Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is an autosomal recessive disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Diagnostic hallmark of HIDS is a constitutively elevated level of serum immunoglobulin D (IgD), although patients have been reported with normal IgD levels. To determine the underlying defect in HIDS, we analysed urine of several patients and discovered increased concentrations of mevalonic acid during severe episodes of fever, but not between crises. Subsequent analysis of cells from four unrelated HIDS patients revealed reduced activities of mevalonate kinase (MK; encoded by the gene MVK), a key enzyme of isoprenoid biosynthesis. Sequence analysis of MVK cDNA from the patients identified three different mutations, one of which was common to all patients. Expression of the mutant cDNAs in Escherichia coli showed that all three mutations affect the activity of the encoded proteins. Moreover, immunoblot analysis demonstrated a deficiency of MK protein in patient fibroblasts, indicating a protein-destabilizing effect of the mutations.

Valproic acid (VPA; 2-n-propylpentanoic acid) is widely used as a major drug in the treatment of epilepsy and in the control of several types of seizures. Being a simple fatty acid, VPA is a substrate for the fatty acid beta-oxidation (FAO) pathway, which takes place primarily in mitochondria. The toxicity of valproate has long been considered to be due primarily to its interference with mitochondrial beta-oxidation. The metabolism of the drug, its effects on enzymes of FAO and their cofactors such as CoA and/or carnitine will be reviewed. The cumulative consequences of VPA therapy in inborn errors of metabolism (IEMs) and the importance of recognizing an underlying IEM in cases of VPA-induced steatosis and acute liver toxicity are two different concepts that will be emphasized.

We report on three patients (two siblings and one unrelated) presenting in infancy with progressive muscle weakness and paralysis of the diaphragm. Metabolic studies revealed a profile of plasma acylcarnitines and urine organic acids suggestive of a mild form of the multiple acyl-CoA dehydrogenation defect (MADD, ethylmalonic/adipic acid syndrome). Subsequently, a profound flavin deficiency in spite of a normal dietary riboflavin intake was established in the plasma of all three children, suggesting a riboflavin transporter defect. Genetic analysis of these patients demonstrated mutations in the C20orf54 gene which encodes the human homolog of a rat riboflavin transporter. This gene was recently implicated in the Brown-Vialetto-Van Laere syndrome, a rare neurological disorder which may either present in infancy with neurological deterioration with hypotonia, respiratory insufficiency and early death, or later in life with deafness and progressive ponto-bulbar palsy. Supplementation of riboflavin rapidly improved the clinical symptoms as well as the biochemical abnormalities in our patients, demonstrating that high dose riboflavin is a potential treatment for the Brown-Vialetto-Van Laere syndrome as well as for the Fazio Londe syndrome which is considered to be the same disease entity without the deafness.

In presymptomatic children with GDD, the onset of neurological disease can be prevented by vigorous treatment of catabolic crises during illnesses together with carnitine supplementation. The importance of dietary therapy remains unclear and needs further evaluation. The potential treatability of GDD calls for increased attention to early presenting signs in order to recognize the disorder and to initiate treatment before the onset of irreversible neurological disease.