Isolated partial 3-methylcrotonyl-CoA carboxylase (MCC) deficiency has been described to be the cause for a distinct relatively mild clinical picture in a single patient. We describe another patient with isolated partial MCC deficiency who suffered from failure to thrive, muscular hypotonia and progressive respiratory insufficiency with fatal outcome at the age of 6.5 months. MCC deficiency was suspected at 3 months of age on the basis of mildly elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine and confirmed by enzyme analysis in lymphocyte and fibroblast homogenates. Residual MCC activity in lymphocytes was 25% of the mean normal value. Residual activity in fibroblasts was lower than in lymphocytes (3.8% of mean normal) and not significantly different from that in patients with complete MCC deficiency. However, the residual incorporation of 14C-isovalerate into macromolecules in intact fibroblasts, was clearly higher (28% of mean normal) than in fibroblasts with complete MCC deficiency (<4%). In both patients with partial deficiency the residual MCC activity was higher in lymphocytes than in fibroblasts. Clinical symptoms and signs in our patient attributable to MCC deficiency include muscular hypotonia, failure to thrive (already present at birth), progressive respiratory failure due to diaphragmatic paresis and a moderate brain atrophy. The clinical presentation was more severe than in many patients with complete MCC deficiency. Dietary therapy was biochemically effective as shown by normalization of organic acid excretion, however, had no effect on the CNS symptoms. Conclusion We speculate that the severity of the disease could be related primarily to deficiency of MCC activity in the brain. Variable MCC activity among various organs may explain the peculiar clinical picture in this patient.