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Hypermanganesemia with dystonia, polycythemia, and cirrhosis(HMNDYT1)

MedGen UID:
412958
Concept ID:
C2750442
Disease or Syndrome
Synonyms: Cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome; Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease; Hepatic Cirrhosis, Dystonia, Polycythemia and Hypermanganesemia; HMNDYT1; Hypermanganesemia with dystonia 1
SNOMED CT: Hypermanganesemia with dystonia, polycythemia, and cirrhosis (702377007); HMDPC - hypermanganesemia with dystonia, polycythemia and cirrhosis (702377007)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): SLC30A10 (1q41)
 
Monarch Initiative: MONDO:0013208
OMIM®: 613280
Orphanet: ORPHA309854

Disease characteristics

Excerpted from the GeneReview: Hypermanganesemia with Dystonia 1
Hypermanganesemia with dystonia 1 (HMNDYT1) 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 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. [from GeneReviews]
Authors:
Karin Tuschl  |  Peter T Clayton  |  Sidney M Gospe, et. al.   view full author information

Additional description

From OMIM
Hypermanganesemia with dystonia-1 (HMNDYT1) 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). Genetic Heterogeneity of Hypermanganesemia With Dystonia See also HMNDYT2 (617013), caused by mutation in the SLC39A14 gene (608736) on chromosome 8p21.  http://www.omim.org/entry/613280

Clinical features

From HPO
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Decreased liver function
MedGen UID:
65430
Concept ID:
C0232744
Finding
Reduced ability of the liver to perform its functions.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Spastic paraparesis
MedGen UID:
52432
Concept ID:
C0037771
Sign or Symptom
Mild or moderate loss of motor function accompanied by spasticity in the lower extremities. This condition is a manifestation of CENTRAL NERVOUS SYSTEM DISEASES that cause injury to the motor cortex or descending motor pathways.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Bradykinesia
MedGen UID:
115925
Concept ID:
C0233565
Sign or Symptom
Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Parkinsonian disorder
MedGen UID:
66079
Concept ID:
C0242422
Disease or Syndrome
Characteristic neurologic anomaly resulting from degeneration of dopamine-generating cells in the substantia nigra, a region of the midbrain, characterized clinically by shaking, rigidity, slowness of movement and difficulty with walking and gait.
Steppage gait
MedGen UID:
98105
Concept ID:
C0427149
Finding
An abnormal gait pattern that arises from weakness of the pretibial and peroneal muscles due to a lower motor neuron lesion. Affected patients have footdrop and are unable to dorsiflex and evert the foot. The leg is lifted high on walking so that the toes clear the ground, and there may be a slapping noise when the foot strikes the ground again.
Sensorimotor neuropathy
MedGen UID:
207266
Concept ID:
C1112256
Disease or Syndrome
Postural instability
MedGen UID:
334529
Concept ID:
C1843921
Finding
A tendency to fall or the inability to keep oneself from falling; imbalance. The retropulsion test is widely regarded as the gold standard to evaluate postural instability, Use of the retropulsion test includes a rapid balance perturbation in the backward direction, and the number of balance correcting steps (or total absence thereof) is used to rate the degree of postural instability. Healthy subjects correct such perturbations with either one or two large steps, or without taking any steps, hinging rapidly at the hips while swinging the arms forward as a counterweight. In patients with balance impairment, balance correcting steps are often too small, forcing patients to take more than two steps. Taking three or more steps is generally considered to be abnormal, and taking more than five steps is regarded as being clearly abnormal. Markedly affected patients continue to step backward without ever regaining their balance and must be caught by the examiner (this would be called true retropulsion). Even more severely affected patients fail to correct entirely, and fall backward like a pushed toy soldier, without taking any corrective steps.
Poor fine motor coordination
MedGen UID:
356863
Concept ID:
C1867864
Finding
An abnormality of the ability (skills) to perform a precise movement of small muscles with the intent to perform a specific act. Fine motor skills are required to mediate movements of the wrists, hands, fingers, feet, and toes.
Polycythemia
MedGen UID:
18552
Concept ID:
C0032461
Disease or Syndrome
Polycythemia is diagnosed if the red blood cell count, the hemoglobin level, and the red blood cell volume all exceed the upper limits of normal.
Rigidity
MedGen UID:
7752
Concept ID:
C0026837
Sign or Symptom
Continuous involuntary sustained muscle contraction. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.
Unconjugated hyperbilirubinemia
MedGen UID:
82786
Concept ID:
C0268306
Disease or Syndrome
An increased amount of unconjugated (indirect) bilurubin in the blood.
Increased total iron binding capacity
MedGen UID:
760319
Concept ID:
C0854060
Finding
An elevation in the total-iron binding capacity, which measures how much serum iron is bound if an excess of radioactive iron is added. A high TIBC corresponds to a high transferrin concentration. The latent (or free) iron binding capacity is the difference between the TIBC and the measured serum iron, corresponding to the transferrin not bound to iron, i.e., free iron binding capacity.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Hypermanganesemia
MedGen UID:
1705178
Concept ID:
C5139128
Finding
An elevation above the normal concentration of manganese in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Hypermanganesemia with dystonia, polycythemia, and cirrhosis in Orphanet.

Recent clinical studies

Etiology

Zaki MS, Issa MY, Elbendary HM, El-Karaksy H, Hosny H, Ghobrial C, El Safty A, El-Hennawy A, Oraby A, Selim L, Abdel-Hamid MS
Clin Genet 2018 Apr;93(4):905-912. Epub 2018 Feb 11 doi: 10.1111/cge.13184. PMID: 29193034

Diagnosis

Tarnacka B, Jopowicz A, Maślińska M
Int J Mol Sci 2021 Jul 22;22(15) doi: 10.3390/ijms22157820. PMID: 34360586Free PMC Article
Tavasoli A, Arjmandi Rafsanjani K, Hemmati S, Mojbafan M, Zarei E, Hosseini S
BMC Pediatr 2019 Jul 9;19(1):229. doi: 10.1186/s12887-019-1611-7. PMID: 31288771Free PMC Article
Ebrahimi-Fakhari D, Van Karnebeek C, Münchau A
Mov Disord 2019 May;34(5):598-613. Epub 2018 Dec 17 doi: 10.1002/mds.27568. PMID: 30557456
Zaki MS, Issa MY, Elbendary HM, El-Karaksy H, Hosny H, Ghobrial C, El Safty A, El-Hennawy A, Oraby A, Selim L, Abdel-Hamid MS
Clin Genet 2018 Apr;93(4):905-912. Epub 2018 Feb 11 doi: 10.1111/cge.13184. PMID: 29193034
Tuschl K, Clayton PT, Gospe SM Jr, Gulab S, Ibrahim S, Singhi P, Aulakh R, Ribeiro RT, Barsottini OG, Zaki MS, Del Rosario ML, Dyack S, Price V, Rideout A, Gordon K, Wevers RA, Chong WK, Mills PB
Am J Hum Genet 2012 Mar 9;90(3):457-66. Epub 2012 Feb 16 doi: 10.1016/j.ajhg.2012.01.018. PMID: 22341972Free PMC Article

Therapy

Tarnacka B, Jopowicz A, Maślińska M
Int J Mol Sci 2021 Jul 22;22(15) doi: 10.3390/ijms22157820. PMID: 34360586Free PMC Article
Dutta A, Majumdar R, Dubey S, Pandit A
Neurology 2021 Jan 19;96(3):123-125. Epub 2020 Dec 2 doi: 10.1212/WNL.0000000000011296. PMID: 33268559
Tavasoli A, Arjmandi Rafsanjani K, Hemmati S, Mojbafan M, Zarei E, Hosseini S
BMC Pediatr 2019 Jul 9;19(1):229. doi: 10.1186/s12887-019-1611-7. PMID: 31288771Free PMC Article
Tuschl K, Mills PB, Parsons H, Malone M, Fowler D, Bitner-Glindzicz M, Clayton PT
J Inherit Metab Dis 2008 Apr;31(2):151-63. Epub 2008 Apr 4 doi: 10.1007/s10545-008-0813-1. PMID: 18392750

Prognosis

Juneja M, Shamim U, Joshi A, Mathur A, Uppili B, Sairam S, Ambawat S, Dixit R, Faruq M
J Gene Med 2018 Apr;20(4):e3012. Epub 2018 Mar 23 doi: 10.1002/jgm.3012. PMID: 29498153

Clinical prediction guides

Juneja M, Shamim U, Joshi A, Mathur A, Uppili B, Sairam S, Ambawat S, Dixit R, Faruq M
J Gene Med 2018 Apr;20(4):e3012. Epub 2018 Mar 23 doi: 10.1002/jgm.3012. PMID: 29498153

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