Familial Persistent Hyperinsulinaemic Hypoglycaemia of Infancy PHHI

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Clinical features

Persistent hyperinsulinaemic hypoglycaemia or PHHI is a disorder of glucose homeostasis that is characterised by unregulated insulin secretion and profound hypoglycaemia. Both familial and sporadic forms have been identified. Familial PHHI is an autosomal recessive disease which occurs at low frequency in Europeans (~1 in 40,000) but reaches incidences as high as 1 in 2,700 live births in Arabic families or Ashkenazi Jews, due to the much higher frequency of consanguineous marriages. It usually manifests at birth or within the first year of life and by the time the disease is recognised and treated, the infant may have suffered severe hypoglycaemia and consequent brain damage. The disease is probably under-diagnosed and may contribute to the incidence of post-natal deaths from unknown causes.

Diagnosis of PHHI is made on the basis of persistent hypoglycaemia associated with raised insulin levels. Glucose infusions are required to maintain the plasma glucose level during diagnosis and so prevent brain damage, but the most effective treatment for PHHI is to remove all or part of the pancreas (>95% is usual). As a consequence, insulin and exocrine pancreatic replacement therapy are often subsequently needed. The K+ channel opener diazoxide is occasionally used to treat PHHI, but many patients do not respond to this drug. In mild cases of the disease, some mothers have even successfully treated the disease by giving their child chocolate bars throughout the day: a practice that certainly appealed to the patient!

Mutation analysis

Linkage analysis of families with PHHI indicated that the gene responsible for the condition was located on chromosome 11, in the region 11p14-15.1 (Thomas et al., 1995a). Subsequently it was found both KATP channel subunits map to the same region, and at least 11 different mutations in SUR1, and 2 in Kir6.2, associated with PHHI have now been reported (Thomas et al., 1995b; 1996; Nestorowicz et al., 1996; Shyng et al., 1998). Mutations in SUR1 are the most common cause of PHHI. These mutations occur throughout the protein but are concentrated in the cytosolic loops and the intracellular ends of the transmembrane domains (Fig. 8.15). They may be grouped into two major classes on the basis of their functional effects. Class I mutations result

Fig Muscles
FIGURE 8.15 MUTATIONS IN KIR6.2 OR SUR1 CAUSE PHHI Putative membrane topology of Kir6.2 and SUR1 with some of the mutations associated with PHHI marked.

in the total loss of functional KATP channel activity, even in excised membrane patches. These include the deletion of a phenylalanine at position 1388 (AF1388), and a mutation within intron 32 that is postulated to activate cryptic splice sites and cause premature truncation of the protein. Class II mutations impair the ability of MgADP to enhance KATP channel activity, but do not alter the inhibitory effect of ATP (Fig. 8.16). Importantly, these mutations also prevent activation of the KATP channel in response to metabolic inhibition (Nichols et al, 1996; Shyng et al., 1998). This has led to the recognition that metabolically-induced changes in MgADP are more important in coupling metabolism to KATP channel activity than are changes in [ATP]i. Some Class II mutations lie within the nucleotide-binding domains (NBDs) of SUR1, and lend support to the idea that MgADP mediates KATP channel activation by interacting with the NBDs. Others, such as F591L, do not and the way in which they produce their functional effects is unclear.

Two PHHI mutations in Kir6.2 have also been identified. One of these is a proline-for-leucine substitution at position 147, which lies within the second TM. It is predicted to disrupt the a-helical structure of the protein, although no functional data have been reported (Thomas et al., 1996). The other is a nonsense mutation that truncates the protein within the first transmembrane domain and is expected to produce a non-functional channel.

Functional consequences of PHHI mutations

Most of the mutations associated with PHHI identified to date appear to fall into two groups: those that result in the total loss of KATP channel activity, even in excised patches, and those in which the regulation of the KATP channel by MgADP is abolished. In the latter case, channel activity can be observed on patch excision, but in the intact cell the KATP channel is always closed because MgADP is unable to relieve the inhibitory effect of [ATP]i. As a consequence, the ^-cells of these PHHI patients lack KATP channel activity, even at low blood

WT F591L T1139M R1215Q G1382S G1479R

FIGURE 816 LACK OF MgADP STIMULATION OF PHHI MUTANT

katp channels

Addition of ATP to the intracellular surface of both wild-type (WT) and PHHI mutant KATP channels produces a similar degree of inhibition, as shown by the white bars. However, MgADP was much less effective at reversing the inhibitory effect of ATP when the SUR1 subunit of the channel contained a mutation associated with PHHI, as shown by the black bars. KATP channels were formed by coexpression of Kir6.2 and either wild-type SUR1, or SUR1 containing the mutation indicated. Currents are plotted relative to their amplitude in the absence of ATP: white bars were recorded in the presence of 100 ju,M ATP, black bars in 100 ju,M ATP + 0.5 mM ADP (Mg2+, ~1 mM). From Shyng et al. (1998).

WT F591L T1139M R1215Q G1382S G1479R

FIGURE 816 LACK OF MgADP STIMULATION OF PHHI MUTANT

katp channels

Addition of ATP to the intracellular surface of both wild-type (WT) and PHHI mutant KATP channels produces a similar degree of inhibition, as shown by the white bars. However, MgADP was much less effective at reversing the inhibitory effect of ATP when the SUR1 subunit of the channel contained a mutation associated with PHHI, as shown by the black bars. KATP channels were formed by coexpression of Kir6.2 and either wild-type SUR1, or SUR1 containing the mutation indicated. Currents are plotted relative to their amplitude in the absence of ATP: white bars were recorded in the presence of 100 ju,M ATP, black bars in 100 ju,M ATP + 0.5 mM ADP (Mg2+, ~1 mM). From Shyng et al. (1998).

glucose levels. This results in a continuous depolarisation of the S-cell and thereby a high resting intracellular Ca2+ concentration (Kane et al., 1996), which explains the constitutive insulin secretion characteristic of PHHI patients.

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