Mitochondrial dysfunction multiple syndrome ..., (Multiple mitochondrial dysfunctions syndrome) - Genes NFU1 or BALL 3.

The syndrome of multiple mitochondrial dysfunction is a disorder characterized by impaired mitochondria. While certain mitochondrial changes are due to deterioration of a single stage energy production, individuals with multiple mitochondrial dysfunction syndrome have an impaired function of more than one stage. Signs and symptoms of the disease may include encephalopathy, which may cause hypotonia, seizures and psychomotor retardation, growth retardation, lactic acidosis, hyperglycinemia or hyperglycemia, pulmonary hypertension or cardiomyopathy. These signs and symptoms appear early in life and usually, those affected do not live beyond infancy.

The syndrome of multiple mitochondrial dysfunction may be due to mutations in the gene NFU1, located on the short arm of chromosome 2 (2p15-p13) or BOLA3 gene, located on the short arm of chromosome 2 (2p13.1). The proteins encoded from each of these genes appear to be involved in the formation of molecules called iron sulfide groups (Fe-S) or at the junction of these groups to other proteins. Certain proteins require binding of Fe-S groups to function properly. The NFU-1 and BOLA3 proteins play an important role in mitochondria. In these structures, several proteins carry out a series of chemical processes to convert the energy of food in a way that the cells can use. Many of the proteins involved in these steps require the function of Fe-S groups, including protein complexes called complex I, II, III complex and complex.

The Fe-S clusters are also required for the operation of other mitochondrial protein that is involved in modifying additional proteins that help in energy production in mitochondria, including dehydrogenase complex oxoglutarate dehydrogenase complex complex pyruvate and, also known oxoglutarate dehydrogenase complex like. This modification is also critical for the system function glycine cleavage, a set of proteins that decomposes the amino acid glycine when the concentrations are too high.

They have identified several mutations in the gene NFU1 and at least three mutations in the gene BOLA3 in people with multiple mitochondrial dysfunction syndrome. These genetic changes reduce or eliminate production of the respective protein, which impairs the formation of Fe-S clusters. Accordingly, the proteins affected by the presence of Fe-S groups, including those involved in energy production and decomposition of glycine, can not function normally. The reduced activity of complex I, II, or III, pyruvate dehydrogenase, or ketoglutarate dehydrogenase alpha causes potentially fatal lactic acidosis, encephalopathy, and other signs and symptoms of multiple mitochondrial dysfunction syndrome. In some affected individuals, system damage glycine cleavage leads to hyperglycinemia.

This disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.  

Tests in IVAMI: in IVAMI perform detection of mutations associated with multiple mitochondrial dysfunction syndrome by complete PCR amplification of the exons of BALL NFU1 and 3, respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).