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Hypermanganesemia with dystonia 2(HMNDYT2)

MedGen UID:
934732
Concept ID:
C4310765
Disease or Syndrome
Synonym: HMNDYT2
SNOMED CT: HMNDYT2 - hypermanganesemia with dystonia 2 (768554008); Hypermanganesemia with dystonia 2 (768554008)
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): SLC39A14 (8p21.3)
 
Monarch Initiative: MONDO:0014864
OMIM®: 617013
Orphanet: ORPHA521406

Disease characteristics

Excerpted from the GeneReview: SLC39A14 Deficiency
SLC39A14 deficiency is typically characterized by evidence of delay or loss of motor developmental milestones (e.g., delayed walking, gait disturbance) between ages six months and three years. Early in the disease course, children show axial hypotonia followed by dystonia, spasticity, dysarthria, bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor. By the end of the first decade, they develop severe, generalized, pharmaco-resistant dystonia, limb contractures, and scoliosis, and lose independent ambulation. Cognitive impairment appears to be less prominent than motor disability. Some affected children have died in their first decade due to secondary complications such as respiratory infections. One individual with disease onset during the late teens has been reported, suggesting that milder adult presentation can occur. [from GeneReviews]
Authors:
Karin Tuschl  |  Allison Gregory  |  Esther Meyer, et. al.   view full author information

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/617013
From MedlinePlus Genetics
Hypermanganesemia with dystonia is an inherited disorder in which excessive amounts of the element manganese accumulate in the body (hypermanganesemia). One place manganese builds up in particular is in a region of the brain responsible for the coordination of movement, causing neurological problems that make controlling movement difficult. Consequently, the condition is characterized by involuntary, sustained muscle contractions (dystonia) and other uncontrolled movements. Two types of hypermanganesemia with dystonia, called hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC) and hypermanganesemia with dystonia 2, have been identified. They are distinguished by their genetic causes and certain specific features.

In HMDPC (also known as hypermanganesemia with dystonia 1), manganese accumulates in the blood, brain, and liver. Signs and symptoms of the condition can begin in childhood (early-onset), typically between ages 2 and 15, or in adulthood (adult-onset). Most children with the early-onset form of HMDPC experience dystonia in the arms and legs, which often leads to a characteristic high-stepping walk described as a "cock-walk gait." Other neurological symptoms in affected children include involuntary trembling (tremor), unusually slow movement (bradykinesia), and slurred speech (dysarthria). The adult-onset form of HMDPC is characterized by a pattern of movement abnormalities known as parkinsonism, which includes bradykinesia, tremor, muscle rigidity, and an inability to hold the body upright and balanced (postural instability).

Individuals with HMDPC have an increased number of red blood cells (polycythemia) and low levels of iron stored in the body. Additional features of HMDPC can include an enlarged liver (hepatomegaly) due to manganese accumulation in the organ, scarring (fibrosis) in the liver, and irreversible liver disease (cirrhosis).

In hypermanganesemia with dystonia 2, manganese accumulates in the blood and brain. Signs and symptoms of this type of the disorder usually begin between ages 6 months and 3 years. Development of motor skills, such as sitting and walking, may be delayed, or if already learned, they may be lost. Dystonia can affect any part of the body and worsens over time. By late childhood, the sustained muscle contractions often result in joints that are permanently bent (contractures) and an inability to walk unassisted. Some affected individuals have an abnormal curvature of the spine (scoliosis). People with hypermanganesemia with dystonia 2 can have other neurological problems similar to those in HMDPC, such as tremor, bradykinesia, parkinsonism, and dysarthria. Unlike in HMDPC, individuals with hypermanganesemia with dystonia 2 do not develop polycythemia or liver problems.  https://medlineplus.gov/genetics/condition/hypermanganesemia-with-dystonia

Clinical features

From HPO
Ankle clonus
MedGen UID:
68672
Concept ID:
C0238651
Finding
Clonus is an involuntary tendon reflex that causes repeated flexion and extension of the foot. Ankle clonus is tested by rapidly flexing the foot upward.
Lower limb hypertonia
MedGen UID:
375612
Concept ID:
C1845245
Finding
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.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Hypokinesia
MedGen UID:
39223
Concept ID:
C0086439
Finding
Abnormally diminished motor activity. In contrast to paralysis, hypokinesia is not characterized by a lack of motor strength, but rather by a poverty of movement. The typical habitual movements (e.g., folding the arms, crossing the legs) are reduced in frequency.
Opisthotonus
MedGen UID:
56246
Concept ID:
C0151818
Sign or Symptom
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Scissor gait
MedGen UID:
68547
Concept ID:
C0231698
Finding
A type of spastic paraparetic gait in which the muscle tone in the adductors is marked. It is characterized by hypertonia and flexion in the legs, hips and pelvis accompanied by extreme adduction leading to the knees and thighs hitting, or sometimes even crossing, in a scissors-like movement. The opposing muscles (abductors) become comparatively weak from lack of use.
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).
Clumsiness
MedGen UID:
66690
Concept ID:
C0233844
Sign or Symptom
Lack of physical coordination resulting in an abnormal tendency to drop items or bump into objects.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Parkinsonism
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.
Tip-toe gait
MedGen UID:
98104
Concept ID:
C0427144
Finding
An abnormal gait pattern characterized by the failure of the heel to contact the floor at the onset of stance during gait.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk. In general, this can refer to neurological diseases but also fractures or other sources of pain that is triggered upon walking. However, in the current context gait disturbance refers to difficulty walking on the basis of a neurological or muscular disease.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Limb dystonia
MedGen UID:
152944
Concept ID:
C0751093
Sign or Symptom
A type of dystonia (abnormally increased muscular tone causing fixed abnormal postures) that affects muscles of the limbs.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Generalized dystonia
MedGen UID:
341342
Concept ID:
C1848954
Finding
A type of dystonia that affects all or most of the body.
Progressive neurologic deterioration
MedGen UID:
381506
Concept ID:
C1854838
Finding
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Oromandibular dystonia
MedGen UID:
473560
Concept ID:
C2242577
Sign or Symptom
A kind of focal dystonia characterized by forceful contractions of the face, jaw, and/or tongue causing difficulty in opening and closing the mouth and often affecting chewing and speech.
Brisk reflexes
MedGen UID:
382164
Concept ID:
C2673700
Finding
Tendon reflexes that are noticeably more active than usual (conventionally denoted 3+ on clinical examination). Brisk reflexes may or may not indicate a neurological lesion. They are distinguished from hyperreflexia by the fact that hyerreflexia is characterized by hyperactive repeating (clonic) reflexes, which are considered to be always abnormal.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Hyperintensity of cerebral white matter on MRI
MedGen UID:
811125
Concept ID:
C2938912
Pathologic Function
A brighter than expected signal on magnetic resonance imaging emanating from the cerebral white matter.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Achilles tendon contracture
MedGen UID:
98052
Concept ID:
C0410264
Anatomical Abnormality
A contracture of the Achilles tendon.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Limb joint contracture
MedGen UID:
369611
Concept ID:
C1969879
Anatomical Abnormality
A contracture (chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin) that prevent normal movement of one or more joints of the limbs.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Hypermanganesemia
MedGen UID:
1705178
Concept ID:
C5139128
Finding
An elevation above the normal concentration of manganese in the blood.
Impaired mastication
MedGen UID:
66779
Concept ID:
C0239043
Finding
An abnormal reduction in the ability to masticate (chew), i.e., in the ability to crush and ground food in preparation for swallowing.
Hypomimic face
MedGen UID:
208827
Concept ID:
C0813217
Finding
A reduced degree of motion of the muscles beneath the skin of the face, often associated with reduced facial crease formation.
Hyperhidrosis
MedGen UID:
5690
Concept ID:
C0020458
Finding
Abnormal excessive perspiration (sweating) despite the lack of appropriate stimuli like hot and humid weather.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

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