Branched-chain organic acidurias.

PURPOSE To present the CT and MR findings in children with propionic and methylmalonic acidemia. METHODS Twenty-three new patients with methylmalonic and 20 with propionic acidemia were examined with CT and/or MR of the brain. In total 52 CT and 55 MR studies were done. Twenty-six previously published cases were also reviewed. RESULTS The findings were similar in the two syndromes. During the first month of life the examinations were either normal or showed white matter attenuation. Later during the first year moderate or even severe widening of sulci and fissures was seen, especially in infants with propionic acidemia. During therapy, these changes often resolved, especially in the patients with methylmalonic acidemia. Mild to moderate delay in myelination was also a common finding in both disorders. Basal ganglia changes, predominately in the globus pallidus, were seen in five patients with methylmalonic acidemia and in two children with propionic acidemia; in two patients these changes were transient. CONCLUSION Children who have methylmalonic or propionic acidemia, in addition to widening of cerebrospinal fluid spaces and some delay in myelination, also often show symmetric involvement of the basal ganglia.

http://www.ajnr.org/content/ajnr/15/8/1459.full.pdf

CT and MR of the brain in disorders of the propionate and methylmalonate metabolism.

Inborn errors of metabolism are individually rare, but collectively numerous. However, their incidence may well be underestimated as diagnostic errors are frequent. As a whole, they can not be recognized through systematic neonatal screening tests, which are too slow, too expensive, or unreliable. This makes it an absolute necessity to teach primary care physicians a simple method of clinical screening before deciding to initiate sophisticated biochemical investigations. Clinical diagnosis of inborn errors of metabolism may at times be diffi­cult. A number of generally accepted ideas contribute to this difficulty: (1) Many physicians think that because individual inborn errors are rare, they should be considered only after more common conditions (like sepsis) have been excluded. (2) In view of the large number of inborn errors, it might appear that their diagnosis requires precise knowledge of a large number of biochemical pathways and their interrelationships. As a matter of fact, adequate diagnostic approach can be based on the proper use of only a few screening tests. (3) The neonate has an apparently limited repertoire of responses to severe overwhelming illness and the predominant clinical signs and symptoms are nonspecific: poor feeding, lethargy, failure to thrive, etc. It is certain that many patients with such defects succumb in the newborn period without having received a specific diagnosis, death often having been attributed to sepsis or other common causes. (4) Classical autopsy findings in such cases are often unspecific and unrevealing. Infection is often suspected as the cause of the death, whereas sepsis is the common accompaniment of metabolic disorders. (5) Many general practitioners and pediatricians only think of inborn errors of metabolism in inadequate and very unspecific clinical circumstances like psychomotor retardation or seizures. Conversely, they ignore most of the highly specific symptoms which are excellent keys to the diagnosis. Another common mistake is to confuse “syndrome” (such as Leigh syndrome or Reye syndrome), which is a set of symptoms possibly due to different causes, with the etiology itself. (6) Although most genetic metabolic errors are hereditary and transmitted as recessive disorders, the majority of cases appear sporadic, because of the small size of sibships in developed countries. Finally, “hereditary” does not mean “congenital”, and many patients can present a late onset form in childhood, adolescence, or even in adulthood.

Clinical Approach to Inherited Metabolic Diseases

https://www.journal-of-hepatology.eu/article/S0168-8278(05)00299-0/pdf

Clinical, biochemical and morphological features of hepatocerebral syndrome with mitochondrial DNA depletion due to deoxyguanosine kinase deficiency

Neurological manifestations are very common and can be the leading and/or presenting feature in organic acid disorders, sometimes in the absence of metabolic derangement. Review of the time course and presentation of neurological disease in organic acid disorders reveals characteristic clinical findings of ataxia, myoclonus, extrapyramidal symptoms, metabolic stroke and megalencephaly. A group of organic acid disorders presents exclusively with neurological symptoms. These include glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I), succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria), mevalonic aciduria, N-acetylaspartic aciduria (Canavan disease) and L-2-hydroxyglutaric aciduria. As a group these "cerebral" organic acid disorders appear to remain often undiagnosed and their true incidence is much less well-known than that of the "classical" organic acid disorders. Unfortunately, stringent guidelines for a clinical preselection of neuropaediatric patients to be investigated for organic acid disorders cannot be provided. Today, screening for neurometabolic disorders should be as comprehensive as possible and include determinations of amino acids, purines and pyrimidines and markers of peroxisomal function in addition to organic acid analysis.

Neurological manifestations of organic acid disorders.

Every newborn with unexplained neurological deterioration, ketosis, metabolic acidosis or hypoglycaemia should be suspected of having an inherited error of intermediary metabolism. Many of these conditions can be diagnosed clinically with the aid of simple laboratory investigations. Since a substantial number of these diseases respond well to treatment but may otherwise be fatal, and in order to assure adequate prenatal diagnosis in subsequent pregnancies, a high index of suspicion and rapid diagnosis are necessary in the face of the clinical presentations described. According to three major clinical presentations observed in 218 neonates with inborn errors of intermediary metabolism (neurological distress ‘intoxication’ type, neurological distress ‘energy deficiency’ type and hypoglycaemia with liver dysfunction) and according to the proper use of few laboratory investigations, we propose a method of diagnosis which groups these children into five categories. Initial therapy, and sophisticated investigations can be planned on the basis of this grouping.

Clinical approach to inherited metabolic diseases in the neonatal period: a 20-year survey.

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Clinical approach to inherited metabolic diseases in the neonatal period: a 20-year survey.