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FH Genetic Mutations - Fumarate Hydratase Deficiency

This article is not intended to be medical or healthcare advice. Before starting on any health related regimen, speak your Primary Care Physician or an M.D. first.

Mutations on the FH (Fumarate Hydratase), are pretty uncommon, but they tend to be very significant.

Clinical characteristics

Fumarate hydratase (FH) deficiency results in severe neonatal and early infantile encephalopathy that is characterized by poor feeding, failure to thrive, hypotonia, lethargy, and seizures. Dysmorphic facial features include frontal bossing, depressed nasal bridge, and widely spaced eyes. Many affected individuals are microcephalic. A spectrum of brain abnormalities are seen on magnetic resonance imaging, including cerebral atrophy, enlarged ventricles and generous extra-axial cerebral spinal fluid (CSF) spaces, delayed myelination for age, thinning of the corpus callosum, and an abnormally small brain stem. Brain malformations including bilateral polymicrogyria and absence of the corpus callosum can also be observed. Development is severely affected: most affected individuals are nonverbal and nonambulatory, and many die during early childhood. Less severely affected individuals with moderate cognitive impairment and long-term survival have been reported."[1]


Isolated increased fumaric acid and alpha-ketoglutarate on urine organic acid analysis, combined with increased succinyladenosine on urine purines and pyrimidines is highly suggestive of FH deficiency. The diagnosis of FH deficiency is established in a proband with reduced fumarate hydratase enzyme activity in fibroblasts or leukocytes and/or biallelic pathogenic variants in FH identified by molecular genetic testing. [1]


Treatment of manifestations: Evaluation and management by a pediatric neurologist to treat seizures; gastrostomy tube to optimize nutrition and prevent aspiration in hypotonic or lethargic children; feeding therapy as needed; special needs services to address developmental deficits; physical therapy to minimize contractures; wheelchair and/or other mobility devices; management of scoliosis by orthopedist.[1]

Clinical findings[1]

  • Neonatal and early-infantile severe encephalopathy, which may include poor feeding, hypotonia, and decreased levels of consciousness (lethargy, stupor, and coma)

  • Seizures, present in many but not all affected individuals

  • Intellectual disability / developmental delay

  • Dysmorphic facial features including frontal bossing, depressed nasal bridge, and widely spaced eyes

Laboratory findings[1]

  • Finding of isolated increased fumaric acid and alpha-ketoglutarate on urine organic acid analysis combined with increased succinyladenosine on urine purines and pyrimidines is highly suggestive of FH deficiency.

  • Reduced fumarate hydratase enzyme activity. Fumarate hydratase enzyme activity can be measured in fibroblasts or leukocytes. Fumarate hydratase enzyme activity in severely affected individuals is often less than 10% of the control mean; however, residual fumarate hydratase enzyme activity in some affected individuals can be 11%-35% of the control mean. FH deficiency is evident in both isozymes – the mitochondrial form and the cytosolic form (see Molecular Genetics).

Definition and History[2]

Fumarase hydratase (FH) deficiency belongs to the group of inborn errors of metabolism of the tricarboxylic acid cycle. FH deficiency is also named fumaric aciduria, since it results in excessive urinary excretion of fumarate.

Fumarase deficiency was first described in 1983 by Whelan who reported fumaric aciduria in two adult sibs with mental retardation and speech impairment. The enzyme defect was discovered three years later by Zinn in 1986 in a patient with the clinical picture of an early-onset severe encephalopathy. The first molecular diagnosis was published in 1994 by Bourgeron. Generally, the disease is characterized by early-onset encephalopathy with seizures and hypotonia, associated with excessive fumaric acid excretion. Milder cases are also described. In 2002, heterozygous germline mutations of FH were described in patients with multiple cutaneous and uterine leiomyomas.

  • Loss of FH function results in increased levels of fumarate in cells [2]

  • Increased fumarate acts as competitive inhibitor of prolyl hydroxylase domain-containing proteins or PHDs (EGLN, HPH)[2]

  • Inhibition of these proteins prevents hydroxylation, and therefore pVHL-mediated proteosomic degradation, of HIF-1[2]

  • This results in HIF-1 overexpression and consequent transcription of multiple downstream products and carcinogenesis [2]

High Fat / Low Carb Diet

"Fumarate hydratase deficiency (FHD) caused by biallelic alterations of the FH (fumarate hydratase) gene is a rare disorder of the tricarboxylic acid cycle, classically characterized by encephalopathy, profound psychomotor retardation, seizures, a spectrum of brain abnormalities and early death in childhood. Less common milder phenotypes with moderate cognitive impairment and long-term survival have been reported. In addition, heterozygous mutations of the FH gene are responsible for hereditary leiomyomatosis and renal cell cancer (HLRCC). There is currently no recommended disease modifying treatment for FHD and only isolated reports of unsuccessful dietary modifications. Herein, we describe the safe and possibly disease modifying effect of a high fat, low carbohydrate diet in a 14-year-old female with severe FHD."[4]


1. Fumarate Hydratase Deficiency. Synonyms: Fumarase Deficiency, Fumaric Aciduria. David Coman, MBBS, MPhil, FRAC, Kamil R Kranc, MD, DPhil, and John Christodoulou, MBBS PhD. Gene Reviews. Initial Posting: July 5, 2006; Last Update: April 23, 2020.

2. Fumarate Hydratase; Inherited fumarate hydratase (FH) mutations cause a susceptibility to renal cancers and lipomatous skin lesions by a similar mechanism. From: Clinical Molecular Medicine, 2020

3. Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma

Andrea Katharina Lindner1 Gennadi Tulchiner. MINI REVIEW article. Front. Oncol., 15 July 2022

Sec. Genitourinary Oncology. Volume 12 - 2022 |

Women in Genitourinary Oncology Vol II: 2022. View all 7 Articles

4. Fumarase Deficiency: A Safe and Potentially Disease Modifying Effect of High Fat/Low Carbohydrate Diet. B. Ryder,13 F. Moore,et. al. S. Balasubramaniam, Email: moc.liamtoh@923saras.

JIMD Rep. 2018; 40: 77–83. Published online 2017 Oct 21. doi: 10.1007/8904_2017_65

PMCID: PMC6122040. PMID: 29052812

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