Lysosomal storage disorders (LSDs) are rare genetic disorders, with heterogeneous clinical manifestations and severity. Treatment options, such as enzyme replacement therapy (ERT), substrate ...replacement therapy, and pharmacological chaperone therapy, are available for several LSDs, including Gaucher disease (GD), Fabry disease (FD), and Hunter syndrome (mucopolysaccharidosis type II MPS II). However, patients in some countries face challenges accessing treatments owing to limited availability of locally licensed, approved drugs.
The Takeda LSD Charitable access program aims to meet the needs of individuals with GD, FD or MPS II with the greatest overall likelihood of benefit, in selected countries, through donation of ERT to nonprofit organizations, and support for medical capacity-building as well as family support via independent grants. Long-term aims of the program are to establish sustainable healthcare services delivered by local healthcare providers for patients with rare metabolic diseases. Patients receiving treatment through the program are monitored regularly, and their clinical data and progress are reviewed annually by an independent medical expert committee (MEC). The MEC also selects patients for enrollment completely independent from the sponsoring company.
As of 31 August, 2019, 199 patients from 13 countries were enrolled in the program; 142 with GD, 41 with MPS II, and 16 with FD. Physicians reported improvements in clinical condition for 147 (95%) of 155 patients with follow-up data at 1 year.
The response rate for follow-up data at 1 year was high, with data collected for > 90% of patients who received ERT through the program showing clinical improvements in the majority of patients. These findings suggest that the program can benefit selected patients previously unable to access disease-specific treatments. Further innovative solutions and efforts are needed to address the challenges and unmet needs of patients with LSDs and other rare diseases around the world.
Mucopolysaccharidosis (MPS) type III (Sanfilippo syndrome) comprises a group of rare, lysosomal storage diseases caused by the deficiency of one of four enzymes involved in the degradation of heparan ...sulfate. The clinical hallmark of the disease is severe neurological deterioration leading to dementia and death in the second decade of life. Adult MPS patients are generally of short stature. To date there is no clear description of the physical development of MPS III patients. The aim of this study was to document growth reference data for MPS III patients. We collected growth data of 182 German MPS III patients and were able to develop growth charts for this cohort. Growth curves for height, weight, head circumference, and body mass index were calculated and compared to German reference charts.
Birth height, weight and head circumference were within the physiological ranges. Both genders were significantly taller than healthy children at 2 years of age, while only male patients were taller at the age of four. Growth velocity decelerated after the ages of 4.5 and 5 years for female and male patients, respectively. Both genders were significantly shorter than the reference group at the age of 17.5 years. Head circumference was larger compared to healthy matched controls within the first 2 years of life and remained enlarged until physical maturity.
MPS III is a not yet treatable severe neuro-degenerative disease, developing new therapeutic strategies might change the course of the disease significantly. The present charts contribute to the understanding of the natural history of MPS III. Specific growth charts represent an important tool for families and physicians as the expected height at physical maturity can be estimated and therapeutic effects can be monitored.
Glutaric aciduria type 1 (GA1) is an inherited neurometabolic disorder caused by mutations in the GCDH gene encoding glutaryl-CoA dehydrogenase (GCDH), which forms homo- and heteromeric complexes in ...the mitochondrial matrix. GA1 patients are prone to the development of encephalopathic crises which lead to an irreversible disabling dystonic movement disorder. The clinical and biochemical manifestations of GA1 vary considerably and lack correlations to the genotype. Using an affinity chromatography approach we report here for the first time on the identification of mitochondrial proteins interacting directly with GCDH. Among others, dihydrolipoamide S-succinyltransferase (DLST) involved in the formation of glutaryl-CoA, and the β-subunit of the electron transfer flavoprotein (ETFB) serving as electron acceptor, were identified as GCDH binding partners. We have adapted the yellow fluorescent protein-based fragment complementation assay and visualized the oligomerization of GCDH as well as its direct interaction with DLST and ETFB in mitochondria of living cells. These data suggest that GCDH is a constituent of multimeric mitochondrial dehydrogenase complexes, and the characterization of their interrelated functions may provide new insights into the regulation of lysine oxidation and the pathophysiology of GA1.
Every year in early August, a breeze borne by silent messengers from another time blows through Iowa. It carries a whiff of something wonderful, something far off and a bit unclear, yet oddly ...familiar. It's a reminder that an extraordinary annual event is about to take place, just as it has for more than 150 years: the Iowa State Fair.In 2013, Kurt Ullrich set out to chronicle the magic of the Iowa State Fair in words and photographs. Join him as August days and nights blow warm and easy over the fairgrounds, brushing lightly against fellow travelers on this earth, both human and not. He captures precious moments of extreme joy and unbridled delight in these beautiful black-and-white images, celebrating the brash rural energy of the fair, from Big Wheel races to people-watching goats, fair queen contestants to arm wrestlers, Percherons to ponies. Prize pigs, prize sheep, prize apples, and the famous butter cow all have their moment in the limelight. Iowa's very best ear of corn and old friends reminiscing outside their RVs draw the photographer's fond eye, as do brightly lit beer stands and the brilliant arc of the Ferris wheel against the night sky.If you always go to the Iowa State Fair, this book is for you. If you've never been, it will show you what you're missing-and you'll understand why it's well past time you dropped by.
Glycogen storage disease type I (GSD I) is a relatively rare metabolic disease and therefore, no metabolic centre has experience of large numbers of patients. To document outcome, to develop ...guidelines about (long-term) management and follow-up, and to develop therapeutic strategies, the collaborative European Study on GSD I (ESGSD I) was initiated. This paper is a descriptive analysis of data obtained from the retrospective part of the ESGSD I. Included were 231 GSD Ia and 57 GSD Ib patients. Median age of data collection was 10.4 years (range 0.4-45.4 years) for Ia and 7.1 years (0.4-30.6 years) for Ib patients. Data on dietary treatment, pharmacological treatment, and outcome including mental development, hyperlipidaemia and its complications, hyperuricaemia and its complications, bleeding tendency, anaemia, osteopenia, hepatomegaly, liver adenomas and carcinomas, progressive renal disease, height and adult height, pubertal development and bone maturation, school type, employment, and pregnancies are presented. Data on neutropenia, neutrophil dysfunction, infections, inflammatory bowel disease, and the use of granulocyte colony-stimulating factor are presented elsewhere (Visser et al. 2000, J Pediatr 137:187-191; Visser et al. 2002, Eur J Pediatr DOI 10.1007/s00431-002-1010-0).
there is still wide variation in methods of dietary and pharmacological treatment of glycogen storage disease type I. Intensive dietary treatment will improve, but not correct completely, clinical and biochemical status and fewer patients will die as a direct consequence of acute metabolic derangement. With ageing, more and more complications will develop of which progressive renal disease and the complications related to liver adenomas are likely to be two major causes of morbidity and mortality.
Deficiency of phenylalanine hydroxylase activity in phenylketonuria (PKU) causes an excess of phenylalanine (Phe) throughout the body, predicting impaired synthesis of catecholamines in the brain. To ...test this hypothesis, we used positron emission tomography (PET) to measure the utilization of 6-18Ffluoro-l-dopamine (FDOPA) in the brain of adult patients suffering from PKU and in healthy controls. Dynamic 2-h long FDOPA emission recordings were obtained in seven adult PKU patients (five females, two males; age: 21 to 27 years) with elevated serum Phe levels, but lacking neurologic deficits. Seven age-matched, healthy volunteers were imaged under identical conditions. The utilization of FDOPA in striatum was calculated by linear graphical analysis (k3S, min−1), with cerebellum serving as a nonbinding reference region. The time to peak activity in all brain time—radioactivity curves was substantially delayed in the PKU patients relative to the control group. The mean magnitude of k3S in the striatum of the PKU patients (0.0052±0.0004 min−1) was significantly lower than in the control group (0.0088±0.0009 min−1) (P<0.001). There was no significant correlation between individual serum Phe levels and k3S. The unidirectional clearance of FDOPA to brain was impaired in adult patients suffering from PKU, presumably reflecting the competitive inhibition of the large neutral amino acid carrier by Phe. Assuming this competition to be spatially uniform, the relationship between striatum and cerebellum time—activity curves additionally suggests inhibition of DOPA efflux, possibly also due to competition from Phe. The linear graphical analysis shows reduced k3S in striatum, indicating reduced DOPA decarboxylase activity.
Glycogen storage disease type I (GSD I) is a relatively rare metabolic disease and therefore, no metabolic centre has experience of large numbers of patients. To document outcome, to develop ...guidelines about (long-term) management and follow-up, and to develop therapeutic strategies, the collaborative European Study on GSD I (ESGSD I) was initiated. This paper is an descriptive analysis of data obtained from the retrospective part of the ESGSD I. Included were 231 GSD Ia and 57 GSD Ib patients. Median age of data collection was 10.4 years (range 0.4-45.4 years) for Ia and 7.1 years (0.4-30.6 years) for Ib patients. Data on dietary treatment, pharmacological treatment, and outcome including mental development, hyperlipidaemia and its complications, hyperuricaemia and its complications, bleeding tendency, anaemia, osteopenia, hepatomegaly, liver adenomas and carcinomas, progressive renal disease, height and adult height, pubertal development and bone maturation, school type, employment, and pregnancies are presented. Data on neutropenia, neutrophil dysfunction, infections, inflammatory bowel disease, and the use of granulocyte colony-stimulating factor are presented elsewhere (Visser et al. 2000, J Pediatr 137:187-191; Visser et al. 2002, Eur J Pediatr DOI 10.1007/s00431-002-1010-0). Conclusion: there is still wide variation in methods of dietary and pharmacological treatment of glycogen storage disease type I. Intensive dietary treatment will improve, but not correct completely, clinical and biochemical status and fewer patients will die as a direct consequence of acute metabolic derangement. With ageing, more and more complications will develop of which progressive renal disease and the complications related to liver adenomas are likely to be two major causes of morbidity and mortality. PUBLICATION ABSTRACT
Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. The disease occurs in early life with developmental delay or arrest and ...several neurological symptoms, e.g., seizures and dyskinesia. Both the deficiency of high-energy phosphates in neurons and the neurotoxic action of the accumulated metabolite guanidinoacetate (GAA) are candidate mechanisms for the pathophysiology of this disease. To examine a potential role of GAA accumulation, we analyzed the electrophysiological responses of neurons induced by GAA application in primary culture and acute murine brain slices. GAA evoked picrotoxin- and bicuculline-sensitive GABAA receptor-mediated chloride currents with an EC50 of 167 is a subset of M in cortical neurons. Pathophysiologically relevant GAA concentrations hyperpolarized globus pallidus neurons and reduced their spontaneous spike frequency with an EC50 of 15.1 is a subset of M. Furthermore, GAA acted as a partial agonist at heterologously expressed GABAA but not GABAB receptors. The interaction of GAA with neuronal GABAA receptors represents a candidate mechanism explaining neurological dysfunction in GAMT deficiency.
Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). Previous studies have suggested that the ...highly variable metabolic phenotypes of PAH deficiency correlate with
PAH genotypes. We identified both causative mutations in 686 patients from seven European centers. On the basis of the phenotypic characteristics of 297 functionally hemizygous patients, 105 of the mutations were assigned to one of four arbitrary phenotype categories. We proposed and tested a simple model for correlation between genotype and phenotypic outcome. The observed phenotype matched the predicted phenotype in 79% of the cases, and in only 5 of 184 patients was the observed phenotype more than one category away from that expected. Among the seven contributing centers, the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4%–23% (
P<.0001), suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype-phenotype inconsistencies. Our data indicate that the
PAH-mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency. In the present study, the classification of 105
PAH mutations may allow the prediction of the biochemical phenotype in >10,000 genotypes, which may be useful for the management of hyperphenylalaninemia in newborns.
Pregnancies in glycogen storage disease type Ia Martens, Daniëlle H.J., MD; Rake, Jan Peter, MD, PhD; Schwarz, Martin, MD ...
American journal of obstetrics and gynecology,
06/2008, Volume:
198, Issue:
6
Journal Article
Peer reviewed
Open access
Objective Reports on pregnancies in women with glycogen storage disease type Ia (GSD-Ia) are scarce. Because of improved life expectancy, pregnancy is becoming an important issue. We describe 15 ...pregnancies by focusing on dietary treatment, biochemical parameters, and GSD-Ia complications. Study Design Carbohydrate requirements (milligrams per kilogram per minute), triglyceride and uric acid levels, liver ultrasonography, and creatinine clearance were investigated before, during, and after pregnancy. Data from the newborn infants were obtained from the records. Results In the first trimester, a significant increase in carbohydrate requirements was observed ( P = .007). Most patients had acceptable triglyceride and uric acid levels during pregnancy. No increase in size or number of adenomas was seen. In 3 of 4 patients, a decrease in glomerular filtration rate was observed after pregnancy. In 3 pregnancies, lactic acidosis developed during delivery with severe multiorgan failure in 1. All but 1 of the children are healthy and show good psychomotor development. Conclusion Successful pregnancies are possible in patients with GSD-Ia, although specific GSD-Ia–related risks are present.
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