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Therapy should extend beyond childhood

By systematically analysing MRI changes occuring in the brains of children with the metabolic disease glutaric aciduria type I researchers at Heidelberg University Hospital have succeeded for the first time in demonstrating reversible and permanent brain damage as well as elucidating its temporal evolution.

The Heidelberg researchers now assume that during the course of the disease, the products of metabolism cause not only acute, but chronic toxic damage as well. Therapy should thus be extended to prevent long-term brain damage.

These new insights enhance the understanding of the natural course of the disease and confirm the benefit and consequently the necessity of newborn screening for rare metabolic diseases and neonatal therapy. The study was published in the prestigious journal Brain.

Permanent damage when treatment is delayed

One of 100,000 newborns suffers from the rare metabolic disorder glutaric aciduria type I. Affected children are unable to break down certain amino acids (lysine, hydroxylysine, and tryptophan), which are components of proteins, but produce pathological metabolites that accumulate and can damage the developing brain.

Even before birth, brain changes indicating delayed development occur, which however are reversible if they receive adequate treatment in time. Permanent brain damage usually occurs in clinically inconspicuous babies if the diagnosis is not made in time and treatment is delayed.

Babies are initially free of symptoms / Severe crises during infancy and childhood

As newborns and young babies, the patients are initially inconspicuous. If not treated, they undergo a severe crisis at the age of 3 to 36 months. As the same deep regions of the brain are affected as in Huntington's disease, the children have similar movement disorders but their intelligence is usually spared by the neurodegenerative process.

However, the children's prognosis is favourable if the disease is detected early by newborn screening, which -using a drop of blood taken from the heel- is carried out in Germany for all newborns. The diagnosis after birth is the most important condition for successful treatment, i.e. normal development and prevention of irreversible cerebral injury. The therapy consists of a special diet low in the amino acid lysine, and supplemented with carnitine, an endogenous carrier for fatty acids, which is lost through urine in this disease. In addition, intensive emergency treatment of the metabolism must be carried out to prevent a metabolic crisis during febrile infections.

For their study, an international interdisciplinary research group of neuroradiologists and pediatricians headed by Dr. Stefan Klker from the Center for Pediatric and Youth Medicine and Dr. Inga Harting from the Department of Neuroradiology examined 38 patients from newborns to adulthood, comparing MRI changes with neurological symptoms and analyzing the time patterns.

Reversible and irreversible changes occur

They discovered that MRI changes in certain regions of the brain (e.g. in the white matter and cerebral cortex) occured frequently and in all patients, whereas changes in the basal ganglia occurred only in patients who had experienced encephalopathic crises. The changes outside of the basal ganglia were quite variable, some were reversible, and some were apparent as early as the neonatal stage and had no clinical significance. In contrast, the changes in the basal ganglia were irreversible and were clearly associated with the development of severe movement disorders.

The Heidelberg researchers now assume that during the course of the disease, the products of metabolism cause not only acute, but chronic toxic damage as well. Therapy should thus be extended to prevent long-term brain damage.

The Heidelberg researchers hypothesize that in the course of the disease, abnormally accumulating metabolites not only give rise to acute, but also to chronic toxic damage. For treatment purposes, this would mean that the duration of current therapy should be extended beyond childhood to prevent long-term changes and damage to the brain. This remains to be elucidated by follow-up studies.

Heidelberg Metabolism Center screens 100,000 newborns annually

Newborn screening in Germany is carried out to detect glutaric aciduria type I and 13 other diseases. The Metabolism Center of the Heidelberg Clinic for Pediatric and Youth Medicine carries out newborn screening for 100,000 newborns annually. The current guidelines in Germany and three other European countries for the diagnosis and therapy of children with this rare metabolic disease were compiled by an international guideline group headed by Dr. Klker. Parallel to this, the same working group carried out translational studies to examine new therapy approaches in a mouse model.


Contact: Dr. med. Inga Harting
University Hospital Heidelberg

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