Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence
Abstract
1. Introduction
2. Mitochondrial Disorders Categorized by Metabolic Pathways
2.1. OXPHOS Pathway
2.2. Pyruvate Metabolism Pathway
Mitochondrial Disorder | Gene(s) | Clinical Features | Inheritance | References |
---|---|---|---|---|
Leigh Syndrome | SURF1 | Hypotonia, dystonia, hypopnea, dysphagia, epilepsy, failure to thrive, encephalopathy, basal ganglia and brainstem lesions | AR | [12] |
AHS | POLG | Intractable epilepsy, psychomotor regression, liver disease | AR | [15] |
MELAS | MT-TL1/MT-TF/MT-TV/MT-TQ | Stroke—like episodes, deafness, Diabetes Melitus, pigmented retinopathy, cardiomyopathy, cerebellar ataxia, seizures, encephalopathy, lactic acidosis, mitochondrial myopathy | M | [19] |
NARP | MT-ATP6 | Sensorimotor neuropathy, ataxia, pigmentary retinopathy, seizures, learning disability, dementia, proximal neurogenic muscle weakness, basal ganglia abnormalities | M | [21] |
LHON | 11778G > A (ND4), 14484T > C (ND6), 3460G > A (ND1) | Subacute bilateral vision loss due to optic atrophy and rarely tremors, dystonia, MS-like symptoms | M (mutations in the mtDNA) | [24] |
LD | EPM2A or EPM2B | Asymptomatic until adolescence, patients undergo first insidious then rapid progressive myoclonus epilepsy toward a vegetative state and death within a decade. Neurodegenerative due to lysosomal dysfunction | AR | [26] |
KSS | Mitochondrial tRNA tyrosine gene | Ophthalmoplegia, ptosis, progressive nature, muscle weakness beyond the eyes, fatigue, droopy mouth, cardiomyopathy | M | [18] |
MERRF | MT-TK/MT-TF/MT-TL1/MT-TP | Progressive myoclonic epilepsy, ataxia, weakness, retinopathy, sensorineural hearing loss, lactic acidosis, lipomata, spasticity, cardiac function defects | M | [20] |
FRDA | FXN | Iron accumulation, increasing oxidative damage | AR | [23] |
CLA | PDHA1 | Progressive neuromuscular weakness, accumulation of lactate in the blood (acidosis), urine and/or CSF | X, AR | [28] |
MNGIE | TYMP | Peripheral neuropathy, leukoencephalopathy, ophthalmoplegia, ptosis, cachexia, gastrointestinal and dysmotility, progressively degenerative, leads to death at an average age of 37.6 years. | AR | [29] |
GA -I | GCDH | Neurodegeneration due to encephalopathic crises, striatal vulnerability | AR | [31] |
2.3. Fatty Acid β-Oxidation Pathway
2.4. Amino Acid Metabolism and Phospholipid Remodeling Pathways
2.5. Multi-System Pathways
Mitochondrial Disorder | Gene(s) | Clinical Features | Inheritance | References |
---|---|---|---|---|
Sengers Syndrome | AGK | Congenital Cataracts, Hypertrophic Cardiomyopathy, Lactic Acidosis, Myopathy, Exercise Intolerance | AR | [34] |
GA-II | ETFA or ETFB or ETFDH | Hepatomegaly, non-ketotic hypoglycemia, metabolic acidosis, hypotonia, and in neonatal onset cardiomyopathy | AR | [31] |
GSD- IV | GBE1 (severe mutations) | Profound skeletal muscle weakness, respiratory failure, death during early infancy, cardiomyopathy | AR | [37] |
APBD | GBE1 (Milder mutations) | Neurogenic bladder dysfunction, spastic paraplegia, axonal neuropathy, cognitive symptoms, dementia | AR | [37] |
Megdel Syndrome | SERAC1 | Sensorineural hearing loss, encephalopathy, failure to thrive, hypotonia, psychomotor delay, dystonia, spasticity, hypoglycemia, hepatopathy, lactic acidosis | AR | [39] |
Fragile X Syndrome | FMR1 | Depends on whether premutation (tremor, ataxia)/full mutation (postpubertal macroorchidism, long face, large, everted ears, autism, hypermobile joints) | X- Dominant | [41] |
A-T | ATM | Progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, increased metabolic diseases | AR | [43] |
OTCD | OTC | All due to hyperammonemia: somnolence, lethargy, coma, acute encephalopathy, frequent migraine headaches, seizures, tremor, ataxia, dysarthria, stroke-like episodes, transient visual loss, chorea, and protracted visual loss), psychiatric and gastrointestinal clinical manifestations | X | [44] |
Pearson Syndrome | Large scale deletions in mtDNA | Sideroblastic anemia of childhood associated with exocrine or endocrine pancreatic dysfunction, pancytopenia, renal tubulopathy | M | [47] |
Fahr’s Syndrome | SLC20A2, PDGFB, PDGFRB, XPR1 | Parkinsonism, dystonia, chorea, dementia, mood changes, seizures, speech and swallowing difficulties | AD, (in some cases AR) | [55] |
Rett Syndrome | MECP2 | Metabolic dysfunctions, cardiovascular abnormalities, breathing irregularities, and gastrointestinal issues | X | [54] |
2.6. Neurodegeneration with Brain Iron Accumulation
Mitochondrial Disorder | Gene(s) | Clinical Features | Inheritance | References |
---|---|---|---|---|
PKAN | PANK2 | Dystonia, parkinsonism, spasticity, pigmentary retinopathy, acanthocytosis, neuropsychiatric features | AR | [57] |
PLAN | PLA2G6 | Psychomotor regression, ataxia, autism, dystonia, parkinsonism, optic atrophy | AR | [61] |
Neuroferritinopathy | FLT | Adult- onset chorea or dystonia with subtle cognitive defects | AR | [69] |
MPAN | C190rf12 | Spasticity, dystonia, dementia, peripheral nerve involvement | AR | [63] |
CoPAN | CoASY | Intellectual disability, dystonia, spasticity, behavioral problems | AR | [59] |
BPAN | WDR45 | Intellectual disability, little to no language, mixed seizure types, juvenile parkinsonism, autism | X | [65] |
KRS | ATP13A2 | Juvenile parkinsonism, dementia | AR | [67] |
Aceruloplasminemia | CP | Adult- onset retinal degeneration, diabetes mellitus, chorea/dystonia/ataxia | AR | [70] |
WSS | DCAF17 | Movement disorders, endocrine dysfunction, sensorineural hearing loss, intellectual disability, dysmorphic facial features | AR | [71] |
3. Genetic and Metabolic Complexity of Mitochondrial Disorders in the Era of Precision Medicine
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AGK | Acylglycerol Kinase |
ATP | Adenosine Triphosphate |
APBD | Adult Polyglucosan Body Disease |
AHS | Alpers-Huttenlocher Syndrome |
A-T | Ataxia Telangiectasia |
BPAN | Beta-propeller protein-associated neurodegeneration |
Ca2+ | Calcium |
CNS | Central Nervous System |
CPEO | Chronic Progressive External Ophthalmoplegia |
CoPAN | CoA synthase protein-associated neurodegeneration |
CoA | Coenzyme A |
CLA | Congenital Lactic Acidosis |
Cyto c | Cytochrome c |
ETF | Electron Transfer Flavoprotein |
ETFA | Electron Transfer Flavoprotein Alpha Subunit |
ETFB | Electron Transfer Flavoprotein Beta Subunit |
ETFDH | Electron Transfer Flavoprotein-Ubiquinone Oxidoreductase |
ETC | Electron Transport Chain |
ER | Endoplasmic Reticulum |
FMRP | Fragile X Mental Retardation Protein |
FRDA | Friedreich’s Ataxia |
GABA | Gamma-Aminobutyric acid |
GA-I | Glutaric Acidemia Type I |
GCDH | Glutaryl-CoA Dehydrogenase |
GBE | Glycogen Branching Enzyme |
GSD IV | Glycogen Storage Disease Type IV |
KSS | Kearns-Sayre Syndrome |
KRS | Kufor-Rakeb disease |
LBs | Lafora Bodies |
LD | Lafora Disease |
LHON | Leber’s Hereditary Optic Neuropathy |
mtACP | Mitochondrial Acyl Carrier Protein |
mtDNA | Mitochondrial DNA |
MELAS | Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes |
MPAN | Mitochondrial Membrane Protein-Associated Neurodegeneration |
mPTP | Mitochondrial Permeability Transition Pore |
MRT | Mitochondrial Replacement Therapy |
MADD | Multiple Acyl-CoA Dehydrogenase Deficiency |
MERRF | Myoclonic Epilepsy with Ragged-Red Fibers |
MNGIE | Myoneurogastroencephalopathy |
NARP | Neuropathy, Ataxia, and Retinitis Pigmentosa |
nDNA | Nuclear DNA |
OTCD | Ornithine Transcarbamylase Deficiency |
OXPHOS | Oxidative Phosphorylation |
PKAN | Pantothenate Kinase-Associated Neurodegeneration |
PiT2 | Phosphate Transporter 2 |
PLAN | Phospholipase A2-associated neurodegeneration |
PDGFRB | Platelet-Derived Growth Factor Receptor B |
PDGFB | Platelet-Derived Growth Factor Subunit B |
PDH | Pyruvate Dehydrogenase Complex |
ROS | Reactive Oxygen Species |
rAAV | recombinant Adeno-associated Viruses |
RGCs | Retinal ganglion cells |
TCA | Tricarboxylic Acid |
WSS | Woodhouse-Sakati Syndrome |
XPR1 | Xenotropic and Polytropic Retrovirus Receptor |
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Makridou, A.; Sintou, E.; Chatzianagnosti, S.; Dermitzakis, I.; Gargani, S.; Manthou, M.E.; Theotokis, P. Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence. Curr. Issues Mol. Biol. 2025, 47, 504. https://doi.org/10.3390/cimb47070504
Makridou A, Sintou E, Chatzianagnosti S, Dermitzakis I, Gargani S, Manthou ME, Theotokis P. Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence. Current Issues in Molecular Biology. 2025; 47(7):504. https://doi.org/10.3390/cimb47070504
Chicago/Turabian StyleMakridou, Anna, Evangelie Sintou, Sofia Chatzianagnosti, Iasonas Dermitzakis, Sofia Gargani, Maria Eleni Manthou, and Paschalis Theotokis. 2025. "Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence" Current Issues in Molecular Biology 47, no. 7: 504. https://doi.org/10.3390/cimb47070504
APA StyleMakridou, A., Sintou, E., Chatzianagnosti, S., Dermitzakis, I., Gargani, S., Manthou, M. E., & Theotokis, P. (2025). Mapping Disorders with Neurological Features Through Mitochondrial Impairment Pathways: Insights from Genetic Evidence. Current Issues in Molecular Biology, 47(7), 504. https://doi.org/10.3390/cimb47070504