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Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease

, MD, , MD, , MD, PhD, and , PhD.

Author Information
, MD
Clinical and Molecular Genetics Unit
UCL Institute of Child Health
London, United Kingdom
, MD
Clinical and Molecular Genetics Unit
UCL Institute of Child Health
London, United Kingdom
, MD, PhD
Departments of Neurology and Pediatrics
University of Washington
Seattle Children’s Hospital
Seattle, Washington
, PhD
Clinical and Molecular Genetics Unit
UCL Institute of Child Health
London, United Kingdom

Initial Posting: ; Last Revision: November 8, 2012.

Summary

Disease characteristics. The disorder dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease is characterized by:

  • Hepatomegaly with variable hepatic fibrosis/cirrhosis;
  • A movement disorder resulting from manganese accumulation in the basal ganglia;
  • Polycythemia with hemoglobin concentrations between 15.9 and 22.5 g/dL; and
  • Whole-blood manganese concentrations that often exceed 2000 nmol/L (normal: <320 nmol/L).

Neurologic findings can either manifest in childhood (ages 2-15 years) as four-limb dystonia, leading to a characteristic high-stepping gait (“cock-walk gait”), dysarthria, fine tremor, and bradykinesia or on occasion spastic paraplegia, or in adulthood as Parkinsonism (shuffling gait, rigidity, bradykinesia, hypomimia, and monotone speech) unresponsive to L-dopa treatment. Hepatic involvement determines life expectancy.

Diagnosis/testing. The diagnosis is suggested by characteristic clinical and brain MRI findings, elevated whole-blood concentration of manganese, and polycythemia. It is confirmed by identification of biallelic mutations in SLC30A10.

Management. Treatment of manifestations: Regular chelation therapy with intravenous disodium calcium edetate in two affected individuals improved blood manganese levels and neurologic findings and caused signs of liver disease to disappear. In addition, supplementation with oral iron therapy (despite normal serum iron levels) can reduce blood manganese levels and resolve polycythemia. Liver transplantation should be considered in individuals with end-stage liver disease, although it has not yet been attempted in this disorder.

Prevention of primary manifestations: Chelation therapy and iron supplementation may prevent primary disease manifestations in affected asymptomatic sibs.

Prevention of secondary complications: Modifying treatment if adverse effects of disodium calcium edetate chelation therapy (hypocalcemia, nephrotoxicity, trace metal and vitamin deficiency, and thrombocytopenia and leukopenia) or iron supplementation (iron toxicity) become evident.

Agents/circumstances to avoid: Foods very high in manganese: cloves; saffron; wheat; nuts; mussels; dark chocolate; and pumpkin, sesame, and sunflower seeds

Evaluation of relatives at risk: Because chelation therapy and iron supplementation could prevent primary disease manifestations in affected asymptomatic individuals, it is recommended that at-risk sibs of a proband be evaluated either by molecular genetic testing (if the disease-causing mutations in the family are known) or by periodic monitoring whole-blood manganese concentration.

Genetic counseling. Dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the disease-causing mutations have been identified in the family, prenatal testing is possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

The diagnosis of dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease is suggested by characteristic clinical and brain MRI findings. It is confirmed by identification of biallelic mutations in SLC30A10 [Quadri et al 2012, Tuschl et al 2012].

Clinical findings. An early- and a late-onset form exist, both associated with chronic liver disease:

  • Childhood-onset form (between ages 2 and 15 years). Usually four-limb dystonia (leading to a characteristic high-stepping gait (“cock-walk gait”), dysarthria, fine tremor, and bradykinesia [Tuschl et al 2012] or on occasion spastic paraplegia [Gospe et al 2000]
  • Adult-onset form. Parkinsonism (shuffling gait, rigidity, bradykinesia, hypomimia, and monotone speech) unresponsive to L-dopa treatment [Quadri et al 2012]

Brain MRI. T1-weighted images show characteristic hyperintensity of the basal ganglia including the globus pallidus; putamen; and caudate, subthalamic, and dentate nuclei with sparing of the thalamus and ventral pons. When the disease is extensive, white matter and anterior pituitary involvement can be present.

T2-weighted images also show changes, however, to a much lesser extent: they are often reported as normal.

Note: Normalization of manganese blood levels (see Management) improves the findings on brain MRI [Quadri et al 2012, Tuschl et al 2012].

See Figure 1

Figure 1

Figure

Figure 1. Representative brain MRI of an affected individual
A. Transaxial T1-weighted images: Note abnormally high signal return from all white matter as well as more prominent signal return from the putamen and globus pallidus bilaterally. (more...)

Hypermanganesemia

Affected individuals. Whole-blood manganese concentrations are elevated in all affected individuals. Average in affected individuals is greater than 2000 nmol/L (normal: <320 nmol/L). In contrast, blood manganese concentration in acquired hypermanganesemia is usually less than 2000 nmol/L.

Note: (1) Due to limited data, the onset of hypermanganesemia is not accurately known. Raised whole-blood manganese concentrations have been recorded in affected children as young as age five years. However, given that clinical manifestations can be apparent in the first two years of life, it is expected that hypermanganesemia develops concurrently or prior to onset of clinical manifestations. (2) Hypermanganesemia due to environmental overexposure (including parenteral nutrition) and acquired hepatocerebral degeneration in persons with end-stage liver disease must be excluded. See Differential Diagnosis. (3) Quadri et al [2012] reported one affected individual whose blood manganese concentration was only minimally increased on one occasion; therefore, a single measurement of manganese concentration could be misleading and repeat measurements are recommended when the clinical suspicion is strong. (4) Chelation therapy and iron supplementation can normalize blood manganese concentration (see Management) [Quadri et al 2012, Tuschl et al 2012].

Heterozygotes. Blood manganese concentrations of carriers are within normal limits or are mildly elevated. Gospe et al [2000] reported a borderline high blood manganese concentration of 380 nmol/L in an obligate heterozygous parent and Tuschl et al [2012] reported levels between 380 and 649 nmol/L in three heterozygous parents (normal: <320 nmol/L).

Corroborative features

  • Polycythemia. Manganese induces expression of the gene encoding erythropoietin [Ebert & Bunn 1999]. Characteristically, affected individuals are polycythemic with hemoglobin concentrations between 15.9 and 22.5 g/dL (mean: 18.6 g/dL) and can have elevated erythropoietin levels [Quadri et al 2012, Tuschl et al 2012].
  • Markers of depleted iron stores. Manganese and iron compete for the same serum-binding protein (transferrin) and membranous transporter protein (divalent metal transporter 1). Therefore, affected individuals show low serum ferritin concentration and serum iron levels while total iron binding capacity is elevated [Quadri et al 2012, Tuschl et al 2012].
  • Chronic liver disease. Hepatic involvement may be present with variable severity and is not pathognomonic for this disease but when present should further suggest the diagnosis:
    • The majority of affected individuals reported to date (15/20) have evidence of hepatic involvement that includes hepatomegaly, elevated transaminases (alanine transaminase [ALT], aspartate transaminase [AST]), and unconjugated hyperbilirubinemia.
    • Liver ultrasound examination or MRI can confirm hepatomegaly and features of liver cirrhosis.
    • Pathologic features on liver biopsy in six affected individuals included fibrosis, steatosis, and micronodular cirrhosis. Note: One individual with hepatomegaly and micronodular cirrhosis had no laboratory evidence of hepatic dysfunction.
    • Hepatic manganese content is elevated. Rhodanine staining confirms deposition of manganese in hepatocytes [Gospe et al 2000, Tuschl et al 2008, Quadri et al 2012, Tuschl et al 2012].
  • Family history consistent with autosomal recessive inheritance, including parental consanguinity

Molecular Genetic Testing

Gene. SLC30A10 is the only gene in which mutations are known to cause dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease. Affected individuals have biallelic mutations.

Research testing

Table 1. Summary of Molecular Genetic Testing Used in Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
SLC30A10Sequence analysisSequence variants 29/10 3
Deletion / duplication analysis 4Exonic or whole-gene deletions1/10 5

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Twenty individuals from ten families (9 with childhood-onset forms, 1 with the adult-onset form) [Quadri et al 2012, Tuschl et al 2012]. Sequence analysis in affected individuals of nine families identified homozygous SLC30A10 mutations.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Four affected sibs from one family were homozygous for a large genomic SLC30A10 deletion involving exons 1 and 2 [Tuschl et al 2012].

Interpretation of test results. When biallelic SLC30A10 mutations are identified in an individual with hypermanganesemia, typical clinical phenotype and characteristic MRI brain changes the diagnosis is confirmed.

For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Neurologic findings: childhood onset. In the childhood-onset form of dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease affected individuals present with neurologic signs between ages two and 15 years. Many become wheelchair bound in their teens.

The neurologic signs and symptoms of the childhood-onset form are primarily extrapyramidal and include dystonia, dysarthria, and rigidity. Four-limb dystonia manifests with difficulties walking and a high-stepping gait (“cock walk gait”), dystonic posturing, and painful extensor spasms. Fine motor impairment causes problems with writing and drawing and inability to perform rapid alternating movements of the hands (dysdiadochokinesis). Dystonia of the tongue can lead to dysarthria [Quadri et al 2012, Tuschl et al 2012].

Isolated corticospinal tract involvement has been described in one affected individual. Typical neurologic signs of spastic paraparesis (e.g., spasticity, hyperreflexia, extensor plantar responses) were found [Gospe et al 2000].

Neurologic findings: adult onset. Quadri et al [2012] reported two brothers who presented at ages 47 years and 57 years with progressive gait disturbance and bradykinesia. Neurologic examination showed features of Parkinsonism including hypomimia, monotone speech, mild rigidity, global bradykinesia, wide-based gait with freezing and starting hesitation, and moderate postural instability without evidence of tremor, dystonia, or cerebellar or pyramidal disturbances. Treatment with L-dopa and dopamine agonists did not improve neurologic findings.

Sensory-motor axonal polyneuropathy has been described in two affected individuals with the late-onset neurologic presentation [Quadri et al 2012].

Polycythemia. All affected individuals have polycythemia. Polycythemia can precede the onset of neurologic manifestations and, therefore, affected individuals often undergo repeat phlebotomies prior to recognition of the correct diagnosis [Quadri et al 2012, Tuschl et al 2012]. Polycythemia has been described in affected children from age three years; however, earlier presentation of polycythemia cannot be excluded because of insufficient data. Individuals in whom neurologic symptoms do not manifest until late adulthood have had polycythemia since as early as the third decade.

Liver disease. The spectrum of hepatic involvement ranges from mild hepatomegaly to hepatic failure in early adulthood [Tuschl et al 2012]. However, pure neurologic phenotypes presenting with dystonia alone have been reported [Quadri et al 2012].

Hepatic involvement determines life expectancy. In the majority of affected individuals, transaminases are mildly elevated [Quadri et al 2012, Tuschl et al 2012]. Three of the 20 known affected individuals died of complications of liver cirrhosis between ages 18 and 46 years. As most of the affected individuals known to the authors are still in their teens or early adulthood, no long-term follow-up data are available.

Significant phenotypic variability even within the same family is apparent: The two brothers reported by Quadri et al [2012], who are now in their sixties and severely affected by dystonia, did not show hepatic involvement. Both had normal liver function and liver ultrasound examination throughout their lives. However, while the affected sister had minimal neurologic involvement, she developed liver cirrhosis in the third decade and died of liver failure at age 46 years.

Intellect appears normal in all affected individuals. Quadri et al [2012] described one individual who developed cognitive and behavioral problems, thought to be alcohol related. However, environmental manganese exposure is known to cause cognitive and psychiatric disturbances (so called “manganese madness”) including emotional lability, hallucinations, and compulsive behavior. Hence, cognitive and psychiatric symptoms could be part of the clinical phenotype [Racette et al 2012].

Pica. Several affected individuals had pica during early childhood [Brna et al 2011, unpublished data].

Darker skin tone. Some affected individuals have been described to have a purple or dark skin discoloration to an extent that parents are able to distinguish affected and unaffected children prior to the manifestation of clinical symptoms [unpublished data].

Genotype-Phenotype Correlations

Ten homozygous SLC30A10 sequence alterations have been documented in ten unrelated families with either childhood- or adult-onset disease [Quadri et al 2012, Tuschl et al 2012]. Due to the small number of known cases, no firm genotype-phenotype correlation can be made. However, it is interesting that the mutation in the sibship presenting with adult-onset parkinsonism is toward the end of the fourth (last) exon of SLC30A10. This mutation (p.Gln412Argfs*26; c.1235delA) is predicted to cause a frameshift that introduces a premature stop codon and the translation of a protein lacking the last 49 amino acids [Quadri et al 2012]. It is possible that this mutant allele produces a protein with residual function.

Prevalence

This inborn error of manganese metabolism has only recently been identified. A total of 20 affected individuals from ten families are known worldwide [Quadri et al 2012, Tuschl et al 2012]. The prevalence is yet to be determined.

Differential Diagnosis

The following are included in the differential diagnosis of dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease.

Acquired hypermanganesemia: Overexposure to manganese is known to be neurotoxic and causes ‘‘manganism’’ – a distinct syndrome of extrapyramidal movement disorder (dystonia/Parkinsonism) combined with high signal intensity of the basal ganglia on T1-weighted MR images of the brain resulting from manganese accumulation in the basal ganglia [Racette et al 2012].

  • Environmental exposure has been described in workers in mining and welding industries who inhale manganese-laden dust or fumes, in individuals ingesting contaminated drinking water, and in drug addicts who use intravenous methcathinone contaminated with potassium permanganate [Stepens et al 2008, Bouchard et al 2011, Racette et al 2012].
  • Total parenteral nutrition has been associated with manganese toxicity because the control mechanisms of manganese absorption in the gut and subsequent hepatic excretion are bypassed [Chalela et al 2011].
  • Acquired hepatocerebral degeneration is observed in those with advanced hepatic cirrhosis or portosystemic shunts in which impaired biliary excretion of manganese results in manganese accumulation in the basal ganglia causing a debilitating movement disorder [Meissner & Tison 2011].

Wilson disease

Parkinson disease and its differential diagnoses, including:

Inherited forms of dystonia, including:

Neurodegenerative diseases associated with dystonia including:

Cerebral palsy. Familial and acquired spastic paraplegia; see Hereditary Forms of Spastic Paraplegia Overview.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease, the following evaluations are recommended:

  • Neurologic examination for dystonia, parkinsonism, and spasticity, including evaluation of ambulation and speech
  • Assessment of the liver including liver function tests, liver ultrasound examination, and liver biopsy if indicated. Consultation with a hepatologist is advised.
  • Assessment for physiotherapy, occupational therapy, and/or speech therapy
  • Medical genetics consultation

Treatment of Manifestations

Chelation Therapy with Disodium Calcium Edetate

In two patients on regular chelation therapy with intravenous disodium calcium edetate, blood manganese levels and neurologic symptoms improved and signs of liver disease disappeared [Tuschl et al 2008, Quadri et al 2012, Tuschl et al 2012].

Short term. The response of an individual to disodium calcium edetate is determined by a single five-day course of twice-daily disodium calcium edetate at 20 mg/kg/dose (made up in 250 ml of 0.9% sodium chloride, given intravenously over 1 hour) and daily measurement of plasma manganese concentration and 24-hour urine manganese levels. Other monitoring includes: serum concentrations of electrolytes, calcium, phosphate, and magnesium; renal and liver function; full blood count; and serum concentrations of trace metals such as zinc, copper, and selenium. Note: To avoid hypocalcemia, disodium calcium edetate infusions need to be administered slowly over at least one hour. If the calcium level (corrected for albumin concentration) is low, infusions should be administered over a longer time span (i.e., >3 hours).

Long term. If chelation therapy proves to be effective in the short term, monthly five-day courses of disodium calcium edetate (intravenous 20 mg/kg/dose 2x/day) are expected to lower blood manganese levels and normalize hemoglobin concentration and iron indices [Tuschl et al 2008, Tuschl et al 2012, Quadri et al 2012]. Chelation therapy should be continued lifelong. While on treatment, monitoring once every two months includes: serum concentration of electrolytes, calcium, phosphate, magnesium; renal and liver function; full blood count; and serum concentrations of trace metals such as zinc, copper, and selenium (see Prevention of Secondary Complications).

Iron Therapy

Iron is a competitive inhibitor of intestinal manganese uptake; hence, supplementation with iron given orally (despite normal serum iron levels) can reduce blood manganese levels and resolve polycythemia [Tuschl et al 2008, Tuschl et al 2012]. The high serum transferrin levels seen in affected individuals are thought to reduce the risk of manganese toxicity.

Note: Iron indices need to be monitored frequently (every ~3 months) in those receiving iron supplements (see Prevention of Secondary Complications).

Liver Transplantation

Liver transplantation should be considered in individuals with end-stage liver disease; however, it has not been attempted in individuals with this disorder and, hence, no data are available.

Other

Dystonia can result in physical deformities and pain. Physiotherapy, occupational therapy, and/or speech therapy should be provided. Symptomatic treatment with antispasticity medications and L-dopa has been attempted with limited success.

Prevention of Primary Manifestations

Chelation therapy and iron supplementation may prevent primary disease manifestations in affected sibs who are asymptomatic (see Treatment of Manifestations).

Prevention of Secondary Complications

Potential adverse effects of chelation therapy with disodium calcium edetate include hypocalcemia, nephrotoxicity, trace metal and vitamin deficiency, and thrombocytopenia and leukopenia [Lamas et al 2012].

Renal function is assessed at baseline and should be monitored at least every other month. Additionally, the following need to be monitored: trace metal levels including manganese, zinc, copper, and selenium; liver function; electrolytes; calcium and phosphate concentrations; and complete blood count. Trace metal supplements are provided as needed.

Potential toxicity of iron supplementation. In order to avoid iron toxicity, serum iron and total iron binding capacity need to be monitored regularly. If serum iron exceeds 80% of total iron binding capacity, iron supplementation should be stopped or reduced.

Surveillance

Close monitoring of liver function and disease markers such as hemoglobin, iron indices, and whole-blood manganese is required at three-month intervals.

Routine follow up with a neurologist and hepatologist should be provided with repeat assessment of MRI brain, and liver ultrasound and biopsy when clinically indicated (e.g., worsening of liver function) and for monitoring of treatment.

Agents/Circumstances to Avoid

Foods very high in manganese (cloves; saffron; wheat; nuts; mussels; dark chocolate; and pumpkin, sesame and sunflower seeds) should be avoided.

Evaluation of Relatives at Risk

Because chelation therapy and iron supplementation could prevent primary disease manifestations in affected asymptomatic individuals, it is recommended that at-risk sibs of a proband be evaluated either by molecular genetic testing if the disease-causing mutations are known or by periodic monitoring of whole-blood manganese concentration.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For an affected fetus, no prenatal treatment is recommended as the disease does not manifest before early childhood.

For an affected mother, no data or information on pregnancy management are available.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. No data on fertility in individuals with dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease are available.

Assuming that reproduction is possible the offspring of an affected individual are obligate heterozygotes (carriers) for a disease-causing mutation in SLC30A10.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
SLC30A101q41Zinc transporter 10SLC30A10 @ LOVDSLC30A10

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease (View All in OMIM)

611146SOLUTE CARRIER FAMILY 30 (ZINC TRANSPORTER), MEMBER 10; SLC30A10
613280HYPERMANGANESEMIA WITH DYSTONIA, POLYCYTHEMIA, AND CIRRHOSIS; HMDPC

Molecular Genetic Pathogenesis

SLC30A10 has recently been identified as the gene in which mutation causes a syndrome of dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease. While the SLC30A10 protein (named zinc transporter 10) was presumed to be a zinc transporter in the past [Sreedharan et al 2011], expression studies in a manganese-sensitive yeast strain have shown that SLC30A10 protects cells from manganese toxicity and functions as a potent manganese transporter [Tuschl et al 2012]. SLC30A10 belongs to the cation diffusion facilitator (CDF) family of metal transporters that are involved in the efflux of heavy metals from the cytosol into the extracellular space or organelles thereby protecting cells from excessive heavy metal concentrations. Quadri et al [2012] have confirmed the expression of the SLC30A10 protein in hepatocytes and bile ducts, and in neurons from the globus pallidus and spinal cord. Although manganese is critical for cell function, overexposure is known to be neuro- and hepatotoxic. Therefore, manganese homeostasis is tightly controlled in the human body. Deleterious mutations in SLC30A10 cause dysfunction of this manganese transporter with accumulation of manganese in the liver and brain, thereby leading to liver disease and movement disorder [Quadri et al 2012, Tuschl et al 2012].

Normal allelic variants. SLC30A10 has four exons. Twenty normal allelic variants have been reported in SLC30A10.

Pathologic allelic variants. Homozygous mutations have been documented in all ten families in which affected individuals have been identified (see Table 2). These include missense and nonsense mutations and single-base and larger deletions involving up to two exons of SLC30A10. Mutations are predicted to either (1) cause a significantly truncated protein because of a frameshift and premature stop codon or large deletion, or (2) affect an evolutionary highly conserved area of the protein. Therefore, these sequence changes have detrimental effects on protein function [Quadri et al 2012, Tuschl et al 2012].

Table 2. Selected SLC30A10 Pathologic Allelic Variants

OnsetDNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
Childhood 1, 2g.chr11:218.057.426_218.158.564del101139NCBI Build 36.3
c.266T>Cp.Leu89ProNM_018713​.2
NP_061183​.2
c.292_402delp.Val98_Phe134del
c.314_322delp.Ala105_Pro107del
c.500T>Cp.Phe167Ser
c.507delGp.Pro170Leufs*22
c.585del p.Thr196Profs*17
c.765_767del p.Val256del
c.922C>Tp.Gln308*
c.1046T>Cp.Leu349Pro
Adult 1c.1235delAp.Gln412Argfs*26

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Quadri et al [2012]

2. Tuschl et al [2012]

Normal gene product. SLC30A10 is a member of the SLC30 solute carrier subfamily of the cation diffusion facilitator (CDF) family. Human SLC30A10 is a protein of 485 amino acids [Tuschl et al 2012]. The protein is a transmembranous manganese transporter expressed in liver and brain that is involved in the regulation of intracellular manganese concentrations and facilitates tight homeostatic control of body manganese levels [Quadri et al 2012, Tuschl et al 2012]. Quadri et al [2012] showed that SLC30A10 expression and the levels of the encoded protein are under strict control by extracellular manganese levels in vitro. Exposure to high manganese concentrations leads to significant increase of SLC30A10 mRNA and protein expression.

Abnormal gene product. SLC30A10 mutations described in affected individuals (Table 2) have deleterious effects on protein function. While wild-type SLC30A10 expressed in manganese-sensitive yeast cells rescues growth in high manganese concentrations, SLC30A10 with missense and nonsense sequence changes fails to restore manganese resistance [Tuschl et al 2012]. Furthermore, SLC30A10 mutations lead to loss of immunoreactivity in liver and brain tissues of affected individuals [Quadri et al 2012]. In humans, impaired function of SLC30A10 results in accumulation of manganese in liver and brain.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

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