Fumarate hydratase deficiency is a rare, inherited metabolic disorder that significantly impacts the body’s ability to produce energy. This condition primarily affects the brain and nervous system, leading to severe neurological complications. It is considered a very rare disorder, with approximately 100 cases reported worldwide. Its severity varies, but it often leads to profound health challenges.
Genetic and Metabolic Basis
Fumarate hydratase deficiency is caused by alterations in the FH gene. This gene provides the instructions for creating an enzyme also known as fumarate hydratase or fumarase. The fumarate hydratase enzyme plays a role in the Krebs cycle, also known as the citric acid cycle, which is a series of chemical reactions within cells that generate energy.
The enzyme’s function involves converting fumarate into malate. When mutations occur in the FH gene, the body cannot produce enough functional fumarate hydratase. This disrupts the Krebs cycle, causing fumarate to build up within cells.
The accumulation of fumarate is harmful, especially to developing brain cells, as it interferes with energy production. This disorder is inherited in an autosomal recessive pattern. An individual must inherit two altered copies of the FH gene, one from each parent, to develop the condition. If a child inherits one working copy and one faulty copy of the gene, they will be a carrier but will not show symptoms of the deficiency.
Clinical Presentation
Symptoms of fumarate hydratase deficiency manifest in infancy or early childhood, primarily affecting the nervous system. Affected infants display severe developmental delays, impacting their motor skills, speech, and cognitive abilities. This can result in significant challenges with learning and physical development.
Individuals with the condition exhibit abnormal brain structures, which can be observed through imaging studies. These abnormalities may include microcephaly (abnormally small head size) and polymicrogyria (where the brain’s surface has too many small folds). Other findings may include white matter abnormalities, hydrocephalus (fluid buildup in the brain), and a thinning or absence of the corpus callosum, which connects the two brain hemispheres.
Affected individuals experience weak muscle tone (hypotonia), making movement control difficult. Severe and difficult-to-treat seizures are also a common symptom. Other signs include poor feeding, failure to gain weight and grow at the expected rate, and distinctive facial features such as a prominent forehead, low-set ears, or widely spaced eyes.
Detection and Carrier Implications
Diagnosis of fumarate hydratase deficiency begins with metabolic screening tests. These tests look for elevated levels of substances, such as fumaric acid and alpha-ketoglutarate, in the urine. While these findings can suggest the disorder, a definitive diagnosis is confirmed through genetic testing.
Genetic testing involves analyzing the DNA, specifically sequencing the FH gene, to identify mutations. This testing identifies the genetic changes responsible for the condition. Once diagnosed, genetic counseling becomes important for affected families.
Genetic counseling helps families understand the inheritance pattern and the implications for future pregnancies. Carriers, individuals with one mutated FH gene, do not develop fumarate hydratase deficiency. However, they have an increased susceptibility to certain types of tumors. These include kidney cancer (specifically papillary renal cell carcinoma type 2), benign uterine fibroids (non-cancerous uterine growths), and benign tumors of the skin (cutaneous leiomyomas).
Current Management and Prognosis
There is no specific cure for fumarate hydratase deficiency. Management focuses on providing symptomatic and supportive care to address the severe neurological symptoms from the condition. This involves a comprehensive approach aimed at improving the quality of life for affected individuals.
Treatment strategies include anti-seizure medications to control frequent and challenging seizures. Physical therapy helps manage weak muscle tone and improve motor skills. Occupational therapy assists individuals in developing daily living skills, while speech therapy addresses communication difficulties and feeding challenges.
Nutritional support is also a component of care, especially when feeding difficulties are present. A multidisciplinary team of healthcare professionals, including neurologists, geneticists, therapists, and nutritionists, works together to provide comprehensive care. The prognosis for individuals with fumarate hydratase deficiency is severe. Due to the profound neurological involvement, the condition often leads to significant morbidity and a reduced life expectancy, with many children not surviving beyond early childhood. Some rare instances of milder forms have been reported, allowing individuals to live into adulthood.