We presented two MPAN sisters with typical phenotypes and new gene site of mutation. The proband and her second sister also have similar clinical symptoms, and the two sisters both showed hypo-intensity in bilateral SN and GP on T(2)WI, FLAIR and SWI of MRI without the “eye-of-the-tiger” sign. These findings indicate that the main clinical symptoms, as well as the imaging findings of these patients with the novel mutation loci were similar with previously reported MPAN patients with other types of genetic mutation loci [
12]. Optic atrophy, a typical symptom of MPAN for patients with early onset, was absent in our patients [
13‐
15]. The second sister denied any vision loss during four years of follow-up. Although the two sisters suffered from the same gene mutation, the proband had faster disease progression. The condition in the proband rapidly switched to progressive deterioration after childbirth.
C19orf12 encodes a small transmembrane protein that is involved in the synthesis of free fatty acids and the expression of valine leucine and isoleucine biochemical in mitochondria to reduce the level of coenzyme A (CoA) [
16,
17]. In MPAN, the changes in physiological hormones and lipid metabolism caused by pregnancy could also influence CoA metabolism, and thus accelerate the deterioration [
18]. In addition, liver peptide hepcidin is a main regulator of systemic iron homeostasis, which controls serum iron to a relatively stable level by degrading iron transporters in enterocytes cells and macrophages [
19]. Hepcidin expression is often inhibited by iron deficiency, expansion of erythropoiesis, anemia/hypoxia and so on. Obviously, gravida are more likely than normal people to suffer from the above-mentioned conditions to cause inhibition of the expression of the iron modulators, and finally to give rise to iron overload including brain tissue [
20]. There were no studies that combined the gestation history to MPAN till now, further studies are required to verify the association. We also found that proband had refractory incontinence and severe mental symptoms at the end of the disease, but her sister did not show any of these symptoms during the course of the disease. Furthermore, fecal incontinence has never been reported in previous studies. This finding was consistent with a study from Russian, which reported that paraplegia and incontinence were symptoms indicative of disease deterioration [
21]. Therefore, incontinence, especially fecal incontinence, maybe a symbol of the advanced stage of the disease.
To date, the therapeutic options for NBIA disorders remain largely thorny. Treatments including dopaminergic drugs, anticholinergics, tetrabenazine and even deep brain stimulation surgery is unsatisfactory and none of them cannot slow the disease progression [
22]. Recently, the efficacy of DFP in iron removal for some PKAN patients has been gradually recognized and some studies shows that the earlier the disease, the more obvious the benefits [
23‐
26]. DFP is also currently considered safe in the treatment of PKAN, with no serious adverse effects and no deaths due to the use of DFP in any patients. A study with 86 PKAN patients found that anemia was the most common adverse effect in the DFP treatment group compared to the placebo group, accounting for approximately 20% of adverse effects, but none of the patients discontinued treatment due to anemia. Only three patients discontinued DFP treatment because of moderate neutropenia [
25]. DFP has also been used to treat Friedreich ataxia [
27]. The researchers found that patients tolerated small doses of DFP well (on DFP 20 mg/kg/day), some patients showed a little decline in the left ventricular mass index, and only one patient experienced reversible neutropenia, but none developed agranulocytosis. However, more adverse events, such as exacerbating ataxia, occurred in excess of 40 mg/kg/day. This study shows that in addition to the importance of detecting blood cells and cardiac ultrasound during DFP treatment, it is essential to have the correct dose of medication. Unfortunately, there were few therapeutic studies on iron chelators in MPAN. A 13-year-old patient with a 2-year treatment of DFP remained clinically stable and showed slowly decreasing brain iron contents in the SN [
28]. Another 35-years-old MPAN patient received DFP treatment for “nonsense talking”, but the therapy had to be discontinued due to gastrointestinal side effects. After the drug was stopped, he developed severe mental symptoms and incontinence soon [
1]. Our study used DFP to treat two adult sisters with MPAN, but the therapeutic effects were different. The iron deposition was a little heavier and widely in the proband (Fig.
1I and K) than that in her second sister (Fig.
1M and O), and the proband also had heavier clinical symptoms. Previous studies had shown that iron deposition was associated with disease severity, suggesting that iron overload may not represent the initiating factor that triggers neurodegeneration but remains one of the major steps in the pathological cascade [
29]. A recent study found extensive oxidative damage to lipids and proteins in neurons in 35-year-old MPAN patients’ biopsied cortical tissues indicating that iron overload likely contributed to oxidative brain damage [
1]. In the MPAN cell model, the reduction of iron levels by DFP could also alleviate oxidative damage [
30]. The findings of these studies provide a theoretical basis for the DFP treatment of MPAN. In addition, since the course of the proband’s disease was shorter than that of the second sister, it is also possible that the iron deposition rate in her brain tissue was faster than the second sister resulting in her neurological function not having time to compensate. It is worth paying attention to the proband showed initial symptoms at the age of 26, while the second sister had onset of disease at 18. A previous study also reported that MPAN in some late-onset adult patients progressed more rapidly than patients with early-onset [
31]. We also do not rule out that worsening symptoms in proband patients may be influenced by a combination of age of onset, disease severity, and pregnancy. However, the second sister did not have any serious adverse reactions during 4 years of DFP use, and the four-year stable condition in the second sister suggests that early DFP treatment may be useful in preventing further deterioration of neural function.