A number sign (#) is used with this entry because of evidence that hypermanganesemia with dystonia-2 (HMNDYT2) is caused by homozygous mutation in the SLC39A14 gene (608736) on chromosome 8p21.

Hypermanganesemia with dystonia-2 (HMNDYT2) is an autosomal recessive neurodegenerative disorder characterized predominantly by loss of motor milestones in the first years of life. Affected individuals then develop rapidly progressive abnormal movements, including dystonia, spasticity, bulbar dysfunction, and variable features of parkinsonism, causing loss of ambulation. Cognition may be impaired, but is better preserved than motor function. The disorder results from abnormal accumulation of manganese (Mn), which is toxic to neurons. Chelation therapy, if started early, may provide clinical benefit (summary by Tuschl et al., 2016).

For a discussion of genetic heterogeneity of HMNDYT, see HMNDYT1 (613280).

Tuschl et al. (2016) reported 9 children from 5 unrelated consanguineous families with a severe neurodegenerative disorder with loss of developmental milestones and progressive dystonia appearing between 6 months and 3 years of age. By the end of the first decade, they had generalized pharmacoresistant dystonia, limb contractures and scoliosis, and loss of independent ambulation. More variable neurologic features included spasticity, oromandibular or bulbar dysfunction, axial hypotonia, and parkinsonism, with hypomimia, tremor, and bradykinesia. Cognition was highly variable: 2 sibs had intellectual disability, were nonverbal, and were unable to follow commands; 3 sibs from another family had learning disabilities only; 1 only child was cognitively normal; another only child did not achieve language; and 2 sibs from another family were not noted to have cognitive defects but were lost to follow-up. Brain MRI showed Mn deposition in the deep gray matter, including the globus pallidus and, to a lesser extent, the striatum, with sparing of the thalamus. There was also extensive white matter involvement including the cerebellum, spinal cord, and dorsal pons. Some patients had evidence of cerebral and cerebellar atrophy. Whole blood levels of Mn were markedly increased compared to controls, whereas iron, zinc, and cadmium levels, assessed in 2 patients, were normal. None of the patients developed polycythemia or liver disease, and liver imaging of 1 patient was normal. Three patients died at ages 13 months, 4 years, and 8 years. Postmortem examination of the patient who died at age 4 years showed neuronal loss in the globus pallidus, with relative preservation of neurons in the cortex, caudate, putamen, and thalamus.

Anazi et al. (2017) reported a 24-month-old patient who had developmental regression at 9 months of age. On examination, she had microcephaly, hypertonia, and hyperreflexia. Brain MRI demonstrated abnormal signal intensity of the globus pallidus, and an EMG and nerve conduction study demonstrated radiculoneuropathy affecting the upper limbs and axonal neuropathy of the lower limbs. Laboratory testing showed elevated manganese in the plasma and whole blood, low serum iron, and low transferrin saturation. She had a similarly affected, deceased sister.

Rodan et al. (2018) reported 2 unrelated children from the United Arab Emirates with HMNDYT2. Patient 1, born to consanguineous parents, had early developmental delay and required a feeding tube for failure to thrive. An early brain MRI showed T1 hyperintensities in the globus pallidus and substantia nigra. She had elevated serum manganese and normal liver function testing. She developed progressive dystonia and dysarthria with spared intellectual functioning. Brain MRI at age 7 years showed mineralization evidenced as T1 hyperintensities of the basal ganglia, hypothalamus, anterior commissure, amygdala, cerebral peduncles, and other brain regions. Patient 2 had normal early development with rapid developmental regression at 18 months of age. She also had elevated serum manganese with normal liver function. She developed a progressive movement disorder and progressive brain mineralization, but was lost to follow-up.

Juneja et al. (2018) reported a 1-year-old patient who had developmental regression at 9 months of age and the development of hypotonia and paucity of movements. She then developed dystonia of the upper and lower limbs. On examination at 1 year of age she had increased tone, dystonia of the limbs and trunk, spasticity, and brisk deep tendon reflexes. Brain MRI showed bilateral abnormalities in the globus pallidus, periventricular region, subcortical area, cerebellar white matter and corpus callosum. Blood manganese levels were elevated and iron levels were normal.

Zeglam et al. (2019) reported a patient who presented with unsteady gait and stiff muscles at 30 months of age and recent onset of difficulty swallowing. On examination at 3 years of age, her speech was difficult to understand, and she had increased muscle tone and generalized dystonia. Laboratory studies demonstrated low serum iron, iron deficiency anemia, and elevated blood manganese levels. A brain MRI showed abnormal signal in the brainstem and basal ganglia lentiform nucleus with an 'eye of the tiger' appearance.

Namnah et al. (2020) reported a 65-year-old woman with a long history of dysarthria and dystonia. She had changes in her handwriting starting at 18 years of age, with impaired gait and balance and unintelligible speech developing the following year. She remained stable from a clinical standpoint for the following 4 decades. On examination, she had impaired ocular convergence, dysarthria, bradykinesia, dystonia, and gait spasticity. Brain MRI demonstrated hyperintense lesions in the basal ganglia and subcortical white matter. Laboratory studies showed elevated blood manganese levels.

Tuschl et al. (2016) found that 1 patient with HMNDYT2 who began treatment with a Mn chelator at age 5 years showed dramatic clinical improvement and regained the ability to walk. In contrast, an unrelated patient who began treatment at age 17 years showed reduction of blood Mn levels, but continued to deteriorate in motor function.

Anazi et al. (2017) reported a 24-month-old patient who had HMNDYT2 and elevated manganese in the plasma and whole blood. After treatment with calcium disodium EDTA for chelation, she had improvement in her blood manganese level.

Rodan et al. (2018) reported a 9-year-old girl from the United Arab Emirates with HMNDYT2 who began chelation therapy at the age of 5 years and had reduced urine levels of manganese but unchanged plasma levels of manganese. The patient was treated intermittently because she returned for long periods to the UAE. The authors suspected that she had clinical stabilization associated with the chelation therapy, because when therapy was stopped, she had significant acceleration of symptoms. The patient was also treated with a manganese-depleted formula starting at 7 years of age.

The transmission pattern of HMNDYT2 in the families reported by Tuschl et al. (2016) was consistent with autosomal recessive inheritance.

In 8 patients from 5 unrelated consanguineous families with HMNDYT2, Tuschl et al. (2016) identified 5 different homozygous mutations in the SLC39A14 gene (608736.0001-608736.0005), including 2 truncating and 3 missense mutations. Transfection of the missense mutations in HEK293 cells showed that the mutant protein was expressed and localized normally, but resulted in decreased Mn uptake compared to wildtype, consistent with a loss of function. One of the patients had a mutation that affected only isoform 2, which is not expressed in the brain. However, the phenotype of this patient was similar to that of the other patients, suggesting that cerebral deposition of Mn in this disorder arises secondarily from an increased systemic load of Mn rather than from a primary defect of Mn clearance in the brain. Tuschl et al. (2016) postulated that loss-of-function mutations in SLC39A14 lead to impaired hepatic Mn uptake with resultant hypermanganesemia and downstream neurotoxic effects.

By whole-exome sequencing in 2 unrelated children from the United Arab Emirates, Rodan et al. (2018) identified homozygosity for the same intronic mutation in the SLC39A14 gene (608736.0007). The parents of 1 patient were confirmed to be heterozygous for the mutation.

In a 1-year-old girl with HMNDYT2, Juneja et al. (2018) identified a homozygous missense mutation in the SLC39A14 gene (R128W; 608736.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. Functional studies were not performed.

In an Arab Libyan patient, born to consanguineous parents, with HMNDYT2, Zeglam et al. (2019) identified a homozygous missense mutation in the SLC39A14 gene (P379L; 608736.0009). The mutation was found by whole-exome sequencing. Functional studies were not performed.

In a 65-year-old Ashkenazi Jewish woman, born to consanguineous parents, with HMNDYT2, Namnah et al. (2020) identified a homozygous missense mutation in the SLC39A14 gene (G356S; 608736.0010). The mutation was found by whole-exome sequencing. Functional studies were not performed. The patient had a clinical history of long-term dysarthria and dystonia and an elevated blood manganese level.

Tuschl et al. (2016) found that knockdown of the slc39a14 gene in zebrafish resulted in increased Mn levels, but unchanged Fe, Zn, and Cd levels. The mutant animals survived into adulthood without any obvious morphologic or developmental defects. However, exposure to Mn resulted in decreased locomotor activity and increased sensitivity to Mn-induced toxicity compared to wildtype. Mn accumulated predominantly in the brain of mutant animals, but not in the viscera. Treatment of mutant larvae with a chelator resulted in decreased levels of Mn uptake.