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Phosphorylase kinase deficient liver glycogenosis: progression to cirrhosis in infancy associated with PHKG2 mutations (H144Y and L225R)
  1. * Institut für Physiologische Chemie, Ruhr-Universität Bochum, D-44780 Bochum, Germany
  2. The Sheffield Children's Hospital, University of Sheffield, Division of Child Health, Sheffield S10 2TH, UK
  1. Dr Kilimann,manfred.kilimann{at}

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Editor—Deficiency of phosphorylase kinase (Phk), a regulatory protein kinase in glycogen metabolism, is the most frequent cause of hepatic glycogen storage disease (GSD). Patients typically present as infants with hepatomegaly, growth retardation, and raised triglycerides, cholesterol, and transaminases. Compared to other types of liver GSD, the condition is usually mild and its course is benign such that patients may even become asymptomatic as they grow up. Hypoglycaemia and lactic acidosis, for example, are uncommon in Phk deficiency in contrast to glucose-6-phosphatase deficiency (GSD type I). Hepatic architecture typically remains normal, unlike GSD III (debranching enzyme deficiency) in which hepatic fibrosis is common, and unlike GSD IV (branching enzyme deficiency) which usually progresses to cirrhosis in infancy. Only two infants with Phk deficiency and cirrhosis have been reported. Development of fibrosis and even cirrhosis was found in five older Japanese patients, but it remains to be clarified whether this observation can be generalised and also applies to other ethnic groups.1-5

Phk is a complex enzyme consisting of four different subunits, (αβγδ)4, and isoforms or splice variants exist for each subunit. This gives rise to genetic and phenotypic heterogeneity of Phk deficiency.6 A muscle specific form of Phk deficiency is caused by mutations in the gene for the muscle isoform of the α subunit, PHKA1, which resides on the long arm of the X chromosome, whereas liver Phk deficiency can be caused by mutations in three genes: PHKA2,PHKB, and PHKG2. PHKA2 encodes the liver isoform of the α subunit. It is located on the short arm of the X chromosome and therefore involved in most (male) cases of liver Phk deficiency.7 PHKB, located on human chromosome 16, encodes the β subunit that is expressed in all tissues. PHKB mutations therefore cause autosomal recessive Phk deficiency of both liver and muscle, but liver symptoms predominate and the biochemical muscle involvement is often not clinically apparent. Ten different mutations in thePHKB gene have been identified in seven patients.8-10 PHKG2, also autosomal, encodes the testis/liver isoform of the catalytic γ subunit. PHKG2 mutations seem to be the rarest variant with only five patients described to date, all of them homozygous offspring of consanguineous parents.11 12

A genotype-phenotype correlation is emerging in liver Phk deficiency. The functional impact of PHKB mutations, both on residual enzyme activity and clinical condition, appears to be mildest. In contrast, PHKG2 mutations seem to concentrate at the opposite end of the spectrum of severity with very low residual Phk activities, very high plasma lipids and transaminases, and other abnormalities that are uncommon in Phk deficiency, such as lactic acidosis, abnormal glucagon response, or hepatocellular adenoma. Most strikingly, the only two published cases of Phk deficiency who developed liver cirrhosis in infancy were both found to carry translation terminating mutations in thePHKG2 gene.11 12 In the present study, we have identified PHKG2mutations in another patient with liver Phk deficiency and early cirrhosis, further substantiating that PHKG2mutations are associated with a more severe phenotype and particularly with a high risk of cirrhosis.

A male infant, the first child of healthy, unrelated English parents, presented with abdominal distension from 5 months, and three early morning episodes of eye rolling, pallor, and clamminess at 7 months. Examination showed poor growth, muscle wasting, and hepatomegaly 11 cm below the costal margin. Abnormal findings included low prefeed plasma glucose (0.5 mmol/l), raised plasma alanine aminotransferase (587, normal <45 U/l), aspartate aminotransferase (>2000, normal <45 U/l), and γ-glutamyltranspeptidase (2150, normal <40 U/l), and raised plasma cholesterol (18.4, normal 2.5-4.4 mmol/l) and triglycerides (9.3, normal 1.5-1.8 mmol/l). Phk activity was 1.6 U/g Hb (normal, 6-30) in erythrocytes and <1 U/g wet weight (normal, >20) in liver. Hepatic branching and debranching enzyme activities were normal. Liver histology showed fibrous expansion of portal tracts with portal-portal bridging and gross parenchymal glycogen deposition with minimal fat. Overnight nasogastric feeds and two-hourly daytime feeds were necessary to prevent hypoglycaemia and lactic acidosis. Firm irregular hepatomegaly and raised plasma transaminases persisted. Repeat liver biopsy at 3 years showed that glycogen deposition had diminished but cirrhosis was present, with broad bands of interportal fibrosis encircling parenchymal nodules.

Genomic DNA was purified from a blood sample and thePHKG2 gene amplified in four segments and analysed by direct sequencing in both directions, as described previously.12 The patient was found to be heterozygous for two single nucleotide replacements: a C to T transition replacing histidine 144 with tyrosine, and a T to G transversion replacing leucine 225 with arginine (fig 1). H144 is not only conserved in both Phk γ subunit isoforms from several species, but also in the catalytic domains of nearly all serine/threonine protein kinases, where it resides in subdomain VI A.13 Similarly, the counterparts of L225 in more than 100 protein kinase sequences (subdomain IX) are most frequently leucines, methionines, or other hydrophobic or uncharged amino acids, but never charged residues (fig1).13 Analysis of parental DNA showed that the H144Y allele had been inherited from the father and the L225R allele from the mother, together accounting for the patient's enzyme deficiency.

Figure 1

PHKG2 missense mutations in a patient with Phk deficiency and liver cirrhosis. Sequencer tracings are shown on the left, with heterozygous sequence positions marked by asterisks. On the right, the high conservation of the mutated amino acids is illustrated by alignment of the corresponding sequence regions from the testis/liver (PHKG2) and muscle (PHKG1) isoforms of the Phk γ subunit from human, rat, and rabbit, and from bovine protein kinase A (α isoform), bovine protein kinase C (α isoform), and yeast CDC28 kinase as examples of other serine/threonine kinases. See refs 11 and 13 for sequence references and alignment of additional protein kinase sequences.

The patient described here is the first male case and the first to be found compound heterozygous forPHKG2 mutations, whereas all previousPHKG2 cases were female, homozygous offspring of consanguineous parents. All sevenPHKG2 mutations identified to date in different subjects are unique. Including the patient described here, three liver Phk deficiency cases with early cirrhosis have now been analysed for mutations, and PHKG2 mutations were identified in all three. This suggests strongly that this rare complication of Phk deficient liver glycogenosis is generally caused byPHKG2 mutations. Among the first group of three other patients not selected for clinical severity in whichPHKG2 mutations were identified, one had a mild course whereas two developed fibrosis but not cirrhosis at an early age together with other complications uncommon in Phk deficiency.11 A feature shared by all previous cases and the present one is a very low residual Phk activity and pronounced secondary biochemical abnormalities. Missense as well as truncating mutations are found among both the cirrhotic and the non-cirrhotic patients, so that no obvious correlation between mutation severity and cirrhosis is evident. These observations suggest that patients withPHKG2 mutations have a much higher risk of severe liver disease than those with PHKA2or PHKB mutations. The malignant potential of cirrhosis in this small subgroup is unknown.


We thank Dr S K Hanumara for referring the case and Dr S Variend for histology. This work was supported by grants from the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie.