Hypermanganesemia with dystonia

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

The two types of hypermanganesemia with dystonia have different genetic causes. HMDPC is caused by mutations in the SLC30A10 gene, and hypermanganesemia with dystonia 2 is caused by mutations in the SLC39A14 gene. These genes provide instructions for making proteins that transport manganese across cell membranes. Manganese is important for many cellular functions, but large amounts are toxic, particularly to brain and liver cells. The SLC30A10 and SLC39A14 proteins are thought to work together to remove excess manganese from the body.

Both proteins are found in the membranes surrounding several types of cells, as well as in the membranes of structures within these cells. Studies suggest that when too much manganese builds up in the blood, the SLC39A14 protein transports the element into liver cells. From there, the SLC30A10 protein moves the manganese out of the liver cells into bile so that it can be removed from the body. Bile is a fluid produced in the liver that is important for digestion and the removal of waste material. The SLC30A10 protein may also transport manganese out of brain cells to protect them from an accumulation of the element.

Mutations in the SLC39A14 gene impair the transport of manganese into liver cells, allowing the element to build up in the blood. When levels are high in the blood, manganese accumulates in brain cells. Mutations in the SLC30A10 gene impair the transport of manganese out of liver cells and possibly brain cells, leading to its accumulation in the blood and brain.

Manganese accumulation in the brain damages the cells, resulting in the movement problems characteristic of HMDPC and hypermanganesemia with dystonia 2. It is unclear why some of the movement problems differ between the two conditions despite both being caused by excess manganese. Damage from manganese buildup in the liver leads to liver abnormalities in people with HMDPC. Because SLC39A14 gene mutations prevent manganese from entering liver cells, people with hypermanganesemia with dystonia 2 do not have liver damage. High levels of manganese help increase the production of red blood cells, so excess amounts of this element may underlie polycythemia in people with HMDPC. It is unknown why individuals with hypermanganesemia with dystonia 2 do not develop polycythemia.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Hypermanganesemia with dystonia is inherited in an autosomal recessive pattern, which means both copies of the SLC30A10 or SLC39A14 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The prevalence of hypermanganesemia with dystonia is unknown. A small number of cases of each type have been described in the scientific literature.

Which doctor should you see?

The suggested department for discussing Hypermanganesemia with dystonia is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Hypermanganesemia with dystonia. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.