Hypermanganesemia With Dystonia 2

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.

Description

Hypermanganesemia with dystonia-2 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).

Clinical Features

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.

Clinical Management

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.

Inheritance

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

Molecular Genetics

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.

Animal Model

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.