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Letters to the Editor J Med Genet: First Published As 10.1136/Jmg.37.5.382 on 1 May 2000 376 Letters Letters to the Editor J Med Genet: first published as 10.1136/jmg.37.5.382 on 1 May 2000. Downloaded from J Med Genet 2000;37:376–377 Phosphorylase kinase deficient liver some 16, encodes the â subunit that is expressed in all tissues. PHKB mutations therefore cause autosomal reces- glycogenosis: progression to cirrhosis sive Phk deficiency of both liver and muscle, but liver symp- in infancy associated with PHKG2 toms predominate and the biochemical muscle involvement is often not clinically apparent. Ten diVerent mutations in mutations (H144Y and L225R) the PHKB gene have been identified in seven patients.8–10 PHKG2, also autosomal, encodes the testis/liver isoform of the catalytic ã subunit. PHKG2 mutations seem to be the EDITOR—Deficiency of phosphorylase kinase (Phk), a rarest variant with only five patients described to date, all of 11 12 regulatory protein kinase in glycogen metabolism, is the most them homozygous oVspring of consanguineous parents. frequent cause of hepatic glycogen storage disease (GSD). A genotype-phenotype correlation is emerging in liver Patients typically present as infants with hepatomegaly, Phk deficiency. The functional impact of PHKB mutations, growth retardation, and raised triglycerides, cholesterol, and both on residual enzyme activity and clinical condition, transaminases. Compared to other types of liver GSD, the appears to be mildest. In contrast, PHKG2 mutations seem condition is usually mild and its course is benign such that to concentrate at the opposite end of the spectrum of patients may even become asymptomatic as they grow up. severity with very low residual Phk activities, very high Hypoglycaemia and lactic acidosis, for example, are uncom- plasma lipids and transaminases, and other abnormalities mon in Phk deficiency in contrast to glucose-6-phosphatase that are uncommon in Phk deficiency, such as lactic acido- deficiency (GSD type I). Hepatic architecture typically sis, abnormal glucagon response, or hepatocellular ad- remains normal, unlike GSD III (debranching enzyme defi- enoma. Most strikingly, the only two published cases of ciency) in which hepatic fibrosis is common, and unlike GSD Phk deficiency who developed liver cirrhosis in infancy IV (branching enzyme deficiency) which usually progresses were both found to carry translation terminating mutations to cirrhosis in infancy. Only two infants with Phk deficiency in the PHKG2 gene.11 12 In the present study, we have iden- and cirrhosis have been reported. Development of fibrosis tified PHKG2 mutations in another patient with liver Phk and even cirrhosis was found in five older Japanese patients, deficiency and early cirrhosis, further substantiating that but it remains to be clarified whether this observation can be PHKG2 mutations are associated with a more severe phe- generalised and also applies to other ethnic groups.1–5 notype and particularly with a high risk of cirrhosis. Phk is a complex enzyme consisting of four diVerent A male infant, the first child of healthy, unrelated English subunits, (áâãä)4, and isoforms or splice variants exist for parents, presented with abdominal distension from 5 each subunit. This gives rise to genetic and phenotypic months, and three early morning episodes of eye rolling, heterogeneity of Phk deficiency.6 A muscle specific form of pallor, and clamminess at 7 months. Examination showed Phk deficiency is caused by mutations in the gene for the poor growth, muscle wasting, and hepatomegaly 11 cm http://jmg.bmj.com/ muscle isoform of the á subunit, PHKA1, which resides on below the costal margin. Abnormal findings included the long arm of the X chromosome, whereas liver Phk defi- low prefeed plasma glucose (0.5 mmol/l), raised plasma ciency can be caused by mutations in three genes: PHKA2, alanine aminotransferase (587, normal <45 U/l), aspartate PHKB, and PHKG2. PHKA2 encodes the liver isoform of aminotransferase (>2000, normal <45 U/l), and the á subunit. It is located on the short arm of the X ã-glutamyltranspeptidase (2150, normal <40 U/l), and chromosome and therefore involved in most (male) cases of raised plasma cholesterol (18.4, normal 2.5-4.4 mmol/l) liver Phk deficiency.7 PHKB, located on human chromo- and triglycerides (9.3, normal 1.5-1.8 mmol/l). Phk activity on September 27, 2021 by guest. Protected copyright. GACTGTTCTCNATGCCAA A CA 230 * 240 Hum PHKG2 V S F L H A N N I Rat PHKG2 V N F L H V N N I 144 Hum PHKG1 I C T L H K L N I Paternal S F L H A N N Rat PHKG1 V C T L H K L N I mutation AGC TTT CTC CAT GCC AAC AAC Rbt PHKG1 I C A L H K L N I TAT Bov cAPKα F E Y L H S L D L Y Bov PKCα L F F L H K R G I Yea CDC28 I A Y C H S H R I TTGGGGG TTCACACT TCCCC T 250 * 260 Hum PHKG2 I L F T L L A G S Rat PHKG2 I L F T L L A G S 225 Hum PHKG1 I M Y T L L A G S Maternal L F T L L A G Rat PHKG1 I M Y T L L A G S mutation TTG TTC ACA CTC CTG GCT GGC Rbt PHKG1 I M Y T L L A G S CGC Bov cAPKα L I Y E M A A G Y R Bov PKCα L L Y E M L A G Q Yea CDC28 I F A E M C N R K 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 ã subunit from human, rat, and rabbit, and from bovine protein kinase A (á isoform), bovine protein kinase C (á 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. Letters 377 was 1.6 U/g Hb (normal, 6-30) in erythrocytes and <1 U/g biochemical abnormalities. Missense as well as truncating wet weight (normal, >20) in liver. Hepatic branching and mutations are found among both the cirrhotic and the J Med Genet: first published as 10.1136/jmg.37.5.382 on 1 May 2000. Downloaded from debranching enzyme activities were normal. Liver histology non-cirrhotic patients, so that no obvious correlation showed fibrous expansion of portal tracts with portal-portal between mutation severity and cirrhosis is evident. These bridging and gross parenchymal glycogen deposition with observations suggest that patients with PHKG2 mutations minimal fat. Overnight nasogastric feeds and two-hourly have a much higher risk of severe liver disease than those with daytime feeds were necessary to prevent hypoglycaemia and PHKA2 or PHKB mutations. The malignant potential of cir- lactic acidosis. Firm irregular hepatomegaly and raised rhosis in this small subgroup is unknown. plasma transaminases persisted. Repeat liver biopsy at 3 We thank Dr S K Hanumara for referring the case and Dr S Variend for histol- years showed that glycogen deposition had diminished but ogy. This work was supported by grants from the Deutsche Forschungsgemein- cirrhosis was present, with broad bands of interportal fibro- schaft and the Fonds der Chemischen Industrie. sis encircling parenchymal nodules. BARBARA BURWINKEL* Genomic DNA was purified from a blood sample and M STUART TANNER† PHKG2 MANFRED W KILIMANN* the gene amplified in four segments and analysed *Institut für Physiologische Chemie, Ruhr-Universität Bochum, D-44780 by direct sequencing in both directions, as described Bochum, Germany previously.12 The patient was found to be heterozygous for †The SheYeld Children’s Hospital, University of SheYeld, Division of two single nucleotide replacements: a C to T transition Child Health, SheYeld S10 2TH, UK replacing histidine 144 with tyrosine, andaTtoG Correspondence to: Dr Kilimann, [email protected] transversion replacing leucine 225 with arginine (fig 1). 1 Chen YT, Burchell A. Glycogen storage diseases. In: Scriver CR, Beaudet H144 is not only conserved in both Phk ã subunit isoforms AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited dis- from several species, but also in the catalytic domains of ease. 7th ed. Vol 1. New York: McGraw-Hill, 1995:935-65. nearly all serine/threonine protein kinases, where it resides 2 Willems PJ, Gerver WJM, Berger R, Fernandes J. The natural history of liver 13 glycogenosis due to phosphorylase kinase deficiency: a longitudinal study in subdomain VI A. Similarly, the counterparts of L225 in of 41 patients. Eur J Pediatr 1990;149:268-71. 3 Shiomi S, Saeki Y, Kim K, et al. A female case of type VIII glycogenosis who more than 100 protein kinase sequences (subdomain IX) developed cirrhosis of the liver and hepatocellular tumor. Gastroenterol Jpn are most frequently leucines, methionines, or other hydro- 1989;24:711-14. 4 Kagalwalla AF, Kagalwalla YA, Al Ajaji S, Gorka W, Ali MA. Phosphorylase phobic or uncharged amino acids, but never charged resi- J Pediatr 13 b kinase deficiency glycogenosis with cirrhosis of the liver. 1995; dues (fig 1). Analysis of parental DNA showed that the 127:602-5. 5 Aikawa J, Ohura T, Iinuma K, Narisawa K. Management of phosphorylase H144Y allele had been inherited from the father and the kinase deficiency - outcome and control of phosphorylase kinase deficiency. L225R allele from the mother, together accounting for the J Inherit Metab Dis 1997;20:84.
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