Fumarase deficiency (or fumaric aciduria) is an exceedingly rare autosomal recessive metabolic disorder in the 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 a community in Arizona that has practiced successive endogamy. 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. 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.
Trichotillomania has a high overlap with post traumatic stress disorder, and some cases of trichotillomania may be triggered by stress. Another school of thought emphasizes hair pulling as addictive or negatively reinforcing, as it is associated with rising tension beforehand and relief afterward. A neurocognitive model — the notion that the basal ganglia play a role in habit formation and that the frontal lobes are critical for normally suppressing or inhibiting such habits — sees trichotillomania as a habit disorder.Abnormalities in the caudate nucleus are noted in OCD, but there is no evidence to support that these abnormalities can also be linked to trichotillomania. One study has shown that individuals with trichotillomania have decreased cerebellar volume. These findings suggest some differences between OCD and trichotillomania. There is a lack of structural MRI studies on trichotillomania. In several MRI studies that have been conducted, it has been found that people with trichotillomania have more gray matter in their brains than those who do not have the disorder.It is likely that multiple genes confer vulnerability to trichotillomania. One study identified mutations in the SLITRK1 gene. Diagnosis
Patients may be ashamed or actively attempt to disguise their symptoms. This can make diagnosis difficult as symptoms are not always immediately obvious, or have been deliberately hidden to avoid disclosure. If the patient admits to hair pulling, diagnosis is not difficult; if patients deny hair pulling, a differential diagnosis must be pursued.