A rare treatable cause of levodopa unresponsive generalized dystonia

Dear Editor, Manganese (Mn) is a trace element with antioxidant properties and is essential for various metabolic pathways involving neurotransmitter production.[1] Acquired manganese neurotoxicity has been widely reported and is popularly referred to as “manganism.” However, the inherited disorders of manganese homeostasis received the first genetic signature in 2012.[2,3] These disorders involve mutations in three manganese transporter genes: SLC30A10 and SLC39A14, which lead to manganese overload, and SLC39A8, which leads to manganese deficiency.[2] Here we report a case of generalized dystonia due to the homozygous mutation of SLC30A10 gene causing neurotoxicity presenting as hypermanganesemia with dystonia (HMNDYT) and polycythemia. A 17-year-old adolescent girl, born of nonconsanguineous parents, presented with levodopa-unresponsive generalized dystonia since the age of 14 years; none in her family had similar complaints. The patient was diagnosed as adolescent onset, generalized, progressive, persistent, complex dystonia [Videos 1 and 2] (Axis 1), with possible inherited or acquired etiology (Axis 2). The Unified Dystonia Rating Scale (UDRS) score was 20. She underwent a brain magnetic resonance imaging (MRI) with and without contrast, which demonstrated T1 hyperintensities in the bilateral basal ganglia (caudate, lentiform nucleus, globus pallidus), midbrain, and dorsal pons with pathognomonic sparing of ventral pons [Figure 1]. Laboratory evaluation indicated polycythemia with an elevated hemoglobin of 19.7 g/dl (normal 12–15), elevated bilirubin of 1.7 mg/dl (normal < 1.1), and a normal liver architecture on the ultrasound abdomen. Serum iron levels were high at 207 µg/dl (normal 35–145), ferritin 193 ng/ml (normal 10–120), and total iron binding capacity (TIBC) >500 μg/dl (normal 250–400). Serum manganese levels were elevated at 1.97 μg/L (normal 0.3–1.04). {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 1","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_4p5ciinr"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 2","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_4p5ciinr"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} Figure 1: MRI Brain T1W axial image showing hyperintensities in the globus pallidus (GP) (a) and putamen (b), cerebral peduncles of midbrain (c), dorsal pons and pathognomonic sparing of the ventral pons (d)Whole exome sequencing (WES) showed homozygous mutations in SLC30A10 gene (NM_ 018713.3), exon 1 with stop gained c.511C>T (p.Gln171Ter) variant in SLC30A10 gene. This was considered the likely pathogenic variant for the phenotype of our patient (HMNDYT 1). She was treated with oral ferrous sulfate (200 mg/day) supplementation and chelation with calcium disodium edetate (EDTA) in a dose of 1 gm/m2 infusion (with strict monitoring of other essential heavy metals) for 5 days/month for 6 months. Dietary advice was provided to restrict food sources rich in manganese (e.g., whole grains, legumes, sea food, and nuts) [Supplementary File 1]. She showed the earliest response in the form of improved lingual dystonia and is being closely monitored. HMNDYT 1 is characterized by hypermanganesemia, dystonia, liver disease, and polycythemia.[4] Neurological manifestations occur early at an age of 2–15 years, and patients may be bed-bound within 5–10 years of illness.[4] A characteristic high steppage “ slow cock walk” gait has been described.[4] Spastic paraparesis, adult-onset levodopa-unresponsive parkinsonism, and rare sensory motor axonal neuropathy have also been reported.[2,4] Cognition is unimpaired in a majority of cases.[2] A study by Garg et al.[5] reported 27 Indian children with HMNDYT, and found a female predominance and early onset age. They recognized the most common neurological features as dystonia, gait abnormality, falls, and parkinsonism, and low response to chelation in those with SLC39A14 variants compared to those with SLC30A10 variants. Lifelong chelation therapy with calcium disodium EDTA initially and oral iron supplementation is the treatment option.[3] Iron acts as a competitive ligand at Mn transporters and causes a reduction in the absorption and stabilization of serum Mn levels.[3] The closest differentials include HMNDYT 2, Wilson’s disease, organic acidemias, neurodegeneration with brain iron accumulation (NBIA), hereditary dystonias, and juvenile-onset Parkinson’s disease.[5] Various authors have described multifarious clinical phenotypes of the SLC30A10 mutation ranging from moderate generalized dystonia, irritability, insomnia, logorrhea, emotional instability, auditory and visual hallucinations,[6,7] ataxia, dysarthria, bradykinesia,[1] late-onset asymmetric parkinsonism, and early postural instability[8] to seizure as a sole neurological symptom.[9] With this case report, we emphasize the need for genetic testing in young patients with levodopa-unresponsive generalized dystonia to identify rare but reversible syndromes caused by SLC30A10 variants. A high index of suspicion to identify illness in its earliest phase and early treatment initiation can intercept poor outcomes in such patients. Acknowledgment We would like to acknowledge all our patients at Movement Disorders Clinic at NIMS. Author contribution Research project: Conception: Akshinthala Kavya, Reshma Sultana Shaik, Sireesha Yareeda, Gowri Barathidasan Organization: Akshinthala Kavya, Reshma Sultana Shaik Execution: Akshinthala Kavya, Reshma Sultana Shaik, Sireesha Yareeda Statistical analysis: Design: Reshma Sultana Shaik Execution: Akshinthala Kavya, Reshma Sultana Shaik Review and Critique: Reshma Sultana Shaik, Sireesha Yareeda Manuscript preparation: Writing of the first draft: Akshinthala Kavya, Reshma Sultana Shaik Review and Critique: Reshma Sultana Shaik, Sireesha Yareeda, Gowri Barathidasan Ethical compliance statement All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.