Aminoacidopathies

Aminoacidopathies are diseases caused by a genetically determined, biochemical abnormality in the metabolic pathway of amino acids. In most cases, the defects implicate the alteration of an enzyme interrupting the normal catabolism of an amino acid; in a few cases, the defects implicate a protein mediator required for amino acids transport. These disorders account for a non-negligible portion of neonatal and paediatric diseases. They are, however, relatively rare globally and give rise to a wide range of clinical manifestations. Neurological manifestations appear to be the main symptoms, often indicative of the underlying metabolic disease, and they may be more or less associated with other, sometimes cutaneous, manifestations (Table I). Broadly, three main forms of aminoacidopathies can be distinguished based on physical expression:

— acute neonatal forms. These forms are observed in newborns who, after a disease-free period of a few hours to a few days, undergo progressive, unexplained neurological deterioration resulting in reduced consciousness and coma in extreme cases;

— acute delayed onset forms. These forms of the disease are observed in infants or children and even in adults and manifest as neurological disorders occurring during acute regressive attacks while between episodes the child is normal and suffers from no mental retardation. Onset at a late age and an absence of mental retardation are therefore not exclusion criteria as regards diagnosis. These acute attacks may be severe, giving rise, for example, to repeated, unexplained comas;

— progressive chronic forms. Numerous aminoacidopathies of late onset are accompanied, in retrospect, by relatively non-specific, insidious, often neurologic signs such as progressive mental retardation, hypotonia, muscle weakness, muscle atrophy and non-specific, extraneurologic symptoms. Gastrointestinal symptoms such as chronic anorexia, recurring vomiting, delayed growth, etc., and cutaneous, hematologic, nephrologic, hepatic, ophthalmologic signs…can be associated.

Cutaneous manifestations are rare. They are most often observed with aminoacidurias affecting the urea cycle and the metabolism of the branched chain amino acids. The most common manifestations are listed in Table II. They are not disorder-specific and variable, except in the following cases:

— in genetic defects occurring with tyrosinemia type II, where the development of cutaneous lesions such as pseudo-warts, and sometimes painful blisters, on the extremities (soles of the feet and palms of the hands) occurs together with the progressive appearance of ocular lesions such as corneal ulcers and keratitis,

— in biotin metabolism disorders (also called multiple carboxylase deficiency since biotin is a coenzyme of the carboxylases). In this situation, cutaneous lesions are usually present and, together with neurolgic symptoms, are key symptoms that should alert the physician and lead to systematic metabolic investigations. A classical clinical presentation is the development of progressive acrodermatitis enteropathica-like lesions and/or alopecia more or less combined with psychomotor retardation.

1 - INFORMATION FOR PATIENTS AND PATHOPHYSIOLOGICAL HYPOTHESES

The non-specificity of the very stereotypical cutaneous abnormalities observed with aminoacidopathies makes it difficult to understand the pathophysiological mechanisms at play and to define the role of the various amino acids in the formation of the lesions. The manifestations could be related to dietary imbalance or, when observed after metabolic decompensation, to a toxic agent. However, such manifestations are rare with aminoaciduria , and, especially, they are not observed in most patients with the same metabolic disease of the same severity and with the same metabolic or nutritional status. Therefore, there are still many unknowns and the causal mechanisms are probably intermingled (nutritional, metabolic and genetic predisposition).

The long-term management of these metabolic diseases falls under the competence of highly specialised paediatric departments. Dermatologists generally only intervene as consultants.