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Dystonia with Brain Manganese Accumulation Resulting From SLC30A10 Mutations: A New Treatable Disorder

Identifieur interne : 000188 ( Pmc/Checkpoint ); précédent : 000187; suivant : 000189

Dystonia with Brain Manganese Accumulation Resulting From SLC30A10 Mutations: A New Treatable Disorder

Auteurs : Maria Stamelou [Royaume-Uni] ; Karin Tuschl [Royaume-Uni] ; W K Chong [Royaume-Uni] ; Andrew K. Burroughs [Royaume-Uni] ; Philippa B. Mills [Royaume-Uni] ; Kailash P. Bhatia [Royaume-Uni] ; Peter T. Clayton [Royaume-Uni]

Source :

RBID : PMC:3664426

Abstract

Background

The first gene causing early-onset generalized dystonia with brain manganese accumulation has recently been identified. Mutations in the SLC30A10 gene, encoding a manganese transporter, cause a syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia.

Methods

We present 10-year longitudinal clinical features, MRI data, and treatment response to chelation therapy of the originally described patient with a proven homozygous mutation in SLC30A10.

Results

The patient presented with early-onset generalized dystonia and mild hyperbilirubinemia accompanied by elevated whole-blood manganese levels. T1-sequences in MRI showed hyperintensities in the basal ganglia and cerebellum, characteristic of manganese deposition. Treatment with intravenous disodium calcium edetate led to clinical improvement and reduction of hyperintensities in brain imaging.

Conclusions

We wish to highlight this rare disorder, which, together with Wilson's disease, is the only potentially treatable inherited metal storage disorder to date, that otherwise can be fatal as a result of complications of cirrhosis. © 2012 Movement Disorder Society


Url:
DOI: 10.1002/mds.25138
PubMed: 22926781
PubMed Central: 3664426


Affiliations:

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PMC:3664426

Le document en format XML

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</TEI>
<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">Mov Disord</journal-id>
<journal-id journal-id-type="iso-abbrev">Mov. Disord</journal-id>
<journal-id journal-id-type="publisher-id">mds</journal-id>
<journal-title-group>
<journal-title>Movement Disorders</journal-title>
</journal-title-group>
<issn pub-type="ppub">0885-3185</issn>
<issn pub-type="epub">1531-8257</issn>
<publisher>
<publisher-name>Wiley Subscription Services, Inc., A Wiley Company</publisher-name>
<publisher-loc>Hoboken</publisher-loc>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">22926781</article-id>
<article-id pub-id-type="pmc">3664426</article-id>
<article-id pub-id-type="doi">10.1002/mds.25138</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Brief Reports</subject>
</subj-group>
</article-categories>
<title-group>
<article-title>Dystonia with Brain Manganese Accumulation Resulting From
<italic>SLC30A10</italic>
Mutations: A New Treatable Disorder</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Stamelou</surname>
<given-names>Maria</given-names>
</name>
<degrees>MD, PhD</degrees>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="author-notes" rid="fn1">*</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Tuschl</surname>
<given-names>Karin</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au2">2</xref>
<xref ref-type="author-notes" rid="fn1">*</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chong</surname>
<given-names>W K</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Burroughs</surname>
<given-names>Andrew K</given-names>
</name>
<xref ref-type="aff" rid="au4">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Mills</surname>
<given-names>Philippa B</given-names>
</name>
<degrees>PhD</degrees>
<xref ref-type="aff" rid="au2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Bhatia</surname>
<given-names>Kailash P</given-names>
</name>
<degrees>FRCP</degrees>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="author-notes" rid="fn1">*</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Clayton</surname>
<given-names>Peter T</given-names>
</name>
<degrees>MD</degrees>
<xref ref-type="aff" rid="au2">2</xref>
<xref ref-type="author-notes" rid="fn1">*</xref>
<xref ref-type="corresp" rid="cor1">†</xref>
</contrib>
<aff id="au1">
<label>1</label>
<institution>Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology</institution>
<addr-line>London, United Kingdom</addr-line>
</aff>
<aff id="au2">
<label>2</label>
<institution>Clinical and Molecular Genetics Unit, University College London Institute of Child Health</institution>
<addr-line>London, United Kingdom</addr-line>
</aff>
<aff id="au3">
<label>3</label>
<institution>Department of Radiology, Great Ormond Street Hospital for Children</institution>
<addr-line>London, United Kingdom</addr-line>
</aff>
<aff id="au4">
<label>4</label>
<institution>The Liver, Pancreatic, Biliary and Transplant Unit, The Wellington Hospital</institution>
<addr-line>London, United Kingdom</addr-line>
</aff>
</contrib-group>
<author-notes>
<corresp id="cor1">
<bold>†Correspondence to:</bold>
Prof. P.T. Clayton, Clinical and Molecular Genetics Unit, University College London Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, United Kingdom;
<email>peter.clayton@ucl.ac.uk</email>
</corresp>
<fn>
<p>
<bold>Funding agencies:</bold>
P.T.C. is funded by the Great Ormond Street Hospital Children's Charity.</p>
</fn>
<fn>
<p>
<bold>Relevant conflicts of interest/financial disclosures:</bold>
Nothing to report.</p>
</fn>
<fn>
<p>Full financial disclosures and author roles may be found in the online version of this article.</p>
</fn>
<fn id="fn1">
<label>*</label>
<p>These authors contributed equally.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub">
<day>01</day>
<month>9</month>
<year>2012</year>
</pub-date>
<pub-date pub-type="epub">
<day>23</day>
<month>8</month>
<year>2012</year>
</pub-date>
<volume>27</volume>
<issue>10</issue>
<fpage>1317</fpage>
<lpage>1322</lpage>
<history>
<date date-type="received">
<day>21</day>
<month>2</month>
<year>2012</year>
</date>
<date date-type="rev-recd">
<day>22</day>
<month>5</month>
<year>2012</year>
</date>
<date date-type="accepted">
<day>03</day>
<month>7</month>
<year>2012</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright © 2012 Movement Disorder Society</copyright-statement>
<copyright-year>2012</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.5/">
<license-p>Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.</license-p>
</license>
</permissions>
<abstract>
<sec>
<title>Background</title>
<p>The first gene causing early-onset generalized dystonia with brain manganese accumulation has recently been identified. Mutations in the
<italic>SLC30A10</italic>
gene, encoding a manganese transporter, cause a syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia.</p>
</sec>
<sec>
<title>Methods</title>
<p>We present 10-year longitudinal clinical features, MRI data, and treatment response to chelation therapy of the originally described patient with a proven homozygous mutation in
<italic>SLC30A10</italic>
.</p>
</sec>
<sec>
<title>Results</title>
<p>The patient presented with early-onset generalized dystonia and mild hyperbilirubinemia accompanied by elevated whole-blood manganese levels. T1-sequences in MRI showed hyperintensities in the basal ganglia and cerebellum, characteristic of manganese deposition. Treatment with intravenous disodium calcium edetate led to clinical improvement and reduction of hyperintensities in brain imaging.</p>
</sec>
<sec>
<title>Conclusions</title>
<p>We wish to highlight this rare disorder, which, together with Wilson's disease, is the only potentially treatable inherited metal storage disorder to date, that otherwise can be fatal as a result of complications of cirrhosis. © 2012 Movement Disorder Society</p>
</sec>
</abstract>
<kwd-group>
<kwd>dystonia</kwd>
<kwd>hypermanganesemia</kwd>
<kwd>cirrhosis</kwd>
<kwd>polycythemia</kwd>
<kwd>SLC30A10</kwd>
</kwd-group>
</article-meta>
</front>
<body>
<p>The first inborn error of manganese metabolism has recently been identified.
<xref ref-type="bibr" rid="b1">1</xref>
This autosomal recessive condition caused by mutations in the
<italic>SLC30A10</italic>
(Solute Carrier Family 30, Member 10) gene, encoding a manganese transporter, results in manganese accumulation, mainly in the basal ganglia and cerebellum, and the liver, and causes a syndrome of early-onset generalized dystonia, cirrhosis, polycythemia, and hypermanganesemia.
<xref ref-type="bibr" rid="b1">1</xref>
–
<xref ref-type="bibr" rid="b3">3</xref>
</p>
<p>Twenty affected individuals from 10 families have been described by two independent groups.
<xref ref-type="bibr" rid="b1">1</xref>
,
<xref ref-type="bibr" rid="b2">3</xref>
Seventeen affected members from eight families presented with young-onset (2–14 years) generalized dystonia, whereas 1 affected member presented with spastic paraparesis without dystonia. Interestingly, the 2 affected individuals from an Italian family presented with late-onset (age 47 and 57 years) asymmetric parkinsonism, early postural instability, and asymptomatic hepatomegaly,
<xref ref-type="bibr" rid="b3">3</xref>
implying that the phenotypical spectrum of this disorder, with regard to both the neurological and hepatic manifestations, is wide. MRI of the brain typically shows hyperintensities in the basal ganglia and subthalamic and dentate nucleus on T1-weighted images, characteristic of manganese deposition.</p>
<p>The metabolic signature of this disorder is the extreme hypermanganesemia with polycythemia and depleted iron stores (e.g., low ferritin and increased total iron binding capacity), whereas laboratory findings reflecting hepatic dysfunction vary even between members of the same family.
<xref ref-type="bibr" rid="b1">1</xref>
,
<xref ref-type="bibr" rid="b2">3</xref>
Manganese induces erythropoietin gene expression and this could be the mechanism leading to polycythemia.
<xref ref-type="bibr" rid="b4">4</xref>
The depleted iron stores can be explained by the fact that hypermanganesemia favors the release of iron from intracellular stores, enhances iron uptake, and decreases iron utilization.
<xref ref-type="bibr" rid="b5">5</xref>
–
<xref ref-type="bibr" rid="b8">8</xref>
</p>
<p>Here, we present longitudinal videos, clinical data, serial MRI images, and treatment response to chelation therapy over 10 years of the originally described case with a proven homozygous mutation in
<italic>SLC30A10</italic>
.
<xref ref-type="bibr" rid="b2">2</xref>
</p>
<sec>
<title>Case Presentation</title>
<p>This 22-year-old lady of Arabic origin was born to healthy first-cousin parents from a normal pregnancy and had an uncomplicated delivery and neonatal period. At the age of 2 years, she developed difficulty walking, which subsided for some years, but worsened again at the age of 11. At 12 years, she was mildly icteric with palpable hepatomegaly. Neurological examination revealed generalized dystonia, reduced arm-swing when walking, and increased tone in all four limbs, but no spasticity and no bradykinesia
<xref ref-type="bibr" rid="b2">2</xref>
(see Video, Segment 1). She had one brother, who presented with a similar clinical syndrome and died after complications of cirrhosis at the age of 18, and seven healthy siblings.</p>
<p>Blood tests revealed polycythemia, hypermanganesemia, unconjugated hyperbilirubinemia, and increased total iron-binding capacity (TIBC) (Supporting
<xref ref-type="table" rid="tbl1">Table 1</xref>
).
<xref ref-type="bibr" rid="b2">2</xref>
MRI of the brain (age 12; 2002) showed hyperintensities on T1-weighted sequences in the basal ganglia (caudate and lentiform nuclei), cerebellum (dentate nuclei and white matter), and anterior pituitary (
<xref ref-type="fig" rid="fig01">Fig. 1</xref>
A); hypointensities in these areas were present, to a much lesser extent, in T2-weighted sequences.
<xref ref-type="bibr" rid="b2">2</xref>
Liver biopsy confirmed micronodular cirrhosis associated with elevated hepatic manganese content (Supporting
<xref ref-type="table" rid="tbl1">Table 1</xref>
).
<xref ref-type="bibr" rid="b2">2</xref>
Recently, genetic testing has identified a homozygous mutation in the
<italic>SLC30A10</italic>
gene (nine-base deletion in exon 1 [c.314_c.322] resulting in a deletion of three amino acids [p.Ala105_Pro107] of the protein).
<xref ref-type="bibr" rid="b1">1</xref>
</p>
<fig id="fig01" position="float">
<label>FIG. 1</label>
<caption>
<p>Serial MRI brain over a 10-year follow-up. (
<bold>A</bold>
) T1-sequences at the age of 12 (2002), before treatment. (
<bold>B</bold>
) T1-sequences at the age of 15 (2005), 3 years after treatment, slightly improved, compared to (
<bold>A</bold>
). (
<bold>C</bold>
) T1-sequences at the age of 16 (2006), 4 years under treatment, 1 year after increasing the frequency of infusions, and 1 month after adding oral ferrous iron, hyperintensities are less pronounced than before. (
<bold>D</bold>
) T1-sequences at the age of 20 (2010), 1 year after reducing chelation therapy, because of a lack of supplies. There is reaccumulation of manganese, compared to MRI 4 years earlier (
<bold>C</bold>
). (
<bold>E</bold>
) T1-sequences at the age of 21 (2011), 1 year after increasing the frequency of infusions, overall 9 years after onset of treatment, hyperintensities have clearly diminished.</p>
</caption>
<graphic xlink:href="mds0027-1317-f1"></graphic>
</fig>
<p>Initial treatment with levodopa (120 mg/day) led to a mild improvement of dystonia. Vitamin E (100 mg/day) and a multivitamin preparation (Ketovite) were started to recover low vitamin E levels (Supporting
<xref ref-type="table" rid="tbl1">Table 1</xref>
). Chelation therapy with oral D-penicillamine (250 mg/6-hourly over 24 hours) led to a mild increase of urinary manganese excretion (from <91 nmol before treatment to 240 nmol after 24 hours).
<xref ref-type="bibr" rid="b2">2</xref>
In contrast, intravenous disodium calcium edetate (CaNa
<sub>2</sub>
-EDTA [ethylenediaminetetraacetic acid]), 1 g twice-daily (BD) over 5 days led to significantly increased 24-hour urinary manganese (12,852 nmol after 5 days) and reduced blood manganese levels (from 2,800 to 1,780 nmol/L after 2 months) and improvement of dystonia.
<xref ref-type="bibr" rid="b2">2</xref>
Hence, CaNa
<sub>2</sub>
-EDTA was the treatment of choice and continued as a 5-day monthly course. Zinc levels decreased during chelation treatment therefore zinc sulphate was added (125 mg BD).</p>
<p>At the age of 15, after 3 years of treatment, icterus had resolved and dystonia moderately improved (Supporting
<xref ref-type="table" rid="tbl1">Table 1</xref>
; see Video, Segment 2). However, brain MRI had only slightly improved (age 15; 2005) (
<xref ref-type="fig" rid="fig01">Fig. 1</xref>
B), and blood manganese levels were still high (2,322 nmol/L); therefore, CaNa
<sub>2</sub>
-EDTA was increased to 8 days/month. Oral ferrous fumarate (Fe) (204 mg/day) was added to decrease intestinal manganese absorption.
<xref ref-type="bibr" rid="b8">8</xref>
One year after these adjustments (age 16; 2006), blood manganese had dramatically fallen; MRI (
<xref ref-type="fig" rid="fig01">Fig. 1</xref>
C) and liver histology had improved (Supporting
<xref ref-type="table" rid="tbl1">Table 1</xref>
). To avoid Fe toxicity, dosage was reduced because serum iron had reached abnormally high levels.</p>
<p>Because of a lack of supplies in her home country, she was treated less frequently with both CaNa
<sub>2</sub>
-EDTA and Fe over the duration of 1 year (from 19 to 20 years). This led to worsening of dystonia, increase in blood manganese levels, and more prominent hyperintensities in brain MRI (age 20; 2010) (
<xref ref-type="fig" rid="fig01">Fig. 1</xref>
D). Treatment was reintroduced and, at the age of 21, dystonia had improved (see Video, Segment 3). MRI showed reduced hyperintensities, compared to previous MRI images (age 21; 2011) (
<xref ref-type="fig" rid="fig01">Fig. 1</xref>
E). No susceptibility-related signal loss was evident on gradient echo images. Dopamine transporter imaging (DaTSCAN) was normal.</p>
</sec>
<sec>
<title>Discussion and Conclusion</title>
<p>Here, we present the clinical description over 10 years, serial brain imaging, and response to chelation treatment of a patient with generalized dystonia, hypermanganesemia, cirrhosis, and polycythemia resulting from
<italic>SLC30A10</italic>
mutations.
<xref ref-type="bibr" rid="b2">2</xref>
Diagnosis of this inherited metal storage disorder should not be missed because it is potentially treatable. Therefore, as for Wilson's disease (WD), we suggest that manganese blood levels should be routinely tested alongside copper and ceruloplasmin in the initial diagnostic work-up of patients with young-onset generalized dystonia.</p>
<p>Inherited disorders with mineralization evident on brain imaging may cause a variety of neurological syndromes, with different age of onset, phenotypes, and associated systemic abnormalities.
<xref ref-type="bibr" rid="b9">9</xref>
These comprise WD, as a result of mutations in the
<italic>ATP7B</italic>
gene, encoding a copper transport ATPase,
<xref ref-type="bibr" rid="b10">10</xref>
brain iron-accumulation syndromes (NBIAs),
<xref ref-type="bibr" rid="b11">11</xref>
,
<xref ref-type="bibr" rid="b2">12</xref>
syndromes with brain calcium depositions (e.g., Fahr's disease),
<xref ref-type="bibr" rid="b13">13</xref>
and the syndrome described here with manganese accumulation. In contrast to manganese deposition, characterized by hyperintensities in T1-sequences, brain MRI in WD shows, among other features, hyperintensities in the basal ganglia in T2-sequences and the pathognomonic “giant panda face” in the midbrain
<xref ref-type="bibr" rid="b14">14</xref>
; NBIAs cause distinct patterns of iron deposition for each disorder in T2* sequences,
<xref ref-type="bibr" rid="b15">15</xref>
,
<xref ref-type="bibr" rid="b2">16</xref>
whereas calcifications are best evident as hyperintensities in CT. A phase II study with the iron chelator, deferiprone, in pantothenate kinase-associated neurodegeneration showed reduced iron in MRI after treatment, but no clinical improvement.
<xref ref-type="bibr" rid="b17">17</xref>
Hence, WD and
<italic>SLC30A10</italic>
mutations are, to date, the only treatable conditions among these disorders.</p>
<p>Hypermanganesemia with brain manganese accumulation has been described in environmental overexposure (e.g., miners and smelters), in acquired hepatocerebral degeneration (AHD), after use of ephedrone, containing potassium permanganate, and in patients receiving parenteral nutrition.
<xref ref-type="bibr" rid="b18">18</xref>
–
<xref ref-type="bibr" rid="b22">22</xref>
The clinical characteristics of these conditions may vary (
<xref ref-type="table" rid="tbl1">Table 1</xref>
).
<xref ref-type="bibr" rid="b18">18</xref>
,
<xref ref-type="bibr" rid="b22">22</xref>
–
<xref ref-type="bibr" rid="b27">27</xref>
For example, patients with environmental manganism present typically with parkinsonism, early postural instability, and psychiatric features, whereas in AHD, ataxia and orobucco-lingual dyskinesias are common. The distribution of hyperintensities in T1-MRI sequences are similar and cannot differentiate between these disorders.
<xref ref-type="bibr" rid="b28">28</xref>
,
<xref ref-type="bibr" rid="b2">29</xref>
Similarly, DaTSCAN is normal in both secondary hypermanganesemia and patients with
<italic>SLC30A10</italic>
mutations.</p>
<table-wrap id="tbl1" position="float">
<label>Table 1</label>
<caption>
<p>Clinical characteristics, laboratory findings, and response to various treatments in manganism resulting from various etiologies</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<th align="left" rowspan="1" colspan="1">Cause of Hypermanganesemia With Brain Manganese Accumulation</th>
<th align="center" rowspan="1" colspan="1">
<italic>SLC30A10</italic>
Mutations
<xref ref-type="bibr" rid="b1">1</xref>
–
<xref ref-type="bibr" rid="b3">3</xref>
,
<xref ref-type="bibr" rid="b35">35</xref>
</th>
<th align="center" rowspan="1" colspan="1">Environmental Overexposure
<xref ref-type="bibr" rid="b20">20</xref>
,
<xref ref-type="bibr" rid="b23">23</xref>
,
<xref ref-type="bibr" rid="b27">27</xref>
,
<xref ref-type="bibr" rid="b28">28</xref>
,
<xref ref-type="bibr" rid="b32">32</xref>
–
<xref ref-type="bibr" rid="b34">34</xref>
,
<xref ref-type="bibr" rid="b37">37</xref>
,
<xref ref-type="bibr" rid="b38">38</xref>
</th>
<th align="center" rowspan="1" colspan="1">AHD
<xref ref-type="bibr" rid="b18">18</xref>
,
<xref ref-type="bibr" rid="b19">19</xref>
,
<xref ref-type="bibr" rid="b30">30</xref>
,
<xref ref-type="bibr" rid="b39">39</xref>
</th>
<th align="center" rowspan="1" colspan="1">Ephedrone
<xref ref-type="bibr" rid="b22">22</xref>
,
<xref ref-type="bibr" rid="b29">29</xref>
,
<xref ref-type="bibr" rid="b40">40</xref>
,
<xref ref-type="bibr" rid="b41">41</xref>
</th>
<th align="center" rowspan="1" colspan="1">Parenteral Nutrition
<xref ref-type="bibr" rid="b21">21</xref>
,
<xref ref-type="bibr" rid="b42">42</xref>
–
<xref ref-type="bibr" rid="b46">46</xref>
</th>
</tr>
</thead>
<tbody>
<tr>
<td align="left" rowspan="1" colspan="1">Age at onset</td>
<td align="center" rowspan="1" colspan="1">Typically childhood (two adults)
<xref ref-type="bibr" rid="b3">3</xref>
</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">Typically >50 (rarely children)</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">Family history</td>
<td align="center" rowspan="1" colspan="1">Recessive</td>
<td align="center" rowspan="1" colspan="1">Typically negative</td>
<td align="center" rowspan="1" colspan="1">Typically negative</td>
<td align="center" rowspan="1" colspan="1">Typically negative</td>
<td align="center" rowspan="1" colspan="1">Typically negative</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">Clinical features</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Bradykinesia/rigidity (typically symmetric)</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">+++</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">+++</td>
<td align="center" rowspan="1" colspan="1">+</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Postural instability (typically early)</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">+++</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">+++</td>
<td align="center" rowspan="1" colspan="1">+</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Tremor (rarely rest-tremor; mostly postural-, action tremor)</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Dystonia</td>
<td align="center" rowspan="1" colspan="1">+++</td>
<td align="center" rowspan="1" colspan="1">++</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">++</td>
<td align="center" rowspan="1" colspan="1">++</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Chorea</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Myoclonus (mainly asterixis)</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">++</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Dyskinesias (typically orobucco-lingual)</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">+++</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Slowing of vertical saccades—SGP</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Dysarthria</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">+</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Ataxia</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">+++</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Spasticity</td>
<td align="center" rowspan="1" colspan="1">(+) One patient
<xref ref-type="bibr" rid="b35">35</xref>
</td>
<td align="center" rowspan="1" colspan="1">− (In some brisk reflexes)</td>
<td align="center" rowspan="1" colspan="1">− (In some brisk reflexes)</td>
<td align="center" rowspan="1" colspan="1">(+) One patient
<xref ref-type="bibr" rid="b40">40</xref>
</td>
<td align="center" rowspan="1" colspan="1">− (In some brisk reflexes)</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Neuropsychiatric features</td>
<td align="center" rowspan="1" colspan="1">(+) One patient
<xref ref-type="bibr" rid="b47">47</xref>
</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">+++</td>
<td align="center" rowspan="1" colspan="1">++</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Cognitive dysfunction</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">++</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">Laboratory findings</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Manganese serum levels (normal: <320 nmol/L)</td>
<td align="center" rowspan="1" colspan="1">↑↑↑ (e.g., range: 1,145−6,370)
<xref ref-type="bibr" rid="b1">1</xref>
</td>
<td align="center" rowspan="1" colspan="1">↑ (e.g., <2,000)</td>
<td align="center" rowspan="1" colspan="1">↑ (e.g., range: 379−989)
<xref ref-type="bibr" rid="b19">19</xref>
</td>
<td align="center" rowspan="1" colspan="1">↑ (e.g., active- [201−2,102; former-users <727]
<xref ref-type="bibr" rid="b30">30</xref>
)</td>
<td align="center" rowspan="1" colspan="1">↑ (e.g., range: 615–1,840)
<xref ref-type="bibr" rid="b45">45</xref>
</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Depleted iron stores</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Polycythemia</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Liver dysfunction</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">+</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1">Treatment</td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
<td rowspan="1" colspan="1"></td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Levodopa
<xref ref-type="table-fn" rid="tf1-1">a</xref>
(PO)</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> CaNa
<sub>2</sub>
-EDTA (IV)</td>
<td align="center" rowspan="1" colspan="1">++</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">+</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Dimercaptosuccinic acid (IV)</td>
<td align="center" rowspan="1" colspan="1">(+) Two siblings
<xref ref-type="bibr" rid="b1">1</xref>
</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Para-aminosalicylic acid (IV)</td>
<td align="center" rowspan="1" colspan="1">(−) One patient
<xref ref-type="bibr" rid="b47">47</xref>
</td>
<td align="center" rowspan="1" colspan="1">+/−</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Trientine (PO)</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">(+) One patient
<xref ref-type="bibr" rid="b36">36</xref>
</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> D-penicillamine (PO)</td>
<td align="center" rowspan="1" colspan="1">(−) One patient
<xref ref-type="bibr" rid="b2">2</xref>
</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
<td align="center" rowspan="1" colspan="1">Not tried</td>
</tr>
<tr>
<td align="left" rowspan="1" colspan="1"> Other</td>
<td align="center" rowspan="1" colspan="1">+++Oral iron supplementation</td>
<td align="center" rowspan="1" colspan="1">−</td>
<td align="center" rowspan="1" colspan="1">Lowering blood ammonia, branched-chain amino acids, liver transplantation</td>
<td align="center" rowspan="1" colspan="1">Substance abstinence, amantadine, clonazepam, cerebrolysin
<xref ref-type="table-fn" rid="tf1-2">b</xref>
<xref ref-type="bibr" rid="b48">48</xref>
</td>
<td align="center" rowspan="1" colspan="1">Supplement withdrawal</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="tf1-1">
<label>a</label>
<p>+Mild to moderate effect; rarely formally tested, mostly in combination with other treatments.</p>
</fn>
<fn id="tf1-2">
<label>b</label>
<p>Cerebrolysin is produced by enzymatic breakdown of purified brain proteins and consists of low-molecular-weight peptides and amino acids.</p>
</fn>
<fn>
<p>Abbreviations: SGP, supranuclear gaze palsy; PO, per oral; IV, intravenously, AHD, acquired hepatocerebral degeneration.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<p>However, there are certain laboratory findings underpinning the syndrome described here that should prompt testing for
<italic>SLC30A10</italic>
mutations in patients with hypermanganesemia. First, hypermanganesemia in
<italic>SLC30A10</italic>
mutations is usually much higher than in other causes of manganism (
<xref ref-type="table" rid="tbl1">Table 1</xref>
).
<xref ref-type="bibr" rid="b1">1</xref>
,
<xref ref-type="bibr" rid="b3">3</xref>
,
<xref ref-type="bibr" rid="b22">22</xref>
,
<xref ref-type="bibr" rid="b26">26</xref>
Second, polycythemia and depleted iron stores (e.g., low ferritin and high TIBC), as observed in patients with
<italic>SLC30A10</italic>
mutations, have not been observed in other causes of manganism (
<xref ref-type="table" rid="tbl1">Table 1</xref>
). Among the various causes of manganism, the main cause that may need to be differentiated from
<italic>SLC30A10</italic>
mutations is AHD, in particular, when the etiology of the primary liver dysfunction is unclear (e.g., cryptogenic liver cirrhosis), whereas the diagnosis of environmental overexposure, ephedrone use, and parenteral nutrition is facilitated by history, in most cases. These parameters may therefore be helpful to correctly identify patients with
<italic>SLC30A10</italic>
mutations. Moreover, because the full phenotypical spectrum of this disorder is, as yet, not known, these parameters may help in identifying patients with other phenotypical manifestations that may belong to this syndrome.</p>
<p>With regard to treatment, this should be initiated early and continued lifelong because the disorder may otherwise be fatal as a result of cirrhosis, but also to alleviate disability, because several patients have become wheelchair bound, when remaining untreated.
<xref ref-type="bibr" rid="b1">1</xref>
CaNa
<sub>2</sub>
-EDTA infusions were effective in our and further patients with
<italic>SLC30A10</italic>
mutations,
<xref ref-type="bibr" rid="b1">1</xref>
,
<xref ref-type="bibr" rid="b2">3</xref>
whereas the effect may vary in patients with other causes of manganism (
<xref ref-type="table" rid="tbl1">Table 1</xref>
).
<xref ref-type="bibr" rid="b22">22</xref>
,
<xref ref-type="bibr" rid="b25">25</xref>
,
<xref ref-type="bibr" rid="b30">30</xref>
,
<xref ref-type="bibr" rid="b31">31</xref>
</p>
<p>Dimercaptosuccinic acid, a further chelating agent, has been suggested to have some effect in 2 siblings with
<italic>SLC30A10</italic>
mutations,
<xref ref-type="bibr" rid="b1">1</xref>
but not in manganese overexposure.
<xref ref-type="bibr" rid="b32">32</xref>
,
<xref ref-type="bibr" rid="b2">33</xref>
Sodium para-aminosalicylic acid may also act as a manganese-chelating agent and has been shown to be useful in patients with environmental manganese exposure and ephedrone users,
<xref ref-type="bibr" rid="b34">34</xref>
but was not beneficial in 1 patient with
<italic>SLC30A10</italic>
mutations.
<xref ref-type="bibr" rid="b1">1</xref>
,
<xref ref-type="bibr" rid="b2">35</xref>
With regard to chelators commonly used in WD, D-penicillamine did not seem to be the treatment of choice in our patient, whereas 1 patient with manganism resulting from environmental overexposure has been reported to have improved with trientine (
<xref ref-type="table" rid="tbl1">Table 1</xref>
).
<xref ref-type="bibr" rid="b36">36</xref>
Chelation therapy needs strict monitoring of other essential heavy metals, such as zinc, that may need to be supplemented. Moreover, additional oral iron supplementation seems to be crucial in the treatment of this syndrome because it limits intestinal dietary manganese absorption by competing with manganese for similar transport proteins (e.g., divalent metal transporter-1 and the transferrin/transferrin receptor system).
<xref ref-type="bibr" rid="b8">8</xref>
</p>
<p>Identification of further families and individuals with
<italic>SLC30A10</italic>
mutations will be important to unravel the true phenotypical spectrum and evolution of this disorder. Moreover, it would be of interest to investigate patients with manganism attributed to other causes for mutations or polymorphisms in this gene, which may explain why some individuals may be more prone to develop manganism than others when overexposed to manganese. Finally, further chelating agents, preferably administrable orally, and long-term follow up of various treatment outcomes are needed.</p>
</sec>
<sec>
<title>Legends to the Video</title>
<p>
<bold>Video Segment 1.</bold>
The patient at the age of 12 before treatment, with dystonia affecting the limbs more on the right than the left, slowness of finger movements without true bradykinesia, dystonic gait, and reduced arm swing on both sides when walking.</p>
<p>
<bold>Video Segment 2.</bold>
The patient at 15, 3 years under treatment with mild improvement of dystonia, mostly on the right hand and improved gait.</p>
<p>
<bold>Video Segment 3.</bold>
The patient 9 years under treatment, with dystonic grimacing and dystonia of the limbs affecting more the left side. There is slowness in tapping, but no true bradykinesia. There is a slight terminal tremor on the left. There is in-turning of the right foot when walking.</p>
</sec>
</body>
<back>
<ack>
<p>The authors thank the patient for the cooperation and the permission to publish the videos.</p>
</ack>
<ref-list>
<title>References</title>
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<person-group person-group-type="author">
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<given-names>K</given-names>
</name>
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<given-names>PT</given-names>
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<suffix>Jr</suffix>
</name>
<etal></etal>
</person-group>
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, a manganese transporter in man</article-title>
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