A novel in-frame 18-bp microdeletion in MT-CYB causes a multisystem disorder with prominent exercise intolerance.

A novel heteroplasmic mitochondrial DNA (mtDNA) microdeletion affecting the cytochrome b gene (MT-CYB) was identified in an Italian female patient with a multisystem disease characterized by sensorineural deafness, cataracts, retinal pigmentary dystrophy, dysphagia, postural and gait instability, and myopathy with prominent exercise intolerance. The deletion is 18-base pair long and encompasses nucleotide positions 15,649-15,666, causing the loss of six amino acids (Ile-Leu-Ala-Met-Ile-Pro) in the protein, but leaving the remaining of the MT-CYB sequence in frame. The defective complex III function was cotransferred with mutant mtDNA in cybrids, thus unequivocally establishing its pathogenic role. Maternal relatives failed to show detectable levels of the deletion in blood and urinary epithelium, suggesting a de novo mutational event. This is the second report of an in-frame intragenic deletion in MT-CYB, which most likely occurred in early stages of embryonic development, associated with a severe multisystem disorder with prominent exercise intolerance.

[Congenital erythropoeietic porphyria treated by haematopoietic stem cell allograft]. / Porphyrie érythropoïétique congénitale traitée par allogreffe de cellules souches hématopoïétiques.

BACKGROUND: Congenital erythropoietic porphyria (CEP) is a genodermatosis associated uroporphyrinogen III synthase deficit that results in porphyrin accumulation in various organs, particularly the skin. It is the most severe form of porphyria associated with haemolytic anaemia and cutaneous phototoxicity. We report a severe case of CEP treated by allogeneic bone marrow transplantation. CASE REPORT: A one-year-old child presented erythrodontia and scarring on exposed areas. The diagnosis of CEP was confirmed by the decline of uroporphyrinogen III synthase activity. Demonstration of p.Cys73Arg mutation confirmed the severity of the disease. Allogeneic bone marrow transplantation resulted in persistent resolution of clinical signs 25 months after grafting. DISCUSSION: Symptomatic treatment is ineffective in this serious disease associated with early mortality. 11 of the 13 patients treated by allogeneic hematopoietic stem cell graft, including our patient, continued to be asymptomatic an average of seven years after transplantation. CONCLUSION: This new case confirms the role of allogeneic hematopoietic stem cell grafting in the treatment of congenital erythropoietic porphyria.

Dentinogenesis imperfecta: a review and case report of a family over four generations.

Dentinogenesis imperfecta (DGI) is one of the most common hereditary disorders of dentin formation. It follows an autosomal dominant pattern of transmission, affecting both the formation and mineralization of dentin. Either or both primary and permanent dentition is affected by it. This paper briefly reviews the manifestations of DGI Type II (DGI1) and presents a case report of a family affected with DGI1 over four generations.

Abnormal dentin structure in two novel gene mutations [COL1A1, Arg134Cys] and [ADAMTS2, Trp795-to-ter] causing rare type I collagen disorders.

Histological and ultrastructural observations of dentin of two patients affected with rare types of type I collagen disorders are presented. In the first case, a homozygous nonsense mutation in ADAMTS2 (substitution of a codon for tryptophan by a stopcodon) causes type VIIC Ehlers-Danlos syndrome (EDS) with multiple tooth agenesis and focal dysplastic dentin defects. In the second case, a missense mutation in COL1A1 (substitution of arginine by cysteine) results in a type I EDS phenotype with clinically normal-appearing dentition. Tooth samples are investigated by using light microscopy (LM), transmission electron microscopy (TEM) and immunostaining for types I and III collagen, and tenascin. These are compared with samples from patients with types III and IV osteogenesis imperfecta (OI) in association with dentinogenesis imperfecta (DI), showing a consistently abnormal appearance of the dentin in all specimens, with variations being primarily those of degree of change. Similarities in histological changes include the alternating presence of normal and severe pathological areas in primary and secondary dentin, the latter being characterized by large canal-like structures in atubular areas. Ultrastructural evidence of pathological dentinogenesis include abnormal distribution, size and organization of collagen fibers, which may also be found in clinically unaffected teeth. The histological and ultrastructural changes seen can be explained on the basis of odontoblast dysfunction which may be secondary to the collagen defect, interfering with different levels of odontoblast cell function and intercellular communication. These observations on (ultra)structural dentin defects associated with the two novel gene mutations are the first ever reported.

[Differential diagnosis of tooth discoloration, staining and pigmentation].

Tooth discoloration and developmental defects of enamel and dentin are frequently observed in the pediatric dental clinic. Proper diagnosis may improve the clinicians dental care in many aspects: caries and risk assessment, esthetic restorations and their prognosis, adhesion of restorations and orthodontic appliances, individual and community perspectives of prevention (dental trauma, fluorosis, genetic counseling, financial considerations), behavioral management, and medico-legal issues. This article presents a differential diagnosis of tooth discoloration. External and internal causes for staining and pigmentation are presented in a form resembling the differential diagnosis of developmental defects of enamel. The correlation between these two entities is emphasized and elaborated to schematically review the etiology for developmental and acquired tooth discolorations.

Apparently new syndrome of sensorineural hearing loss, retinal pigment epithelium lesions, and discolored teeth.

We report on a family with early-onset sensorineural hearing loss, abnormal retinal pigment epithelium granularity, accumulation of creamy-white lesions at the level of the retinal pigment epithelium particularly superior to the arcade, and selective discoloration (brown) of molars or canine deciduous teeth that follows an apparent autosomal recessive inheritance pattern. This appears to be a new syndrome that can be distinguished from the known otodental, oculo-acoustic and flecked retina syndromes by the occurrence of distinct dental and ocular abnormalities.

The polarized light microscopy and ultrastructure of Polynesian pigmented tooth enamel.

Transmitted and polarized light microscopy of unerupted and erupted teeth affected by a pigmented anomaly found in two geographically isolated Polynesian populations, the New Zealand Maori and the French Polynesian Marquesas Islander, showed similar histological characteristics. Mounted in water, the pigmented areas were positively birefringent and covered with a thin negatively birefringent surface layer 200-250 microns thick. Cervical areas were negatively birefringent. Transmission electron microscopy of argon-ion-beam thinned specimens of affected enamel revealed large voids, disruption in the packing of crystals and spacing at prism boundaries. In the surface layer of enamel from erupted and unerupted teeth, the intra- and interprismatic spaces were occluded by fine crystals or amorphous material. A well-defined prism structure and close crystal packing were found in cervical enamel. The ultrastructure of these pigmented enamels was similar to and consistent with a hypomaturation type of amelogenesis imperfecta.

Hereditary ochronosis: hyperpigmented skin overlying cartilaginous structures.

Hereditary ochronosis, or alkaptonuria, results from deficiency of homogentisic acid oxidase. It is an autosomal recessive condition found in geographically isolated populations. The excess homogentisic acid deposits in collagenous structures, leading to unusual pigmentation of the skin overlying cartilaginous structures, but on occasion pigment is also seen in the sclera, in sweat after oxidation, and classically, in urine when left standing at room temperature. This case report highlights the pathogenesis and expression of this rare disorder.

[Incidence of structural disorders of teeth in hereditary epidermolysis bullosa]. / A fogak szerkezeti rendellenességének elöfordulása epidermolysis bullosa hereditariában.

Authors present a 12-year old boy, whose diagnosis was epidermolysis bullosa. Beside the general characteristics of the illness they discuss the dental status of the patient and sum up the literary references together with other anomalies occurring in epidermolysis bullosa hereditaria.

Dental abnormalities and preventive oral care in Schimke immuno-osseous dysplasia.

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a rare, severe, autosomal recessive disorder that results in spondyloepiphyseal dysplasia, renal dysfunction, immunodeficiency, facial dysmorphism and growth failure. Little is known about oral features associated with SIOD. Some of the dental anomalies encountered are specific to SIOD and have only been reported in individuals with SIOD. CASE REPORT: This paper describes the clinical and radiographic dental manifestations of SIOD in two Caucasian brothers. Both lived to be about 10 years old. After a variety of symptoms were reported, a diagnosis of SIOD was finally made when the brothers were, respectively, 5 and 8 years old. At that time, dental anomalies, such as dyschromia, bulbous crowns, short and thin roots, had not been taken into account to establish the diagnosis. However, knowledge of the dental features characteristic of this disease could have helped make the diagnosis. Although both were caries- and periodontal disease-free, special attention was focused on prevention, including dietary counselling, plaque control, oral hygiene instructions and the use of fluoridated toothpaste. FOLLOW-UP: The two patients were followed every 6 months, for over 2 years (until their death), by both a private dentist and a university hospital dentist, which helped them maintain good oral health. Oral hygiene was assessed at each appointment and fissure sealants were placed by the private practitioner on their first permanent molars. CONCLUSION: This report describes dental anomalies specific to SIOD that could facilitate diagnosis. Clinicians and dentists should work in collaboration to diagnose and treat children with SIOD. These patients require regular and specific dental management because of their fragile health and their characteristic dental anomalies. Ideally, preventive visits should be scheduled every 6 months in addition to curative visits as needed.

MMP20 hemopexin domain mutation in amelogenesis imperfecta.

Proteolytic enzymes serve important functions during dental enamel formation, and mutations in the kallikrein 4 (KLK4) and enamelysin (MMP20) genes cause autosomal-recessive amelogenesis imperfecta (ARAI). So far, only 1 KLK4 and 3 MMP20 mutations have been reported in ARAI kindreds. To determine whether ARAI in a family with a hypomaturation-type enamel defect is caused by mutations in the genes encoding enamel proteolytic enzymes, we performed mutational analysis on candidate genes. Mutational and haplotype analyses revealed an ARAI-causing point mutation (c.910G>A, p.A304T) in exon 6 of MMP20 that results in a single amino acid substitution in the hemopexin domain. Western blot analysis showed decreased expression of the mutant protein, but zymogram analysis demonstrated that this mutant was a functional protein. The proband and an affected brother were homozygous for the mutation, and both unaffected parents were carriers. The enamel of newly erupted teeth had normal thickness, but was chalky white and became darker with age.

Novel WDR72 mutation and cytoplasmic localization.

The proven candidate genes for amelogenesis imperfecta (AI) are AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72. We performed mutation analyses on seven families with hypomaturation AI. A novel WDR72 dinucleotide deletion mutation (g.57,426_57,427delAT; c.1467_ 1468delAT; p.V491fsX497) was identified in both alleles of probands from Mexico and Turkey. Haplotype analyses showed that the mutations arose independently in the two families. The disease perfectly segregated with the genotype. Only persons with both copies of the mutant allele were affected. Their hypomineralized enamel suffered attrition and orange-brown staining following eruption. Expression of WDR72 fused to green fluorescent protein showed a cytoplasmic localization exclusively and was absent from the nucleus. We conclude that WDR72 is a cytoplasmic protein that is critical for dental enamel formation.

A dentin sialophosphoprotein mutation that partially disrupts a splice acceptor site causes type II dentin dysplasia.

The dentin sialophosphoprotein (DSPP) gene on chromosome 4q21.3 encodes the major noncollagenous protein in tooth dentin. DSPP mutations are the principal cause of dentin dysplasia type II, dentinogenesis imperfecta type II, and dentinogenesis imperfecta type III. We have identified a DSPP splice junction mutation (IVS2-6T>G) in a family with dentin dysplasia type II. The primary dentition is discolored brown with severe attrition. The mildly discolored permanent dentition has thistle-shaped pulp chambers, pulp stones, and eventual pulp obliteration. The mutation is in the sixth nucleotide from the end of intron 2, perfectly segregates with the disease phenotype, and is absent in 200 normal control chromosomes. An in vitro splicing assay shows that pre-mRNA splicing of the mutant allele generates wild-type mRNA and mRNA lacking exon 3 in approximately equal amounts. Skipping exon 3 might interfere with signal peptide cleavage, causing endoplasmic reticulum stress, and also reduce DSPP secretion, leading to haploinsufficiency.

[Amelogenesis imperfecta. Description of a clinical case]. / Amelogénesis imperfecta. Descripción de un caso clínico.

A family of five was examined. Four of them presented with enamel alteration including changes in colour and loss of enamel surface. A genetic study was undertaken which revealed an autosomal dominant inheritance with complete penetration and variable expressivity. This is reflected in shape, number, extension and depth of the affected areas. Amelogénesis Imperfecta type IV was diagnosed using Shields classification.

Nrf2 deficiency causes tooth decolourization due to iron transport disorder in enamel organ.

Rodents have brownish-yellow incisors whose colour represents their iron content. Iron is deposited into the mature enamel by ameloblasts that outline enamel surface of the teeth. Nrf2 is a basic region-leucine zipper type transcription factor that regulates expression of a range of cytoprotective genes in response to oxidative and xenobiotic stresses. We found that genetically engineered Nrf2-deficient mice show decolourization of the incisors. While incisors of wild-type mice were brownish yellow, incisors of Nrf2-deficient mice were greyish white in colour. Micro X-ray imaging analysis revealed that the iron content in Nrf2-deficient mouse incisors were significantly decreased compared to that of wild-type mice. We found that iron was aberrantly deposited in the papillary layer cells of enamel organ in Nrf2-deficient mouse, suggesting that the iron transport from blood vessels to ameloblasts was disturbed. We also found that ameloblasts of Nrf2-null mouse show degenerative atrophy at the late maturation stage, which gives rise to the loss of iron deposition to the surface of mature enamel. Our results thus demonstrate that the enamel organ of Nrf2-deficient mouse has a reduced iron transport capacity, which results in both the enamel cell degeneration and disturbance of iron deposition on to the enamel surface.

[Kohlschütter syndrome--an example of a rare progressive neuroectodermal disease. Case report and review of the literature]. / Das Kohlschütter-Syndrom--Beispiel einer seltenen progredienten neuroektodermalen Erkrankung. Fallbeschreibung und Literaturübersicht.

Kohlschütter's syndrome is a combination of amelogenesis imperfecta, progressive mental retardation and epileptic seizures. We report on a patient with typical signs of this syndrome. Beneath severe enamal defects of teeth, the patient has been suffering from progressive mental and motoric retardation from the age of six months. Although there is pathologic activity in EEG, seizures have not yet appeared. MRT shows distinct signs of cerebral atrophy. Apart from this patient 15 patients in 4 families have been reported up to now in literature. The article compares diagnostic results in this case with those reported in literature.