Fanin M, Anichini A, Cassandrini D, Fiorillo C, Scapolan S, Minetti C, Cassanello M, Donati MA, Siciliano G, D’Amico A, Lilliu F, Bruno C, Angelini C. Allelic and phenotypic heterogeneity in 49 ...Italian patients with the muscle form of CPT‐II deficiency.
As genotype–phenotype correlations require the study of large patient populations, we investigated 49 Italian patients (33 unreported) with the muscle form of carnitine‐palmitoyl‐transferase‐II (CPT‐II) deficiency and CPT2 gene mutations. CPT enzyme activity below 25% of controls would lead to the development of muscle symptoms, and CPT activity below 15% would cause a relatively severe phenotype of the muscle form. Of the 15 different mutations found, 6 are novel (40%). A functional significance of mutations could be derived only for the two homozygous missense mutations found: both the p.S113L and the p.R631C (recurring in four unrelated patients from a genetic isolate) alleles caused a severe CPT enzyme defect (15% and 7%, respectively) and a relatively severe clinical phenotype of the muscle form. We identified three genotypes (homozygous p.R631C, homozygous p.S113L, and heterozygous null mutations) usually associated with a relatively severe and often life‐threatening condition, which should be considered both in the clinical management of newly diagnosed patients (to prevent symptoms) and in their possible inclusion in therapeutic trials. We confirmed the existence of symptomatic heterozygous patient(s), through a family study, providing an important issue when offering genetic counseling and suggesting the crucial role of polymorphisms or environmental factors in determining the phenotype.
Glycogenosis type II is a multisystem disorder that requires management by a multidisciplinary team. The team should include several specialists, such as a metabolic disease specialist or biochemical ...geneticist, cardiologist, pulmonologist, neurologist, neuromuscular specialist, intensivist, orthopedist, respiratory therapist, physical therapist, occupational therapist, otolaryngologist speech therapist, audiologist, genetic counselor, and a metabolic dietician, who, as a team, will be capable of addressing the different manifestations of the condition. Aspects of functional assessment, rehabilitation, nutritional management, care coordination, nursing, genetic counseling, prenatal diagnosis, and screening are discussed in this article. In addition, treatment of glycogenosis type II is reviewed with attention to emerging therapeutic options.
Glycogen storage disease type IV (GSD-IV) is a clinically heterogeneous autosomal recessive disorder due to glycogen branching enzyme (GBE) deficiency and resulting in the accumulation of an ...amylopectin-like polysaccharide. The typical presentation is liver disease of childhood, progressing to lethal cirrhosis. The neuromuscular form of GSD-IV varies in onset (perinatal, congenital, juvenile, or adult) and severity.
To identify the molecular bases of different neuromuscular forms of GSD-IV and to establish possible genotype/phenotype correlations.
Eight patients with GBE deficiency had different neuromuscular presentations: three had fetal akinesia deformation sequence (FADS), three had congenital myopathy, one had juvenile myopathy, and one had combined myopathic and hepatic features. In all patients, the promoter and the entire coding region of the GBE gene at the RNA and genomic level were sequenced.
Nine novel mutations were identified, including nonsense, missense, deletion, insertion, and splice-junction mutations. The three cases with FADS were homozygous, whereas all other cases were compound heterozygotes.
This study expands the spectrum of mutations in the GBE gene and confirms that the neuromuscular presentation of GSD-IV is clinically and genetically heterogeneous.
Purpose
To evaluate obstetric outcome in women with endometriosis who conceive naturally and receive standard obstetric care in Italy.
Methods
Cases were consecutive women with endometriosis managed ...in eleven Italian referral centers. Controls were women in whom endometriosis was excluded. All women filled in a questionnaire addressing previous natural pregnancies. Marginal logistic regression models were fitted to evaluate the impact of endometriosis on obstetric outcome. A post hoc analysis was performed within the endometriosis group comparing women with severe adenomyosis versus women with absent or mild adenomyosis.
Results
Three hundred and fifty-five pregnancies in endometriosis group and 741 pregnancies in control group were included. Women with endometriosis had a higher risk of preterm delivery < 34 weeks (6.4% vs 2.8%, OR 2.42, 95% CI 1.22–4.82), preterm delivery < 37 weeks (17.8% vs 9.7%, OR 1.98, 95% CI 1.23–3.19), and neonatal admission to Intensive Care Unit (14.1% vs 7.0%, OR 2.04, 95% CI 1.23–3.36). At post hoc analysis, women with endometriosis and severe adenomyosis had an increased risk of placenta previa (23.1% vs 1.8%, OR 16.68, 95% CI 3.49–79.71), cesarean delivery (84.6% vs 38.9%, OR 8.03, 95% CI 1.69–38.25) and preterm delivery < 34 weeks (23.1% vs 5.7%, OR 5.52, 95% CI 1.38–22.09).
Conclusion
Women with endometriosis who conceive naturally have increased risk of preterm delivery and neonatal admission to intensive care unit. When severe adenomyosis is coexistent with endometriosis, women may be at increased risk of placenta previa and cesarean delivery.
Trial registration
Clinical trial registration number: NCT03354793.
ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell ...growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.
Isolated complex I deficiency, the most frequent OXPHOS disorder in infants and children, is genetically heterogeneous. Mutations have been found in seven mitochondrial DNA (mtDNA) and eight nuclear ...DNA encoded subunits, respectively, but in most of the cases the genetic basis of the biochemical defect is unknown. We analyzed the entire mtDNA and 11 nuclear encoded complex I subunits in 23 isolated complex I-deficient children, classified into five clinical groups: Leigh syndrome, progressive leukoencephalopathy, neonatal cardiomyopathy, severe infantile lactic acidosis, and a miscellaneous group of unspecified encephalomyopathies. A genetic definition was reached in eight patients (35%). Mutations in mtDNA were found in six out of eight children with Leigh syndrome, indicating a prevalent association between this phenotype and abnormalities in ND genes. In two patients with leukoencephalopathy, homozygous mutations were detected in two different nuclear-encoded complex I genes, including a novel transition in NDUFS1 subunit. In addition to these, a child affected by mitochondrial encephalomyopathy had heterozygous mutations in NDUFA8 and NDUFS2 genes, while another child with neonatal cardiomyopathy had a complex rearrangement in a single NDUFS7 allele. The latter cases suggest the possibility of unconventional patterns of inheritance in complex I defects.
To evaluate associations between clinicopathological variables and hypercapnia measured in cats with decompensated chronic kidney disease (CKD) on admission to a veterinary hospital.
This is a ...retrospective, cross-sectional study of cats (n = 39) that presented to a tertiary veterinary hospital in Argentina between June 2015 and December 2017 with blood creatinine concentrations >140 μmol/L, and abdominal ultrasound results consistent with CKD. Data recorded included venous partial pressure of CO
(PvCO
), blood pH, haematocrit and concentrations of glucose, potassium, sodium, corrected sodium (Na
), and ionised calcium in blood. A logistic regression model was used to assess associations between the presence of hypercapnia (PvCO
≥ 44.7 mmHg) and the other clinicopathologic variables. The duration of hospitalisation was compared in cats with and without hypercapnia using the Wilcoxon Rank Sum test.
The final study population comprised 39 cats. Eleven cats (28.2%) had hypercapnia. In the logistic regression model, two independent variables were associated with the presence of hypercapnia at admission in cats with CKD: the concentration of creatinine in blood (OR = 1.06 (95% CI = 1.016-1.108); p = 0.007) and Na
(OR = 1.33 (95% CI = 1.08-1.63); p = 0.005). There were no statistically significant differences in the length of hospital stay between the two groups.
There appears to be an association between elevated concentrations of creatinine and Na
in blood, and hypercapnia in cats with CKD, suggesting careful assessment of blood gas and electrolyte parameters during hospitalisation is required. Further prospective studies are needed to evaluate the mechanisms behind this association and the association of hypercapnia with disease outcome including mortality.
This paper compares and describes the tidal volume (Vt) used in mechanically ventilated dogs under a range of clinical conditions. Twenty-eight dogs requiring mechanical ventilation (MV) were ...classified into 3 groups: healthy dogs mechanically ventilated during surgery (group I, n = 10), dogs requiring MV due to extra-pulmonary reasons (group II, n = 7), and dogs that required MV due to pulmonary pathologies (group III, n = 11). The median
used in each group was 16 mL/kg (interquartile range IQR, 15.14-21) for group I, 12.59 mL/kg (IQR, 9-14.25) for group II, and 12.59 mL/kg (IQR, 10.15-14.96) for group III. The Vt used was significantly lower in group III than in group I (
= 0.016). The thoraco-pulmonary compliance was significantly higher in group I than in groups II and III (
= 0.011 and
= 0.006, respectively). The median driving pressure was similar among the groups with a median of 9, 11, and 10 cmH₂O in groups I, II, and III, respectively (
= 0.260). Critically-ill dogs requiring MV due to the primary pulmonary pathology received a significantly lower Vt than healthy dogs but with a range of values that were markedly higher than those recommended by human guidelines.
Although the POSSUM (Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity) score can be used to calculate operative risk, its complexity makes its use unfeasible ...in the immediate clinical setting. The aim of this study was to create a new model, based on ASA status, to predict mortality.
Data were collected in two hospitals. All types of surgery were included except for cardiac surgery and Caesarean delivery. Age, sex and preoperative information, including the presence of cardiocirculatory and/or lung disease, renal failure, diabetes mellitus, hepatic disease, cancer, Glasgow Coma Score, ASA grade, surgical diagnosis, severity of the procedure and type of surgery (elective, urgent or emergency), were recorded for each patient. The model was developed using a data set incorporating data from 1936 surgical patients, and validated using data from a further 1849 patients. Forward stepwise logistic regression was used to build the model. Goodness of fit was examined using the Hosmer–Lemeshow test and receiver operating characteristic (ROC) curve analyses were performed on both data sets to test calibration and discrimination. In the validation data set, the new model was compared with POSSUM and P-POSSUM for both calibration and discrimination, and with ASA alone to compare discrimination.
The following variables were included in the new model: ASA status, age, type of surgery (elective, urgent, emergency) and degree of surgery (minor, moderate or major). Calibration and discrimination of the new model were good in both development and validation data sets. This new model was better calibrated in the validation data set (Hosmer–Lemeshow goodness-of-fit test: χ2=6.8017, P=0.7440) than either P-POSSUM (χ2=14.4643, P=0.1528) or POSSUM, which was not calibrated (χ2=31.8147, P=0.0004). POSSUM and P-POSSUM had better discrimination than the new model, although this was not statistically significant. Comparing the two ROC curves, the new model had better discrimination than ASA alone (difference between areas, 0.077, se 0.034, 95% confidence interval 0.012–0.143, P=0.021).
This new, ASA status-based model is simple to use and can be performed routinely in the operating room to predict operative risk for both elective and emergency surgery.
Background and Aims: Both personality changes and behavioural and psychological symptoms (BPS) may be associated with mild cognitive impairment (MCI) in later life and help identify incipient ...dementia. We wished to investigate the links between personality and BPS in MCI. Method: We studied premorbid personality traits as estimated 5 years back and their changes in 83 control subjects and 52 MCI patients using the revised NEO Personality Inventory for the Five-Factor Model completed by a proxy. Information on BPS was obtained using the Neuropsychiatric Inventory (NPI). Analyses were controlled for current depression and anxiety. Results: Premorbid neuroticism and openness to experience were associated with the total NPI score. The changes in neuroticism, extraversion, openness to experiences, and conscientiousness were associated with apathy and affective symptoms. Conclusions: Personality changes and BPS occur in MCI. The occurrence of affective BPS and apathy is associated with both premorbid personality traits and their changes.
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