Dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease
Tuschl, K; Clayton, PT; Gospe, SM, Jr; Mills, PB
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 either 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 mutation of SLC30A10.
MANAGEMENT: Treatment of manifestations: Regular chelation therapy with intravenous disodium calcium edetate in two affected individuals improved blood manganese levels and neurologic findings and caused 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: Modifying treatment if adverse effects of disodium calcium edetate chelation therapy (hypocalcemia, nephrotoxicity, trace metal and vitamin deficiency, and thrombocytopenia and leukopenia) or iron supplementation (iron toxicity) become evident. Agents/circumstances to avoid: Foods very high in manganese: cloves; saffron; wheat; 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 whole-blood manganese concentration.
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.
Adam, MP; Ardinger, HH; Pagon, RA; Wallace, SE
