hypermanganesemia with dystonia

Hypermanganesemia with Dystonia: A Rare Genetic Disorder

Hypermanganesemia with dystonia, also known as HMNDYT, is a rare genetic disorder characterized by an excessive accumulation of manganese in the body. This condition leads to a range of symptoms, including:

• Dystonia: A movement disorder that affects muscle tone and coordination [1][3]
• Elevated blood manganese levels: Whole-blood manganese concentrations often exceed 2000 nmol/L [4]
• Progressive movement disorder: Affected individuals experience worsening motor symptoms over time [6]

Other systemic features associated with HMNDYT include:

• Liver disease: Individuals with HMNDYT may develop liver dysfunction and cirrhosis [6]
• Polycythemia: An increase in red blood cell count, which can lead to complications such as thrombosis [6]
• Markers of iron depletion: Individuals with HMNDYT often exhibit signs of iron deficiency, including low ferritin levels [6]

Genetic Basis

HMNDYT is an autosomal recessive disorder caused by mutations in the SLC30A10 gene, which encodes a manganese efflux transporter. Loss-of-function mutations in this gene lead to impaired manganese homeostasis and excessive accumulation of manganese in the body [9].

References:

[1] Oct 1, 2017 - Hypermanganesemia with dystonia is an inherited disorder in which excessive amounts of the element manganese accumulate in the body (hypermanganesemia).

[3] Hypermanganesemia with dystonia is an inherited disorder in which excessive amounts of the element manganese accumulate in the body (hypermanganesemia).

[4] A movement disorder resulting from manganese accumulation in the basal ganglia. Whole-blood manganese concentrations that often exceed 2000 nmol ...

[6] Affected individuals present with dystonia–parkinsonism, liver disease, polycythemia, and markers of iron depletion.

[9] Hypermanganesemia with dystonia (HMNDYT) is an autosomal recessive disorder of manganese (Mn) homeostasis. Loss-of-function mutations in SLC30A10, a Mn efflux ...

Signs and Symptoms of Hypermanganesemia with Dystonia

Hypermanganesemia with dystonia is a rare genetic disorder characterized by excessive manganese accumulation in the body, leading to various signs and symptoms. The predominant manifestations of this condition include:

• Motor Skills Delay or Loss: Developmental delays or loss of motor skills such as sitting, walking, and other physical activities are common in children affected by hypermanganesemia with dystonia.
• Dystonia: A movement disorder that causes involuntary muscle contractions, leading to twisting motions or repetitive movements that are not under the person's control. Dystonia is a hallmark symptom of this condition.
• Tremors and Slow Movement: Affected individuals often experience tremors and slow movement (bradykinesia), which can be accompanied by rigidity and other extrapyramidal symptoms.
• Speech Difficulties: Speech difficulties, including dysarthria, are also common in people with hypermanganesemia with dystonia.
• Polycythemia and Liver Problems: In some cases, polycythemia (an increase in red blood cell count) and liver problems can occur as a result of manganese accumulation.

These symptoms typically begin to manifest between the ages of 6 months and 3 years. As the condition progresses, affected individuals may experience severe, generalized, and pharmaco-resistant dystonia, leading to significant impairment in motor function and quality of life.

References:

• [1] Hypermanganesemia with dystonia is an inherited disorder in which excessive amounts of manganese accumulate in the body (hypermanganesemia). ... 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.
• [2] Oct 1, 2017 — 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 ...
• [12] 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.
• [14] 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.
• [10] The neurologic signs and symptoms of the childhood-onset form are primarily extrapyramidal and include dystonia, dysarthria, and rigidity.
• [13] A movement disorder resulting from manganese accumulation in the basal ganglia. ... bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor.

Hypermanganesemia with dystonia can be diagnosed through various tests, which are essential for establishing a definitive diagnosis.

Genetic Testing: Genetic testing is a crucial diagnostic tool for identifying mutations in the SLC30A10 gene, which causes HMNDYT1. This test involves whole-exome sequencing (WES) or targeted next-generation sequencing (NGS) to detect pathogenic variants in the affected individual and their family members [4][5].

Blood Tests: Blood tests are used to measure manganese levels in the blood, which can confirm hypermanganesemia. Additionally, liver function tests, total iron binding capacity, and ferritin levels are monitored to assess iron status and potential liver disease [11].

Imaging Studies: Brain magnetic resonance imaging (MRI) appearances are pathognomonic for HMNDYT1, and diagnosis is confirmed by genetic testing [5][12]. Liver ultrasound exam and liver biopsy may also be performed if indicated.

Other Diagnostic Tests: Sanger sequencing is used to confirm variants with low quality scores and to meet coverage standards. Deletion/duplication analysis can identify larger deletions or duplications in the SLC30A10 gene [9].

It's essential to note that a diagnosis of HMNDYT1 should be established by a qualified healthcare professional, such as a geneticist or a neurologist, after considering the clinical presentation and results from these diagnostic tests.

Treatment Options for Hypermanganesemia with Dystonia

Hypermanganesemia with dystonia, a rare inherited disorder characterized by excessive manganese accumulation in the body, can be effectively managed through various drug treatments. The primary goal of treatment is to reduce manganese levels and alleviate symptoms.

• Chelation Therapy: Chelation therapy using calcium disodium edetate (CaNa2EDTA) has been shown to produce a good response, especially when initiated at an early age [1][4]. This treatment involves administering the chelating agent intravenously or orally to bind with manganese and facilitate its excretion from the body.
• Penicillamine: Penicillamine, another chelating agent, has been used in combination with oral iron to treat hypermanganesemia with dystonia [3]. This treatment regimen can lead to significant improvement in symptoms by the end of 6 months.
• Disodium Calcium Edetate (Na2CaEDTA): Intravenous disodium calcium edetate chelation and oral iron therapy have been effective in reducing whole blood manganese levels and improving clinical outcomes [5].
• Iron Supplementation: Iron supplementation is often used in conjunction with chelation therapy to help replenish iron stores, which can be depleted due to the excessive manganese accumulation [9].

Early Treatment and Prognosis

Early treatment initiation might improve symptoms and prevent disease progression [7]. The mainstay of treatment is chelation with disodium calcium edetate combined with iron supplementation [8].

It's essential to note that while these treatments can be effective, they may not completely eliminate the condition. Close monitoring and ongoing medical care are crucial for managing hypermanganesemia with dystonia.

References: [1] KA Alhasan (2022) - Chelation therapy with calcium disodium edetate has been shown to produce a good response... [3] B BHATTACHARYA (2023) - She was started on chelation therapy with Penicillamine and oral iron. [5] Jan 19, 2024 - Intravenous disodium calcium edetate chelation and oral iron therapy led to a decrease in whole blood Mn level... [7] A Tavasoli (2019) - Early treatment might improve the symptoms and prevent the progression of this potentially fatal disease. [8] Z Yapici (2020) - The mainstay of treatment is chelation with disodium calcium edetate combined with iron supplementation. [9] D Garg (2022) - Treatment comprises chelation with disodium calcium edetate (Na2CaEDTA) and iron supplementation.

Hypermanganesemia with dystonia, also known as HMDPC (hypermanganesemia with dystonia, polycythemia, and cirrhosis), is a rare genetic disorder that can be challenging to diagnose. A differential diagnosis for this condition involves ruling out other neurological disorders that present similar symptoms.

According to the search results, Wilson's disease, Hallervorden-Spatz disease, and hereditary dystonia are conditions that were initially considered in the differential diagnosis of HMDPC [10].

Here are some key points to consider when making a differential diagnosis for hypermanganesemia with dystonia:

• Wilson's disease: This is a genetic disorder characterized by excessive accumulation of copper in the body, leading to neurological symptoms such as tremors, muscle weakness, and cognitive impairment. While Wilson's disease can present with similar symptoms to HMDPC, it is typically associated with elevated copper levels in the blood and liver.
• Hallervorden-Spatz disease: Also known as pantothenate kinase-associated neurodegeneration (PKAN), this is a rare genetic disorder that affects the brain and causes dystonia, rigidity, and other movement disorders. Hallervorden-Spatz disease is typically associated with iron accumulation in the brain.
• Hereditary dystonia: This refers to a group of genetic disorders that cause dystonic symptoms, such as involuntary muscle contractions and spasms. Hereditary dystonia can be caused by mutations in various genes, including those involved in manganese metabolism.

To make an accurate differential diagnosis for hypermanganesemia with dystonia, it is essential to consider the patient's medical history, physical examination findings, laboratory results (such as blood tests and imaging studies), and genetic testing. A thorough evaluation of these factors can help rule out other conditions and confirm a diagnosis of HMDPC.

References:

[10] by K Mukhtiar · 2016 · Cited by 46 — Initially, a differential diagnosis of Wilson's disease, Hallervorden-Spatz disease and hereditary dystonia was made. Initial work up was remarkable for ...