Growth Retardation in the Course of Fanconi Syndrome Caused by the 4977-bp Mitochondrial DNA Deletion: A Case Report

Fanconi syndrome is one of the primary renal manifestations of mitochondrial cytopathies caused by mitochondrial DNA (mtDNA) mutation. The common 4977-bp mtDNA deletion has been reported to be associated with aging and diseases involving multiple extrarenal organs. Cases of Fanconi syndrome caused by the 4977-bp deletion were rarely reported previously. Here, we report a 6-year-old girl with growth retardation in the course of Fanconi syndrome. She had mild ptosis and pigmented retinopathy. Abnormal biochemical findings included low-molecular-weight proteinuria, normoglycemic glycosuria, increased urine phosphorus excretion, metabolic acidosis, and hypophosphatemia. Growth records showed that her body weight and height were normal in the first year and failed to thrive after the age of three. Using a highly sensitive mtDNA analysis methodology, she was identified to possess the common 4977-bp mtDNA deletion. The mutation rate was 84.7% in the urine exfoliated cells, 78.67% in the oral mucosal cells, and 23.99% in the blood sample. After three months of oral coenzyme Q10 and levocarnitine treatment in combination with standard electrolyte supplement, her condition was improved. This is a report of growth retardation as the initial major clinical presentation of Fanconi syndrome caused by the deletion of the 4977-bp fragment. Renal tubular abnormality without any other extrarenal dysfunction may be an initial clinical sign of mitochondrial disorders. Moreover, considering the heterogeneity of the phenotypes associated with mtDNA mutations, the risk of developing Kearns–Sayre syndrome (KSS) with age in this patient should be noted because she had ptosis, retinal involvement, and changes in the brain and skeletal muscle.

Ketogenic diet for mitochondrial disease: a systematic review on efficacy and safety

Background No curative therapy for mitochondrial disease (MD) exists, prioritizing supportive treatment for symptom relief. In animal and cell models ketones decrease oxidative stress, increase antioxidants and scavenge free radicals, putting ketogenic diets (KDs) on the list of management options for MD. Furthermore, KDs are well-known, safe and effective treatments for epilepsy, a frequent symptom of MD. This systematic review evaluates efficacy and safety of KD for MD. Methods We searched Pubmed, Cochrane, Embase and Cinahl (November 2020) with search terms linked to MD and KD. From the identified records, we excluded studies on Pyruvate Dehydrogenase Complex deficiency. From these eligible reports, cases without a genetically confirmed diagnosis and cases without sufficient data on KD and clinical course were excluded. The remaining studies were included in the qualitative analysis. Results Only 20 cases (14 pediatric) from the 694 papers identified met the inclusion criteria (one controlled trial (n = 5), 15 case reports). KD led to seizure control in 7 out of 8 cases and improved muscular symptoms in 3 of 10 individuals. In 4 of 20 cases KD reversed the clinical phenotype (e.g. cardiomyopathy, movement disorder). In 5 adults with mitochondrial DNA deletion(s) related myopathy rhabdomyolysis led to cessation of KD. Three individuals with POLG mutations died while being on KD, however, their survival was not different compared to individuals with POLG mutations without KD. Conclusion Data on efficacy and safety of KD for MD is too scarce for general recommendations. KD should be considered in individuals with MD and therapy refractory epilepsy, while KD is contraindicated in mitochondrial DNA deletion(s) related myopathy. When considering KD for MD the high rate of adverse effects should be taken into account, but also spectacular improvements in individual cases. KD is a highly individual management option in this fragile patient group and requires an experienced team. To increase knowledge on this—individually—promising management option more (prospective) studies using adequate outcome measures are crucial.

Serum biomarkers in primary mitochondrial disorders

The aim of this study was to explore the utility of the serum biomarkers neurofilament light chain (NF-L), fibroblast growth factor 21 (FGF-21) and growth and differentiation factor 15 (GDF-15) in diagnosing primary mitochondrial disorders. We measured serum NF-L, FGF-21 and GDF-15 in 26 patients with a genetically proven mitochondrial disease. FGF-21 and GDF-15 were measured by enzyme-linked immunosorbent assay and NF-L with the Simoa assay. NF-L was highest in patients with multisystemic involvement that included the central nervous system such as those with the m.3242A>G mutation. Mean NF-L was also highest in patients with epilepsy versus those without (49.74 pg/ml versus 19.7 pg/ml (p = 0.015)), while FGF-21 and GDF-15 levels were highest in patients with prominent myopathy, such as those with single mitochondrial DNA deletion. Our results suggest that the combination of NF-L, FGF-21 and GDF-15 is useful in the diagnostic evaluation of mitochondrial disease. GDF-15 and FGF-21 identify those with muscle involvement while NF-L is a clear marker for central nervous system involvement independent of underlying mitochondrial pathology. Levels of NF-L appear to correlate with the degree of ongoing damage suggesting, therefore, that monitoring NF-L levels may provide prognostic information and a way of monitoring disease activity.