Slc39a14 Deficiency
Summary
Clinical characteristics.
SLC39A14 deficiency is characterized by evidence between ages six months and three years of delay or loss of motor developmental milestones (e.g., delayed walking, gait disturbance). Early in the disease course, children show axial hypotonia followed by dystonia, spasticity, dysarthria, bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor. By the end of the first decade they develop severe, generalized, pharmaco-resistant dystonia, limb contractures, and scoliosis, and lose independent ambulation. Cognitive impairment appears to be less prominent than motor disability. Some affected children have succumbed in their first decade due to secondary complications such as respiratory infections.
Diagnosis/testing.
The diagnosis of SLC39A14 deficiency is established in a proband with progressive dystonia-parkinsonism (often combined with other signs such as spasticity and parkinsonian features), characteristic neuroimaging findings, hypermanganesemia, and biallelic pathogenic variants in SLC39A14 on molecular genetic testing.
Management.
Treatment of manifestations: Symptomatic treatment includes physiotherapy and orthopedic management to prevent contractures and maintain ambulation; use of adaptive aids (walker or wheelchair) for gait abnormalities; and use of assistive communication devices. Support by a speech and language/feeding specialist and nutritionist to assure adequate nutrition and to reduce the risk of aspiration. When an adequate oral diet can no longer be maintained, gastrostomy tube placement should be considered. Antispasticity medications (baclofen and botulinum toxin) and L-dopa have had limited success. While chelation therapy with intravenous administration of disodium calcium edetate early in the disease course shows promise, additional studies are warranted.
Prevention of primary manifestations: Unknown, but disodium calcium edetate chelation therapy shows promise; additional studies are warranted.
Surveillance: Routine monitoring of:
- Height and weight using age- and gender-appropriate growth charts;
- Swallowing and diet to assure adequate nutrition;
- Ambulation and speech;
- Whole-blood manganese levels and brain MRI to assess treatment response and disease progression.
Agents/circumstances to avoid:
- Environmental manganese exposure (i.e., contaminated drinking water, occupational manganese exposure in welding/mining industries, contaminated ephedrone preparations)
- High manganese content of total parenteral nutrition
- Foods very high in manganese, including: cloves; saffron; nuts; mussels; dark chocolate; pumpkin, sesame, and sunflower seeds
Evaluation of relatives at risk: Molecular genetic testing for the familial SLC39A14 pathogenic variants of apparently asymptomatic younger sibs of an affected individual allows early identification of sibs who would benefit from prompt initiation of treatment and preventive measures.
Genetic counseling.
SLC39A14 deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. 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 the SLC39A14 pathogenic variants have been identified in an affected family member, carrier testing of at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
SLC39A14 deficiency should be suspected in individuals with typical clinical, neuroimaging, and laboratory findings [Tuschl et al 2016]:
- Clinical findings. Infantile or early-childhood onset of:
- Delay in acquisition of developmental motor milestones or loss of developmental motor milestones;
- Progressive pharmaco-resistant dystonia;
- Parkinsonism signs (tremor, bradykinesia, hypomimia);
- Bulbar dysfunction;
- Dysarthria.
- Neuroimaging. Brain MRI findings characteristic of manganese deposition (Figure 1) including T1-weighted hyperintensity of the following:
- Globus pallidus and striatum, with thalamic sparing;Note: Basal ganglia changes on T1-weighted imaging are accompanied by T2-weighted hypointensity.
- White matter including the cerebellum, spinal cord, and dorsal pons, with sparing of the ventral pons;
- Anterior pituitary gland.
- Laboratory findings. Hypermanganesemia. Whole-blood manganese levels are markedly elevated, usually above 1,000 nmol/L (normal reference range <320 nmol/L).
Figure 1
A. Axial T1-weighted image showing the hyperintensity of the globus pallidus (white arrows), and the cerebral white matter (dashed arrows) B. Axial T2-weighted image showing the hypointensity of the globus pallidus (white arrows)
Establishing the Diagnosis
The diagnosis of SLC39A14 deficiency is established in a proband with progressive dystonia (often combined with other signs such as spasticity and parkinsonian features), characteristic neuroimaging findings, hypermanganesemia, and identification of biallelic pathogenic variants in SLC39A14 on molecular genetic testing [Tuschl et al 2016] (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or a multigene panel) and genomic testing (comprehensive genomic sequencing) depending on the phenotype.
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SLC39A14 deficiency is likely to be broad, children with the suggestive clinical, laboratory, and neuroimaging findings could be diagnosed using gene-targeted testing (see Option 1), whereas those with early-onset dystonia-parkinsonism indistinguishable from other inherited disorders with parkinsonism-dystonia are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the clinical, laboratory, and brain MRI findings suggest the diagnosis of SLC39A14 deficiency, molecular genetic testing approaches can include single-gene testing and use of a multigene panel.
- Single-gene testing. Sequence analysis of SLC39A14 is performed first. If only one pathogenic variant is found, gene-targeted deletion/duplication analysis could be considered; however, to date no exon or whole-gene deletions have been reported.
- A multigene panel that includes SLC39A14 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 provides the best opportunity to identify the genetic cause of condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. (3) 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.
Option 2
When the phenotype is indistinguishable from other movement disorders, molecular genetic testing approaches can include a combination of genomic testing (comprehensive genomic sequencing; recommended) or gene-targeted testing (multigene panel; to consider).
- Recommended testing. Comprehensive genomic testing (when available) includes exome sequencing and genome sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
- Testing to consider. A multigene panel that includes SLC39A14 and other genes of interest (see Differential Diagnosis) may be considered; however, given the rarity of SLC39A14 deficiency, many panels for inherited dystonia-parkinsonism and/or this complex neurologic phenotype may not include this gene. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Table 1.
Molecular Genetic Testing Used in SLC39A14 Deficiency
| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| SLC39A14 | Sequence analysis 3 | 7/7 6 |
| Gene-targeted deletion/duplication analysis 4 | None reported |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 5.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
- 6.
Five reported consanguineous families [Tuschl et al 2016] and two other families, one consanguineous and one nonconsanguineous [Author, personal observation]
Clinical Characteristics
Clinical Description
SLC39A14 deficiency has only recently been identified in 11 individuals from seven families [Tuschl et al 2016; Author, personal observation]; therefore, information on the phenotypic spectrum and disease progression is limited.
Onset occurs between ages six months and three years. Affected children present with delay or loss of motor developmental milestones (e.g., delayed walking, gait disturbance).
Early in the disease course, children show axial hypotonia followed by dystonia, spasticity, dysarthria, bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor.
By the end of the first decade, they develop severe, generalized, pharmaco-resistant dystonia, limb contractures, scoliosis, and loss of independent ambulation.
Although there appears to be relative cognitive sparing (psychometric testing has not been possible), a degree of learning disability is present in all children.
Some affected children succumb in their first decade due to secondary complications such as respiratory infections.
Neuropathology. The neuropathologic findings in one individual with SLC39A14 deficiency [Tuschl et al 2016] included:
- Extensive gliosis and neuronal loss in the globus pallidus and dentate nucleus;
- Preservation of neurons in the cerebral and cerebellar cortex as well as the caudate, putamen, and thalamus;
- A vacuolated myelinopathy with patchy axonal loss in the cerebral and cerebellar white matter.
Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
Prevalence
The disease prevalence is not established. To date only 11 individuals with SLC39A14 deficiency from seven families have been identified. These seven families are from different ethnic backgrounds and six are consanguineous [Tuschl et al 2016; Author, personal observation].
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of SLC39A14 Deficiency
| Disorder | Gene(s) | MOI | Clinical Features of This Disorder | ||
|---|---|---|---|---|---|
| Overlapping w/SLC39A14 Deficiency | Distinguishing from SLC39A14 Deficiency | ||||
| Disorders of manganese homeostasis | Dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease (SLC30A10 deficiency) | SLC30A10 | AR |
|
|
| Acquired hypermanganesemia 1 | N/A | N/A |
| ||
| Acquired hepatocerebral degeneration 2 | N/A | N/A |
| ||
| Early-onset NBIA disorders (see NBIA Overview) | PKAN | PANK2 | AR |
|
|
| PLAN | PLA2G6 | AR | |||
| MPAN | C19orf12 | AR | |||
| BPAN | WDR45 | XL | |||
| FAHN | FA2H | AR | |||
| Kufor-Rakeb syndrome | ATP13A2 | AR | |||
| CoPAN | COASY | AR | |||
| Disorders of copper metabolism | Wilson disease | ATP7B | AR |
|
|
| Inherited forms of dystonia (see Dystonia Overview) | DYT1 early-onset isolated dystonia | TOR1A | AD |
|
|
| KMT2B-related early-onset dystonia | KMT2B | AD | |||
| MECR-related childhood-onset dystonia and optic atrophy 3 | MECR | AR |
| ||
| SLC6A3-related dopamine transporter deficiency syndrome | SLC6A3 | AR |
|
| |
| Tyrosine hydroxylase-deficient dopa-responsive dystonia | TH | AR | |||
| GTP cyclohydrolase 1-deficient dopa-responsive dystonia | GCH1 | AD | |||
| Sepiapterin reductase deficiency dopa-responsive dystonia | SPR | AR | |||
| Inherited Forms of Parkinson Disease (see Parkinson Disease Overview) | |||||
| Inherited neurodegenerative/metabolic disorders (see Dystonia Overview, Table 4 for hereditary neurodegenerative or metabolic disorders characterized by complex dystonia) |
|
| |||
AD = autosomal dominant; AR = autosomal recessive; BPAN = beta-propeller protein-associated neurodegeneration; CoPAN = COASY protein-associated neurodegeneration; FAHN = fatty acid hydroxylase-associated neurodegeneration. Mn = manganese; MOI = mode of inheritance; MPAN = mitochondrial membrane protein-associated neurodegeneration; NBIA = neurodegeneration with brain iron accumulation; PKAN = pantothenate kinase-associated neurodegeneration; PLAN = PLA2G6-associated neurodegeneration; XL = X-linked
- 1.
Mortimer et al [2012], Santos et al [2014], Janocha-Litwin et al [2015]
- 2.
Miletić et al [2014]
- 3.
Heimer et al [2016]
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SLC39A14 deficiency, the following evaluations are recommended:
- Neurologic examination for dystonia, parkinsonism, and spasticity, including evaluation of ambulation and speech
- Assessment for physiotherapy, occupational therapy, and/or speech therapy
- Evaluation of swallowing and nutritional status
- Brain MRI, if not performed as part of the diagnostic evaluation
- Assessment of whole-blood manganese levels, if not performed as part of the diagnostic evaluation
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Symptomatic treatment. 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.
Support by a speech and language/feeding specialist and nutritionist is indicated to assure adequate nutrition and to reduce the risk of aspiration. When an adequate oral diet can no longer be maintained, gastrostomy tube placement should be considered. Gastric feeding tube and/or tracheostomy may be required to prevent aspiration pneumonia.
Note that symptomatic treatment with L-dopa and antispasticity medications including benzodiazepines, baclofen, and botulinum toxin has been attempted with limited success. There has been partial but poorly sustained response to trihexyphenidyl at high doses of 20 mg/day and intrathecal baclofen of 1,500-2,000 µg/day in two older sibs reported by Tuschl et al [2016].
Chelation therapy. Disodium calcium edetate, which primarily promotes the urinary excretion of manganese, was given intravenously (20 mg/kg/dose) twice daily for five days each month to a female age five years with SLC39A14 deficiency [Tuschl et al 2016]. After six months of treatment, neurologic manifestations improved and the child regained the ability to walk.
In contrast, treatment of a female age 17 years with advanced disease (severe generalized dystonia with prominent oromandibular involvement, contractures, and scoliosis) did not affect disease progression as she continued to deteriorate with worsening tremor and stiffness. Hence, it is likely necessary to initiate chelation treatment early in the disease course.
It is anticipated that chelation therapy will need to be lifelong.
Potential adverse effects of disodium calcium edetate chelation therapy include thrombocytopenia and leukopenia, nephrotoxicity, hepatoxicity, hypocalcemia, and trace metal and vitamin deficiencies [Lamas et al 2012]. Monitoring includes the following:
- Complete blood count
- Assessment of renal function including urinalysis assessed at baseline and monthly thereafter. Monitoring may be extended to every other month once on a stable dose.
- Assessment of liver function
- Measurement of the concentrations of electrolytes, calcium, magnesium, and phosphate
- Measurement of the concentrations of trace metals (manganese, zinc, copper, and selenium)
- Assessment of iron status
Treatment may need to be discontinued if:
- White blood count is <3.5x109/L
- Neutrophil count is <2.0x109/L
- Platelet count is <150x109/L
- >2+ proteinuria is detected on more than one occasion (with 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 early death and reduce morbidity in SLC39A14 deficiency, lower cut-off values may be acceptable. For each affected individual, the benefits of clinical treatment need to be carefully weighed against the risk of adverse effects.
Prevention of Primary Manifestations
Chelation therapy with disodium calcium edetate may prevent primary disease manifestations in affected sibs who are asymptomatic (see Treatment of Manifestations).
Surveillance
Routine monitoring of:
- Height and weight using age and gender appropriate growth charts;
- Swallowing and diet to assure adequate nutrition;
- Ambulation and speech;
- Whole-blood manganese levels and brain MRI to assess treatment response and disease progression.
Agents/Circumstances to Avoid
The following should be avoided:
- Environmental manganese exposure (i.e., contaminated drinking water, occupational manganese exposure in welding/mining industries, contaminated ephedrone preparations)
- High manganese content of total parenteral nutrition
- Foods very high in manganese, including: cloves; saffron; nuts; mussels; dark chocolate; and pumpkin, sesame, and sunflower seeds
Evaluation of Relatives at Risk
Molecular genetic testing of apparently asymptomatic younger sibs of an affected individual for the familial SLC39A14 pathogenic variants allows early identification of sibs who would benefit from prompt initiation of treatment and preventive measures (see Agents/Circumstances to Avoid).
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.