Delayed diagnoses of mitochondrial cytopathies in patients presenting with end stage kidney disease: two case reports.

BACKGROUND: Up to one third of patients on renal replacement programmes have an unknown cause of kidney disease, and the diagnosis may only be established following renal transplantation when the disease recurs or if new extra-renal symptoms develop. CASE PRESENTATION: We present two patients who presented with progressive chronic kidney disease of unknown cause. Both patients underwent successful renal transplantation but subsequently developed multisystem abnormalities, and were ultimately diagnosed with mitochondrial cytopathy 10-15 years following transplantation. CONCLUSIONS: Mitochondrial cytopathies are rare inborn errors of metabolism that should be considered in adults with renal impairment, especially in those with a family history of kidney or other multisystem disease. The widespread availability of genetic testing provides the potential for earlier diagnoses, thereby enhancing management decisions, anticipation of complications, avoidance of mitotoxic drugs, and informed prognosis prediction.

Mitochondrial disease heterogeneity: a prognostic challenge.

Mitochondrial diseases are a heterogeneous group of progressive, genetically transmitted, multisystem disorders caused by impaired mitochondrial function. The disease course for individuals with mitochondrial myopathies varies greatly from patient to patient because disease progression largely depends on the type of disease and on the degree of involvement of various organs which makes the prognosis unpredictable both within the same family and among families with the same mutation. This is particularly, but not exclusively, true for mitochondrial disorders caused by mtDNA point mutations, which are maternally inherited and subject to the randomness of the heteroplasmy. For this reason, the prognosis cannot be given by single mitochondrial disease, but should be formulated by any single mitochondrial disease-related event or complication keeping in mind that early recognition and treatment of symptoms are crucial for the prognosis. The following approach can help prevent severe organ dysfunctions or at least allow early diagnosis and treatment of disease-related complications.

SCAF4 variants associated with focal epilepsy accompanied by multisystem disorders.

PURPOSE: The SCAF4 gene encodes serine/arginine-related carboxyl-terminal domain-associated factor 4, which is highly expressed in the brain and potentially affects neurodevelopment. However, the functional significance of SCAF4 variants in human diseases remains unknown. METHODS: Trio-based whole-exome sequencing was performed in three individuals with focal epilepsy. Bioinformatics tools were used to assess the pathogenicity of SCAF4 variants. Knockout scaf4a/b zebrafish were created using CRISPR-Cas9 used to validate the phenotype. RESULTS: SCAF4 variants were identified in three individuals from three unrelated families with focal epilepsy. All patients had focal seizures and focal discharges on EEG recordings, with intellectual disability or motor retardation, skeletal abnormalities, and one had cryptorchidism. However, no recurrence was observed after short-term ASMs treatment. The identified SCAF4 variants included two nonsense variants and one compound heterozygous variant, consisting of a missense and an in-frame variant. A low frequency of SCAF4 variants was observed in gnomAD in this study. Computational modelling has suggested that missense variants lead to functional impairments. In zebrafish, abnormal epileptiform signals, skeletal development, and neurodevelopment have been found in scaf4a/b knockout compared to wild-type zebrafish. CONCLUSION: These results indicate that SCAF4 is associated with focal epilepsy accompanied by multisystem disorders. Otherwise, the management of patients with SCAF4 variants requires more attention to multisystem involvement.

Evaluation of the Effect of Vitamin D Levels During the Last Trimester of Pregnancy on Fetomaternal Outcomes in Patients With Preeclampsia.

Introduction Preeclampsia is a multisystem disorder with hypertension after 20 weeks of gestation. Among many predictors of preeclampsia, vitamin D being one of them is under many studies for establishing a correlation between levels of vitamin D and preeclampsia. Objective To observe a relation between vitamin D levels and preeclampsia and assess related fetomaternal outcomes. Method It is an observational study at the tertiary care center. One hundred twenty patients, out of which 60 were taken as cases with BP>140/90, and 60 were taken as controls with normal BP in a tertiary care center from January 1, 2020, to June 30, 2021. All investigations were sent, and the mode of delivery and the fetomaternal outcome were assessed. Results Compared to normal pregnant patients, preeclamptic patients have significantly lower levels of vitamin D with a p-value of <0.001, which is significant. Conclusion There is a relationship between vitamin D levels and preeclampsia. However, the effects of supplementation of vitamin D on fetomaternal outcomes need further studies.

Endocrine Challenges in Myoclonic Epilepsy With Ragged Red Fibers Syndrome: A Case Report.

Myoclonic epilepsy with ragged red fibers (MERRF) syndrome is a primary mitochondrial disorder characterized by myoclonus, epilepsy, ataxia, and muscle fiber abnormalities. While traditionally associated with neurological features, MERRF's multisystem nature extends to endocrine dysfunction, including diabetes mellitus, thyroid disorders, and adrenal abnormalities. This case report explores the multifaceted nature of MERRF syndrome by presenting the clinical journey of a 70-year-old woman who sought care at the endocrinology clinic due to coexisting Addison's disease and diabetes mellitus, marked by recurrent hypoglycemia and suboptimal metabolic control. Over time, she developed a history of myoclonic epilepsy, effectively managed with lamotrigine, along with mild sensory axonal polyneuropathy and ataxia. The patient was diagnosed with MERRF syndrome following her son's diagnosis, which had a severe form. This case underscores the intricate interplay between mitochondrial dysfunction and endocrine manifestations in MERRF syndrome, highlighting the importance of a comprehensive and multidisciplinary approach to patient care. MERRF syndrome's array of endocrine manifestations substantially impacts patients' quality of life and morbidity. A comprehensive approach, uniting endocrinologists, neurologists, geneticists, and other specialists, is essential for effective patient care. Further research is warranted to unravel the complex mitochondrial-endocrine interactions in MERRF syndrome, offering potential insights for improved management.

Overlapping Machinery in Lysosome-Related Organelle Trafficking: A Lesson from Rare Multisystem Disorders.

Lysosome-related organelles (LROs) are a group of functionally diverse, cell type-specific compartments. LROs include melanosomes, alpha and dense granules, lytic granules, lamellar bodies and other compartments with distinct morphologies and functions allowing specialised and unique functions of their host cells. The formation, maturation and secretion of specific LROs are compromised in a number of hereditary rare multisystem disorders, including Hermansky-Pudlak syndromes, Griscelli syndrome and the Arthrogryposis, Renal dysfunction and Cholestasis syndrome. Each of these disorders impacts the function of several LROs, resulting in a variety of clinical features affecting systems such as immunity, neurophysiology and pigmentation. This has demonstrated the close relationship between LROs and led to the identification of conserved components required for LRO biogenesis and function. Here, we discuss aspects of this conserved machinery among LROs in relation to the heritable multisystem disorders they associate with, and present our current understanding of how dysfunctions in the proteins affected in the disease impact the formation, motility and ultimate secretion of LROs. Moreover, we have analysed the expression of the members of the CHEVI complex affected in Arthrogryposis, Renal dysfunction and Cholestasis syndrome, in different cell types, by collecting single cell RNA expression data from the human protein atlas. We propose a hypothesis describing how transcriptional regulation could constitute a mechanism that regulates the pleiotropic functions of proteins and their interacting partners in different LROs.

Multisystem disorders, severe developmental delay and seizures in two affected siblings, expanding the phenotype of PIGC deficiency.

PIGC (OMIM 601730) encodes the PIGC protein, which is part of an enzyme complex involved in the biosynthesis of the glycosylphosphatidylinositol protein anchor. The other proteins in the complex include PIGA, PIGH, PIGQ, PIGY, PIGP and DPM2. Homozygous and compound heterozygous mutations in PIGC have recently been described to cause severe global developmental delay, intellectual disability, and seizures in two unrelated families, without indication of another system involvement or dysmorphism. Here we describe two siblings, born to second cousin parents, displaying severe psychomotor delay, seizures, organomegaly, cardiopulmonary anomalies, and similar facial dysmorphism. Exome sequencing in the boy revealed a homozygous variant in PIGC gene, c.12_13insTTGTGACTAACA leading to a premature stop codon p.(Gln4_Pro5insLeu*). His affected sister was also found to be homozygous, and their parents were found to be heterozygous. This is the first detailed clinical description of two related patients suggesting that PIGC deficiency can cause a severe recognisable phenotype including multisystem disorders, in association to previously reported severe developmental delay and seizures.

SIL1-related Marinesco-Sjoegren syndrome (MSS) with associated motor neuronopathy and bradykinetic movement disorder.

Marinesco-Sjoegren syndrome (MSS) is a recessively inherited multisystem disorder caused by mutations in SIL1 and characterized by cerebellar atrophy with ataxia, cataracts, a skeletal muscle myopathy, and variable degrees of developmental delay. Pathogenic mechanisms implicated to date include mitochondrial, nuclear envelope and lysosomal-autophagic pathway abnormalities. Here we present a 5-year-old girl with SIL1-related MSS and additional unusual features of an associated motor neuronopathy and a bradykinetic movement disorder preceding the onset of ataxia. These findings suggest that an associated motor neuronopathy may be part of the phenotypical spectrum of SIL1-related MSS and should be actively investigated in genetically confirmed cases. The additional observation of a bradykinetic movement disorder suggests an intriguing continuum between neurodevelopmental and neurodegenerative multisystem disorders intricately linked in the same cellular pathways.