Natural history of three late-diagnosed classic Galactosemia patients.

The authors report the natural history of three patients with late-diagnosed Classic Galactosemia (CG) (at 16, 19 and 28 years). This was due to a combination of factors: absence of neonatal screening, absence of some typical acute neonatal symptoms, and negative galactosemia screening. This report underlines the value of neonatal screening and the importance of further diagnostic testing in case of late-onset manifestations.

Metachromatic leukodystrophy: To screen or not to screen?

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal storage disorder caused by biallelic pathogenic variants in the gene encoding arylsulfatase A. Disease onset is variable (with late infantile, early and late juvenile, and adult forms) and treatment options depend on age and disease symptoms at onset. In the past, allo-hematopoietic stem cell transplantation (allo-HSCT) has been the best treatment option, following strict selection criteria.

MPS I: Early diagnosis, bone disease and treatment, where are we now?

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by α-L-iduronidase deficiency. Patients present with a broad spectrum of disease severity ranging from the most severe phenotype (Hurler) with devastating neurocognitive decline, bone disease and early death to intermediate (Hurler-Scheie) and more attenuated (Scheie) phenotypes, with a normal life expectancy. The most severely affected patients are preferably treated with hematopoietic stem cell transplantation, which halts the neurocognitive decline.

Are GMI gangliosidosis and Morquio type B two different disorders or part of one phenotypic spectrum?

Monosialotetrahexosylganglioside (GMI) gangliosidosis and Morquio type B (MorB) are two lysosomal storage disorders (LSDs) caused by the same enzyme deficiency, β-galactosidase (βgal). GMI gangliosidosis, associated with GMI ganglioside accumulation, is a neurodegenerative condition characterized by psychomotor regression, visceromegaly, cherry red spot, and facial and skeletal abnormalities. MorB is characterized by prominent and severe skeletal deformities due to keratan sulfate (KS) accumulation.

Primary skeletal muscle myoblasts from chronic heart failure patients exhibit loss of anti-inflammatory and proliferative activity.

Background: Peripheral skeletal muscle wasting is a common finding with adverse effects in chronic heart failure (HF). Whereas its clinical relevance is beyond doubt, the underlying pathophysiological mechanisms are not yet fully elucidated. We aimed to introduce and characterize the primary culture of skeletal muscle cells from individual HF patients as a supportive model to study this muscle loss.

Quantifying small molecule phenotypic effects using mitochondrial morpho-functional fingerprinting and machine learning.

In primary fibroblasts from Leigh Syndrome (LS) patients, isolated mitochondrial complex I deficiency is associated with increased reactive oxygen species levels and mitochondrial morpho-functional changes. Empirical evidence suggests these aberrations constitute linked therapeutic targets for small chemical molecules. However, the latter generally induce multiple subtle effects, meaning that in vitro potency analysis or single-parameter high-throughput cell screening are of limited use to identify these molecules.

A complex V ATP5A1 defect causes fatal neonatal mitochondrial encephalopathy.

Whole exome sequencing is a powerful tool to detect novel pathogenic mutations in patients with suspected mitochondrial disease. However, the interpretation of novel genetic variants is not always straightforward. Here, we present two siblings with a severe neonatal encephalopathy caused by complex V deficiency.

Developing outcome measures for pediatric mitochondrial disorders: which complaints and limitations are most burdensome to patients and their parents?

Since some drug intervention effects are only experienced by the patient, organizations such as the Food and Drug Administration prefer clinically meaningful outcome measures. Here, we evaluated which symptoms and limitations in daily life are most burdensome to pediatric patients with mitochondrial disorders and their parents, using two questionnaires. In a study of 78 patients, the most burdensome complaints included fatigue, behavior and speech disturbances, epilepsy and muscle weakness and a high degree of limitations in daily activities was found.

Restoration of complex V deficiency caused by a novel deletion in the human TMEM70 gene normalizes mitochondrial morphology.

We report a fragmented mitochondrial network and swollen and irregularly shaped mitochondria with partial to complete loss of the cristae in fibroblasts of a patient with a novel TMEM70 gene deletion, which could be completely restored by complementation of the TMEM70 genetic defect. Comparative genomics analysis predicted the topology of TMEM70 in the inner mitochondrial membrane, which could be confirmed by immunogold labeling experiments, and showed that the TMEM70 gene is not restricted to higher multi-cellular eukaryotes. This study demonstrates that the role of complex V in mitochondrial cristae morphology applies to human mitochondrial disease pathology.

Mitochondrial ATP synthase: architecture, function and pathology.

Human mitochondrial (mt) ATP synthase, or complex V consists of two functional domains: F(1), situated in the mitochondrial matrix, and F(o), located in the inner mitochondrial membrane. Complex V uses the energy created by the proton electrochemical gradient to phosphorylate ADP to ATP. This review covers the architecture, function and assembly of complex V.

High-throughput assay to measure oxygen consumption in digitonin-permeabilized cells of patients with mitochondrial disorders.

Background: Muscle biopsy analysis is regarded as the gold standard in diagnostic workups of patients with suspected mitochondrial disorders. Analysis of cultured fibroblasts can provide important additional diagnostic information. The measurement of individual OXPHOS complexes does not always provide sufficient information about the functional state of the complete mitochondrial energy-generating system.

A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy.

To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing.