2-methyl-3-hydroxybutyric aciduria

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Alternate names[edit | edit source]

HSD10 deficiency; 3H2MBD deficiency; 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency; Hydroxyacyl-CoA dehydrogenase II deficiency; 2M3HBA; 17 beta-hydroxysteroid dehydrogenase type 10 deficiency; 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency; MHBD deficiency; HSD10 mitochondrial disease; 2-methyl-3-hydroxybutyric aciduria

Definition[edit | edit source]

HSD10 disease (also known as 2-methyl-3-hydroxybutyric aciduria) is an inherited disorder in which the body cannot effectively process the amino acid isoleucine. HSD10 disease is a disorder that affects the nervous system, vision, and heart. It is typically more severe in males than in females.

Epidemiology[edit | edit source]

HSD10 disease is a very rare disorder. Its prevalence is less than 1 in 1 million people.

Cause[edit | edit source]

  • HSD10 disease is caused by mutations in the HSD17B10 gene, which provides instructions for making the HSD10 protein.
  • This protein is located within mitochondria, the energy-producing centers inside cells, where it is involved in the production (synthesis) of proteins.
  • While most protein synthesis occurs in the fluid surrounding the nucleus (cytoplasm), a few proteins are synthesized in the mitochondria.
  • During protein synthesis, in either the mitochondria or the cytoplasm, molecules called transfer RNAs (tRNAs) help assemble protein building blocks (amino acids) into chains that form proteins.
  • The HSD10 protein is part of a group of proteins (a complex) that is involved in making functional mitochondrial tRNA molecules, which aid in the synthesis of mitochondrial proteins.
  • Normal mitochondrial protein production is essential for the formation of the groups of proteins that convert the energy from food into a form cells can use.

Gene mutations[edit | edit source]

  • The HSD17B10 gene mutations that cause HSD10 disease reduce the amount of HSD10 protein in cells, impair their structure or function, or both, which leads to a deficiency of the functional complex in which it plays a part. This deficiency impairs the production of mitochondrial tRNAs.
  • Without enough tRNAs, the mitochondrial synthesis of proteins involved in cellular energy production is reduced.
  • A shortage of these proteins results in insufficient energy production in cells of the brain, eyes, and heart, leading to the characteristic features of HSD10 disease.

Inheritance[edit | edit source]

X-linked dominant inheritance

It has an X-linked dominant pattern of inheritance.

Signs and symptoms[edit | edit source]

  • Signs and symptoms of this condition usually develop in infancy or early childhood and include metabolic acidosis, hypoglycemia, hypotonia, seizures, movement problems, retinal degeneration, and hearing loss.
  • Affected males have severe neurodegeneration with loss of developmental milestones, whereas females have mild to moderate developmental delay.

Clinical presentation[edit | edit source]

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

30%-79% of people have these symptoms

  • Delayed speech and language development(Deficiency of speech development)
  • Developmental regression(Loss of developmental milestones)
  • Elevated urinary 3-hydroxybutyric acid
  • Global developmental delay
  • Intellectual disability, moderate(IQ between 34 and 49)
  • Progressive visual loss(Progressive loss of vision)
  • Seizure
  • Specific learning disability

5%-29% of people have these symptoms

  • Abnormal social behavior(Abnormal social behaviour)
  • Ataxia
  • Autistic behavior
  • Choreoathetosis
  • Chronic lactic acidosis
  • Dysarthria(Difficulty articulating speech)
  • Focal white matter lesions
  • Frontotemporal cerebral atrophy
  • Gait disturbance(Abnormal gait)
  • Hearing impairment(Deafness)
  • Infantile muscular hypotonia(Decreased muscle tone in infant)
  • Myoclonus
  • Optic atrophy
  • Short attention span(Poor attention span)

1%-4% of people have these symptoms

Diagnosis[edit | edit source]

  • Although the diagnosis can be aided by the observation of increased urinary levels of metabolites of isoleucine breakdown (2-methyl-3 hydroxybutyrate and tiglylglycine), there is not a correlation between these laboratory features and the phenotype.
  • In addition, patients do not develop severe metabolic crises in the neonatal period as observed in other organic acidurias, but may show persistent lactic acidosis, most likely reflecting mitochondrial dysfunction.

Treatment[edit | edit source]

  • There is no effective treatment for the disease. A low-protein, high-energy dietary regimen with carnitine supplementation reduces the accumulation of isoleucine metabolites in blood and urine, but does not improve psychomotor deterioration.
  • Due to its ability to interfere with mitochondrial energy metabolism, valproic acid should be avoided.

NIH genetic and rare disease info[edit source]

2-methyl-3-hydroxybutyric aciduria is a rare disease.

2-methyl-3-hydroxybutyric aciduria Resources
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