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Wolcott-Rallison syndrome.

Julier C, Nicolino M - Orphanet J Rare Dis (2010)

Bottom Line: Molecular genetic testing confirms the diagnosis.Prognosis is poor and most patients die at a young age.Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inserm UMR-S 958, Faculté de Médecine Denis-Diderot, Paris, France. cecile.julier@inserm.fr

ABSTRACT
Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disease, characterized by neonatal/early-onset non-autoimmune insulin-requiring diabetes associated with skeletal dysplasia and growth retardation. Fewer than 60 cases have been described in the literature, although WRS is now recognised as the most frequent cause of neonatal/early-onset diabetes in patients with consanguineous parents. Typically, diabetes occurs before six months of age, and skeletal dysplasia is diagnosed within the first year or two of life. Other manifestations vary between patients in their nature and severity and include frequent episodes of acute liver failure, renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Bone fractures may be frequent. WRS is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3), also known as PKR-like endoplasmic reticulum kinase (PERK). PERK is an endoplasmic reticulum (ER) transmembrane protein, which plays a key role in translation control during the unfolded protein response. ER dysfunction is central to the disease processes. The disease variability appears to be independent of the nature of the EIF2AK3 mutations, with the possible exception of an older age at onset; other factors may include other genes, exposure to environmental factors and disease management. WRS should be suspected in any infant who presents with permanent neonatal diabetes associated with skeletal dysplasia and/or episodes of acute liver failure. Molecular genetic testing confirms the diagnosis. Early diagnosis is recommended, in order to ensure rapid intervention for episodes of hepatic failure, which is the most life threatening complication. WRS should be differentiated from other forms of neonatal/early-onset insulin-dependent diabetes based on clinical presentation and genetic testing. Genetic counselling and antenatal diagnosis is recommended for parents of a WRS patient with confirmed EIF2AK3 mutation. Close therapeutic monitoring of diabetes and treatment with an insulin pump are recommended because of the risk of acute episodes of hypoglycaemia and ketoacidosis. Interventions under general anaesthesia increase the risk of acute aggravation, because of the toxicity of anaesthetics, and should be avoided. Prognosis is poor and most patients die at a young age. Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.

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Schematic representation of PERK and all mutations reported to date. PERK is composed of a signal peptide (sp), followed by a regulatory domain and a catalytic domain that contains two serine-threonine kinase domains (orange bars). PEK mutations that result in missense mutations are all located within or in the near vicinity of kinase domains (orange blocks). Nonsense (X) and frameshift (FS) mutations, that result in truncated proteins are represented below, and are spread over the length of the protein. Mutations that were found as compound heterozygous in WRS patients are labelled with a "(c)", all others were found in the homozygous state in WRS patients. Mutations homozygous in patients with a relatively late diabetes onset (14 and 30 months) are noted by "(1)" and those homozygous in patients with a relatively longer survival (32 and 35 years) are noted by "(2)". Two mutations were splice mutations located in intron and are not represented. PERK sequence and the position of mutations are provided relative to NCBI RefSeq (NP_004827).
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Figure 4: Schematic representation of PERK and all mutations reported to date. PERK is composed of a signal peptide (sp), followed by a regulatory domain and a catalytic domain that contains two serine-threonine kinase domains (orange bars). PEK mutations that result in missense mutations are all located within or in the near vicinity of kinase domains (orange blocks). Nonsense (X) and frameshift (FS) mutations, that result in truncated proteins are represented below, and are spread over the length of the protein. Mutations that were found as compound heterozygous in WRS patients are labelled with a "(c)", all others were found in the homozygous state in WRS patients. Mutations homozygous in patients with a relatively late diabetes onset (14 and 30 months) are noted by "(1)" and those homozygous in patients with a relatively longer survival (32 and 35 years) are noted by "(2)". Two mutations were splice mutations located in intron and are not represented. PERK sequence and the position of mutations are provided relative to NCBI RefSeq (NP_004827).

Mentions: In subsequent studies, many mutations have been reported in the EIF2AK3 gene in WRS patients [2-4]. These mutations are either nonsense or frameshift mutations resulting in premature termination of the protein, or missense mutations located in the kinase domains of the protein (Figure 4). Overall, a total of 39 distinct mutations have been reported, 25 (64%) of which are frameshift or nonsense mutations, 12 (31%) missense and 2 (5%) splice mutations. In most families (39/42) these mutations were homozygous, as a consequence of consanguineous or endogamic marriages, and in three cases they were compound heterozygous. To date, all patients presenting "typical" clinical manifestations of WRS have been found to carry homozygous or compound heterozygous mutations in EIF2AK3, responsible for the disease. However, in a single patient born from a consanguineous marriage presenting the association of early onset insulin-dependent diabetes (age 18 months) and multiple epiphyseal dysplasia, EIF2AK3 mutations and involvement of this gene were excluded [2]. In contrast to all other WRS patients, this patient had none of the other clinical manifestations characteristic of the disease, including episodes of hepatic failure, and had a border-line level of GAD autoantibodies. This may be a variant form of WRS, or it may be a fortuitous association. In another family, a novel mutation in the PTHR1 gene was found to be responsible for a form of very rare epiphyseal dysplasia, Eiken syndrome [18], that has been described only in this family [19]; one of the four Eiken patients studied had Type 1 Diabetes (T1D), with juvenile onset and the presence of GAD autoantibodies, which is likely to represent a fortuitous association. It should be noted that syndromic disease presentations occurring in consanguineous families, even in the case of rare diseases, may also reflect coincidental associations.


Wolcott-Rallison syndrome.

Julier C, Nicolino M - Orphanet J Rare Dis (2010)

Schematic representation of PERK and all mutations reported to date. PERK is composed of a signal peptide (sp), followed by a regulatory domain and a catalytic domain that contains two serine-threonine kinase domains (orange bars). PEK mutations that result in missense mutations are all located within or in the near vicinity of kinase domains (orange blocks). Nonsense (X) and frameshift (FS) mutations, that result in truncated proteins are represented below, and are spread over the length of the protein. Mutations that were found as compound heterozygous in WRS patients are labelled with a "(c)", all others were found in the homozygous state in WRS patients. Mutations homozygous in patients with a relatively late diabetes onset (14 and 30 months) are noted by "(1)" and those homozygous in patients with a relatively longer survival (32 and 35 years) are noted by "(2)". Two mutations were splice mutations located in intron and are not represented. PERK sequence and the position of mutations are provided relative to NCBI RefSeq (NP_004827).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2991281&req=5

Figure 4: Schematic representation of PERK and all mutations reported to date. PERK is composed of a signal peptide (sp), followed by a regulatory domain and a catalytic domain that contains two serine-threonine kinase domains (orange bars). PEK mutations that result in missense mutations are all located within or in the near vicinity of kinase domains (orange blocks). Nonsense (X) and frameshift (FS) mutations, that result in truncated proteins are represented below, and are spread over the length of the protein. Mutations that were found as compound heterozygous in WRS patients are labelled with a "(c)", all others were found in the homozygous state in WRS patients. Mutations homozygous in patients with a relatively late diabetes onset (14 and 30 months) are noted by "(1)" and those homozygous in patients with a relatively longer survival (32 and 35 years) are noted by "(2)". Two mutations were splice mutations located in intron and are not represented. PERK sequence and the position of mutations are provided relative to NCBI RefSeq (NP_004827).
Mentions: In subsequent studies, many mutations have been reported in the EIF2AK3 gene in WRS patients [2-4]. These mutations are either nonsense or frameshift mutations resulting in premature termination of the protein, or missense mutations located in the kinase domains of the protein (Figure 4). Overall, a total of 39 distinct mutations have been reported, 25 (64%) of which are frameshift or nonsense mutations, 12 (31%) missense and 2 (5%) splice mutations. In most families (39/42) these mutations were homozygous, as a consequence of consanguineous or endogamic marriages, and in three cases they were compound heterozygous. To date, all patients presenting "typical" clinical manifestations of WRS have been found to carry homozygous or compound heterozygous mutations in EIF2AK3, responsible for the disease. However, in a single patient born from a consanguineous marriage presenting the association of early onset insulin-dependent diabetes (age 18 months) and multiple epiphyseal dysplasia, EIF2AK3 mutations and involvement of this gene were excluded [2]. In contrast to all other WRS patients, this patient had none of the other clinical manifestations characteristic of the disease, including episodes of hepatic failure, and had a border-line level of GAD autoantibodies. This may be a variant form of WRS, or it may be a fortuitous association. In another family, a novel mutation in the PTHR1 gene was found to be responsible for a form of very rare epiphyseal dysplasia, Eiken syndrome [18], that has been described only in this family [19]; one of the four Eiken patients studied had Type 1 Diabetes (T1D), with juvenile onset and the presence of GAD autoantibodies, which is likely to represent a fortuitous association. It should be noted that syndromic disease presentations occurring in consanguineous families, even in the case of rare diseases, may also reflect coincidental associations.

Bottom Line: Molecular genetic testing confirms the diagnosis.Prognosis is poor and most patients die at a young age.Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inserm UMR-S 958, Faculté de Médecine Denis-Diderot, Paris, France. cecile.julier@inserm.fr

ABSTRACT
Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disease, characterized by neonatal/early-onset non-autoimmune insulin-requiring diabetes associated with skeletal dysplasia and growth retardation. Fewer than 60 cases have been described in the literature, although WRS is now recognised as the most frequent cause of neonatal/early-onset diabetes in patients with consanguineous parents. Typically, diabetes occurs before six months of age, and skeletal dysplasia is diagnosed within the first year or two of life. Other manifestations vary between patients in their nature and severity and include frequent episodes of acute liver failure, renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia and recurrent infections. Bone fractures may be frequent. WRS is caused by mutations in the gene encoding eukaryotic translation initiation factor 2α kinase 3 (EIF2AK3), also known as PKR-like endoplasmic reticulum kinase (PERK). PERK is an endoplasmic reticulum (ER) transmembrane protein, which plays a key role in translation control during the unfolded protein response. ER dysfunction is central to the disease processes. The disease variability appears to be independent of the nature of the EIF2AK3 mutations, with the possible exception of an older age at onset; other factors may include other genes, exposure to environmental factors and disease management. WRS should be suspected in any infant who presents with permanent neonatal diabetes associated with skeletal dysplasia and/or episodes of acute liver failure. Molecular genetic testing confirms the diagnosis. Early diagnosis is recommended, in order to ensure rapid intervention for episodes of hepatic failure, which is the most life threatening complication. WRS should be differentiated from other forms of neonatal/early-onset insulin-dependent diabetes based on clinical presentation and genetic testing. Genetic counselling and antenatal diagnosis is recommended for parents of a WRS patient with confirmed EIF2AK3 mutation. Close therapeutic monitoring of diabetes and treatment with an insulin pump are recommended because of the risk of acute episodes of hypoglycaemia and ketoacidosis. Interventions under general anaesthesia increase the risk of acute aggravation, because of the toxicity of anaesthetics, and should be avoided. Prognosis is poor and most patients die at a young age. Intervention strategies targeting ER dysfunction provide hope for future therapy and prevention.

Show MeSH
Related in: MedlinePlus