a) Glycogen storage diseases are inherited metabolic disorders. Metabolism is a mechanism to supply energy to the body and various enzymes are associated with it. Types of GSD are classified based on the deficiency of any of the enzymes associated with it. GSD type 0 also called glycogen synthetase deficiency attacks only liver and the major difference between this type and the rest is that it doesn’t store abnormal glycogen but only stores decreased glycogen in liver. This is due to mutation in gene at locus 12p12. Diagnostics include measuring serum glucose levels and serum lipids and imaging tests like skeletal radiography. (Lerardi-curto L, 2010)
GSD type 1a caused due to mutation at loci 17q21 leading to the deficiency of true enzyme glucose 6 phosphatase (G6Pase) and GSD type 1b caused due to mutation at loci 11q23 that leads to the deficiency of glucose 6-phosphate transporter (G6PT). Diagnosis is usually based on analysis of various genetic mutations and Initial test is to measure blood for glucose levels with electrolytes, CBC count, Ultrasonography of Liver and kidneys. (Roth K S, 2009) Molecular Genetic Testing is usually done for the genes, G6PC and SLC37A4 that result in the disease. (Bali D S and Chen Y T, 2008).
GSD type II is due to the deficiency of activity of acid alpha-glucosidase that is caused by the mutation at 17q23. Muscle biopsy and activity of alpha-glucosidase is measured for diagnosis and imaging studies include echocardiography (Ibrahim J and McGovern M M, 2010). Sequence analysis and deletion/duplication analysis are molecular testing methods that help in analysis of genetic mutations. (Tinkle B T and Leslie N, 2010).
GSD type III is due to mutation at AGL gene (Amylo-1, 6-glucosidase) and this result in dysfunction of liver and muscle. Four forms of GSD III have been observed till date. Liver function is accessed for prothrombin and transaminases levels and DNA is isolated from blood and analysis of AGL gene is performed clinically. Various imaging methods include ultrasonography of abdomen and electromyography. (Tegay D H and Jose R, 2009).
GSD type IV or Andersen disease is due to mutation at 3p12 and activity of GBE1 (glycogen-branching enzyme) is reduced. This results in failure and cirrhosis of liver. Various tests include CBC count and assessing albumin and bilirubin levels. CT and MRI scan help to notice hepatic cirrhosis. Prenatal testing and molecular diagnosis is performed. (Lerardi-Curto L, 2009) GSD type V or McArdie disease is due to genetic mutation of PGYM gene at 11q13 that result in the deficiency of myophosphorylase. Laboratory tests include checking elevated serum creatine kinase levels and other tests include electromyography, muscle biopsy and 31P-NMR. (Copier E J, 2009)
The gene encoding muscle form of glycogen phosphorylase, PYGM is tested using molecular testing methods such as targeted mutational analysis, sequence analysis. (Arenas J et al, 2009) GSD type VI in classic form is due to deficiency of liver phosphorylase; phosphorylase b kinase and mutations are observed in PHKA2, PHKB, and PHKG2 genes. Tests include assessing urine ketone levels and serum ketone bodies and liver volume quantitative tests by MRI or CT scan. Definitive methods include liver biopsy, enzyme analysis. (Lerardi-Curto L, 2010)
Genetic testing of PYGL gene that is associated with the disease is done for accurate results. (Dali A I and Weinstein D A, 2009) GSD type VII also called tarui disease; is due to deficiency of phosphofructokinase enzyme that plays key role in regulating glycolysis. The disease is caused due to frameshift mutations in the gene that codes for PFK-M subunit at locus 12p13. Definite diagnosis include muscle biopsy and biochemical test involved is to assess the of serum creatine kinase, bilirubin levels and imaging tests like brain imaging scans and phosphorous 31-NMR are useful in diagnosis. (Lerardi-Curto L, 2009)
Screening tests usually performed are glucagon tolerance tests and other biochemical data obtained from serum is evaluated and best possibility to diagnose hepatic GSD is using peripheral blood cells. (Maire I et al., 1991) Controls used in diagnostic methods are usually of age and sex matched and were also checked for their exercise levels with the patients. As soon as the tests finish comparison is made between patients and controls and these tests are usually based on type of GSD. (Mundy H R et al., 2005).
b) Family1 Based on the data provided it is clearer that Philip has disease with genotype rr and this provide information that their children are carriers of the disease. It’s clearly mentioned that III 2 and III 6 are grand children of Philip. This shows the only possibility of Philip being father to Joe Smith and other with carrier genotype. Joe Smith is married to Ethel of normal genotype and their child is normal with 50% of them carriers i.e. Jack (III 2) and III 3 are carriers. Philip’s another child is also carrier and when he is married to another carrier there is a 1 in 4 chance of their children getting affected i.e.