Hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC) is an autosomal recessive metabolic disorder characterized by increased serum manganese, motor neurodegeneration with extrapyramidal features, polycythemia, and hepatic dysfunction, which leads to cirrhosis in some cases. Intellectual function is preserved ... Hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC) is an autosomal recessive metabolic disorder characterized by increased serum manganese, motor neurodegeneration with extrapyramidal features, polycythemia, and hepatic dysfunction, which leads to cirrhosis in some cases. Intellectual function is preserved (summary by Tuschl et al., 2012 and Quadri et al., 2012).
Tuschl et al. (2008) reported an Arabic girl with a constellation of clinical features consisting of hypermanganesemia, liver cirrhosis, an extrapyramidal motor disorder, and polycythemia. She was born to healthy first-cousin parents. The pregnancy, delivery, and neonatal period ... Tuschl et al. (2008) reported an Arabic girl with a constellation of clinical features consisting of hypermanganesemia, liver cirrhosis, an extrapyramidal motor disorder, and polycythemia. She was born to healthy first-cousin parents. The pregnancy, delivery, and neonatal period were uneventful, and her development was normal until the age of 2 years, when difficulty with walking became apparent. This corrected itself until she presented again with walking difficulties at age 11. Her motor problems affected both her gait and fine movements of her hands. Apart from the movement disorder, her general physical health and development were normal for age. At 12 years of age her height and weight were at the 50th percentile, but her head circumference was 50.1 cm (2nd percentile). She showed mild icterus but no stigmata of chronic liver disease; liver and spleen were normal. Neurologic exam showed toe walking, increased tone of all 4 extremities, and dysdiadochokinesis. There was no dysmetria. Ocular exam was normal with no evidence of Kayser-Fleischer rings. She had polycythemia with a hemoglobin of 18 g/dl, unconjugated hyperbilirubinemia, and increased blood manganese concentrations (3,285 nmol/L, normal less than 320 nmol/L). Total iron binding capacity was increased. Plasma copper and zinc levels were normal. Prothrombin time and activated partial thromboplastin time were somewhat prolonged. Liver biopsy showed bridging fibrosis and cirrhosis with patchy moderate to severe portal and periportal chronic inflammatory cell infiltrate. Abdominal ultrasound showed an enlarged liver with coarse echotexture and a mildly enlarged spleen suggestive of cirrhosis and early portal hypertension. Hepatic manganese content was elevated (3.4 microg/g wet weight, normal 1-2 microg/g). Muscle biopsy was microscopically normal, but manganese content was elevated 3-fold. Copper was borderline high in both liver and muscle but not in the range of Wilson disease (277900). MRI of the brain showed hyperintense signal from the anterior pituitary, caudate, lentiform, and dentate nuclei and cerebellar white matter in the T1 sequence but normal T2 sequence consistent with manganese deposition in these regions. MRI of the spine was unremarkable. The patient had 4 healthy brothers and 3 healthy sisters; 1 older brother died at the age of 18 years from gastrointestinal hemorrhage secondary to cirrhosis. His clinical course was very similar to that of his sister, including microcephaly and MRI showing manganese deposition in the basal ganglia. Tuschl et al. (2008) excluded mutation in the ATP2C2 (613082) and ATP2A3 (601929) genes as the cause of the disorder in their patient. Gospe et al. (2000) reported a 14-year-old white male, the product of a nonconsanguineous union, who presented with stiffness of gait and progressive leg weakness. He had spastic paraparesis of the lower extremities. MRI of the spinal cord was normal but MRI of the brain showed high signal in the lenticular and dentate nuclei, brain stem, and pituitary, consistent with deposition of manganese. Brain stem atrophy was also present. Whole-blood manganese measured 3.48 micromol/l. There was no evidence of environmental exposure. His liver biopsy showed evidence of micronodular cirrhosis with no evidence of steatosis or of increased iron storage. There was no indication of hepatic copper deposition. Liver manganese concentration was approximately 3 times normal. During 11 years of clinical observation, the patient had progressive spastic weakness of the legs leading to loss of ambulation and painful extensor spasms. Whole-blood magnesium ranged from 2.93 to 3.66 micromol/l. The patient had persistent polycythemia, requiring phlebotomy twice weekly. Sahni et al. (2007) and Brna et al. (2011) reported a Canadian girl who presented at age 5 years with pica, emotional lability, decreased speech output, echolalia, and social withdrawal. Her motor coordination had deteriorated, and she had lost fine motor skills and was unable to walk independently. Neurologic examination shoed a narrow-based, high stepping gait, mild truncal ataxia, and action tremor. Brain MRI showed hyperintensities in the basal ganglia, and laboratory studies showed increased serum manganese, low iron, and polycythemia. Liver biopsy was normal, but showed increased manganese. Results of extensive environmental studies did not explain the toxicity, suggesting a metabolic disorder. Chelation therapy resulted in some neurologic improvement, as well as improvement of brain lesions. At age 10 years, she had a stable neurologic status and was able to walk short distances, but preferred using a wheelchair. Cognition was unimpaired and she functioned at an appropriate level in school. Tuschl et al. (2012) reported 15 individuals from 8 families with HMDPC, including 4 patients from 3 families previously reported by Gospe et al. (2000), Tuschl et al. (2008), Sahni et al. (2007), and Brna et al. (2011). The patients presented between 2 and 15 years of age with gait disturbances and hypertonia, with some becoming wheelchair-bound. Most had a pure 4-limb dystonia, with a high stepping gait and fine motor impairment, sometimes with dysarthria, fine tremor, and bradykinesia; 1 had pure spastic paraparesis without extrapyramidal features. Intellectual development was normal. All had pathognomonic MRI brain scans with hyperintensities of the globus pallidus, putamen, caudate, subthalamic and dentate nucleus and sparing of the thalamus and ventral pons on T1-weighted images. Those with more extensive disease showed white matter and anterior pituitary involvement. Most patients had liver impairment with raised transaminases and unconjugated hyperbilirubinemia; 2 died of cirrhosis. Other features included polycythemia associated with high erythropoietin levels, decreased iron stores, and increased total iron binding capacity. Liver tissue and blood showed significantly increased Mn content, and parental blood Mn levels were mildly increased in 3 families, consistent with a carrier status. Chelation therapy in some patients resulted in improvement of the neurologic symptoms. Quadri et al. (2012) reported 2 consanguineous families, of Italian and Dutch descent, respectively, in which a total of 5 patients had hypermanganesemia associated with degenerative motor symptoms. The patients were adults at the time of the report, ranging in age from 46 to 65 years. In the Italian family, 2 brothers presented at age 47 and 57 years, respectively, with parkinsonism, including gait disturbances, bradykinesia, hypomimia, rigidity, and postural instability. Both also had polycythemia, hepatomegaly, and brain MRI lesions in the basal ganglia, midbrain, thalamus, cerebellum, and corticospinal tract. One patient had a sensorimotor axonal polyneuropathy. Laboratory studies showed markedly increased manganese, increased transferrin, and decreased ferritin. Chelation therapy resulted in clinical improvement. There were 3 affected sibs in the Dutch family. All developed polycythemia in early childhood. Neurologic symptoms appeared at ages 2, 14, and 10 years, respectively, but the features were variable between patients. The oldest brother developed walking difficulties and limb spasms at age 14. This progressed and he developed generalized dystonia and became wheelchair-bound. Brain MRI showed no gross abnormalities. His younger brother developed walking difficulties at age 2 years. He had progressive dystonia and was wheelchair-bound at age 34. Both had increased serum manganese and increased total iron binding capacity, but normal iron. Brain MRI of the older brother was normal, but that of the younger brother showed hyperintense lesions of the globus pallidus. Neither had liver involvement. However, their younger sister died at age 46 of liver cirrhosis, portal hypertension, splenomegaly, and hepatic encephalopathy. She developed gait difficulties at the age of about 10, but there was no clear documentation of dystonia. Manganese levels were never determined, and neuroimaging was never performed.
By homozygosity mapping followed by candidate gene analysis of 2 consanguineous families with HMDPC, Tuschl et al. (2012) identified a deletion in the SLC30A10 gene (611146.0001) in the family reported by Tuschl et al. (2008). The other family ... By homozygosity mapping followed by candidate gene analysis of 2 consanguineous families with HMDPC, Tuschl et al. (2012) identified a deletion in the SLC30A10 gene (611146.0001) in the family reported by Tuschl et al. (2008). The other family had a large deletion encompassing exons 1 and 2 of the SLC30A10 gene. Subsequent mutation analysis in 6 additional families with the disorder identified homozygous mutations in all patients (see, e.g., 611146.0002-611146.0003). Some of the patients had previously been reported (Gospe et al., 2000; Sahni et al., 2007; Brna et al., 2011). When DNA from parents was available, they were found to be heterozygous carriers. In vitro functional expression studies of 2 of the mutant proteins in a yeast strain lacking a manganese transporter demonstrated that both mutant proteins were nonfunctional.