Infantile onset encephalomyopathy, retinopathy, optic atrophy, and mitochondrial DNA depletion associated with a novel pathogenic DHX16 variant.

We studied a patient with mitochondrial DNA depletion in skeletal muscle and a multiorgan phenotype, including fatal encephalomyopathy, retinopathy, optic atrophy, and sensorineural hearing loss. Instead of pathogenic variants in the mitochondrial maintenance genes, we identified previously unpublished variant in DHX16 gene, a de novo heterozygous c.1360C>T (p. Arg454Trp). Variants in DHX16 encoding for DEAH-box RNA helicase have previously been reported only in five patients with a phenotype called as neuromuscular oculoauditory syndrome including developmental delay, neuromuscular symptoms, and ocular or auditory defects with or without seizures. We performed functional studies on patient-derived fibroblasts and skeletal muscle revealing, that the DHX16 expression was decreased. Clinical features together with functional data suggest, that our patient's disease is associated with a novel pathogenic DHX16 variant, and mtDNA depletion could be a secondary manifestation of the disease.

Evaluating clinical mitochondrial respiratory chain enzymes from biopsy specimens presenting skewed probability distribution of activity data.

Due to the relative rarity of mitochondrial diseases, generating reference ranges is problematic in evaluation of respiratory chain activities particularly in pediatric cases. We determined the sample distribution of respiratory chain enzyme activities in skeletal muscle biopsies collected from pediatric patients suspected of neuromuscular disorders. Activities of NADH-ubiquinone reductase, NADH-cytochrome c reductase, succinate-cytochrome c reductase; ubiquinol-cytochrome c reductase and cytochrome c oxidase activities have log-normal distributions even when confirmed mitochondrial diseases were ruled out. Impact of the log-normal distribution of the respiratory chain enzyme activities on clinical diagnostics is discussed.

Mitochondrial DNA Depletion and Deletions in Paediatric Patients with Neuromuscular Diseases: Novel Phenotypes.

OBJECTIVE: To study the clinical manifestations and occurrence of mtDNA depletion and deletions in paediatric patients with neuromuscular diseases and to identify novel clinical phenotypes associated with mtDNA depletion or deletions. METHODS: Muscle DNA samples from patients presenting with undefined encephalomyopathies or myopathies were analysed for mtDNA content by quantitative real-time PCR and for deletions by long-range PCR. Direct sequencing of mtDNA maintenance genes and whole-exome sequencing were used to study the genetic aetiologies of the diseases. Clinical and laboratory findings were collected. RESULTS: Muscle samples were obtained from 104 paediatric patients with neuromuscular diseases. mtDNA depletion was found in three patients with severe early-onset encephalomyopathy or myopathy. Two of these patients presented with novel types of mitochondrial DNA depletion syndromes associated with increased serum creatine kinase (CK) and multiorgan disease without mutations in any of the known mtDNA maintenance genes; one patient had pathologic endoplasmic reticulum (ER) membranes in muscle. The third patient with mtDNA depletion was diagnosed with merosine-deficient muscular dystrophy caused by a homozygous mutation in the LAMA2 gene. Two patients with an early-onset Kearns-Sayre/Pearson-like phenotype harboured a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content. CONCLUSIONS: Novel encephalomyopathic mtDNA depletion syndrome with structural alterations in muscle ER was identified. mtDNA depletion may also refer to secondary mitochondrial changes related to muscular dystrophy. We suggest that a large-scale mtDNA deletion, minor multiple deletions and high mtDNA content associated with Kearns-Sayre/Pearson syndromes may be secondary changes caused by mutations in an unknown nuclear gene.

HbA1c Predicts Time to Diagnosis of Type 1 Diabetes in Children at Risk.

Prediction of type 1 diabetes is based on the detection of multiple islet autoantibodies in subjects who are at increased genetic risk. Prediction of the timing of diagnosis is challenging, however. We assessed the utility of HbA1c levels in predicting the clinical disease in genetically predisposed children with multiple autoantibodies. Cord blood samples from 168,055 newborn infants were screened for class II HLA genotypes in Finland, and 14,876 children with increased genetic risk for type 1 diabetes were invited to participate in regular follow-ups, including screening for diabetes-associated autoantibodies. When two or more autoantibodies were detected, HbA1c levels were analyzed at each visit. During follow-up, multiple (two or more) autoantibodies developed in 466 children; type 1 diabetes was diagnosed in 201 of these children (43%, progressors), while 265 children remained disease free (nonprogressors) by December 2011. A 10% increase in HbA1c levels in samples obtained 3-12 months apart predicted the diagnosis of clinical disease (hazard ratio [HR] 5.7 [95% CI 4.1-7.9]) after a median time of 1.1 years (interquartile range [IQR] 0.6-3.1 years) from the observed rise of HbA1c. If the HbA1c level was ≥5.9% (41 mmol/mol) in two consecutive samples, the median time to diagnosis was 0.9 years (IQR 0.3-1.5, HR 11.9 [95% CI 8.8-16.0]). In conclusion, HbA1c is a useful biochemical marker when predicting the time to diagnosis of type 1 diabetes in children with multiple autoantibodies.