Fumarase deficiency

Fumarase deficiency (or fumaric aciduria) is an exceedingly rare autosomal recessive metabolic disorder in Krebs cycle characterized by a deficiency of the enzyme fumarate hydratase, which causes a buildup of fumaric acid in the urine, and a deficiency of malate. Only 13 cases were known worldwide in 1990, after which a cluster of 20 cases was documented in an inbred community in Arizona.

Presentation

Fumarase deficiency causes encephalopathy, severe intellectual disabilities, unusual facial features, brain malformation, and epileptic seizures due to an abnormally low amount of fumarase in cells. It can initially present with polyhydramnios on prenatal ultrasound. Affected neonates may demonstrate nonspecific signs of poor feeding and hypotonia. Laboratory findings in neonates may indicate polycythemia, leukopenia, or neutropenia. As they age, neurological deficits begin to manifest with seizures, dystonias, and severe developmental delay.

Pathophysiology

Fumarase deficiency is caused by a mutation in the fumarate hydratase (FH) gene in humans, which encodes the enzyme that converts fumarate to malate in the mitochondria. Other mutant alleles of the FH gene, located on human Chromosome 1 at position 1q42.1, cause multiple cutaneous and uterine leiomyomata, hereditary leiomyomatosis and renal cell cancer. Fumarase deficiency is one of the few known deficiencies of the Krebs cycle or tricarboxylic acid cycle, the main enzymatic pathway of cellular aerobic respiration.

Fumarase deficiency has an autosomal recessive pattern of inheritance.

The condition is an autosomal recessive disorder, and it is therefore usually necessary for an affected individual to receive the mutant allele from both parents. A number of children diagnosed with the disorder have been born to parents who were first cousins. It can also be associated with uniparental isodisomy.

Diagnosis

Fumarate hydratase (FH) deficiency should be suspected in individuals with the following clinical, laboratory, and imaging findings.

Clinical findings

• 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

• 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).

Imaging findings. Abnormalities on brain MRI examination, including enlarged ventricles and polymicrogyria, may not be present in mildly affected individuals.

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.

Treatment

There is a deficiency of malate in patients because fumarase enzyme can't convert fumarate into it therefore treatment is with oral malic acid which will allow the Krebs cycle to continue, and eventually make ATP. The goal of management is to improve symptoms, prevent complications, and increase quality of life. Examples of management options include:

• Standard anticonvulsant medications for seizures.
• Placement of a feeding tube (if needed) for optimal nutrition and to prevent aspiration.
• Special needs services for support with motor, language, and social development.

Epidemiology

Fumarase deficiency is extremely rare - until around 1990 there had only been 13 diagnosed and identified cases worldwide.

A cluster of 20 cases has since been documented in the twin towns of Colorado City, Arizona and Hildale, Utah among an inbred community of 10,000 members of the Fundamentalist Church of Jesus Christ of Latter Day Saints. Nicknamed "Polygamist's Down's", the syndrome has been blamed on cousin marriage, but in a larger sense is related to the reproductive isolation of a community among whom 85% are blood relatives of John Y. Barlow or Joseph Smith Jessop.

See also

• Hereditary leiomyomatosis and renal cell cancer
• Founder effect

External links

Classification	ICD-10: E88.8 OMIM: 606812 DiseasesDB: 29835
External resources	Orphanet: 24