| 1. |
- Hansson, Emma, et al.
(författare)
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Review of Dercum's disease and proposal of diagnostic criteria, diagnostic methods, classification and management
- 2012
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 7
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Forskningsöversikt (refereegranskat)abstract
- Definition and clinical picture: We propose the minimal definition of Dercum's disease to be generalised overweight or obesity in combination with painful adipose tissue. The associated symptoms in Dercum's disease include fatty deposits, easy bruisability, sleep disturbances, impaired memory, depression, difficulty concentrating, anxiety, rapid heartbeat, shortness of breath, diabetes, bloating, constipation, fatigue, weakness and joint aches. Classification: We suggest that Dercum's disease is classified into: I. Generalised diffuse form A form with diffusely widespread painful adipose tissue without clear lipomas, II. Generalised nodular form - a form with general pain in adipose tissue and intense pain in and around multiple lipomas, and III. Localised nodular form - a form with pain in and around multiple lipomas IV. Juxtaarticular form - a form with solitary deposits of excess fat for example at the medial aspect of the knee. Epidemiology: Dercum's disease most commonly appears between the ages of 35 and 50 years and is five to thirty times more common in women than in men. The prevalence of Dercum's disease has not yet been exactly established. Aetiology: Proposed, but unconfirmed aetiologies include: nervous system dysfunction, mechanical pressure on nerves, adipose tissue dysfunction and trauma. Diagnosis and diagnostic methods: Diagnosis is based on clinical criteria and should be made by systematic physical examination and thorough exclusion of differential diagnoses. Advisably, the diagnosis should be made by a physician with a broad experience of patients with painful conditions and knowledge of family medicine, internal medicine or pain management. The diagnosis should only be made when the differential diagnoses have been excluded. Differential diagnosis: Differential diagnoses include: fibromyalgia, lipoedema, panniculitis, endocrine disorders, primary psychiatric disorders, multiple symmetric lipomatosis, familial multiple lipomatosis, and adipose tissue tumours. Genetic counselling: The majority of the cases of Dercum's disease occur sporadically. A to G mutation at position A8344 of mitochondrial DNA cannot be detected in patients with Dercum's disease. HLA (human leukocyte antigen) typing has not revealed any correlation between typical antigens and the presence of the condition.
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| 2. |
- Jester, S., et al.
(författare)
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Haploidentical stem cell transplantation in two children with mucopolysaccharidosis VI: clinical and biochemical outcome
- 2013
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 8:134
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mucopolysaccharidosis VI (MPS VI) is an autosomal recessive progressive multiorgan disorder due to mutation in the gene encoding the enzyme Arylsulfatase B (ARSB). Dysfunctional ARSB causes lysosomal accumulation of glycosaminoglycans (GAG). Currently, enzyme replacement therapy (ERT) is preferred to hematopoietic stem cell transplantation (SCT) due to the treatment-related risks of the latter. However, ERT constitutes an expensive life-long treatment. Increased experience and safety of SCT-procedures in recent years suggest that SCT should be further explored as a treatment option. This is the first report on haploidentical SCT in patients with MPS VI. The primary objective was to assess the treatment safety and clinical and biochemical outcome. Patients and methods: Two siblings diagnosed with MPS VI at 10 months of age and at birth with genotype p. C192R, reported as mild to intermediate phenotype, underwent unrelated umbilical cord blood transplantation pre-symptomatic. Due to graft failure, both patients were urgently re-transplantated with haploidentical SCT with the father as donor. Continuous clinical and biochemical status was monitored and concluded 3.8 and 4.6 years after the haploidentical SCT. Results: Haploidentical SCT resulted in prompt and sustained engraftment. Complete donor chimerism was achieved in both patients, apart from mixed B cells chimerism in patient 2. ARSB activity in leukocytes post transplant increased from 0.0 to 19.0 mu kat/kg protein (patient 1) and from 3.6 to 17.9 mu kat/kg protein (patient 2) (ref. 17-40). Total urinary GAG normalized in both patients, although patient 2's values slightly exceed normal range since 6 months. However, dermatan sulfaturia was substantially normalized since 16 months and 12 months post-SCT, respectively. Height was -1.85 SD and -1.27 SD at follow-up. Patient 1 had impaired visual acuity and discrete hepatomegaly. Patient 2 had elevated intraocular pressure and X-ray revealed steep acetabular angles and slightly flattened lumbar vertebrae. Conclusion: This study demonstrates that young children with MPS VI tolerate haploidentical SCT. Normalization of enzyme production and dermatan sulfaturia indicates correction of the inborn error of metabolism and coincide with no obvious symptoms of progressive MPS VI up to 4.6 years post-SCT.
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| 3. |
- Yildiz, Yildiz, et al.
(författare)
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Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease
- 2013
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gaucher disease (GD) is the most common inherited lysosomal storage disorder in humans, caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). GD is clinically heterogeneous and although the type of GBA1 mutation plays a role in determining the type of GD, it does not explain the clinical variability seen among patients. Cumulative evidence from recent studies suggests that GBA2 could play a role in the pathogenesis of GD and potentially interacts with GBA1. Methods: We used a framework of functional and genetic approaches in order to further characterize a potential role of GBA2 in GD. Glucosylceramide (GlcCer) levels in spleen, liver and brain of GBA2-deficient mice and mRNA and protein expression of GBA2 in GBA1-deficient murine fibroblasts were analyzed. Furthermore we crossed GBA2-deficient mice with conditional Gba1 knockout mice in order to quantify the interaction between GBA1 and GBA2. Finally, a genetic approach was used to test whether genetic variation in GBA2 is associated with GD and/or acts as a modifier in Gaucher patients. We tested 22 SNPs in the GBA2 and GBA1 genes in 98 type 1 and 60 type 2/3 Gaucher patients for single-and multi-marker association with GD. Results: We found a significant accumulation of GlcCer compared to wild-type controls in all three organs studied. In addition, a significant increase of Gba2-protein and Gba2-mRNA levels in GBA1-deficient murine fibroblasts was observed. GlcCer levels in the spleen from Gba1/Gba2 knockout mice were much higher than the sum of the single knockouts, indicating a cross-talk between the two glucosylceramidases and suggesting a partially compensation of the loss of one enzyme by the other. In the genetic approach, no significant association with severity of GD was found for SNPs at the GBA2 locus. However, in the multi-marker analyses a significant result was detected for p.L444P (GBA1) and rs4878628 (GBA2), using a model that does not take marginal effects into account. Conclusions: All together our observations make GBA2 a likely candidate to be involved in GD etiology. Furthermore, they point to GBA2 as a plausible modifier for GBA1 in patients with GD.
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| 4. |
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| 5. |
- Cassiman, David, et al.
(författare)
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A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report.
- 2009
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Ingår i: Orphanet journal of rare diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- A male patient, born to unrelated Belgian parents, presented at 4 months with epistaxis, haematemesis and haematochezia. On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. Serum transaminases were elevated to 5-10 times upper limit of normal, alkaline phosphatases were 1685 U/L (<720), total bilirubin was 2.53 mg/dl (<1.0), ammonaemia 69 microM (<32), prothrombin time less than 10%, thromboplastin time >180 s (<60) and alpha-fetoprotein 29723 microg/L (<186). Plasma tyrosine (651 microM) and methionine (1032 microM) were strongly increased. In urine, tyrosine metabolites and 4-oxo-6-hydroxyheptanoic acid were increased, but succinylacetone and succinylacetoacetate--pathognomonic for tyrosinemia type I--were repeatedly undetectable. Delta-aminolevulinic acid was normal, which is consistent with the absence of succinylacetone. Abdominal ultrasound and brain CT were normal.Fumarylacetoacetase (FAH) protein and activity in cultured fibroblasts and liver tissue were decreased but not absent. 4-hydroxyphenylpyruvate dioxygenase activity in liver was normal, which is atypical for tyrosinemia type I. A novel mutation was found in the FAH gene: c.103G>A (Ala35Thr). In vitro expression studies showed this mutation results in a strongly decreased FAH protein expression.Dietary treatment with phenylalanine and tyrosine restriction was initiated at 4 months, leading to complete clinical and biochemical normalisation. The patient, currently aged 12 years, shows a normal physical and psychomotor development.This is the first report of mild tyrosinemia type I disease caused by an Ala35Thr mutation in the FAH gene, presenting atypically without increase of the diagnostically important toxic metabolites succinylacetone and succinylacetoacetate.
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| 6. |
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| 7. |
- Eggens, Veerle Rc, et al.
(författare)
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EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations.
- 2014
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Ingår i: Orphanet journal of rare diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1.
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| 8. |
- Fujioka, Shinsuke, et al.
(författare)
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Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics.
- 2013
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Ingår i: Orphanet journal of rare diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 8
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Forskningsöversikt (refereegranskat)abstract
- Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments.
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| 9. |
- Ristoff, E, et al.
(författare)
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Inborn errors in the metabolism of glutathione
- 2007
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Ingår i: Orphanet journal of rare diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 2, s. 16-
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Tidskriftsartikel (refereegranskat)
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| 10. |
- Sofou, Kalliopi, et al.
(författare)
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A multicenter study on Leigh syndrome: disease course and predictors of survival.
- 2014
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Ingår i: Orphanet journal of rare diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Leigh syndrome is a progressive neurodegenerative disorder, associated with primary or secondary dysfunction of the mitochondrial oxidative phosphorylation. Despite the fact that Leigh syndrome is the most common phenotype of mitochondrial disorders in children, longitudinal natural history data is missing. This study was undertaken to assess the phenotypic and genotypic spectrum of patients with Leigh syndrome, characterise the clinical course and identify predictors of survival in a large cohort of patients.
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