Leigh syndrome in individuals bearing m.9185T>C MTATP6 variant. Is hyperventilation a factor which starts its development?

Leigh syndrome (LS), subacute necrotizing encephalomyelopathy is caused by various genetic defects, including m.9185T>C MTATP6 variant. Mechanism of LS development remains unknown. We report on the acid-base status of three patients with m.9185T>C related LS. At the onset, it showed respiratory alkalosis, reflecting excessive respiration effort (hyperventilation with low pCO2). In patient 1, the deterioration occurred in temporal relation to passive oxygen therapy. To the contrary, on the recovery, she demonstrated a relatively low respiratory drive, suggesting that a "hypoventilation" might be beneficial for m.9185T>C carriers. As long as circumstances of the development of LS have not been fully explained, we recommend to counteract hyperventilation and carefully dose oxygen in patients with m.9185T>C related LS.

Ocorrência do SNP c.767G>T no gene DNM1responsável pelo colapso induzido pelo exercício em cães da raça Labrador Retriever no estado de São Paulo / Occurrence of DNM1 SNP c.767G>T responsible for exercise-induced collapse in Labrador Retriever in the Sao Paulo state

O colapso induzido pelo exercício (EIC) é considerado uma síndrome autossômica recessiva que afeta principalmente cães da raça Labrador Retriever. A doença é caracterizada por fraqueza muscular e colapso após exercício intenso. Usualmente, ocorre recuperação clínica após o episódio, mas alguns animais podem vir a óbito. Os sinais clínicos são decorrentes do polimorfismo de base única (SNP) c.767G>T no gene Dynamin 1 (DNM1). O objetivo deste trabalho foi determinar a ocorrência deste SNP em 321 cães da raça Labrador Retriever do Estado de São Paulo. Primers específicos para a amplificação de todo o exon 6 do gene DNM1 foram usados nas PCRs utilizando DNA a partir de amostras de sangue ou swab bucal, a avaliação final foi realizada com sequenciamento direto dos produtos da PCR. Dentre os 321 animais estudados, 3,4 % (11/321) eram homozigotos para o SNP c.767G>T no gene DNM1 e 24,6% (79/321) eram heterozigotos. Somente um dos 11 animais homozigotos apresentavam sinais clínicos compatíveis com a EIC. Este é o primeiro estudo sobre a ocorrência deste SNP no Brasil e considerando que quase 25% dos animais estudados eram heterozigotos, a genotipagem dos animais para este SNP pode ser importante antes dos acasalamentos para cães desta raça. A EIC deve ser considerada nos diagnósticos diferenciais de enfermidades neuromusculares em cães da raça Labrador Retriever.

The exercise-induced collapse (EIC) is considered an autosomal recessive syndrome that mainly affects Labrador Retriever dogs. The disease is characterized by muscle weakness and collapse after intense exercise. Recovery usually occurs after exercise but some animals may die. The clinical signs occurs due to the single-nucleotide polymorphism (SNP) c.767G>T in Dynamin 1 (DNM1) gene. The aim of this study was to evaluate the occurrence of this SNP in 321 Labrador Retriever dogs from São Paulo state. Specific primers for amplification of the entire exon 6 of the DNM1 gene were used in a PCR performed with DNA from blood or buccal swab samples, direct sequencing was performed for the final evaluation. Among 321 animals studied, 3.4% (11/321) of animals were homozygous for the DNM1 SNP (c.767G>T) and 24.6% (79/321) were heterozygous. Only one of the 11 homozygous animals in this study had previous clinical signs compatible with this disease. This is the first study that evaluated the occurrence of DNM1 SNP (c.767G>T) gene in Brazil and considering that almost 25% of the studied animals were heterozygous, the routinely evaluation of this SNP may be important before this breed mating The EIC should be include in the differential diagnosis of neuromuscular diseases in Labrador Retriever dogs.

A new mutation in the gene encoding mitochondrial seryl-tRNA synthetase as a cause of HUPRA syndrome.

BACKGROUND: HUPRA syndrome is a rare mitochondrial disease characterized by hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis. This syndrome was previously described in three patients with a homozygous mutation c.1169A > G (p.D390G) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. CASE PRESENTATION: Here we report the clinical and genetic findings in a girl and her brother. Both patients were clinically diagnosed with the HUPRA syndrome. Analysis of the pedigree identified a new homozygous mutation c.1205G > A (p.R402H) in SARS2 gene. This mutation is very rare in the population and it is located at the C-terminal globular domain of the homodimeric enzyme very close to p.D390G. CONCLUSION: Several data support that p.R402H mutation in SARS2 is a new cause of HUPRA syndrome.

Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome.

An uncharacterized multisystemic mitochondrial cytopathy was diagnosed in two infants from consanguineous Palestinian kindred living in a single village. The most significant clinical findings were tubulopathy (hyperuricemia, metabolic alkalosis), pulmonary hypertension, and progressive renal failure in infancy (HUPRA syndrome). Analysis of the consanguineous pedigree suggested that the causative mutation is in the nuclear DNA. By using genome-wide SNP homozygosity analysis, we identified a homozygous identity-by-descent region on chromosome 19 and detected the pathogenic mutation c.1169A>G (p.Asp390Gly) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. The same homozygous mutation was later identified in a third infant with HUPRA syndrome. The carrier rate of this mutation among inhabitants of this Palestinian isolate was found to be 1:15. The mature enzyme catalyzes the ligation of serine to two mitochondrial tRNA isoacceptors: tRNA(Ser)(AGY) and tRNA(Ser)(UCN). Analysis of amino acylation of the two target tRNAs, extracted from immortalized peripheral lymphocytes derived from two patients, revealed that the p.Asp390Gly mutation significantly impacts on the acylation of tRNA(Ser)(AGY) but probably not that of tRNA(Ser)(UCN). Marked decrease in the expression of the nonacylated transcript and the complete absence of the acylated tRNA(Ser)(AGY) suggest that this mutation leads to significant loss of function and that the uncharged transcripts undergo degradation.

[A newborn infant with hyperventilation]. / Et nyfødt barn med hyperventilasjon.

Respiratory alkalosis is an early sign of urea cycle disorder. A high level of plasma ammonia will strengthen this suspicion. It is of great importance to transfer the infant as soon as possible to a unit capable of giving specific treatment with Na-benzoate, Na-phenylbutyrate, argininchloride and carglumic acid. The early treatment may also include haemodialysis, which is preferred over peritoneal dialysis or exchange transfusion. We here describe an infant with respiratory alkalosis within the first two days of life and a high plasma level of ammonia (> 700 micromol/L). He did not respond to conventional therapy and died 48 hours after birth in spite of specific treatment. DNA-analysis showed a gene defect in the OTC gene, c.67C >T (p.R23X), a known mutation leading to urea cycle disorder (OTC). It is important to detect carriers among older siblings and to inform the parents of the possibility of prenatal diagnostics.

Compulsory hyperventilation and hypocapnia of patients with Leigh syndrome associated with SURF1 gene mutations as a cause of low serum bicarbonates.

Experimental data show that elevation of intracellular pH leads to severe lesions of brain cells. Acidification of intracellular fluid by accumulation of lactate may compensate the effect of respiratory alkalosis. Increased serum pH, and low PCO2, associated with hyperlactataemia (sometimes incorrectly called 'acidosis') have been reported in children with Leigh syndrome (LS). The aim of the study was to determine whether respiratory alkalosis is characteristic of patients with LS due to SURF1 mutations. All venous blood gas data (88 samples) of 18 spontaneously breathing LS patients with recently established SURF1 mutations, hospitalized during 1986-2000, were retrospectively reviewed. The data of an affected boy who survived on a respirator for more than 3 months (79 daily samples) were analysed separately. In spontaneously breathing patients, the data indicated that the patients had compensated or partially compensated respiratory alkalosis (pH 7.388+/-0.060, Pco2 29.2+/-5.7 mmHg, HCO3- 17.4+/-3.0 mmol/L, BE -6.7+/-3.2 mmol/L). Bicarbonate excretion was detected in urine of two examined LS cases in spite of decreased serum HCO3-. In the affected child maintained on a respirator, simple manipulation of the inspired CO2 tension to establish a normal pressure of 35-45 mmHg automatically caused an increase of serum HCO3- concentration to a normal value of 26.3+/-2.9 mmol/L (and BE to +2.2+/-3.1 mmol/L), in spite of cytochrome oxidase (COX) deficiency due to a confirmed SURF1 mutation. We suggest that respiratory alkalosis (hypocapnia) of Leigh syndrome patients with SURF1 mutations results from compulsory hyperventilation and speculate that hypocapnia may contribute to Leigh-like brain damage in the SURF1-deficient patients as well as in other patients presenting with Leigh-like syndrome. The supposition that accumulation of lactate may protect the brain of LS patients from alkalosis-related damage requires further study. Avoidance of any factors stimulating hyperventilation of LS patients and caution when attempting to correct low plasma bicarbonate are suggested.