[Congenital Central Hypoventilation Syndrome: neonatal diagnosis and management]. / Síndrome de Hipoventilación Central Congénito: diagnóstico y manejo neonatal.

Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic condition affecting the autonomic nervous system and respiratory center due to mutations in the PHOX2B gene, and it is associated with alveolar hypoventilation during sleep and sudden death. It requires early invasive mechanical ventilation (IMV). OBJECTIVE: To report a neonatal case successfully treated with non-invasive ventilatory support (NVS), avoiding tracheostomy. CLINICAL CASE: Full-term newborn, whose mother uses nocturnal NVS due to CCHS. During the transition period, she presented desaturations associated with hypercapnia and respiratory acidosis, without pulmonary involvement. She developed severe hypoventilation during sleep, with no respiratory effort, peripheral oxygen saturation (SpO2) < 80%, plus respiratory acidosis. While awake, she had good respiratory effort and normal SpO2 without assistance. Noninvasive continuous positive airway pressure and oxygen therapy worsened her condition while sleeping. Complete NVS with nasal interface and bi-level airway positive pressure, inspiratory/expiratory pressure 14-16/4 cm H2O, normalized SpO2 during sleep, and arterial blood gases while awake. Sequencing of the PHOX2B gene confirmed the presence of a heterozygous pathogenic variant with the 20/26 genotype. At 2 months of age, she was discharged maintaining NVS with nasal interface and 0 PEEP, achieving adequate neurodevelopment. CONCLUSION: We highlight the importance of genetic diagnosis of CCHS in neonates with clinical presentation of early alveolar hypoventilation, especially if there is a family history. We are not aware of other reports of neonatal onset in which NVS prevents IMV, in this potentially lethal pathology.

DCTN1-related neurodegeneration: Perry syndrome and beyond.

Perry syndrome (PS) is a rare hereditary neurodegenerative disease characterized by autosomal dominant parkinsonism, psychiatric symptoms, weight loss, central hypoventilation, and distinct TDP-43 pathology. The mutated causative gene for PS is DCTN1, which encodes the dynactin subunit p150Glued. Dynactin is a motor protein involved in axonal transport; the p150Glued subunit has a critical role in the overall function. Since the discovery of DCTN1 in PS, it has been increasingly recognized that DCTN1 mutations can exhibit more diverse phenotypes than previously thought. Progressive supranuclear palsy- and/or frontotemporal dementia-like phenotypes have been associated with the PS phenotypes. In addition, DCTN1 mutations were identified in a family with motor-neuron disease before the discovery in PS. In this review, we analyze the clinical and genetic aspects of DCTN1-related neurodegeneration and discuss its pathogenesis. We also describe three families with PS, Canadian, Polish, and Brazilian. DCTN1 mutation was newly identified in two of them, the Canadian and Polish families. The Canadian family was first described in late 1970's but was never genetically tested. We recently had the opportunity to evaluate this family and to test the gene status of an affected family member. The Polish family is newly identified and is the first PS family in Poland. Although still rare, DCTN1-related neurodegeneration needs to be considered in a differential diagnosis of parkinsonian disorders, frontotemporal dementia, and motor-neuron diseases, especially if there is family history.

Three families with Perry syndrome from distinct parts of the world.

OBJECTIVES: Perry syndrome consists of autosomal dominant Parkinsonism, depression, weight loss, and central hypoventilation. Eight mutations in 16 families have been reported: p.F52L, p.G67D, p.G71R, p.G71E, p.G71A, p.T72P, p.Q74P, and p.Y78C located in exon 2 of the dynactin 1 (DCTN1) gene on chromosome 2p13.1. METHODS: Genealogical, clinical, genetic, and functional studies were performed in three kindreds from New Zealand, the United States, and Colombia. A diaphragmatic pacemaker was implanted in the proband from the Colombian family to treat her respiratory insufficiency. Dopaminergic therapy was initiated in probands from two families. RESULTS: Besides the probands, 17 symptomatic relatives from all families were identified. The cardinal signs of Perry syndrome were present in all three probands with symptomatic disease onset in their fifth or sixth decade of life. Parkinsonism was moderate with a partial response to dopaminergic treatment. All affected persons but two died of respiratory insufficiency. The proband from the Colombian family is alive most likely due to early diagnosis and implantation of a diaphragmatic pacemaker. Two-and-a-half-year follow-up examination has revealed that the diaphragmatic pacemaker is optimally functioning without any major complications. In the Colombian and US families, the DCTN1 p.G71R and in the New Zealand family the DCTN1 p.Y78C mutations were identified. In functional assays, both mutations altered microtubule binding consistent with a pathogenic role. CONCLUSIONS: Perry syndrome is a rare condition, but new cases are expected to be diagnosed worldwide. Early diagnosis prevents life-threatening acute respiratory failure. Diaphragmatic pacemakers should be considered as an effective symptomatic treatment option.

Later-onset congenital central hypoventilation syndrome due to a heterozygous 24-polyalanine repeat expansion mutation in the PHOX2B gene.

AIM: to describe a family with later onset congenital central hypoventilation syndrome (LO-CCHS) and heterozygosity for a 24-polyalanine repeat expansion mutation in the PHOX2B gene, rendered phenotypically apparent with exposure to anesthetics. CASE SUMMARY: An otherwise healthy 2.75-year-old boy presented with alveolar hypoventilation after adenoidectomy and tonsillectomy for obstructive sleep apnea, requiring invasive ventilatory support during sleep. He had a heterozygous 24-polyalanine repeat expansion in the PHOX2B gene (20/24 genotype), a genotype that has not been previously described in association with CCHS or LO-CCHS symptoms. Clinical findings in members of the family with the same 20/24 genotype ranged from asymptomatic to prolonged sedation after benzodiazepines. CONCLUSION: CCHS should be suspected in individuals presenting with unexplained hypoventilation and/or seizures after anesthetics or sedatives. This is the first report of LO-CCHS in a kindred with the PHOX2B 20/24 genotype. The incomplete penetrance observed in this family suggests a gene-environment interaction.