Clinical characteristics.

SLC39A8-CDG is characterized by mild-to-profound developmental delay, intellectual disability, hypotonia, feeding difficulties with poor weight gain and growth deficiency, dystonia, spasticity, epilepsy, ophthalmologic manifestations including cortical blindness and strabismus, and sensorineural hearing impairment.

Diagnosis/testing.

The diagnosis of SLC39A8-CDG is established in a proband with characteristic clinical features and suggestive laboratory findings (decreased whole blood manganese, elevated xanthine on urinary purines/pyrimidines, and evidence of altered glycosylation) by identification of biallelic pathogenic variants in SLC39A8 on molecular genetic testing.

Management.

Targeted therapy: Manganese supplementation with titration to identify adequate manganese dose prior to adding galactose supplementation.

Supportive care: Developmental and educational support; standard treatments for spasticity, seizures, feeding issues, ophthalmologic involvement, hearing impairment, and musculoskeletal complications; family support and care coordination as needed.

Surveillance: Assess for abnormal glycosylation using mass spectrometry, and measure blood manganese levels as needed to titrate manganese dose; brain MRI every one to two years; assess developmental progress, educational needs, seizures, changes in tone, movement disorders, growth, nutrition, feeding, mobility, self-help skills, clinical evidence of scoliosis, and family needs at each visit; assess visual acuity and for strabismus with frequency per ophthalmologist; annual aspartate transaminase, alanine transaminase, and albumin in those with evidence of liver disease; assess for osteopenia/osteoporosis every one to two years or as needed; DXA scan every three to five years starting in adolescence.

Agents/circumstances to avoid: Fever, hepatotoxic drugs, and drugs contraindicated in mitochondriopathies.

Evaluation of relatives at risk: All at-risk sibs of any age should have molecular genetic testing for the familial SLC39A8 pathogenic variants in order to identify as early as possible those who would benefit from prompt initiation of manganese and galactose supplementation.

Genetic counseling.

SLC39A8-CDG is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC39A8 pathogenic variant, each sib of an affected individual has at conception 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 SLC39A8 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

SLC39A8-CDG should be suspected in probands with the following clinical, laboratory, imaging, and family history findings.

Clinical findings

• Mild-to-profound developmental delay and/or intellectual disability
• Generalized hypotonia of infancy
• Feeding difficulties with poor weight gain and growth deficiency
• Movement disorder with marked dystonia
• Spasticity
• Epilepsy, especially severe infantile epileptic spasms not responding to conventional treatment
• Ophthalmologic manifestations including cortical blindness and strabismus
• Sensorineural hearing impairment

Laboratory findings

• Decreased whole blood manganese concentration
• Elevated transaminases (aspartate transaminase, alanine transaminase)
• Elevated xanthine (xanthine oxidase) in urinary purines/pyrimidines detected by mass spectrometry [Park et al 2015]
• Altered glycosylation
  • A type II pattern of dysglycosylation of serum transferrin can be detected by isoelectric focusing, high-performance liquid chromatography, capillary zone electrophoresis, or mass spectrometry-based analysis of serum transferrin glycosylation.
  • Hypogalactosylation of glycans can be detected by glycome profiling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, especially an increase of the asialo-agalactosylated precursor N-glycan A2G1S1.

Brain MRI findings

• Bilateral T₂-hyperintense lesions in the basal ganglia, especially the globus pallidus (similar to imaging findings in Leigh syndrome)
• Cerebral and cerebellar atrophy
• Craniosynostoses
• Lacunar skull

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SLC39A8-CDG is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in SLC39A8 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic SLC39A8 variants of uncertain significance (or of one known SLC39A8 pathogenic variant and one SLC39A8 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with comprehensive genomic testing (exome sequencing, genome sequencing). Other options include use of a multigene panel or SLC39A8 single-gene testing depending on the phenotype.

Clinical Description

SLC39A8-CDG is characterized by a severe, primarily neurologic phenotype with developmental delay, intellectual disability, muscular hypotonia, and variable additional neurologic symptoms including dyskinetic movements and spasticity. To date, 15 individuals have been identified with pathogenic variants in SLC39A8 [Boycott et al 2015, Park et al 2015, Riley et al 2017, Park et al 2020, Bonaventura et al 2021]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID). All known individuals exhibit varying degrees of DD and subsequent ID. Milestones of motor development are typically reached with major delays, although some are never reached. Most older individuals have severe ID that does not allow for standardized testing. Communication is usually limited to single words and/or gestures.

Other neurodevelopmental features

• Hypotonia. All described individuals presented with truncal muscular hypotonia, often more pronounced in early life. Head control is reduced but can be achieved in more mildly affected individuals.
• Infant feeding difficulties. Feeding difficulties necessitating at least transient tube feeding are common in individuals with SLC39A8-CDG.
• Movement disorders, especially marked dystonia, were reported in several individuals, at times overlapping with spasticity and thus resulting in spastic dystonia.
• Spasticity to varying degrees has been observed in several affected individuals, correlating with a more severe disease course.
• Reduced nerve conduction velocities, both motor and sensory, have been reported in several individuals with SLC39A8-CDG.

Epilepsy. The majority of reported individuals suffer from seizures, with onset in the first months of life. Some individuals have relatively mild well-controlled seizures. However, severely affected individuals often present with infantile epileptic spasms and hypsarrhythmia unresponsive to intense treatment including corticosteroids. Manganese treatment was associated with improved seizure control in singular case reports [Park et al 2018].

Growth. Poor weight gain with subsequent growth deficiency is a common feature of SLC39A8-CDG. While not all individuals have short stature at birth, many develop proportionate or disproportionate short stature with short limbs during childhood. Head size can be reduced, although this is not a consistent or common feature.

Ophthalmologic involvement. Strabismus has been described in the vast majority of affected individuals. Loss of vision has been identified, although it can be attributed to cortical blindness in some individuals. No specific ophthalmologic abnormalities have been described, but such manifestations cannot be ruled out based on the limited number of described individuals.

Hearing impairment. Sensorineural hearing impairment of variable severity has been observed in some individuals with SLC39A8-CDG and was typically detected on newborn hearing screen.

Liver disease. Elevated liver enzymes are routinely observed, although not usually clinically significant (e.g., resulting in liver failure). Treatment for liver disease is rarely required but might be indicated on an individual basis. Treatment response is poorly characterized.

Osteopenia. Osteopenia is frequently observed in affected individuals. Whether this is a primary manifestation of SLC39A8-CDG or secondary due to disuse is unclear.

Prognosis. The overall prognosis is highly variable. To date, three of the reported 15 individuals are deceased due to secondary complications of infections accompanied by exacerbations of seizures. In contrast, two mildly affected individuals diagnosed in adulthood have a stable phenotype without a progressive neurologic disorder [J Park, personal communication].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

In 2009 the nomenclature for all types of CDG was changed to include the official gene (not italicized) followed by "-CDG" [Jaeken et al 2009].

Prevalence

The prevalence of SLC39A8-CDG is unknown. To date, 15 individuals have been described in the literature [Boycott et al 2015, Park et al 2015, Riley et al 2017, Park et al 2020, Bonaventura et al 2021]. Including additional unreported individuals, approximately 20 affected individuals are known.

Of note, the founder variant c.112G>C (p.Gly38Arg) has been identified in the North American Hutterite population [Boycott et al 2015, Park et al 2015].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SLC39A8-CDG, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Fever. It is well established that increases in body temperature are associated with further impairment of the residual glycosylation in congenital disorders of glycosylation. Therefore, antipyretic treatment to reduce and/or prevent fever is recommended.

Hepatotoxic drugs. In those with evidence of liver dysfunction, hepatotoxic agents should be avoided or used with extreme caution.

Drugs contraindicated in mitochondriopathies. Due to secondary impairment of mitochondrial function, agents contraindicated in mitochondriopathies (e.g., valproate) should be avoided in individuals with SLC39A8-CDG.

Evaluation of Relatives at Risk

All at-risk sibs of any age should have molecular testing for the familial SLC39A8 pathogenic variants in order to identify as early as possible those who would benefit from prompt initiation of manganese and galactose supplementation. This is especially recommended if additional – seemingly non-related – neuropsychiatric symptoms are present.

For at-risk newborn sibs, analysis of blood and urine manganese levels as well as protein N-glycosylation should be performed simultaneously with molecular genetic testing, as results from these tests are potentially available earlier than results of genetic testing. Altered glycosylation and severely reduced blood manganese levels are indicative of SLC39A8-CDG.

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. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

SLC39A8-CDG is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an SLC39A8 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC39A8 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an SLC39A8 pathogenic variant, each sib of an affected individual has at conception 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. To date, individuals with SLC39A8-CDG are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC39A8 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC39A8 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 and discussion of the availability of prenatal/preimplantation genetic 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 carriers or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. An SLC39A8 founder variant has been identified in individuals of Hutterite descent (see Table 7).

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC39A8 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SLC39A8 encodes the metal cation symporter ZIP8, a major manganese uptake channel [Fujishiro & Kambe 2022] (see Figure 1). SLC39A8 pathogenic variants disrupting the function of the protein result in decreased blood levels of manganese and subsequent intracellular manganese depletion [Choi et al 2018].

Figure 1.

Molecular pathogenesis of SLC39A8-CDG. Dysfunction of the manganese transporter SLC39A8 causes intracellular manganese depletion. (A) A reduced Mn²⁺ concentration in the Golgi apparatus impairs the function of manganese-dependent glycosylation enzymes. (more...)

Due to its relevance as a cofactor for a plethora of enzymes [Chen et al 2018], manganese depletion in SLC39A8-CDG causes a varied and multisystem phenotype. Importantly, the manganese dependence of both galactosyl transferases and the mitochondrial superoxide dismutase results in a combined mitochondrial and glycosylation disorder phenotype.

Mechanism of disease causation. Loss of function, with impaired manganese transport across the channel encoded by SLC39A8 [Choi et al 2018]

Author Notes

Julien H Park (ed.retsneumku@krap.neiluj) and Thorsten Marquardt (ed.retsneum-inu@tauqram) are actively involved in clinical and preclinical research regarding individuals with SLC39A8-CDG. They would be happy to communicate with persons who have any questions regarding diagnosis and treatment of SLC39A8-CDG or other considerations.

They are also interested in hearing from clinicians treating families affected by SLC39A8-CDG in whom no causative variant has been identified through molecular genetic testing.

See the Congenital Metabolic Diseases working group at Universitätsklinikum Münster.

Acknowledgments

The authors acknowledge the commitment of the patients and families supporting the ongoing research in the field of SLC39A8-CDG.

Revision History

• 6 April 2023 (sw) Review posted live
• 22 December 2022 (jp) Original submission

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