Molecular and biochemical investigations in fumarase deficiency

Deschauer, Marcus; Gizatullina, Zemfira; Schulze, A.; Pritsch, Michael; Knöppel, C.; Knape, M.; Zierz, Stephan; Gellerich, Frank N.

doi:10.1016/j.ymgme.2006.01.007

Cited by 33 publications

(24 citation statements)

References 28 publications

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“…FH deficiency (FHD) is a recessive, severe neurological condition caused by homozygous or compound heterozygous mutations in the FH gene [8]. Despite the partially overlapping mutation spectrum, the phenotype of the heterozygous FH mutation carriers in the FHD families is less prominent than in the HLRCC families.…”

Section: Renal Tumorsmentioning

confidence: 99%

“…However, since individuals at risk for leiomyomas and RCC or leiomyomas only cannot be a priori distinguished, name HLRCC should be preferred. Biallelic FH germline mutations cause a rare recessive syndrome called FH deficiency (FHD or fumaric aciduria, MIM 606812), characterized by severe neurological symptoms such as psychomotor retardation, muscular hypotonia and microcephaly [7,8]. Dramatic reduction of the FH enzyme activity in patients' tissues (from 0.5 to 23%) results in a metabolic crisis causing death usually as an infant [7][8][9].…”

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confidence: 99%

“…Biallelic FH germline mutations cause a rare recessive syndrome called FH deficiency (FHD or fumaric aciduria, MIM 606812), characterized by severe neurological symptoms such as psychomotor retardation, muscular hypotonia and microcephaly [7,8]. Dramatic reduction of the FH enzyme activity in patients' tissues (from 0.5 to 23%) results in a metabolic crisis causing death usually as an infant [7][8][9]. To date, approximately 180 families with an FH germline mutation have been reported, but many are still likely to remain undiagnosed or unpublished [10].…”

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confidence: 99%

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Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

2011

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Hereditary leiomyomatosis and renal cell cancer (HLRCC, also known as multiple cutaneous and uterine leiomyomatosis, MCUL) is a highly penetrant autosomal dominant tumor predisposition syndrome characterized by benign leiomyomas of the skin and the uterus. Renal cell carcinomas, occurring in a subset of the HLRCC families, are exceptionally aggressive. Therefore careful, frequent surveillance strategies are recommended. Association of malignant smooth-muscle tumors, leiomyosarcomas, with HLRCC has been observed but the risk appears to be smaller than initially estimated. To date inactivating heterozygous mutations in the fumarate hydratase (FH, fumarase) gene, predisposing to HLRCC, have been found in approximately 180 families worldwide. The most extensively studied hypothesis on molecular mechanisms of HLRCC tumorigenesis is activation of the hypoxia pathway due to aberrant stabilization of the HIF1 transcription factor. HIF1 regulates transcription of genes relevant for vascularization, glucose transport and glycolysis, processes that facilitate tumor growth. However, additional mechanisms underlying tumor formation are likely to exist.

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Section: Renal Tumorsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

2011

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“…Fumarase deficiency is a rare inborn error of the metabolism inherited in an autosomal recessive way, with less than 30 unrelated families described to date [Allegri et al, 2010;Bayley et al, 2008;Bonioli et al, 1998;Bourgeron et al, 1994;Coughlin et al, 1998;Deschauer et al, 2006;Gellera et al, 1990;Kerrigan et al, 2000;Loeffen et al, 2005;Manning et al, 2000;Maradin et al, 2006;Phillips et al, 2006;Remes et al, 2004;Whelan et al, 1983;Zeman et al, 2000;Zeng et al, 2006;Zinn et al, 1986], and references therein]. The metabolic disorder is severe, characterized by neurological impairment in early childhood with encephalopathy and seizures, often leading to death in the first years of life.…”

Section: Introductionmentioning

confidence: 99%

Clinical and biochemical heterogeneity associated with fumarase deficiency

et al. 2011

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Fumarase deficiency (FD), caused by biallelic alteration of the Fumarase Hydratase gene (FH), and a rare metabolic disorder that affects the Krebs cycle, causes severe neurological impairment and fumaric aciduria. Less than 30 unrelated cases are known to date. In addition, heterozygous mutations of the FH gene are responsible for hereditary leiomyomatosis and renal cell cancer (HLRCC). We report three additional patients with dramatically different clinical presentations of FD and novel missense mutations in the FH gene. One patient had severe neonatal encephalopathy, polymicrogyria, <1% enzyme activity, and mildly increased levels of urinary fumarate. The second patient had microcephaly, mental retardation, 20% of fumarase activity, and intermediate levels of urinary fumarate. The third patient had mild mental retardation, polymicrogyria, 42-61% enzyme activity in different cell types and massive amounts of urinary fumarate. In silico analysis predicted minor yet significant structural changes in the encoded proteins. The nuclear translocation of hypoxia-inducible factor (HIF)-1alpha (HIF1A) in cultured fibroblasts was similar to controls. These results extend the range of clinical and biochemical variation associated with FD, supporting the notion that patients with moderate increases in fumarate excretion should be investigated for this disease. The tumoral risk in the patients and their relatives requires adequate screening protocols.

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“…Bei einer homozygoten Mutation des FH-Gens kommt es zur Ausbildung eines seltenen Syndroms namens FH-Defizienz (FHD). Klinisch imponieren schwere neurologische Symptome wie geistige Retardierung und eine muskuläre Hypotonie [7,8].…”

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Disseminated cutaneous leiomyomas

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Megahed

2012

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Cutaneous leiomyomas are benign smooth muscle tumors. Depending on the site of origin, one distinguishes three different types--piloleiomyoma, angioleiomyoma and genital leiomyoma. They appear between the first and third decades of life. A 56-year-old woman presented with painful red - brown papules and nodules on her trunk. Based on clinical and histological criteria the diagnosis of disseminated cutaneous leiomyomas was made. Because of the widespread cutaneous involvement, surgical treatment was not possible. Therefore we decided to employ a pharmacologic anti-depressive treatment. With this approach, the patient experienced considerable pain reduction.

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Molecular and biochemical investigations in fumarase deficiency

Cited by 33 publications

References 28 publications

Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

Clinical and biochemical heterogeneity associated with fumarase deficiency

Disseminated cutaneous leiomyomas

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