RESUMEN
Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.
Asunto(s)
Dolor Crónico/genética , Enfermedades del Tejido Conjuntivo/genética , Variaciones en el Número de Copia de ADN/genética , Disautonomía Familiar/genética , Enfermedades Gastrointestinales/genética , Prurito/genética , Enfermedades de la Piel/genética , Triptasas/sangre , Triptasas/genética , Adolescente , Adulto , Anciano , Niño , Dolor Crónico/sangre , Dolor Crónico/enzimología , Enfermedades del Tejido Conjuntivo/sangre , Enfermedades del Tejido Conjuntivo/enzimología , Disautonomía Familiar/sangre , Disautonomía Familiar/enzimología , Femenino , Enfermedades Gastrointestinales/sangre , Enfermedades Gastrointestinales/enzimología , Humanos , Masculino , Persona de Mediana Edad , Prurito/sangre , Prurito/enzimología , Enfermedades de la Piel/sangre , Enfermedades de la Piel/enzimología , Adulto JovenRESUMEN
Familial dysautonomia (FD), a recessive neurodegenerative disease, is caused by mutations in the IKBKAP gene that result in the production of nonfunctional IKAP protein. Manifestations of FD include autonomic crises characterized by hypertension, tachycardia, diaphoresis, and vomiting. Elevated plasma levels of norepinephrine (NE) and dopamine observed during autonomic crises and an exaggerated hypertensive response to low doses of NE prompted an examination of monoamine oxidase (MAO) levels, key isoenzymes responsible for degrading biogenic and dietary monoamines, in individuals with FD. Fetal tissue homozygous for the common FD-causing mutation and peripheral blood cells of individuals with FD have reduced MAO A mRNA levels. FD-derived cells, stimulated with tocotrienols or EGCG to produce increased levels of functional IKAP, express increased amounts of MAO A mRNA transcript and protein. Administration of tocotrienol to individuals with FD results in increased expression of both functional IKAP and MAO A transcripts in their peripheral blood cells. These findings provide new insight into the pathophysiology of FD and demonstrate the value of therapeutic approaches designed to elevate cellular levels of functional IKAP and MAO A.
Asunto(s)
Proteínas Portadoras/metabolismo , Disautonomía Familiar/enzimología , Monoaminooxidasa/metabolismo , Tocotrienoles/farmacología , Secuencia de Bases , Proteínas Portadoras/genética , Cartilla de ADN , Disautonomía Familiar/tratamiento farmacológico , Humanos , Monoaminooxidasa/genética , ARN Mensajero/genética , Tocotrienoles/uso terapéutico , Factores de Elongación TranscripcionalRESUMEN
Tyrosine hydroxylase antigen was localized immunohistochemically in sympathetic neurons from human autopsy tissue. The reaction persists in paraffin-embedded tissue, and the method is applicable to archival specimens. Increased amounts in this antigen per cell may partially compensate for decreased numbers of sympathetic neurons in familial dysautonomia.
Asunto(s)
Disautonomía Familiar/enzimología , Adolescente , Adulto , Niño , Preescolar , Disautonomía Familiar/patología , Ganglios Autónomos/enzimología , Ganglios Autónomos/patología , Humanos , Lactante , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The mean value of serum dopamine-beta-hydroxylase (D beta H) in patients with familial dysautonomia, 1 to 5 years of age, does not differ significantly from control children of the same age (24.0 plus or minus 21.06 S.D. as compared to 34.0 plus or minus 33.12). Among patients 6 years of age and over, the mean value was slightly but significantly lower than in control subjects (62.7 plus or minus 49.61, as compared to control values of 86.1 plus or minus 54.31 p less than 0.025). However, the determination of serum D beta H does not contribute to the diagnosis of familial dysautonomia because well over half the children have levels within 1 S.D. of the mean levels of the control subjects. There is no correlation with clinical symptomatology. The disease process may tend to depress the level of serum D beta H but the effect is neither consistent nor decisive.