form has also been described (type II, moderate or mild form), as having later onset, usually within the first years of life, slight to moderate psychomotor retardation and transient contact disturbances. Diagnosis is facilitated by demonstration of SAICAr and S-Ado in extracellular fluids such as plasma, cerebrospinal fluid and/or followed by genomic and/or cDNA sequencing and characterization of mutant proteins. Over 50 ADSL mutations have been identified and their effects on protein biogenesis, structural stability and activity as well as on purinosome assembly were characterized. To date there is no specific and effective therapy for ADSL deficiency.
Background
Transaldolase deficiency (TALDO‐D) is a rare autosomal recessive inborn error of the pentose phosphate pathway. Since its first description in 2001, several case reports have been ...published, but there has been no comprehensive overview of phenotype, genotype, and phenotype–genotype correlation.
Methods
We performed a retrospective questionnaire and literature study of clinical, biochemical, and molecular data of 34 patients from 25 families with proven TALDO‐D. In some patients, endocrine abnormalities have been found. To further evaluate these abnormalities, we performed biochemical investigations on blood of 14 patients.
Results and conclusions
Most patients (n = 22) had an early‐onset presentation (prenatally or before 1 month of age); 12 patients had a late‐onset presentation (3 months to 9 years). Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly. An older sib of two affected patients was asymptomatic until the age of 9 years, and only after molecular diagnosis was hepatomegaly noted. In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle‐stimulating hormone (FSH) abnormalities later in life. This overview provides information that can be helpful for managing patients and counseling families regarding prognosis. Diagnostic guidelines, possible genotype–phenotype correlations, treatment options, and pathophysiological disease mechanisms are proposed.
Liver involvement in Gaucher disease (GD) is a result of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) infiltration of macrophages. The long-term liver-related ...complications of GD could include liver fibrosis and cirrhosis. The aim of the study was to evaluate clinical utility and relevance of TE by FibroScan in GD patients by assessing two parameters: controlled attenuation parameter (CAP) and liver stiffness (LS), in regard of GD-related variables, type of GD, age of patients, enzymatic replacement therapy (ERT), and metabolic features.
59 Polish patients (55 adults, 4 children) with GD (43 patients with type 1 and 16 patients with type 3) aged 7–86 years, underwent TE by FibroScan; elevated CAP was defined as >250 dB/m and elevated LS as >7 kPa. All patients, except five patients with type 1 GD (patients' refusal), were treated by ERT.
Elevated CAP was present in 23% of GD1 patients and 19% of GD3 patients. Elevated LS was present in 21% of GD1 patients and 13% of GD3 patients. CAP was fairly, positively (ρ = 0.356) correlated with BMI. LS was fairly, positively (ρ = 0.4) correlated with patient's age, as well as the age at start of ERT (ρ = 0.326). CAP was strongly, negatively (ρ = −0.52) correlated with the age at start of ERT. LS and CAP were correlated (strongly, positively) only in GD3.
TE by FibroScan could be considered as an additional method for evaluating GD patients for non-invasive assessment of CAP and LS. The investigation of serial TE measurements in untreated as well as treated GD patients is needed to better determine whether this technology should be added to recommendations for monitoring GD patients. TE by FibroScan could be performed in GD patients with increased BMI and especially those with metabolic syndrome as they have other important risks for liver disease. After our analysis we think these risks factors are independent of GD but still very important for their overall health.
Hunter syndrome is caused by deficiency of the lysososmal enzyme iduronate-2-sulphatase that cleaves O-linked sulphate moieties from dermatan sulphate and heparan sulphate and leads to accumulation ...of GAGs. The disease is a X-linked condition affecting males and rarely females, clinically divided into severe (2/3) and attenuated types. Children with severe form, diagnosed at 12-36 months, have coarse facial feature, short stature, joint stiffness, short neck, broad chest, large head circumference, watery diarrhea, skeletal changes, progressive and profound mental retardation, retinal degeneration' hearing loss, cardiomyopathy, valvular involvement, with progressive thickening and stiffening of the valve leaflets leading to mitral and aortic regurgitation and stenosis . Recurrent and prolonged rhinitis with persistent nasal discharge are the first symptoms of airway disease that manifests itself as noisy breathing and later sleep apnea. Some patients develop ivory-colored skin lesions on the upper back and sides of the upper arms, pathogenomic of Hunter syndrome. The scalp hair becomes coarse, straight and bristly. Inguinal and umbilical hernias occur caused by the disturbed structure of connective tissue and increased liver and spleen volume. Patients with attenuated form have normal intelligence and a milder phenotype. Physical features diagnosed later are similar but less pronounced but progress to severe disease. Sceening is by quantitative assessment of urinary GAGs excretion. Qualitative assessment of GAG by electrophoresis can distinguish the type of mucopolysaccharidosis. Definitive diagnosis is based on enzyme activity assay in leukocytes, fibroblasts or plasma. Molecular testing is recommended mainly for genetic counseling and carrier detection. Limited experience of Haematopoietic stem cell therapy in MPS II showed progressive neurodegeneration. Recombinant 125 Idursulfase, is indicated for long-term treatment. The response appears to depend on the severity of the disease and the age treatment is started, Improvements in a composite endpoint comprising: change in walking distance percentage of predicted forced vital capacity (%FVC) ,decrease in liver and spleen volume and urinary GAG levels were encouraging. Current research is focused on pharmacological chaperones, gene therapy and substrate reduction therapy and therapies that, unlike Idursulfase, do cross the blood-brain barrier.
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