Clinical characteristics.

The disorder dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease is characterized by the following:

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

Neurologic findings can 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 failure, secondary complications of cirrhosis, and the neurologic disorder shorten 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 pathogenic variants in SLC30A10.

Management.

Treatment of manifestations: Regular chelation therapy with intravenous disodium calcium edetate improves blood manganese levels and neurologic findings and causes 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: Early initiation of physiotherapy and orthopedic management aims to prevent contractures and maintain ambulation.

Symptomatic treatment with antispasticity medications (including baclofen and botulinum toxin) and levodopa may be attempted. Swallowing evaluation and regular dietary assessments are indicated to assure adequate nutrition. In order to prevent aspiration pneumonia gastric feeding tube and/or tracheostomy may be required. The potential for complications from chelation therapy and/or iron supplementation can be lessened by careful surveillance

Agents/circumstances to avoid: Foods very high in manganese: cloves; saffron; 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 pathogenic variants in the family are known) or by periodic monitoring of whole-blood manganese concentration and hemoglobin.

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. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the SLC30A10 pathogenic variants in the family are known.

Suggestive Findings

Dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease should be suspected in individuals with typical clinical, brain MRI, and laboratory findings.

Clinical findings. An early- and a late-onset form exist:

• 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, Quadri et al 2015] 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. See Figure 1.

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.

• 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 show corresponding hypointensity changes. However, these changes are often less pronounced and, hence, may be reported as normal.
• Note: Normalization of manganese blood levels (see Management) improves the findings on brain MRI [Quadri et al 2012, Stamelou et al 2012, Tuschl et al 2012].

Laboratory findings. Hypermanganesemia:

• 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.

Corroborative Features

• Polycythemia. Manganese induces expression of the gene encoding erythropoietin [Ebert & Bunn 1999]. Characteristically, affected individuals are polycythemic. Hemoglobin concentrations reported in the literature range from 15.9 to 22.5 g/dL (mean: 18.6 g/dL). Some individuals studied have been found to have elevated erythropoietin levels [Gospe et al 2000, 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; when present, however, hepatic involvement should further suggest the diagnosis:
  • The majority of affected individuals reported to date 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/post-mortem examination 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 [Gospe et al 2000, Tuschl et al 2008, Quadri et al 2012, Tuschl et al 2012, Lechpammer et al 2014].
  • Hepatic manganese content is highly elevated. Rhodanine staining confirms deposition of manganese in hepatocytes. Copper and zinc content can also be affected with mild elevation in hepatic levels [Gospe et al 2000, Tuschl et al 2008, Quadri et al 2012, Tuschl et al 2012, Lechpammer et al 2014].
• Family history consistent with autosomal recessive inheritance, including parental consanguinity

Establishing the Diagnosis

The diagnosis of dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease is established in a proband with identification of biallelic pathogenic variants of SLC30A10 on molecular genetic testing [Quadri et al 2012, Tuschl et al 2012] (see Table 1).

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

• Single-gene testing. Sequence analysis of SLC30A10 is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
• A multigene panel that includes SLC30A10 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

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, Quadri et al 2015].
  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].
• 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].

Hypermanganesemia: Whole-blood manganese concentrations are elevated in all affected individuals.

• 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.
• 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.
• 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.

Note: Blood manganese concentrations of heterozygotes (i.e., carriers of one SLC30A10 pathogenic variant) 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).

Polycythemia. All affected individuals reported to date had polycythemia at the time of diagnosis. 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; earlier presentation of polycythemia cannot be ruled out 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. Polycythemia can resolve upon treatment with chelation therapy or iron. There is evidence from one patient whose polycythemia resolved without treatment during advanced stage of disease [Lechpammer et al 2014].

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].

In the majority of affected individuals, transaminases are mildly elevated [Quadri et al 2012, Tuschl et al 2012]. To date, three 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. While environmental manganese exposure is known to cause cognitive and psychiatric disturbances (so called "manganese madness") including emotional lability, hallucinations, and compulsive behavior [Racette et al 2012], this has not yet been observed in patients with dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease.

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

Pathology. Post-mortem studies in an individual with SLC30A10 deficiency showed yellow-grey mottling of the basal ganglia associated with severe neuronal loss, astrocytosis, myelin loss, spongiosis, and rhodanine-positive deposits particularly in the globus pallidus, while other basal ganglia were affected to a lesser extent. Gliosis of the white matter and axonal loss of the corticospinal tracts were observed [Lechpammer et al 2014].

Genotype-Phenotype Correlations

Fourteen homozygous SLC30A10 pathogenic variants and one homozygous multiexon deletion 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 pathogenic variant in the sibship presenting with adult-onset parkinsonism is toward the end of the fourth (last) exon of SLC30A10. This pathogenic variant (p.Gln412ArgfsTer26; 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 specific allele produces a protein with residual function.

Prevalence

This inborn error of manganese metabolism has only recently been identified. A total of 28 affected individuals from ten families are known worldwide [Quadri et al 2012, Tuschl et al 2012, Avelino et al 2014, Quadri et al 2015, Mukhtiar et al 2016]. The prevalence is yet to be determined.

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
• Brain MRI
• Assessment of the liver including liver function tests, liver ultrasound examination, and liver biopsy if indicated. Consultation with a hepatologist is advised.
• Establishment of whole blood manganese levels
• Assessment for physiotherapy, occupational therapy, and/or speech therapy
• Evaluation of swallowing and nutritional status
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

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

Early initiation of physiotherapy and orthopedic management aims to prevent contractures and maintain ambulation. As needed, individuals should be referred for adaptive aids (e.g., a walker or wheelchair for gait abnormalities) and assistive communication devices.

Symptomatic treatment with antispasticity medications including baclofen and botulinum toxin, and levodopa has been attempted with limited success.

Swallowing evaluation and regular dietary assessments are indicated to assure adequate nutrition. Once an adequate oral diet can no longer be maintained, gastrostomy tube placement should be considered. In order to prevent aspiration pneumonia gastric feeding tube and/or tracheostomy may be required.

The potential for complications from chelation therapy and/or iron supplementation can be lessened by careful surveillance.

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.

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].

Complete blood count and renal function including urinalysis are assessed at baseline and monthly thereafter. Monitoring may be extended to every other month once on a stable dose. Additionally, the following need to be monitored: trace metal levels including manganese, zinc, copper, and selenium; liver function; electrolytes; calcium, magnesium, and phosphate concentrations; and iron status. Trace metal supplements are provided as needed.

Treatment may need to be discontinued if:

• White blood count <3.5x10^9/L
• Neutrophils <2.0x10^9/L
• Platelets <150x10^9/L
• >2+ proteinuria on >1 occasion (and no evidence of infection)

The above cut-off values are based on guidelines for D-penicillamine treatment [Chakravarty et al 2008]. Because chelation treatment with disodium calcium edetate may prevent mortality and morbidity in SLC39A14-related early-onset parkinsonism-dystonia, lower cut-off values may be acceptable. The clinical treatment benefit needs to be carefully weighed against occurring adverse effects for each affected individual.

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.

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Chelation therapy and iron supplementation can potentially prevent primary disease manifestations in asymptomatic individuals.

Evaluations include:

• Molecular genetic testing if the SLC30A10 pathogenic variants in the family are known;
• Periodic monitoring of whole-blood manganese concentration and hemoglobin if the pathogenic variants in the family are not known.

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 in the US and www.ClinicalTrialsRegister.eu in Europe 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.

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 (i.e., carriers of one SLC30A10 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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 pathogenic variant in SLC30A10.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of an SLC30A10 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the SLC30A10 pathogenic variants in the family.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SLC30A10 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease are possible.

Literature Cited

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Revision History

• 9 February 2017 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 8 November 2012 (cd) Revision: sequence analysis and deletion/duplication analysis for mutations in SLC30A10 available clinically
• 30 August 2012 (me) Review posted live
• 1 June 2012 (kt) Original submission