2-hydroxy glutaric aciduria

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Classification according to ICD-10
E72.8 Other specified disorders of amino acid metabolism
ICD-10 online (WHO version 2019)

The 2-hydroxy-Glutaraciduria is a group of very rare congenital to the Glutarazidurien associated metabolic disorders with very different clinical picture. Main signs are increased levels of 2-hydroxyglutaric acid in the blood serum , in the cerebrospinal fluid and in the urine .

Classification

2-Hydroxyglutaric acid can occur as a mirror image isomer, ie there is a (dextrorotatory) D-2-hydroxyglutaric acid and a (levorotatory) L-2-hydroxyglutaric acid. The following forms arise for the disease:

  • D-2-hydroxyglutaric aciduria ( D2-HGA ) with various metabolic, neurological and dysmorphic symptoms.
  • L-2-hydroxyglutaric aciduria ( L2-HGA ) with psychomotor retardation, cerebellar ataxia, and epilepsy .
  • D- & L-2-hydroxy-glutaric aciduria as a combination of both

distribution

The frequency is given as less than 1 in 1,000,000, so far fewer than 300 patients have been described.

root cause

  • The D-2-HGA are mutations in D2HGDH - gene on chromosome 2 gene locus q37.3 (Type I) and in the IDH2 gene on chromosome 15 q26.1 (type II) is based. The IDH2 genes instruct mitochondrial enzymes. When deficiencies in the enzyme develop, toxic build-up of D-2-hydroxyglutarate occurs. This results in damage to the brain cells. It is not yet clear why cardiomyopathies occur in some cases.
  • The L-2-HGA mutations in the L2HGDH gene on chromosome 14 q22.1
  • The combination disease mutations in SLC25A1 - gene on chromosome 22 q11.21 encoding proteins within the mitochondria for energy production of a cell and moreover some for transporting molecules such. B. citrate, in and out of the mitochondria, are responsible. Mutations in this gene reduce the protein function that normally transports both D-2-hydroxyglutarate and L-2-hydroxyglutarate out of the cell. The dysfunction of the enzymes leads to an accumulation of D- or L-2-glutarate within the affected cells, which can lead to a high degree of damage to the cell or even to cell death. The cells of the brain are very vulnerable to this toxic amount, which leads to the conclusion that symptoms are almost exclusively cerebral. Scientists suspect that the imbalance of molecules, particularly citrate, may contribute to the remaining symptoms of the combined form.

The hydroxy Glutarazidurien are very rarely occurring neurological metabolic diseases with autosomal - recessive inheritance. The exception is D-2-HGA, which is inherited dominantly.

Clinical manifestations

  • In D-2-HGA, the main signs are developmental delay , seizures , hypotonia, and abnormalities in large areas of the brain. This influences movement, language, sight, thinking, emotions and memory. Type II tends to start earlier and often causes several serious health problems compared to type I. In addition, type II can be associated with cardiomyopathies .
  • L-2-HGA causes severe disorders of the central nervous system , especially in the cerebellum . The first clinical signs usually appear between the ages of six months and one year of life. Those affected initially experience normal development or a slight psychomotor developmental delay , and ultimately pyramidal and extrapyramidal symptoms such as dystonia , myoclonus and spasticity . Many sufferers have problems with balance and muscle coordination ( ataxia ). It is not uncommon for epilepsy, macrocephaly and changes in behavior to occur.
  • The combination of the D, L-2-HGA causes brain abnormalities that appear in infancy. Affected children suffer from seizures, weak muscle tone (hypotension), breathing and feeding problems. In most cases, survival is only guaranteed until childhood.

diagnosis

A screening for organic acids reveals a massive increase in the hydroxy-glutaric acid level in urine, plasma and cerebrospinal liquor, as well as secondary carnitine deficiency. The diagnosis of L-2-HGA can be confirmed biochemically by a chiral separation. Due to the slow course of the disease, it may be diagnosed late. The imaging procedures (MRT and CT) show increases in intensity in subcortical and paraventricular areas, as well as atrophy of the cerebellum and encephalopathy of the white matter of the brain . Mutational analysis and measurement of L-2-hydroxy-glutaric acid in amniotic fluid a is prenatal diagnosis possible in principle.

therapy

No specific treatment is known to date.

forecast

The prognosis is considered unfavorable due to the progression, but most patients reach adulthood.

literature

  • O. Hussmann, D. Haas, BA Neubauer, B. Kruse, M. Huegens-Penzel, C. Jakobs, A. Hahn: L-2-hydroxy- glutaric aciduria - a rare differential diagnosis of macrocephaly. In: Clinical Pediatrics. Vol. 218, No. 2, 2006 Mar-Apr, pp. 72-73, doi: 10.1055 / s-2005-836848 , PMID 16506106 .
  • EA Struys: D-2-Hydroxyglutaric aciduria: unraveling the biochemical pathway and the genetic defect. In: Journal of inherited metabolic disease. Vol. 29, No. 1, February 2006, pp. 21-29, doi: 10.1007 / s10545-006-0317-9 , PMID 16601864 (review).
  • Y. Shafeghati, G. Vakili, A. Entezari: L-2-hydroxyglutaric aciduria: a report of six cases and review of the literature. In: Archives of Iranian medicine. Vol. 9, No. 2, April 2006, pp. 165-169, PMID 16649364 .

Individual evidence

  1. ↑ a b c 2-hydroxyglutaric aciduria. In: Orphanet (Rare Disease Database).
  2. ↑ L-2-hydroxyglutaryl aciduria. In: Orphanet (Rare Disease Database).
  3. ^ D- & L-2-hydroxy-glutaric aciduria. In: Orphanet (Rare Disease Database).
  4. ^ D-2-hydroxyglutaric aciduria.  In: Online Mendelian Inheritance in Man . (English)
  5. ^ L-2-hydroxyglutaric aciduria.  In: Online Mendelian Inheritance in Man . (English)
  6. ↑ Combined D-2- and L-2-hydroxyglutaric aciduria.  In: Online Mendelian Inheritance in Man . (English)

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