ARTICLE
Glutaric aciduria type I (GA-I) is an
autosomal recessive disorder of lysine, hydroxylysine and tryptophan metabolism
which results in an accumulation and increased excretion of glutaric acid
and its metabolites [1].
Glutaryl-coenzyme A dehydrogenase (GCDH) is a multifunctional enzyme
responsible for the dehydrogenation and decarboxylation of glutaryl-CoA
to crotonyl-CoA in the degradative pathway of L-lysine, L-hydroxylysine,
and L-tryptophan metabolism. The enzyme exists in the mitochondrial matrix
as a homotetramer of 45-kD subunits. Using a cDNA for human GCDH, Greenberg
et al. mapped the GCDH gene to 19p13.2 by in situ hybridization
and somatic cell hybrid analysis [2]. GA-I was first described in 1975
[3], and the frequency may be as high as 1: 30,000 [4]. GA-I is clinically
characterized by macrocephaly and a progressive neurological symptomatology,
in particular a dystonic-dyskinetic movement disorder following acute
encephalopathic crises, resulting in progressive loss of all motor abilities,
while the intelligence is unaffected. Untreated, most children die during
the first decade of life. GA-I is a distinct disorder among the different
aminoacidurias, such as methylmalonic and propionic acidurias, maple syrup
urine disease, where an associated erythematous skin rash has been observed.
So far, however, no report describes the skin status of children with
GA-I. We present a case of GA-I in a 5-year-old Turkish girl who developed
an acrodermatitis enteropathica-like skin rash.
Case report
In a 5-year-old Turkish girl, born as the first child to consanguineous,
healthy parents, GA-I was diagnosed at six months of age, subsequent to
an acute encephalopathic crisis which led to a severe dystonic-dyskinetic
movement disorder. She was treated with a low protein, lysine and tryptophan
restricted diet. Because of vomiting and feeding difficulties a percutaneous
endoscopic gastrostomy was applied at the age of two years. Nevertheless,
she failed to thrive. Therefore, a high-calorie, protein-rich diet was
instituted at the age of 5 years via a jejunal tube. Four weeks later
inflammatory skin lesions appeared on the face. Subsequently only a diminished
portion of the diet (approximately 0.5 g protein and 75 kcal/kg per day)
was given to her over the next six weeks because of feeding problems.
Then a further aggravation of the erythemato-squamous skin rash was noted.
The dermatitis started with moist, erythematous lesions on the face
(Fig. 1) and the back
(Fig. 2), expanding to
the neck and occipital region, the dorsal aspect of hands and feet, the
forearms and lower legs (Fig.
3), the axillary intertrigines and the diaper region. Laboratory
examinations revealed hypoproteinaemia and hypoalbuminaemia as well as
low levels of isoleucine and zinc (plasma protein 52 g/L, plasma albumin
26 g/L, plasma isoleucine 33 mumol/L; normal 40-90 mumol/L, plasma leucine
63 mumol/L; normal 50-215 mumol/L, serum zinc 7.2 mumol/L; normal 9.8-18.1
mumol/L, serum selenium 0.24 mumol/ L; normal 0.77-1.44 mumol/L).
She was treated again with a high-calorie, protein-rich diet (125 kcal/kg
respectively 3.0 g/kg per day) together with supplementation of zinc,
selenium and vitamins and initially with albumine infusions. Under this
therapy she slowly recovered over a period of four weeks. The cutaneous
lesions disappeared completely, leaving a slight hyperpigmentation within
the affected areas, and the values of laboratory examinations improved
(plasma protein 77 g/L, plasma albumin 42 g/L, plasma isoleucine 59 mumol/L,
plasma leucine 137 mumol/L, serum zinc 10.6 mumol/L, serum selenium 0.32
mumol/L).
Discussion
Acrodermatitis enteropathica (AE)-like skin lesions have previously
been described in patients with branched-chain organic acid disorders
(methylmalonic and propionic acidurias, maple syrup urine disease) [5-8].
For this cutaneous disorder the name acrodermatitis acidemica (AA) has
been proposed [9]. In some cases an amino acid deficiency was suspected
of being the major factor leading to cutaneous lesions. This view is supported
by the observations of Shipley and Pittelkow [10], who studied the influence
of various nutritional components on the growth and differentiation of
human keratinocytes cultured in serum-free media. Their investigations
revealed that depletion of several essential amino acids in the basal
medium arrested the growth of keratinocytes; the most critical protein
appeared to be isoleucine [5].
Similar skin changes are found in AE that is caused by a primary or
secondary deficiency of zinc, which is supposed to affect the activity
of zinc-dependent enzymes in fibroblasts, e.g., 5'-nucleotidase
[11].
Skin manifestations and histopathological findings of AA are very similar
to those of AE. It is thus impossible to differentiate AA from AE based
on the cutaneous findings alone. In both AE and AA, the skin lesions typically
develop gradually over a few weeks, are especially painful and oozing.
The erosive erythema shows an affinity to the diaper region, the neck
folds, the periorificial areas (mouth, nose, ears, eyes, and perineum)
and the extremities. Initially, a vesiculobullous eruption with erosions
develops. Later these vesiculobullous lesions become dry, hyperkeratotic,
and psoriasiform in appearance. With the exception of cheilitis and glossitis,
the mucous membranes are usually spared, but diffuse hair loss occurs.
Histopathological changes show pallor of the
upper part of the epidermis with necrosis of keratinocytes. A diffuse
parakeratosis is seen overlying the pale epidermal cells. Sometimes a
subcorneal vesicle is present above the area of paleness of the epidermis
[5].
The differential diagnosis of both AA and AE includes staphylococcal
scalded skin syndrome, chronic mucocutaneous candidiasis, necrolytic migratory
erythema, and multiple carboxylase deficiency.
In our patient, both organic aciduria and zinc deficiency were present.
Furthermore, we found a depletion of selenium and a low level of vitamin
B6 (5.9 mug/L; normal 3.6-18 mug/L), which are essential factors
in cutaneous metabolism [12]. Treatment with an adequate protein-rich,
high-calorie diet together with supplementation of zinc, selenium and
vitamins led to a recovery of our patient as well as to a normalization
of laboratory findings.
CONCLUSION
In total we could not identify a single cause for the manifestation of
AA in our patient, but pathological levels of several factors, all of
which have been associated with AE-like lesions (isoleucine, zinc, selenium,
vitamin B6). Therefore, it seems possible that in our patient
AA is a result of a protein-depleted nutrition, rather than being primarily
associated with GA-I itself. This observation stresses the need for children
with metabolic disorders and dietary treatment to have regular comprehensive
investigations to identify nutritional deficiencies early on.
Article accepted on 29/1/01
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