**3. Other vitB6-responsive conditions**

The therapeutic effect of vitB6 supplementation have been also described in other disease conditions. The following section outlines some examples.

## **3.1 Hyperphosphatasia with mental retardation syndrome**

Hyperphosphatasia with mental retardation (HPMR) syndrome (OMIM Phenotypic Series: PS239300) refers to a group of congenital disorders caused by defects in the biosynthetic pathway of glycosyl phosphatidylinositol (GPI) anchor. GPI-anchor is a glycolipid that is required for tethering of TNSALP and several other proteins (more than 150 in total) to the cell surface and at the blood–brain barrier (BBB) [6, 61]. Six subtypes of HPMR syndrome have been identified to date with variable phenotypic spectrum that extends from mild nonsyndromic intellectual disability (ID) to more complex forms with severe ID, seizures, increased serum alkaline phosphates and dysmorphic features [141–143]. Low serum PLP has been detected in some patients which may be ascribed to the elevated serum level of alkaline phosphate [144]. Seizures in some HPMR subtypes like PIGV deficiency [144] and PIGO deficiency [143] have been shown to respond to pyridoxine treatment.

## **3.2 PL kinase deficiency**

PL kinase (PLK) is an important enzyme in the vitB6 salvage pathway (**Figure 2**). It is responsible for phosphorylating different vitameric compounds which is a pre-requisite step for their subsequent conversion to the active cofactor PLP (**Figure 2**). Biallelic mutations in the gene encoding PLK (*PDXK*) have been recently shown to cause an autosomal recessive disorder that is characterized by axonal peripheral polyneuropathy and optic atrophy [145]. Affected subjects had low plasma PLP and treatment with PLP supplementation was associated with biochemical and clinical improvements [145].

#### **3.3 Molybdenum cofactor deficiency**

Molybdenum cofactor (MoCoF) deficiency is a severe inherited metabolic disease that causes intractable seizures, developmental delay and structural brain defects. It is due to recessive mutations in either *MOCS1*, *MOCS2* or *GPHN*, all of which are important genes in the MoCoF biosynthetic pathway [146]. MoCoF deficiency impairs the activity of three MoCoF-dependent enzymes; sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase [146, 147]. Patients with MoCoF deficiency excrete elevated levels of a number of metabolites, most notably sulfite and α-AASA [147] (the latter is the same metabolite that accumulates in PDE-ADLH7A1). *In vitro* experiments [147] demonstrated that sulfite inhibits the activity of ADLH7A1 which explains the accumulation of α-AASA in MoCoF deficiency. It is postulated that increased α-AASA, and consequently its cyclic form P6C, may lead to nonenzymatic trapping of PLP [148], in a mechanism analogous to that seen in PDE-ADLH7A1 (**Figure 6**). In line with this, Footitt et al. [149] described low CSF PLP levels in two MoCoF deficiency patients. Struys et al. [148] reported pyridoxine-responsive seizures in two patients with MoCoF deficiency due to *MOCS2* mutations.
