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Phosphorylase Kinase Deficiency

Glycogen Storage Disease Type 9

Phosphorylase kinase deficiency is a type of glycogen storage disorder with two main subtypes, namely the liver and muscle subtypes. Manifestations range from hepatomegaly and growth restriction to muscle hypotonia, pain, and weakness.


Presentation

Phosphorylase kinase deficiency (PKD) is a genetic disorder and also a type of glycogen storage disease (GSD) that is inherited in either an X-linked or autosomal recessive pattern. There are several types of PKD, stemming from the deficiency of either liver phosphorylase kinase, muscle phosphorylase kinase, or both. PKD has been referred to by several different names in the past, however, it is now commonly known as GSD IX. Furthermore, the enzyme phosphorylase kinase (PK) has alpha, beta, gamma, and delta subunits, in which specific mutations can occur. These characteristics of PK lead to a wide range of clinical manifestations of PKD. The liver subtypes present similarly and thus have no clinical distinction. The muscle PKD subtype is extremely rare.

The features of liver PKD are usually mild, although severe cases have been reported [1] [2]. The illness often presents in early childhood, with hepatomegaly, hyperketotic hypoglycemia, ketosis, weakness and poor development of muscles, impaired growth, and delay in motor and other developmental domains. [2] [3]. The growth restriction is self-limiting and is typically corrected until adulthood, although puberty may be delayed [4] [5].

Organs that can be involved in PKD include the liver, kidneys, ovaries, and spleen. Conditions such as renal tubular acidosis, splenomegaly, liver fibrosis and cirrhosis, and polycystic ovary syndrome have been described [2] [6]. Symptoms and positive biochemical markers diminish with age, thus most adults are asymptomatic [5] [7].

The onset of muscle PKD may be in childhood or adulthood. Most of the manifestations exhibited relate to the musculoskeletal system, exemplified by myalgia, cramps, weakness, exercise intolerance, and myoglobinuria. Similar to liver PKD, presentation varies greatly, but the disease course is mild [8].

Forearm Pain
  • METHODS: Patient 1 (39 years old) had mild exercise-induced forearm pain, and EMG showed a myopathic pattern. Patient 2 (69 years old) had raised levels of creatine kinase (CK) for more than 6 months after statin treatment.[ncbi.nlm.nih.gov]
  • Methods: Patient 1 (39 years old) had mild exercise-induced forearm pain, and EMG showed a myopathic pattern. Patient 2 (69 years old) had raised levels of creatine kinase (CK) for more than 6 months after statin treatment.[neurology.org]
Increased Energy
  • Structured therapy with frequent doses of uncooked cornstarch and protein supplementation was initiated, and both children responded with improved growth velocity, increased energy, decreased hepatomegaly and improved well-being.[ncbi.nlm.nih.gov]
Projectile Vomiting
  • Severe reflux was problematic, and he had a history of projectile vomiting that most frequently occurred in the morning.[ncbi.nlm.nih.gov]
Proximal Muscle Weakness
  • Some patients may have a purely myopathic syndrome with progressive proximal muscle weakness and episodes of myoglobinuria, exercise intolerance, and easy fatigue.[mda.org.au]
  • Neurological examination at the age of 9 years showed mild proximal muscle weakness.[jnnp.bmj.com]
Diplopia
  • […] arrhythmia Wolff–Parkinson–White Aneurysm: Cerebral (Basilar or Aortic); Aortic Aorta: Stiff Cerebral atherosclerotic angiopathy Mutations: Ala237Val; Gly293Arg 13 Dolichoectasia: Basilar & Internal carotid arteries Stroke Other Eye: Unilateral ptosis; Diplopia[neuromuscular.wustl.edu]
Abnormal Eye Movement
  • eye movements, ptosis, optic neuropathy; epilepsy; sensorineural hearing loss; lactic acidemia See footnote 4 See footnote 4 Myodenylate deaminase deficiency (OMIM 615511 ) AR Exercise-induced myalgia, rhabdomyolysis, &/or increased serum CK Disorders[ncbi.nlm.nih.gov]
Dysmenorrhea
  • While the frequency of fertility issues has not been well studied, dysmenorrhea, menstrual irregularity, and oligomenorrhea have been reported [ Cho et al 2013 ]. Other.[ncbi.nlm.nih.gov]

Workup

The diagnosis of PKD relies on physical findings and genetic testing. Biochemical assessments of phosphorylase kinase in various body tissues are also routine. Serum studies of patients with liver PKD may reveal high aspartate aminotransferase (AST) and alanine aminotransferase (ALT), hyperlipidemia, hypoglycemia, and increased ketones [1] [2]. Glucagon response may be deranged [9]. Moreover, on microscopic examination, the liver histology may appear altered, as abnormal hepatocytes, fibrosis, and inflammation are sometimes observed.

Muscle PKD may cause high serum creatine kinase and dysfunction in glycogen metabolism in response to submaximal exercise [10] [11]. The electrical activity of muscle tissue, measured via electromyography, is often negative for signs of disease. Muscle biopsy and histology may reveal the accumulation of glycogen, supported by biochemical findings of elevated muscle glycogen. Muscle PKD does not affect the liver, thus no signs of the disorder are found in the latter.

Certain laboratory tests are used to determine the severity of disease, and these include serial blood glucose and ketone measurements, as well as a basic metabolic panel and creatine kinase. Clotting and lipid studies may also be performed. Radiological evaluation of the liver via computed tomography (CT), magnetic resonance imaging (MRI), or ultrasound is recommended.

Pericardial Effusion
  • effusion Disorders distinguished by enzymatic & molecular genetic testing ACADVL Very long-chain specific acyl-CoA dehydrogenase, mitochondrial Muscle PhK deficiency Glycogen storage disease type V (GSDV) AR Cramps Exercise intolerance Fatigue Muscle[ncbi.nlm.nih.gov]

Treatment

  • These endocrinological and metabolic abnormalities and clinical symptoms were improved with uncooked cornstarch treatment. Uncooked cornstarch treatment may be helpful in hepatic phosphorylase deficiency.[ncbi.nlm.nih.gov]
  • Treatment of disease manifestations has traditionally been based upon symptoms, and it is widely believed that some individuals require no treatment at all.[ncbi.nlm.nih.gov]
  • There is no current treatment except a heart transplant. Infants succumb to heart failure and/or respiratory compromise due to pulmonary compression. This is a rare entity; only three cases have been reported to our knowledge.[ncbi.nlm.nih.gov]
  • Management and treatment Most patients require no specific treatment. Hypoglycemia can be controlled by adequate dietary treatment (frequent meals rich in carbohydrates, and supplements of uncooked starch).[orpha.net]
  • Phosphorylase-kinase was undetectable in the haemolysates of erythrocytes (3 patients) or in the liver (one patient) before, and still undetectable in the haemolysates of the four patients during treatment, thus pointing to X-linked phosphorylase-kinase[ncbi.nlm.nih.gov]

Prognosis

  • Prognosis Prognosis is generally good. Last updated: 5/1/2011[rarediseases.info.nih.gov]
  • Prognosis - Muscular phosphorylase kinase deficiency Not supplied. Treatment - Muscular phosphorylase kinase deficiency Not supplied. Resources - Muscular phosphorylase kinase deficiency Not supplied.[checkorphan.org]
  • Prognosis (prediction of future health) is generally considered good for the liver forms of the disease; however, prognosis for the muscle forms is still unknown.[agsdus.org]
  • Prognosis The clinical course is benign with patients reaching their full height and weight during adulthood. Life expectancy is normal. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • Prognosis : mostly death by age 4, due to cirrhosis and portal hypertension. Type V: McArdle's disease See the separate article on McArdle's Glycogen Storage Disease.[patient.info]

Etiology

  • Etiology Phosphorylase kinase (PhK) is an enzyme which plays a key role in the regulation of glycogenolysis as it is required for glycogen phosphorylase activation.[rarediseases.info.nih.gov]
  • Ongoing controversies regarding etiology, diagnosis, treatment In 2002, guidelines from the European Study on Glycogen Storage Disease Type I (ESGSDI) recommended liver transplantation in patients with type I GSD and unresectable hepatocellular adenomas[clinicaladvisor.com]

Epidemiology

  • Epidemiology The disease is very rare with less than 30 patients reported in the literature. Clinical description The disease starts generally in adolescence or adulthood.[rarediseases.info.nih.gov]
  • Summary Epidemiology The prevalence at birth is estimated at around 1/100,000.[orpha.net]
  • Summary Epidemiology It is the most common presentation of glycogen storage disease due to PhK deficiency (see this term) with an incidence estimated at less than 1/100,000 births.[orpha.net]
  • Glycogenosis type 9C - Glycogenosis type IXa - Glycogenosis type IXc - XLG Classification (Orphanet): - Inborn errors of metabolism - Rare genetic disease - Rare hepatic disease Classification (ICD10): - Endocrine, nutritional and metabolic diseases - Epidemiological[csbg.cnb.csic.es]
  • The GSD classification is based on the enzyme deficiency and the affected tissue. [ 3 ] Epidemiology The overall GSD incidence is estimated at 1 case per 20,000-43,000 live births. [ 4 ] Type I is the most common (25% of all GSDs).[patient.info]
Sex distribution
Age distribution

Pathophysiology

  • J Inherit Metab Dis 38:545–550 CrossRef PubMed Google Scholar Derks TGJ, van Rijn M (2015) Lipids in hepatic glycogen storage diseases: pathophysiology monitoring of dietary management and future directions.[doi.org]
  • Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test Glycogen storage diseases (GSDs) are a group of inherited metabolic conditions caused by deficiency of enzymes responsible for[mayomedicallaboratories.com]
  • Lipids in hepatic glycogen storage diseases: pathophysiology monitoring of dietary management and future directions.[ncbi.nlm.nih.gov]

Prevention

  • Like R531Q, this mutation reduces the binding of AMP and ATP to the isolated nucleotide-binding domains, and prevents activation of the heterotrimer by metabolic stress in intact cells.[ncbi.nlm.nih.gov]
  • Prevention - Muscular phosphorylase kinase deficiency Not supplied. Diagnosis - Muscular phosphorylase kinase deficiency signs and symptoms of Muscular phosphorylase kinase deficiency may vary on an individual basis for each patient.[checkorphan.org]
  • Get optimal test results with guidance on error detection, correction, and prevention as well as cost-effective test selection.[books.google.de]
  • Any immunizations that may prevent illness, such as influenza leading to hypoglycemia, should be offered. Surgery/anesthesia.[ncbi.nlm.nih.gov]
  • Hypoglycemia can be prevented with frequent daytime feedings that are high in complex carbohydrates and protein. When hypoglycemia or ketosis is present, Polycose or fruit juice is given orally as tolerated or glucose by IV.[ncbi.nlm.nih.gov]

References

Article

  1. Morava E, Wortmann SB, van Essen HZ, Liebrand van Sambeek R, Wevers R, van Diggelen OP. Biochemical characteristics and increased tetraglucoside excretion in patients with phosphorylase kinase deficiency. J Inherit Metab Dis. 2005;28(5):703-706.
  2. Beauchamp NJ, Dalton A, Ramaswami U, et al. Glycogen storage disease type IX: High variability in clinical phenotype. Mol Genet Metab. 2007;92(1-2):88-99.
  3. Burwinkel B, Amat L, Gray RG, et al. Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene. Hum Genet. 1998;102(4):423–429.
  4. Schippers HM, Smit GP, Rake JP, Visser G. Characteristic growth pattern in male X-linked phosphorylase-b kinase deficiency (GSD IX). J Inherit Metab Dis. 2003;26(1):43–47.
  5. Willems PJ, Gerver WJ, Berger R, Fernandes J. The natural history of liver glycogenosis due to phosphorylase kinase deficiency: a longitudinal study of 41 patients. Eur J Pediatr. 1990;149(4):268–271.
  6. Lee PJ, Leonard JV. The hepatic glycogen storage diseases--problems beyond childhood. J Inherit Metab Dis. 1995;18(4):462–472.
  7. Hendrickx J, Coucke P, Hors-Cayla MC, et al. Localization of a new type of X-linked liver glycogenosis to the chromosomal region Xp22 containing the liver alpha-subunit of phosphorylase kinase (PHKA2) Genomics. 1994;21(3):620–625.
  8. Wehner M, Clemens PR, Engel AG, Kilimann MW. Human muscle glycogenosis due to phosphorylase kinase deficiency associated with a nonsense mutation in the muscle isoform of the alpha subunit. Hum Mol Genet. 1994;3(11):1983–1987.
  9. Burwinkel B, Rootwelt T, Kvittingen EA, et al. Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene. Pediatr Res. 2003b;54(6):834–839.
  10. Haller RG. Fueling around with glycogen: the implications of muscle phosphorylase b kinase deficiency. Neurology. 2008;70(20):1872–1873.
  11. Ørngreen MC, Schelhaas HJ, Jeppesen TD, et al. Is muscle glycogenolysis impaired in X-linked phosphorylase b kinase deficiency? Neurology. 2008;70(20):1876–1882.

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Last updated: 2019-07-11 20:06