Novel mutations in the HADHB gene causing a mild phenotype of mitochondrial trifunctional protein (MTP) deficiency.

Mitochondrial trifunctional protein (MTP) deficiency is an ultrarare hereditary recessive disorder causing a broad spectrum of phenotypes with lethal infantile cardiomyopathy at the most severe end. Attenuated forms with polyneuropathy have been reported combined with myoglobinuria or rhabdomyolysis as key features. We here report three young adults (two siblings) in which three variants in the HADHB-gene were identified. All three cases had a similar mild phenotype with axonal neuropathy and frequent intermittent weakness episodes but without myoglobinuria. Special dietary precautions were recommended to minimize complications especially during infections and other catabolic states. MTP deficiency is therefore an important differential diagnosis in patients with milder fluctuating neuromuscular symptoms. Take­home message: Axonal neuropathy and recurrent muscular weakness without concomitant rhabdomyolysis may be due to MTP deficiency.

Health-related quality of life in Norwegian adults with Fabry disease: Disease severity, pain, fatigue and psychological distress.

Health-related quality of life (HRQOL) is reduced in Fabry disease (FD) and associated with clinical disease manifestations, but few have used Fabry-specific severity scores to study how disease burden interferes with quality of life. We investigated how the Fabry DS3, consisting of four somatic domains and one patient-reported item, associates with HRQOL, while also evaluating fatigue, pain and psychological distress as possible predictors. Thirty-six adults with FD completed the Short-form Health Survey (SF-36), the hospital anxiety and depression scale (HADS), the brief pain inventory (BPI) and reported fatigue on a visual analog scale. Clinical data were collected from the last multidisciplinary hospital visit. Using correlation and hierarchical linear regression analyses, we examined associations between demographic, clinical and self-reported predictors and the SF-36 physical (PCS) and mental (MCS) component summary scores. Males scored lower than the general population in all SF-36 domains (P < .05). General health and social functioning were reduced in females. Before including self-reported symptom scores, DS3 showed associations with PCS (P = .009). Our fully adjusted model explained 66% of the variation in PCS, where education (P = .040) and fatigue (P = .002) retained significance. With HADS depression score (P = .001) as the sole significant factor, our regression model explained 56% of the variation in MCS. The DS3 score has implications for HRQOL in FD. Low education and fatigue represent major barriers to physical well-being, while depression strongly influences mental quality of life. Fatigue should be recognized as an important endpoint in future FD trials. Increased efforts to diagnose and treat affective disorders are warranted.

The impact of demographic and clinical characteristics on the trajectories of health-related quality of life among patients with Fabry disease.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by multiorgan dysfunction. Since individuals with FD usually experience progressive clinical disease manifestations, their health-related quality of life (HRQOL) is expected to change over time. However, there is limited longitudinal research examining HRQOL outcomes in individuals with FD. We aimed to: assess longitudinal outcomes in HRQOL in adults with FD; examine the physical- and mental HRQOL trajectories at the initial registration (baseline), 3-5 year, and 7-13 year follow-ups; and evaluate the possible associations of age, sex and medical complications with the physical- and mental HRQOL trajectories. METHODS: Forty-three individuals with FD (53% female) who were aged 18 to 81 years at baseline attended clinical follow-up visits between 2006 and 2020. Medical records were extracted retrospectively. Demographics and the 36-item Short-Form Health Survey (SF-36) were recorded at scheduled visits, except for the last data collection which was prospectively obtained in 2020. The physical (PCS) and mental (MCS) composite scores (SF-36) were chosen as outcome measures. RESULTS: The eight SF-36 domain scores were stable over a span of 13 years, and only physical- and social functioning domains worsened clinically over this follow-up period. Mean baseline SF-36 domain scores were all significantly lower (decreased HRQOL) in the FD sample compared with Norwegian population norms. Two hierarchical linear models were run to examine whether demographics and medical complications (measured at the last clinical visit) predicted physical and mental HRQOL trajectories. Age above 47 years (p < 0.001), male sex (p = 0.027), small fibre neuropathy (p < 0.001), renal dysfunction (p < 0.001), and cerebrovascular events (p = 0.003) were associated with lower HRQOL over time. No significant interactions were found between the time of follow up and the abovementioned predictors of HRQOL. CONCLUSIONS: Overall HRQOL trajectories remained stable between baseline, 3-5 year, and 7-13 year follow-ups, with the majority of individuals reporting decreased physical and mental HRQOL. Medical complications in combination with older age and male sex are important predictors of lower HRQOL in FD. Awareness of this relationship is valuable both for health care providers and for patients. The findings provide indicators that can guide treatment decisions to improve physical and mental HRQOL outcomes.

Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these "unusual" PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations.

Can untreated PKU patients escape from intellectual disability? A systematic review.

BACKGROUND: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. METHODS: To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 µmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. RESULTS: In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. CONCLUSIONS: Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.

The Wedensky test predicts malignant ventricular arrhythmias after myocardial infarction.

OBJECTIVES: Better tools are needed for detection of future malignant ventricular arrhythmias post myocardial infarct (MI). Wedensky Modulation (WM) is a new semi-invasive method: A short low-amplitude electrical impulse is applied synchronized to the QRS between a precordial and dorsal thoracic patch, and changes in the following QRS-T are registered. DESIGN: A total of 357 (MI) ICD patients underwent WM testing. QRS-T wavelet analysis provided WM Indexes for the QRS complex (WMI-R) and T wave (WMI-T). Outcome was the time to first occurrence of appropriate device therapy for ventricular arrhythmia. Patients were followed at 6-month intervals for 2 years. RESULTS: No arrhythmia was induced by the testing. Two-year appropriate arrhythmia treatment occurred in 35% (WMI-R positive) versus 25% (WMI-R negative, p = 0.014), and. 45% versus 26% (p = 0.001) for WMI-T positive versus negative. Two-year event rates of WMI-R or WMI-T positive versus WMI-R and WMI-T negative were 36% versus 22% (p = 0.004). In Cox proportional hazard model, the combination of WMI-R and WMI-T was the only statistically significant event predictor (p = 0.003). CONCLUSION: Potentially life-threatening ventricular arrhythmic events could be predicted by the WM test. In combination with other risk factors WMI may be useful in these patients.

The effect of aortic valve replacement on N-terminal natriuretic propeptides in patients with aortic stenosis.

BACKGROUND: Increased plasma concentrations of natriuretic peptides have been demonstrated to be associated with increased intracardiac pressure and left ventricular (LV) hypertrophy. After aortic valve replacement (AVR) in aortic stenosis patients, there is a relief of the left outflow obstruction with a substantial hemodynamic improvement. This is followed by a gradual regression of the LV hypertrophy. HYPOTHESIS: After AVR, reduction in LV filling pressure is expected to occur rapidly, while regression of LV hypertrophy will take place over a longer time period. On this basis we hypothesized that the plasma levels of N-terminal proatrial natriuretic peptide (NT-proANP) would be reduced early in the postoperative period, while N-terminal probrain natriuretic peptide (NT-proBNP), through its closer reflection of LV hypertrophy, would be sustained for a longer period. METHODS: Two groups of patients with aortic stenosis undergoing AVR were followed for 4 and 12 months, respectively. Plasma concentrations of NT-proANP and NT-proBNP were measured before and after AVR and related to preoperative findings and changes in the aortic valve area index. RESULTS: Before AVR, the patients had significantly increased plasma levels of NT-proANP and NT-proBNP. After AVR, NT- proANP was decreased at 4 and 12 months but remained elevated compared with controls. N-terminal-proBNP tended to decrease, but did not change significantly. When the patients were followed for 12 months, only those with elevated preoperative pulmonary capillary wedge pressure had decreased peptide levels (NT-proANP: p = 0.017, NT-proBNP: p = 0.058). There was no regression of LV hypertrophy. The patients with the largest postoperative valve area index [1.27 (1.10-1.55) cm2/m2] had the largest reduction of NT-proBNP (47%). Those with the smallest valve area index [0.67 (0.54-0.73) cm2/m2] had no decrease in NT-proBNP. CONCLUSIONS: Our study suggests that a reduction in left atrial pressure is the main factor causing the change of NT-proANP level after AVR. A small prosthetic valve orifice area with a high aortic valve gradient might prevent regression of LV hypertrophy, thus representing a stimulus for increased cardiac secretion of NT-proBNP.