Treatment of Mitochondrial Phenylalanyl-tRNa-Synthetase Deficiency (FARS2) with Oral Phenylalanine.

OBJECTIVE: By loading transfer RNAs with their cognate amino acids, aminoacyl-tRNA synthetases (ARS) are essential for protein translation. Both cytosolic ARS1-deficiencies and mitochondrial ARS2 deficiencies can cause severe diseases. Amino acid supplementation has shown to positively influence the clinical course of four individuals with cytosolic ARS1 deficiencies. We hypothesize that this intervention could also benefit individuals with mitochondrial ARS2 deficiencies. METHODS: This study was designed as a N-of-1 trial. Daily oral L-phenylalanine supplementation was used in a 3-year-old girl with FARS2 deficiency. A period without supplementation was implemented to discriminate the effects of treatment from age-related developments and continuing physiotherapy. Treatment effects were measured through a physiotherapeutic testing battery, including movement assessment battery for children, dynamic gait index, gross motor function measure 66, and quality of life questionnaires. RESULTS: The individual showed clear improvement in all areas tested, especially in gross motor skills, movement abilities, and postural stability. In the period without supplementation, she lost newly acquired motor skills but regained these upon restarting supplementation. No adverse effects and good tolerance of treatment were observed. INTERPRETATION AND CONCLUSION: Our positive results encourage further studies both on L-phenylalanine for other individuals with FARS2 deficiency and the exploration of this treatment rationale for other ARS2 deficiencies. Additionally, treatment costs were relatively low at 1.10 €/day.

Nicotinamide Riboside for Ataxia Telangiectasia: A Report of an Early Treated Individual.

A first study on nicotinamide riboside treatment of 24 individuals with ataxia telangiectasia with a mean age of 17.5 years showed improved ataxia scores and immunoglobulin levels. We here present the effect of nicotinamide riboside in another individual with ataxia and recurrent infections in whom treatment started as early as at the age of 3 years and 6 months.During 11 months of follow-up, mean total Scale-for-the-Assessment-and-Rating-of-Ataxia decreased from 27 to 9 points and mean total Score for the Gross-Motor-Function-Measure increased from 61 to 78%. Improvement in drawing skills was observed by ICF-based ergotherapeutic examination. Use of antibiotics and frequency of hospitalizations due to infections were reduced by more than 90%. Immunological parameters in blood remained unchanged. No adverse effects occurred.While the effects on motor and speech improvement might be partly explained by development, our study replicates the previous finding of a positive effect of nicotinamide riboside treatment in ataxia telangiectasia. One could even hypothesize that the early treatment will lead to even better outcome. Given the absence of adverse effects, we strongly encourage to consider nicotinamide riboside in all individuals with ataxia telangiectasia.

A TSHZ3 Frame-Shift Variant Causes Neurodevelopmental and Renal Disorder Consistent with Previously Described Proximal Chromosome 19q13.11 Deletion Syndrome.

Heterozygous deletions at 19q12-q13.11 affecting TSHZ3, the teashirt zinc finger homeobox 3, have been associated with intellectual disability and behavioural issues, congenital anomalies of the kidney and urinary tract (CAKUT), and postnatal growth retardation in humans and mice. TSHZ3 encodes a transcription factor regulating the development of neurons but is ubiquitously expressed. Using exome sequencing, we identified a heterozygous frameshift variant c.119_120dup p.Pro41SerfsTer79 in TSHZ3 in a 7-year-old girl with intellectual disability, behavioural issues, pyelocaliceal dilatation, and mild urethral stenosis. The variant was present on the paternal TSHZ3 allele. The DNA from the father was not available for testing. This is the first report of a heterozygous point mutation in TSHZ3 causing the same phenotype as reported for monoallelic deletions in the same region. This confirms TSHZ3 as a novel disease gene for neurodevelopmental disorder in combination with behavioural issues and CAKUT.

Ketogenic Diet Treatment of Defects in the Mitochondrial Malate Aspartate Shuttle and Pyruvate Carrier.

The mitochondrial malate aspartate shuttle system (MAS) maintains the cytosolic NAD+/NADH redox balance, thereby sustaining cytosolic redox-dependent pathways, such as glycolysis and serine biosynthesis. Human disease has been associated with defects in four MAS-proteins (encoded by MDH1, MDH2, GOT2, SLC25A12) sharing a neurological/epileptic phenotype, as well as citrin deficiency (SLC25A13) with a complex hepatopathic-neuropsychiatric phenotype. Ketogenic diets (KD) are high-fat/low-carbohydrate diets, which decrease glycolysis thus bypassing the mentioned defects. The same holds for mitochondrial pyruvate carrier (MPC) 1 deficiency, which also presents neurological deficits. We here describe 40 (18 previously unreported) subjects with MAS-/MPC1-defects (32 neurological phenotypes, eight citrin deficiency), describe and discuss their phenotypes and genotypes (presenting 12 novel variants), and the efficacy of KD. Of 13 MAS/MPC1-individuals with a neurological phenotype treated with KD, 11 experienced benefits-mainly a striking effect against seizures. Two individuals with citrin deficiency deceased before the correct diagnosis was established, presumably due to high-carbohydrate treatment. Six citrin-deficient individuals received a carbohydrate-restricted/fat-enriched diet and showed normalisation of laboratory values/hepatopathy as well as age-adequate thriving. We conclude that patients with MAS-/MPC1-defects are amenable to dietary intervention and that early (genetic) diagnosis is key for initiation of proper treatment and can even be lifesaving.

Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes.

OBJECTIVE: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. METHODS: Whole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients. RESULTS: We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants' pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). INTERPRETATION: Our results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. ANN NEUROL 2022;91:225-237.