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Introduction Although the nature of basal ganglia hyperechogenicity in transcranial sonography (TCS) examinations remains unclear, many studies have shown associations between hyperechogenicity and iron accumulation. The role of iron in basal ganglia hyperechogenicity raises interest in the use of TCS in forms of neurodegeneration with brain iron accumulation (NBIA). Here we analyzed TCS and magnetic resonance imaging (MRI) findings among patients affected by one type of NBIA, mitochondrial membrane protein-associated neurodegeneration (MPAN). Methods Investigations using MRI and TCS were performed on 13 patients exhibiting a C19orf12 gene mutation. Results The use of T2/T2* MRI revealed hypointense lesions restricted to the globus pallidus and substantia nigra. Using TCS examination, 12 patients exhibited bilateral hyperechogenicity of the lenticular nucleus, while no patients showed substantia nigra hyperechogenicity. Conclusion Investigations with TCS revealed a distinctive hyperechogenicity pattern of the basal ganglia in MPAN patients, which might be useful for differential diagnostics. The variable TCS imaging findings in NBIA patients may result from the presence of different iron content, iron binding partners, such as ferritin and neuromelanin, as well as structural changes, such as gliosis.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a relentlessly progressive neurodegenerative disorder caused by mutations in the C19orf12 gene. C19orf12 has been implicated in playing a role in lipid metabolism, mitochondrial function, and autophagy, however, the precise functions remain unknown. To identify new robust cellular targets for small compound treatments, we evaluated reported mitochondrial function alterations, cellular signaling, and autophagy in a large cohort of MPAN patients and control fibroblasts. We found no consistent alteration of mitochondrial functions or cellular signaling messengers in MPAN fibroblasts. In contrast, we found that autophagy initiation is consistently impaired in MPAN fibroblasts and show that C19orf12 expression correlates with the amount of LC3 puncta, an autophagy marker. Finally, we screened 14 different autophagy modulators to test which can restore this autophagy defect. Amongst these compounds, carbamazepine, ABT-737, LY294002, oridonin, and paroxetine could restore LC3 puncta in the MPAN fibroblasts, identifying them as novel potential therapeutic compounds to treat MPAN. In summary, our study confirms a role for C19orf12 in autophagy, proposes LC3 puncta as a functionally robust and consistent readout for testing compounds, and pinpoints potential therapeutic compounds for MPAN.

Background Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare and devastating disease caused by pathogenic mutations in C19orf12 gene. MPAN is characterized by pathological iron accumulation in the brain and fewer than 100 cases of MPAN have been described. Although the diagnosis of MPAN has achieved a great breakthrough with the application of the whole exome gene sequencing technology, the therapeutic effect of iron chelation therapy in MPAN remains controversial. Case presentation We reported that two sisters from the same family diagnosed with MPAN had dramatically different responses to deferiprone (DFP) treatment. The diagnosis of MPAN were established based on typical clinical manifestations, physical examination, brain magnetic resonance imaging (MRI), cerebrospinal fluid analysis (CSF) and gene sequencing results. The clinical presentations of the two sisters with MPAN due to novel gene locus mutations were similar to those previously reported. There is no other difference in basic information except that the proband had a later onset age and fertility history. Both the proband and his second sister were treated with deferiprone (DFP), but they had dramatically different responses to the treatment. The proband’s condition deteriorated sharply after treatment with DFP including psychiatric symptoms and movement disorders. However, the second sister of the proband became relatively stable after receiving the DFP treatment. After four years of follow-up, the patient still denies any new symptoms of neurological deficits. Conclusion The findings of this study enriched the MPAN gene database and indicated that DFP might ameliorate symptom progression in patients without severe autonomic neuropsychiatric impairment at the early stage of the disease.

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare diseases associated with genetic mutations in several genes including C19orf12. To explore the underlying mechanism of NBIA pathogenesis, we investigated a mouse homolog of human C19orf12 gene knockout mouse model. In the brains of knockout mice, an age-dependent accumulation of abundant axonal spheroids, alongside brain iron accumulation, neuroinflammation, α-synuclein and ubiquitin pathology was observed. Axonal spheroids were associated with abnormal ER and damaged mitochondria in knockout mice. These abnormal spheroids consistently contained the tubular ER protein reticulon 3 (RTN3) even at younger ages which preceded the onset of motor symptoms. The abnormal localized expansion of axonal ER underlies swollen axon terminals of dopaminergic neurons. The accumulated neuroaxonal swellings likely impair functioning of the dopaminergic system in the substantia nigra, striatum, and other brain regions, which ultimately led to motor function deficits in knockout mice. Altogether, the absence of C19orf12 in mouse brains recapitulates cardinal features of neuropathology in human NBIA, suggesting that C19orf12 is essential to maintain the tubular ER homeostasis in neuronal axon.

Background Mitochondrial membrane protein‐associated neurodegeneration (MPAN) is caused by pathogenic sequence variants in C19orf12. Autosomal recessive inheritance has been demonstrated. We present evidence of autosomal dominant MPAN and propose a mechanism to explain these cases. Methods Two large families with apparently dominant MPAN were investigated; additional singleton cases of MPAN were identified. Gene sequencing and multiplex ligation‐dependent probe amplification were used to characterize the causative sequence variants in C19orf12. Post‐mortem brain from affected subjects was examined. Results In two multi‐generation non‐consanguineous families, we identified different nonsense sequence variations in C19orf12 that segregate with the MPAN phenotype. Brain pathology was similar to that of autosomal recessive MPAN. We additionally identified a preponderance of cases with single heterozygous pathogenic sequence variants, including two with de novo changes. Conclusions We present three lines of clinical evidence to demonstrate that MPAN can manifest as a result of only one pathogenic C19orf12 sequence variant. We propose that truncated C19orf12 proteins, resulting from nonsense variants in the final exon in our autosomal dominant cohort, impair function of the normal protein produced from the non‐mutated allele via a dominant negative mechanism and cause loss of function. These findings impact the clinical diagnostic evaluation and counseling. Autosomal recessive inheritance has been demonstrated for mitochondrial membrane protein‐associated neurodegeneration (MPAN). Here we provide 3 lines of evidence for autosomal dominant inheritance in a portion of cases: (1) a dominant inheritance pattern in 2 large, non‐consanguineous families; (2) manifestation of MPAN in 2 cases with single de novo pathogenic sequence variants; (3) a preponderance of heterozygous cases with frameshift/premature stop or nonsense variants clustering in the last exon.

Mitochondrial Membrane Protein-Associated Neurodegeneration is a rare monogenic form of neurodegeneration characterized by iron accumulation in the brain. It is due to variants in the orphan gene C19orf12. Since its definition in 2011, many scientific groups have investigated the clinical features and molecular underpinnings of the disorder. In this review, we summarize the main points of progress in this field, trying to highlight the issues that need further attention and efforts to speed up the diagnostic path, improve the existing treatment options, and define targeted therapies.

Background: Biomarker analysis in neurodegeneration with brain iron accumulation (NBIA) can offer valuable insights into the disease’s pathology and natural history. Methods: Twenty-five patients with C19orf12 mutations causing mitochondrial membrane protein-associated neurodegeneration (MPAN), 12 patients with PANK2 mutations causing pantothenate kinase-associated neurodegeneration (PKAN), and 30 age- and gender-matched controls were studied. Serum levels of MMP-9, S100B, ICAM-1, E- and P-selectins, total α-synuclein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), Tau, ubiquitin-C-terminal hydrolase-L1 (UCH-L1), and brain-derived neurotrophic factor (BDNF) were measured. Clinical status was evaluated with dedicated rating scales. Results: Compared to the control group, MPAN patients had significantly higher serum levels of nearly all biomarkers, except BDNF. NfL, GFAP, and UCH-L1, were elevated by 5, 2, and 3.5 times, respectively. PKAN patients showed no significant differences in GFAP, UCH-L1, and S100B levels compared to controls. However, NfL and Tau levels were increased by 3 and 1.8 times, respectively. A correlation was observed between disease severity and levels of NfL, Tau, and UCH-L1 in MPAN, and GFAP, Tau, and UCH-L1 in PKAN. Conclusions: Patients with MPAN and PKAN showed increased levels of neurodegeneration biomarkers. Elevated inflammation and blood–brain barrier dysfunction biomarkers were specific to MPAN patients.

Neurodegeneration with brain iron accumulation (NBIA) disorders comprise a group of rare but devastating inherited neurological diseases with unifying features of progressive cognitive and motor decline, and increased iron deposition in the basal ganglia. Although at present there are no proven disease-modifying treatments, the severe nature of these monogenic disorders lends to consideration of personalized medicine strategies, including targeted gene therapy. In this review we summarize the progress and future direction towards precision therapies for NBIA disorders. This review considered all relevant publications up to April 2021 using a systematic search strategy of PubMed and clinical trials databases. We review what is currently known about the underlying pathophysiology of NBIA disorders, common NBIA disease pathways, and how this knowledge has influenced current management strategies and clinical trial design. The safety profile, efficacy and clinical outcome of clinical studies are reviewed. Furthermore, the potential for future therapeutic approaches is also discussed. Therapeutic options in NBIAs remain very limited, with no proven disease-modifying treatments at present. However, a number of different approaches are currently under development with increasing focus on targeted precision therapies. Recent advances in the field give hope that novel strategies, such as gene therapy, gene editing and substrate replacement therapies are both scientifically and financially feasible for these conditions. This article provides an up-to-date review of the current literature about Neurodegeneration with Brain Iron Accumulation (NBIA), with a focus on disease pathophysiology, current and previously trialed therapies, and future treatments in development, including consideration of potential genetic therapy approaches.

Key Clinical Message This case report presents a progressively declining 17‐year‐old patient with membrane protein‐associated neurodegeneration who demonstrated symptomatic improvements in her dysarthria, dysphagia, and gait, and objective improvements in her 6‐minute walk test and 5 times sit‐to‐stand test during elamipretide treatment. Elamipretide mechanism of action: Restoration of physiologically normal energetics.

Objective Neurodegeneration with brain iron accumulation (NBIA) comprises rare genetic disorders characterized by predominantly extrapyramidal symptoms and iron deposition in the basal ganglia. Conventional magnetic resonance imaging (MRI) detects qualitative changes but cannot accurately quantify iron accumulation. Quantitative susceptibility mapping (QSM) allows precise in vivo quantification of iron, providing insight into the pathophysiology of the disease. Methods We studied 27 genetically confirmed NBIA patients and 11 age‐matched healthy controls using susceptibility‐weighted imaging (SWI) on a 3 Tesla MRI scanner. Basal ganglia regions of interest (ROIs) were manually delineated and QSM values were extracted. Results Sixteen NBIA patients and 11 controls were analyzed. QSM showed significantly higher iron in the globus pallidus (GP) (p = 0.008), with PKAN patients showing a 2.5‐fold increase in GP iron (p = 0.001). MPAN patients showed 2.5 times higher iron in both GP and substantia nigra (SN). A GP iron level > 0.1133 ppm increased the likelihood of PKAN 18‐fold. Atypical PKAN cases had 2.5 times higher SN iron levels compared to classic cases. Interpretation QSM is a sensitive and noninvasive tool for detecting and quantifying iron accumulation in NBIA. The GP consistently showed the highest susceptibility values across subtypes, emphasizing its significant role in disease pathology. Distinct patterns of iron deposition in different NBIA subtypes may reflect subtype‐specific mechanisms with diagnostic and therapeutic relevance. Age‐related susceptibility changes were found to be significant, reinforcing the need to account for age when interpreting QSM data. More importantly, QSM may serve as a candidate biomarker for longitudinal disease monitoring in future clinical trials targeting disease‐modifying therapies in NBIA.