Background: Pompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alphaglucosidase (GAA) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement. Methods: We report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22-74 years (mean 53.7 years) and were diagnosed at an age range of 11-65 years (mean 43.6 years), often after a history of progressive muscle disease of several years' duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies. Results: Genetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves' disease and testicular cancer. Conclusions: Our study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies.
BackgroundThe nucleotide binding protein-like (NUBPL) gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have NUBPL disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families).MethodsWhole exome sequencing was used to identify patients with compound heterozygous NUBPL variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model (Yarrowia lipolytica) and mitochondrial respiration experiments on patient fibroblasts.ResultsThe previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found in cis with c.815-27T>C, but only two of four families had both variants. The second variant found in trans with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3–18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity.ConclusionWe report on five new patients with NUBPL disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic NUBPL variants.
This paper compares the incidence of the diagnosis of Autistic Spectrum Disorders (ASD) among White and Asian children with reference to data obtained from thirteen local education authorities (LEAs) in England. It begins by outlining some of the theoretical debates associated with the definition, diagnosis and prevalence of ASD. The empirical component underpinning this work uses logistic modelling to ascertain whether the proportion of children with a statement of special educational need (SEN) for ASD is different for Asian and for White children and whether the proportion of children with a statement of SEN for ASD varies betweenLEAs. The discussion speculates as to possible reasons for the differences found and identifies areas for further research.
Fabry disease is an X linked disease caused by pathogenic variants in the GLA gene. The cardiovascular and renal systems are most affected in Fabry patients and may require heart or kidney transplants in the late stages of the disease depending on severity of manifestations. Enzyme replacement therapy (ERT) has proven to delay progression of Fabry disease considerably, especially when started early in life. Current research has shown that individuals who have received cardiac or renal transplants or are currently on dialysis have the greatest probability of developing severe manifestations of COVID-19. It has also been shown that people who contract COVID-19 experience a rapid increase in cytokine levels which can lead to a prothrombotic state and have a greater risk in the presence of comorbidities. A history of cardiac or renal transplants as well as the naturally elevated cytokine levels in Fabry disease make it likely that COVID-19 could have a greater impact on the health of these patients. We report the case of a 67-year-old male with diabetes mellitus, history of kidney transplant, and Fabry disease treated late in progression of the disease first with agalsidase beta ERT, then oral migalastat who developed severe manifestations of COVID-19. The autopsy findings showed acute and organizing hyaline membrane disease consistent with COVID 19 pneumonia and secondary invasive bronchopulmonary aspergillosis with cavitary lesion formation. The sections of the heart showed scattered subendocardial fibrosis, and the transplanted kidneys showed thyroidization and interstitial nephritis potentially secondary to COVID-19, in addition to his long-standing renal disease. This case report serves to chronicle complications in a complex patient with late stage Fabry disease and multiple COVID-19 related complications who succumbed from respiratory failure despite the advanced management for the COVID-19 infection.
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