Clinical and biochemical heterogeneity associated with fumarase deficiency

Abstract

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.

Myopathy in hereditary leiomyomatosis and renal cell cancer in an extended family

“…Therefore, dysfunctions in the mitochondrial TCA cycle may produce changes in oxidative energy production, contributing to skeletal muscle manifestations. Patients with FHD showing FH activity in skeletal muscle below 10% may develop muscular hypotonia . In this study, our patients showed low levels of FH activity in skeletal muscle that could explain the presence of myopathy.…”

“…D ear E ditor , Fumarate hydratase (FH) catalyses the conversion of fumarate to malate as part of the tricarboxylic acid (TCA) cycle . Germline mutations in the FH gene may lead to autosomal recessive mutations causing FH deficiency (FHD), associated with neurological impairment in childhood and muscular hypotonia . Patients with heterozygous mutations may develop multiple cutaneous leiomyomas (CLs) and uterine leiomyomas (ULs), and they more frequently have type II papillary renal cell cancer (RCC) [hereditary leiomyomatosis and RCC (HLRCC)] .…”

Revisiting the TCA cycle: signaling to tumor formation

“…While α-ketoglutarate is necessary for the reaction to occur, succinate, fumarate and oxaloacetate inhibit the prolyl hydroxylases, leading to pseudo-hypoxia in tumor and embryonic cells [31, 32, 34-37] but not in non-transformed cells [30, 36, 38]. Pyruvate, citrate, isocitrate, fumarate and succinate inhibit PHDs in tumor cells, with fumarate showing the strongest effect [36, 39-41].…”

“…Silencing of FH in cultured tumor cells also lead to increased glycolytic metabolism and accumulation of HIF α-subunits [35]. However, no accumulation of HIF-1α was detected in primary fibroblasts with recessive FH defects and fumarate accumulation [30, 38]. It seems thus that intracellular fumarate accumulation triggers the pseudo-hypoxia response in tumor or embryonic cells, but not in primary fibroblasts.…”

Hereditary Kidney Cancer Syndromes

“…59–62 These patients usually do not survive beyond the first few months of life, although some more mildly affected individuals have been described. 63,64 Relatives with only one mutation, can go on to develop papillary type 2 renal cancer. Mutations have not been observed in sporadic RCC, but in part the lack of observation may arise due to the limited number of papillary type 2 tumors included in the screening series.…”