Mitochondrial diseases are a heterogeneous group of diseases resulting from energy deficit and reduced adenosine triphosphate (ATP) production due to impaired oxidative phosphorylation. The manifestation of mitochondrial disease is usually multi-organ. Epilepsy is one of the most common manifestations of diseases resulting from mitochondrial dysfunction, especially in children. The onset of epilepsy is associated with poor prognosis, while its treatment is very challenging, which further adversely affects the course of these disorders. Fortunately, our knowledge of mitochondrial diseases is still growing, which gives hope for patients to improve their condition in the future. The paper presents the pathophysiology, clinical picture and treatment options for epilepsy in patients with mitochondrial disease.

Glycogen storage disease type 1b (GSD 1b) is an inherited metabolic defect caused by biallelic mutations in the SLC37A4 gene encoding microsomal glucose‐6‐phosphate (G6P) transporter in the endoplasmic reticulum (ER) membrane. Ineffective G6P transport into the ER leads to hypoglycaemia, hyperlactatemia, hyperuricemia, hypertriglyceridemia, hepato‐ and/or nephromegaly. Clinical manifestations of the disease include recurrent, severe infections and inflammatory bowel (Crohn‐like) caused by neutropenia and diminished bactericidal and fungicidal activity of neutrophils. Granulocyte colony‐stimulating factor (G‐CSF) administration is currently a standard therapy to prevent adverse effects of neutropenia, but the treatment is associated with a high risk of severe side effects. On the other hand, short‐treatment with sodium‐glucose cotransporter type 2 inhibitor – empagliflozin (EMPA) was reported to act directly on the mechanism of neutropenia and neutrophil dysfunction in GSD 1b. We observed significant improvement in clinical and laboratory parameters after introducing EMPA to treatment, that is reduced frequency of infections, lower number of bowel movements, and improved postoperative wound healing. EMPA is effective in the treatment of neutropenia in our GSD 1b patients, which allows for dose reduction and even withdrawal of G‐CSF. We did not observe any significant side effects of EMPA treatment in our patients.

Neutropenia and neutrophil dysfunction in glycogen storage disease type 1b (GSD1b) are caused by the accumulation of 1,5-anhydroglucitol-6-phosphate in granulocytes. The antidiabetic drug empagliflozin reduces the concentration of 1,5-anhydroglucitol (1,5-AG), thus restoring neutrophil counts and functions, leading to promising results in previous case reports. Here, we present a comprehensive analysis of neutrophil function in 7 patients with GSD1b and 11 healthy donors, aiming to evaluate the immediate (after 3 months) and long-term (after 12 months) efficacy of empagliflozin compared with the reference treatment with granulocyte-colony stimulating factor (G-CSF). We found that most patients receiving G-CSF remained neutropenic with dysfunctional granulocytes, whereas treatment with empagliflozin increased neutrophil counts and improved functionality by inhibiting apoptosis, restoring phagocytosis and the chemotactic response, normalizing the oxidative burst, and stabilizing cellular and plasma levels of defensins and lactotransferrin. These improvements correlated with the decrease in serum 1,5-AG levels. However, neither G-CSF nor empagliflozin overcame deficiencies in the production of cathelicidin/LL-37 and neutrophil extracellular traps. Given the general improvement promoted by empagliflozin treatment, patients were less susceptible to severe infections. G-CSF injections were therefore discontinued in 6 patients (and the dose was reduced in the seventh) without adverse effects. Our systematic analysis, the most extensive reported thus far, has demonstrated the superior efficacy of empagliflozin compared with G-CSF, restoring the neutrophil population and normal immune functions. This trial was registered as EudraCT 2021-000580-78.

Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from abnormal mitochondrial function. Currently, there is no causal treatment for MDs. The aim of the study was to assess the effectiveness and safety of the ketogenic diet (KD) in patients with MD and to analyse selected biochemical and clinical parameters evaluating the effectiveness of KD treatment in patients with MDs. A total of 42 paediatric patients were assigned to four groups: group 1—patients with MD in whom KD treatment was started (n = 11); group 2—patients with MD remaining on an ordinary diet (n = 10); group 3—patients without MD in whom KD treatment was initiated (n = 10), group 4—patients without MD on a regular diet (n = 11). Clinical improvement was observed in 9/11 patients with MD treated with KD. Among patients with MD without KD, the clinical condition deteriorated in 7/10 patients, improved in 2/10 patients, and remained unchanged in one patient. Adverse events of KD occurred with a comparable frequency in groups 1 and 3. There was no significant difference in changes in biomarker concentrations over the course of the study among patients treated and untreated with KD.

Methylmalonic Aciduria (MMA) is a heterogeneous group of rare diseases leading to accumulation of methylmalonic acid in body fluids. One of the causes of the disease is the methylmalonic aciduria, cblA type (cblA - type MMA), conditioned by a mutation in the MMAA gene, which is essential for the proper functioning of a cofactor of the methylmalonyl-CoA mutase. The symptoms of the disease, depending on the cause, may manifest themselves at different ages. Most patients are sensitive to high doses of hydroxycobalamin, which is associated with better prognosis. The purpose of the study was to retrospectively analyze the clinical picture and effects of treatment of patients with methylmalonic aciduria related to mutation in the MMAA gene. Five patients with diagnosed cblA - type MMA were presented. At the time of diagnosis the median of age was 18.8 months, but the symptoms had already appeared since infancy, as recurrent vomiting and delayed psychomotor development. Significant excretion of methylmalonic acid in urine and metabolic acidosis traits with significantly increased anionic gap were observed in all patients. All of them were sensitive to the treatment with vitamin B12. The median of therapy duration and observation is 12.2 years. During the treatment, good metabolic control was achieved in all patients, but their cognitive development is delayed. Three patients have renal failure and pharmacologically treated arterial hypertension. Patients with a mutation in the MMAA gene are sensitive to treatment with hydroxocobalamine, but the inclusion of appropriate treatment does not protect against neurodevelopmental disorders and chronic kidney disease.

This paper discusses the cases of siblings that were born healthy, then diagnosed in their neonatal periods with cardiomyopathy and/or severe metabolic acidosis, which ran progressive courses and contributed to death in infancy. Molecular testing of the children confirmed the presence of an m.3303C>T point mutation in the mitochondrial DNA in the MT-TL1 gene, which was also present in their oligosymptomatic mother and their mother’s sister, an asymptomatic carrier.