The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews.

BACKGROUND: The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance. METHODS: Clinical records of patients with the Q359K/T360K mutation from three CF centers were studied for phenotypic expression and putative mechanism of dysfunction. Computer models of mutant CFTR were constructed. RESULTS: Nine patients (4 homozygous) of Georgian Jewish origin were included. Age at diagnosis was 9.4 (0.25-38.2) years, median (range). Sweat chloride was 106 ±â€¯13 meq/L, mean ±â€¯SD. Nasal Potential Difference performed in three, was abnormal. All had pulmonary symptoms since early childhood and bronchiectasis. Median FEV1 was 88 (40-121)%. Five had chronic mucoid P. aeruginosa. Homozygous patients were pancreatic insufficient. Enzyme supplementation was initiated at 3.8 (1-14.7) years, median (range). Structural models hint at possible interference of this mutation with transmembrane chloride transport. CONCLUSION: In our cohort, the Q359K/T360K mutation resulted in a severe CF phenotype, although with residual early CFTR function. The CFTR2 database should consider defining this mutation as CF-causing.

Prader-Willi syndrome: who can have growth hormone?

Growth hormone (GH) is licensed for treatment for Prader-Willi syndrome (PWS) for improvement of body composition,1(-)3 height velocity, mobility, behaviour and quality of life.4 Recent case reports, however, have pointed out the occurrence of sudden death during initiation of GH, mainly during sleep and possibly related to severe obesity and sleep-disordered breathing (SDB).5(-)15 Concerns for an increased mortality in PWS children starting GH therapy led to a call for cessation of its use. Children with PWS are at risk of developing SDB secondary to both deficient autonomic sleep control and upper airway obstruction (UAO). It has been suggested that GH exacerbates pre-existing gas-exchange deficiencies in three ways: (a) by stimulation of adenotonsillar hypertrophy;16 17 (b) by a rise in basal metabolic rate with a resultant rise in oxygen demand;18 and (c) by normalisation of previously decreased hydration with augmentation of volume load.19 Are we withholding GH therapy, a treatment known to be of benefit in PWS, without adequate evidence to justify our actions? We consider it safe to treat severely obese children with GH once SDB is addressed using respiratory support such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP). In this paper, we evaluate the current evidence for the use of GH in PWS from a respiratory bias and propose a pathway for the identification and monitoring of these "at risk" patients.

Brain lactic alkalosis in Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome is a rare progressive encephalopathy characterized by acquired microcephaly, basal ganglia calcification, and chronic CSF lymphocytosis, raised levels of interferon alpha in CSF and plasma and chill-blain type lesions. A possible mechanism of injury is cytokine related microangiopathy. We report brain imaging and proton (1H) and phosphorus-31 (31P) magnetic resonance spectroscopy (MRS) findings during the first year after birth in two patients. In patient 1 the evolution of brain metabolite ratios and intracellular pH obtained from serial 1H (long TE) and 31P MRS studies are described; in patient 2 a single 1H (short TE) MRS study is described. Imaging findings included basal ganglia calcifications, cerebral atrophy, and leukodystrophy. The MRS results demonstrated that Aicardi-Goutières syndrome is associated with reduced NAA/Cr, reflecting decreased neuronal/axonal density or viability, increased myo-inositol/Cr, reflecting gliosis or osmotic stress and a persisting brain lactic alkalosis. A brain lactic alkalosis has also been observed in those infants surviving perinatal hypoxia-ischaemia but with a poor neurodevelopmental outcome. A possible mechanism leading to brain alkalosis is up-regulation of the Na+/H+ transporter by focal areas of ischaemia related to the microangiopathy or by pro-inflammatory cytokines. Such brain alkalosis may be detrimental to cell survival and may increase glycolytic rate in astrocytes leading to an increased production of lactate.