Table 2 Examples of the main mechanisms of therapeutic procedures for metabolic diseases

Therapeutic procedure

Examples

Activity modification of a genetically defective protein

In Bartter syndrome type 4A (OMIM:602522), tanespimycin (17-allylamino-17-demethoxygeldanamycin or 17-AAG), an Hsp90 inhibitor, enhances the plasma membrane expression of mutant barttins (R8L and G47R) in Madin–Darby canine kidney cells [33].

Activity modification of a genetically defective protein by epigenetic manipulation

HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene, in the treatment of Friedreich’s ataxia (OMIM:229300) [34].

Activity modification of a genetically defective protein by genome editing

CRISPR-Cas9-mediated gene editing is a potential treatment for Hurler syndrome (OMIM:607014) as established in cell and animal based studies [35], [36].

Activity modification of a genetically defective protein by transcriptional or translational modification

Vitamin D in treating hyperprolinemia (OMIM:239500) and recombinant human erythropoietin (rhuEPO) in treating Friedreich’s ataxia (OMIM:229300) are examples of drugs that enhance the activity of PRODH and FXN respectively by transcriptional modulation of PRODH in hyperprolinemia and increasing frataxin expression in Friedrich’s ataxia [37] [38].

Direct complementation of a genetically defective protein

Recombinant human IGF1 (mecasermin) is a form of enzyme replacement therapy in treating insulin-like growth factor I deficiency (OMIM:608747) [39].

Direct complementation of a genetically defective protein by gene therapy

An adeno-associated viral vector containing a porphobilinogen deaminase gene is a treatment for acute intermittent porphyria (OMIM:176000) [40].

Functional complementation of a genetically defective protein by inhibition

Miglustat is a form of substrate reduction therapy (SRT) used to treat Gaucher’s disease (OMIM:230800) where miglustat inhibits the ceramide-specific glucosyltransferase which catalyses the first committed step of GSL synthesis [41].

Procedure to mitigate dominant effect of a genetically abnormal protein

In treating hyperinsulinism-hyperammonemia syndrome (OMIM:606762), diazoxide inhibits insulin release and promotes complete resolution of hypoglycemia [42].

Dietary exclusion

A valine-restricted diet is a treatment for patients suffering from isobutyryl-CoA dehydrogenase deficiency (OMIM:611283), which inolves valine metabolism [43].

Dietary supplementation

Beneprotein and uncooked cornstarch as high sources of protein and carbohydrates are used to prevent long-term complications in glycogen storage disease IXb (OMIM:261750) patients [44].

Metabolite replacement

Hydrocortisone is a replacement therapy for patients with 17-alpha-hydroxylase deficiency (OMIM:202110) [45].

Functional complementation of a genetically defective protein by stimulation

Sodium valproate activates the expression of one glycogen phosphorylase isoform, GP-BB, which in turn results in a decrease in intracellular glycogen accumulation, a dominant feature of glycogen storage disease type V (OMIM:232600) [46].