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Congenital erythrocytosis recognizes heterogeneous genetic basis and despite the use of NGS technologies, more than 50% of cases are still classified as idiopathic. Herein, we describe the case of a 3-year-old boy with a rare metabolic disorder due to SLC30A10 bi-allelic mutations and characterized by hypermanganesemia, congenital erythrocytosis and neurodegeneration, also known as hypermanganesemia with dystonia 1 (HMNDYT1). The patient was treated with iron supplementation and chelation therapy with CaNa2EDTA, resulting in a significative reduction of blood manganese levels and erythrocytosis indexes. Although it couldn't be excluded that the patient's developmental impairment was part of the phenotypic spectrum of the disease, after three months from starting treatment no characteristic extrapyramidal sign was detectable. Our findings suggest the importance of assessing serum manganese levels in patients with unexplained polycythemia and increased liver enzymes. Moreover, we highlight the importance of extended genetic testing as a powerful diagnostic tool to uncover rare genetic forms of congenital erythrocytosis. In the described patient, identifying the molecular cause of erythrocytosis has proven essential for proper clinical management and access to therapeutic options.

BackgroundManganese (Mn) is an essential trace metal necessary for good health; however, excessive amounts in the body are neurotoxic. To date, three genes (SLC30A10, SLC39A8, and SLC39A14) have been discovered to cause inborn errors in Mn metabolism in humans. As very rare diseases, the clinical features require further clarification.MethodsA male Chinese patient who mainly presented with hypermanganesemia and progressive parkinsonism–dystonia was recruited for this study. We collected and analyzed clinical information, performed whole-exome sequencing (WES), and reviewed the relevant literature.ResultsThe motor-developmental milestones of the patient were delayed at the age of 4 months, followed by rapidly progressive dystonia. The patient displayed elevated Mn concentrations in blood and urine, and brain magnetic resonance imaging (MRI) showed symmetrical hyperintensity on T1-weighted images and hypointensity on T2-weighted images in multiple regions. A novel homozygous variant of the SLC39A14 gene (c.1058T > G, p.L353R) was identified. The patient was treated with disodium calcium edetate chelation (Na2CaEDTA). Three months later, mild improvement in clinical manifestation, blood Mn levels, and brain MRI was observed. To date, 15 patients from 10 families have been reported with homozygous mutations of SLC39A14, with a mean age of onset of 14.9 months. The common initial symptom is motor regression or developmental milestone delay, with a disease course for nearly all patients involving development of progressive generalized dystonia and loss of ambulation before treatment. Additionally, hypermanganesemia manifests as Mn values ranging from 4- to 25-fold higher than normal baseline levels, along with brain MRI results similar to those observed in the recruited patient. Nine SLC39A14 variants have been identified. Seven patients have been treated with Na2CaEDTA, and only one patient achieved obvious clinical improvement.ConclusionWe identified a novel SLC39A14 mutation related to autosomal recessive hypermanganesemia with dystonia-2, which is a very rare disease. Patients present motor regression or delay of developmental milestones and develop progressive generalized dystonia. Chelation therapy with Na2CaEDTA appears to effectively chelate Mn and increase urinary Mn excretion in some cases; however, clinical response varies. The outcome of the disease was unsatisfactory. This study expands the genetic spectrum of this disease.

Abstract Background Congenital portosystemic shunt (CPSS) is a rare malformation that leads to hyperammonemia, hypermanganesemia, and various symptoms. CPSSs are divided into intrahepatic and extrahepatic shunts. In patients with persistent CPSS including an intrahepatic portosystemic shunt (IPSS), early intervention to occlude the shunt reverses the associated complications. Case presentation The patient was a 1-year-and-7-month-old girl. She presented with hypergalactosemia and elevation of blood ammonia level (75 μg/dL) and total bile acid levels (68.2 μmol/L) during the neonatal period. Two IPSSs were detected using ultrasound and enhanced computerized tomography. Magnetic resonance imaging (MRI) at 1 year and 3 months of age showed abnormally high signal intensity in the pallidum of her brain. Spontaneous closure was not observed. We performed a right hepatectomy at 1 year and 7 months of age. The portal vein pressure was 16 mmHg after temporary occlusion of the right portal vein. Blood ammonia and serum manganese levels decreased immediately after the operation. The abnormal signal on brain MRI disappeared. She had a favorable course with no sign of recurrence of IPSS 5 years postoperatively. Conclusion Liver resection for an IPSS to control the symptoms of a portosystemic shunt is reasonable in a child for whom interventional radiological treatment is not indicated.

Importance: Hypermanganesemia with dystonia type 2 is a rare autosomal recessive neurodegenerative disorder characterized by the loss of previously acquired milestones, dystonia, parkinsonian features, a high serum manganese level, and characteristic neuroimaging findings such as bilateral and symmetrically increased T1 and decreased T2/fluid-attenuated inversion recovery signal intensity in the basal ganglia. This condition is secondary to a mutation in the SLC39A14 gene. Objective: To present a series of three cases of hypermanganesemia with dystonia type 2, which was genetically confirmed secondary to a mutation in the SLC39A14 gene, and to describe the treatment and clinical course in these cases. Design: A retrospective case series. Setting: University, Tertiary hospital. Participants: Three unrelated pediatric patients with hypermanganesemia with dystonia type 2, genetically confirmed to be secondary to a mutation in the SLC39A14 gene. Exposures: Chelation therapy using calcium disodium edetate. Main outcome(s) and measure(s): The response to chelation therapy based on clinical improvements in motor and cognition developments. Results: All three patients were started on chelation therapy using calcium disodium edetate, and two of them showed an improvement in their clinical course. The chelation therapy could alter the course of the disease and prevent deterioration in the clinical setting. Conclusions and Relevance: Early diagnosis and intervention with chelating agents, such as calcium disodium edetate, will help change the outcome in patients with hypermanganesemia with dystonia type 2. This finding highlights the importance of early diagnosis and treatment in improving the outcomes of patients with treatable neurodegenerative disorders.

Abstract Background Manganese is a critical trace element that not only has antioxidant properties, but also is essential for various metabolic pathways and neurotransmitters production. However, it can be toxic at high levels, particularly in the central nervous system. Manganese intoxication can be acquired, but an inherited form due to autosomal-recessive mutations in the SLC30A10 gene encoding a Mn transporter protein has also been reported recently. These mutations are associated with significant failure of manganese excretion and its storage in the liver, brain (especially basal ganglia), and other peripheral tissues, resulting in toxicity. Case presentation A 10-year-old boy from consanguineous parents presented with a history of progressive truncal instability, gait difficulty, and frequent falls for 2 months. He had dystonia, rigidity, ataxia, dysarthria, bradykinesia and a plethoric skin. Investigations showed polycythemia, low serum iron and ferritin levels, and increased total iron binding capacity. A brain MRI revealed symmetric hyperintensities in the basal ganglia and dentate nucleuses on TI images that were suggestive of brain metal deposition together with clinical manifestations. Serum calcium and copper levels were normal, while the manganese level was significantly higher than normal values. There was no history of environmental overexposure to manganese. Genetic testing showed a homozygous missense mutation in SLC30A10 (c.C1006T, p.His336Tyr) and Sanger sequencing confirmed a homozygous state in the proband and a heterozygous state in the parents. Regular treatment with monthly infusions of disodium calcium edetate and oral iron compounds resulted in decreased serum manganese and hemoglobin levels to normal values, significant resolution of MRI lesions, and partial improvement of neurological symptoms during 6 months of follow-up. Conclusion The syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia caused by SLC30A10 mutation is a treatable inherited metal deposition syndrome. The patient may only have pure neurological without hepatic manifestations. Although this is a rare and potentially fatal inborn error of metabolism, early diagnosis and continuous chelation therapy might improve the symptoms and prevent disease progression.

Manganese is an essential element that is ubiquitously present in our diet and water supply. It is a cofactor for several critical physiological processes. Elevated blood levels of Manganese secondary to SLC30A10 gene mutation presents distinctly with dystonia, polycythemia, chronic liver disease and a characteristic high T1 signal in basal ganglia on brain MRI. The primary treatment for this condition is chelation along with iron therapy. We report a previously healthy boy with compound heterozygous SLC30A10 gene mutations who had a unique clinical presentation with prominent seizures, polycythemia, and characteristic T1 hyperintensity in basal ganglia. Seizures have not been previously reported to be associated with this specific mutation.

Abstract Background The SLC39A14, SLC30A10 and SLC39A8 are considered to be key genes involved in manganese (Mn) homeostasis in humans. Mn levels in plasma and urine are useful tools for early recognition of these disorders. We aimed to explore further biomarkers of Mn deposition in the central nervous system in two siblings presenting with acute dystonia and hypermanganesemia due to mutations in SLC39A14. These biomarkers may help clinicians to establish faster and accurate diagnosis and to monitor disease progression after chelation therapy is administered. Results A customized gene panel for movement disorders revealed a novel missense variant (c.311G > T; p.Ser104Ile) in SLC39A14 gene in two siblings presenting at the age of 10 months with acute dystonia and motor regression. Mn concentrations were analyzed using inductively coupled mass spectrometry in plasma and cerebrospinal fluid, disclosing elevated Mn levels in the index case compared to control patients. Surprisingly, Mn values were 3-fold higher in CSF than in plasma. We quantified the pallidal index, defined as the ratio between the signal intensity in the globus pallidus and the subcortical frontal white matter in axial T1-weighted MRI, and found significantly higher values in the SLC39A14 patient than in controls. These values increased over a period of 10 years, suggesting the relentless pallidal accumulation of Mn. Following genetic confirmation, a trial with the Mn chelator Na2CaEDTA led to a reduction in plasma Mn, zinc and selenium levels. However, parents reported worsening of cervical dystonia, irritability and sleep difficulties and chelation therapy was discontinued. Conclusions Our study expands the very few descriptions of patients with SLC39A14 mutations. We report for the first time the elevation of Mn in CSF of SLC39A14 mutated patients, supporting the hypothesis that brain is an important organ of Mn deposition in SLC39A14-related disease. The pallidal index is an indirect and non-invasive method that can be used to rate disease progression on follow-up MRIs. Finally, we propose that patients with inherited defects of manganese transport should be initially treated with low doses of Na2CaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects.