Amelogenesis Imperfecta

• What is amelogenesis imperfecta (AI)?
• What are the different types of AI?
• AI and Mendelian Inheritance
• AI Research

• AI Treatments
• Genes and Enamel Formation

Amelogenesis imperfecta (AI) (amelogenesis – enamel formation; imperfecta – imperfecta) is a relatively rare group of inherited disorders characterized by abnormal enamel formation. The term amelogenesis imperfecta is reserved for hereditary defects of enamel that are not associated with defects in other parts of the body or other health problems. The prevalence of these conditions has been studied in only a few populations and has been reported to range from 1 in 700 to 1 in 15,000 [1-4].

The AI enamel defects are highly variable and include abnormalities that are classified as hypoplastic (defect in amount of enamel), hypomaturation (defect in final growth and maturation of enamel crystallites), and hypocalcified (defect in initial crystallite formation followed by defective growth) [5]. The enamel in both the hypomaturation and hypocalcified AI types is not mineralized to the level of normal enamel and can be described as hypomineralized. AI can be inherited as an x-linked, autosomal recessive (AR), or autosomal dominant (AD) condition.

The diagnosis and classification of AI has traditionally been based on the clinical presentation or phenotype and the inheritance pattern [6]. Although multiple gene defects responsible for causing AI have been identified since 1990, most of the AI types do not have a known molecular basis. As the molecular defects causing AI are identified, the need for a molecular based nomenclature increases. The rapid identification of multiple mutations in multiple genes has lead to the acceptance of standardized nomenclatures for reporting AI associated mutations at the genomic, cDNA and protein level [7]. The most widely accepted classification system for delineating the AI types subdivides AI into four main types based on the enamel defects and then further divides them into14 distinct subtypes based on clinical appearance (phenotype) and mode of inheritance [6].

TYPE I: HYPOPLASTIC AI

All of the hypoplastic AI subtypes are characterized by the primary feature of deficient amount of enamel formed. The decreased amount of enamel varies in the different subtypes and can be characterized by enamel that is pitted, has grooves or furrows, has large areas of missing or very thin enamel surrounded by more normal enamel, or enamel that is very thin over the entire tooth crown. Witkop’s clinical classification of hypoplastic AI recognizes seven subtypes [6].

The four main AI types are shown in Table 1 and brief descriptions of the 14 subtypes are provided. After the name of each subtype are the letters designating mode of inheritance (e.g. AD = autosomal dominant, AR = autosomal recessive, and X-linked). For additional explanation of these different modes of Mendelian Inheritance see the section on Mendelian Inheritance.

Modes of Mendelian Inheritance Associated with AI

• Can have male to male transmission.
• On average, half of the offspring of an affected individual will be affected. There is a 50% chance for the child of an affected individual to be affected.
• Affected males and females have similar clinical presentation.

• Unaffected parents will have affected offspring.
• On average, one in four offspring of carrier parents will be affected.
• More likely to occur when parents are related (consanguineous relationship).

• Do not have male to male transmission.
• All daughters of an affected male are carriers.
• Half of the sons born to a carrier female will be affected.
• Affected males have more severe manifestations than females.
• Females can show no manifestations to severe manifestations due to lyonization. Females express only one X chromosome per cell with the other X chromosome becoming the bar body. If adequate numbers of cells express the X chromosome carrying the mutant allele, they will have varying degrees of the enamel defect.

As the genetic mutations associated with the different AI types become known, our ability to accurately diagnose the different AI conditions is becoming markedly improved. The similarity in clinical features makes differentiating some AI types at the clinical level difficult. Correlation of the genetic mutations with the clinical phenotypes of each AI subtype will be invaluable for managing patients with AI. This knowledge also allows us to better predict which AI types are associated with problems such as calculus formation and skeletal open bites and for selecting the most optimal treatment approaches.

Amelogenin (AMELX) Mutations

Over a 14 mutations have been identified in the AMELX gene. Different phenotypes are associated with different AMELX mutations depending on the mutations effect on the amelogenin protein. All the AMELX mutations resulting in a loss of the C-terminus of the protein or total loss of the protein (signal peptide mutations and large deletions) have hypoplastic enamel. Mutations causing single amino acid changes cause hypomaturation defects that in some cases also have hypoplastic enamel. For a review of the phenotype-genotype associations in X-linked AI see Wright et al. 2003 [38].

The AMELX mutations are presented in Table 2 using a standardized nomenclature [7]. The genomic, cDNA and deduced protein are shown in the first three columns. The accession numbers for the genomic and cDNA sequences are shown below the table.

^ Genomic reference sequence accession number AY040206.
+ cDNA Amelogenin reference sequence accession number Af436849
* Initiator methionine as the +1 position; fs = frameshift; X = stop
[37, 39-48]

Enamelin (ENAM) Mutations

Mutations in the ENAM gene are now known to be associated with at least two clinically distinct AI types. These traits are most often transmitted in an autosomal dominant manner with variable expression being noted. One recent family was reported to be transmitted as autosomal recessive. Four different mutations have been identified to date. All of these mutations result in hypoplastic AI. Mutations resulting in loss of most of the protein such as the p.K53X result in local pitting presumably due to haploinsufficiency. In contrast mutations that cause a substantion portion of an altered protein to be translated produced a generalized thin enamel phenotype presumably due to a dominant negative effect. The ENAM mutations are shown using a standardized nomenclature in Table 3.

a Reference sequence GenBank accession no. AY167999; the A of the initiator ATG is taken as +1.
b Reference sequence GenBank accession no. AF125373; the A of the initiator ATG is taken as +1.
c Initiator methionine as the +1 position.

Enamelysin (MMP20) and Kallikrein 4 (KLK4)Mutations

Mutations in the two major proteinases (MMP20 and KLK4) involved in processing the enamel matrix during development and mineralization are associated with autosomal recessive pigmented hypomaturation amelogenesis imperfecta. The enamel is of normal thickness but has a reduced mineral content and increased protein content. The trait is transmitted in an autosomal recessive manner. MMP20 codes for a matrix metalloproteinase that is highly expressed during the secretory stage of enamel formation. Kallikren 4 codes for a serine proteinase that is maximally expressed by ameloblasts during the maturation stage of enamel development. While mutations in both the major proteinases have been identified, evaluation of families with autosomal recessive pigmented hypomaturation AI have not shown mutations in these two genes suggesting this AI subtype is genetically heterogeneous.

a Reference sequence GenBank accession no AF228497; the A of the initiator ATG is taken as +1.
b Reference sequence GenBank accession no NM_004917; the A of the initiator ATG is taken as +1.
c Initiator methionine at the +1 position.

For additional information on the AI associated genes and molecular defects in AI see the OMIM Web site.

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