Molecular Genetic Defects Research Articles

Molecular genetic defects in endometrial carcinomas: microsatellite instability, PTEN and beta-catenin (CTNNB1) genes mutations

The present study aims to assess the incidence of microsatellite instability (MSI) and mutations in the PTEN and beta-catenin (CTNNB1) genes in endometrial carcinomas and to analyze the detected defects in these factors in relation to each other and to the clinico-pathological features of tumors. In a series of 56 endometrioid endometrial carcinomas, the status of MSI was determined using nine polymorphic markers, and mutations in all exons of the PTEN gene and in exon 3 of the CTNNB1 gene were evaluated by SSCP and sequencing methods. Microsatellite instability was found in 18 carcinomas (32.1%, MSI+); the remaining 38 tumors were microsatellite stable (MSI-). In 15 cases (26.8%), a loss of heterozygosity (LOH) at the studied microsatellite markers also occurred. In 29 carcinomas (51.8%), mutations were found in the PTEN gene and in nine tumors (16.1%) in the CTNNB1 gene. PTEN mutations occurred significantly more frequently in MSI+ than in MSI- tumors (77.8 vs. 39.5%, p = 0.007), but, except for one, none of them was attributable to MSI. In contrast, incidence of CTNNB1 mutations in MSI+ and MSI- tumors no significantly differed between themselves (16.7 vs. 15.8%, p = 0.760). Interestingly, mutations in the CTNNB1 gene most frequently coexisted with mutations in the PTEN gene (7/9, 77.8%). However, this finding requires future verification on a larger group of cases. The incidence of MSI and PTEN, but not CTNNB1 mutations, was significantly more common in poorly, than in well-to-moderately, differentiated tumors (G3 vs. G1 + G2; p = 0.042, 0.039 and 0.958, respectively). We conclude that most frequently occurring mutations in the PTEN gene may be a key event for the tumorigenesis of endometrioid endometrial carcinomas, while coexistence or absence of microsatellite instability or mutations in the CTNNB1 gene may reflect the heterogeneity of molecular mechanisms contributing to the development of these tumors.

Optimal Management Strategies for Rhabdomyosarcoma in Children

Rhabdomyosarcoma is the most common sarcoma of childhood. Fortunately, the goal of cure is realistic for the majority of patients with localized tumors. However, management of these patients remains challenging. The fact that the tumor arises in a wide variety of primary sites, some of which are associated with specific patterns of local invasion, regional lymph node spread, and therapeutic response, requires physicians to be familiar with site-specific staging and treatment details. In addition, rhabdomyosarcoma requires multimodality therapy that can be associated with significant acute toxicities and long-term effects, particularly when administered to young children. These factors sometimes present a dilemma as to the best approach to optimize the chance of cure, minimize toxicity, and respect quality of life. The purpose of this review is to discuss 'optimal' management of this complicated tumor. Since the tumor is relatively rare, requires highly specialized care, and important management questions remain to be answered, optimal management of rhabdomyosarcoma includes enrollment in clinical trials whenever possible. Appropriate management begins with establishing the correct pathologic diagnosis, histologic subtype, primary site, extent of disease (International Society of Pediatric Oncology [SIOP]-TNM-Union Internationale Contre le Cancer stage or Intergroup Rhabdomyosarcoma Study Group [IRSG] stage), and extent of resection (IRSG group). Cooperative groups throughout North America and Europe have defined risk-adapted treatment based on these factors; this treatment requires a coordinated management plan that includes surgery, chemotherapy, and usually radiotherapy. The surgical approach for rhabdomyosarcoma is to excise the primary tumor whenever possible without causing major functional or cosmetic deficits. Wide excision is difficult in some primary sites and can be complicated by the fact that the tumor grows in a locally infiltrative manner so that complete resection is often neither possible nor medically indicated. Incompletely resected tumors are generally treated with radiotherapy. The cooperative groups reduce the dose of radiation based on the response of the tumor to chemotherapy and delayed primary resection to differing degrees. Response-adjusted radiation administration may reduce the long-term effects of radiotherapy, such as bone growth arrest, muscle atrophy, bladder dysfunction, and induction of second malignant neoplasms; however, it may also be associated with an increased risk of tumor recurrence. All patients with rhabdomyosarcoma require chemotherapy. A backbone of vincristine and dactinomycin with either cyclophosphamide (VAC) or ifosfamide (IVA) has been established. Risk-adapted treatment involves reducing or eliminating the alklyating agent for patients with the most favorable disease characteristics. Clinical trials are ongoing to improve outcomes for higher risk patients; newer agents, such as topotecan or irinotecan, in combination with VAC or use of agents in novel ways are being investigated. Acute and long-term toxicities associated with these chemotherapy regimens include myelosuppression, febrile neutropenia, hepatopathy, infertility, and second malignant neoplasms. A 5-year survival rate >70% has been achieved in recent trials for patients with localized rhabdomyosarcoma. However, the outcome for patients who present with metastatic disease remains poor. In the future, risk-adapted classification of rhabdomyosarcoma will likely be based on biologic features, such as the presence of chromosomal translocations or specific gene expression profiles. It is hoped that newer therapies directed at specific molecular genetic defects will benefit all patients with rhabdomyosarcoma.

Kostmann syndrome or infantile genetic agranulocytosis, part one: Celebrating 50 years of clinical and basic research on severe congenital neutropenia

Congenital neutropenia in man was first reported 50 years ago by the Swedish paediatrician Rolf Kostmann. He coined the term "infantile genetic agranulocytosis" for this condition, which is now known as Kostmann syndrome. Recent studies have demonstrated a lack of antibacterial peptides and severe periodontitis in these patients despite recombinant growth factor treatment. Moreover, an increased degree of apoptosis of myeloid progenitor cells in the bone marrow has been shown. Future studies should aim to clarify the underlying molecular genetic defect in Kostmann syndrome.

Identificación de mutaciones en el gen CYBB que llevan al fenotipo de la enfermedad granulomatosa crónica ligada al cromosoma X: Reporte de una nueva mutación

The X-linked form of chronic granulomatous disease (CGD) is a primary immunodeficiency that affects phagocytes of the innate immune system and is characterized by an increased susceptibility to severe bacterial and fungal infections. It is caused by mutations in the CYBB gene, which encodes the 91-kD subunit of phagocyte NADPH oxidase. To identify the mutation in the CYBB gene in two unrelated patients from Chile with the diagnosis of X-linked CGD and their families. The molecular genetic defects of two unrelated patients from Chile with X-linked CGD caused by defects in the CYBB gene were investigated. The underlying mutation was investigated by single strand conformation polymorphism (SSCP) analysis of PCR-amplified genomic DNA and by sequencing of the affected gene region. We found an insertion c.1267_1268insA in exon 10 leading to a frameshift mutation. This mutation is a novel report. We also identified a splice site mutation in the other patient, that presented a c.1326 +1 G>A substitution in intron 10. The mutation was also detectable in his heterozygous mother. This is the first report of the clinical and molecular characterization of Chilean patients with mutations in CYBB gene.

Non-Classical Drug Metabolism Enzymes: The Curious Case of Phenylalanine 4-Monooxygenase

Phenylalanine 4-monooxygenase is a hepatic enzyme that controls the rate of catabolism of Lphenylalanine in man. Genetic defects in the phenylalanine 4-monooxygenase gene are known to be the cause of the majority of cases of phenylketonuria and these defects are now well characterized at the DNA and proteomic levels. However, the role of the phenylalanine 4-monooxygenase in xenobiotic metabolism is poorly understood. This Fe containing non-haem cytosolic monoxygenase is responsible for the S-oxidation of the thioether moiety of the mucoactive drugs, S-carboxymethyl-L-cysteine and S-methyl-L-cysteine, the major route of metabolism of these compounds. This S-oxidation biotransformation is regulated at both the genetic and hormonal level and results in both qualitative and quantitative differences in the metabolic profiles seen in individuals. To date the molecular genetic defects associated with the S-oxidation polymorphism are unknown and remain to be identified. Phenylalanine 4-monooxygenase appears to be like xanthine oxidase, aldehyde oxidase, prostaglandin H synthase, lipooxygenase and dopamine β-hydroxylase. Enzymes of intermediary metabolism are certainly involved in drug metabolism and their role will become more important and widespread in the future. Keywords: Phenylalanine 4-monooxygenase, S-carboxymethyl-L-cysteine, S-oxidation, genetic polymorphism, hormonal regulation

Novel mutations in CLN8 in Italian variant late infantile neuronal ceroid lipofuscinosis: another genetic hit in the Mediterranean

Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive neurodegenerative disorders typically characterized by the accumulation of autofluorescent material in tissues. On the basis of clinical features, age at onset, and molecular genetic defects, it is possible to distinguish at least nine forms. The CLN8 form was first described in Finland, where all the patients are homozygous for a p.Arg24Gly mutation in CLN8. More recently, it has been found that a subset of a Turkish variant of late infantile NCL (v-LINCL) is also associated with CLN8 mutations. To identify the molecular defect in Italian patients with v-LINCL, the CLN8 gene was directly sequenced in 10 patients. Controls were screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Five fluorescent-labeled microsatellite markers covering 1 cM around the gene were used for haplotype analysis. In three Italian v-LINCL patients, identified in a small area in southern Italy, we detected four new mutations in CLN8: c.66delG (p.Gly22fs), c.88G>C (p.Ala30Pro), c.473A>G (p.Tyr158Cys), and c.581A>G (p.Gln194Arg). The single-base deletion was found in two unrelated patients. The novel missense mutations were not identified in ethnically matched control chromosomes. Our findings expand the number of CLN8 variants and corroborate the notion that CLN8 patients are not confined to the Finnish population.

Chronic granulomatous disease in Latin American patients: Clinical spectrum and molecular genetics

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by early onset of recurrent and severe infections. The molecular defects causing CGD are heterogeneous and lead to absence, low expression, or malfunctioning of one of the phagocyte NADPH oxidase components. The aim of this study was to analyze the clinical features and to investigate the molecular genetic defects of Latin American patients with CGD. The study included 14 patients. The diagnosis was based on a history of recurrent severe infections, impaired respiratory burst, and the demonstration of an underlying mutation by single strand conformation polymorphism (SSCP) or RT-PCR analysis, followed by genomic DNA or cDNA sequencing. Seven unrelated patients were found to have the X-linked form of CGD (X-CGD). Heterogeneous mutations affected the CYBB gene: two insertions, one substitution, and four splice site defects; two of them are novel. Seven patients presented with one of the autosomal recessive forms of CGD (A47-CGD); all had the most common mutation, a DeltaGT deletion in exon 2 of the NCF1 gene. Pneumonia was the most frequent clinical feature, followed by pyoderma, sinusitis, otitis, and liver abscess. Patients with X-CGD were more likely to have initial infections before age 2 years and to have inflammatory obstructive granulomas later. None of the patients had severe adverse reactions to BCG immunization. X-CGD patients from Latin America showed a high degree of molecular heterogeneity, including two novel mutations. Their clinical characteristics included early onset of infections and eventual obstructive granulomas. A47-CGD represented 50% of the reported cases, a higher prevalence than reported in other series.

The Beginning of the End of Frustration

The 70th Cold Spring Harbor Symposium, entitled "Molecular Approaches to Controlling Cancer," represented a critical and exciting transition in the fields of cancer research and cancer control. After years of successful research into the molecular genetic and cellular defects that underlie the disease, anticancer agents developed on the basis of these insights are now being used regularly in the treatment of cancer patients. Based on the availability of many more experimental drugs, powerful new methods of analysis, accurate models of the disease, and novel insights into cancer-relevant pathways that affect disease initiation and progression, there is considerable reason for optimism in the ability to one day control cancer.

Molecular genetic defects in congenital hypothyroidism

Recently molecular genetic defects in some cases of congenital hypothyroidism (CH) as well as of rare cases of central hypothyroidism have been identified. These studies have led to the description of so far unexplained forms of these disorders. In some patients with CH early diagnosis by newborn screening and early treatment was not able to lead to a normal mental development. This could subsequently be explained by molecular defects of transcription factors (FOXE-1/FKHL15, NKX2.1) which are important not only for the embryonic development of the thyroid gland but also for other organs including the central nervous system (CNS). These findings will help in understanding the critical role of thyroid hormones in the pre-and postnatal CNS development. However, many questions regarding the molecular defects and their consequences in the majority of patients with CH still remain open and will be addressed in this article.

Aleukemic Mast Cell Leukemia with Abnormal Immunophenotype and C-kit Mutation D816V

Mastocytosis comprises a heterogeneous group of disorders characterized by proliferation and accumulation of mast cells in 1 or more organ systems. Mast cell leukemia (MCL) is an extremely rare subtype of mastocytosis in which a leukemic spread of mast cells and a rapid progression of disease is seen. In typical cases, mast cells are found in the peripheral blood. However, an aleukemic variant of MCL (formerly termed malignant mastocytosis) has also been described. We here report a case of aleukemic MCL with abnormal immunophenotype of mast cells and the classical c-kit point mutation Asp-816-Val ( = D816V). The 75-year-old male patient had a short history of weight loss and lymphadenopathy. There were no urticaria pigmentosa-like skin lesions. The bone marrow was diffusely infiltrated with atypical mast cells that comprised more than 80% of all nucleated cells on a bone marrow smears. As assessed by immunohistochemistry, neoplastic mast cells expressed tryptase, chymase, CD2, CD25, CD68, and the KIT protein (CD117). Mutation analysis revealed the c-kit mutation D816V. Since circulating mast cells could not be detected in the peripheral blood, the diagnosis of aleukemic MCL was established in accordance to the updated WHO consensus classification. This case further supports the notion that the pathogenesis (c-kit mutation D816V) in MCL is closely related to that found in indolent mast cell disorders. However, additional (but yet unknown) molecular (genetic) defects have to be considered to explain the extremely heterogenous clinical course in these patients.

The cytoskeleton in neurodegenerative diseases.

Abundant abnormal aggregates of cytoskeletal proteins are neuropathological signatures of many neurodegenerative diseases that are broadly classified by filamentous aggregates of neuronal intermediate filament (IF) proteins, or by inclusions containing the microtubule-associated protein (MAP) tau. The discovery of mutations in neuronal IF and tau genes firmly establishes the importance of neuronal IF proteins and tau in the pathogenesis of neurodegenerative diseases. Multiple IF gene mutations are pathogenic for Charcot-Marie-Tooth (CMT) disease and amyotrophic lateral sclerosis (ALS)--in addition to those in the copper/zinc superoxide dismutase-1 (SOD1) gene. Tau gene mutations are pathogenic for frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and tau polymorphisms are genetic risk factors for sporadic progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Thus, IF and tau abnormalities are linked directly to the aetiology and pathogenesis of neurodegenerative diseases. In vitro and transgenic animal models are being used to demonstrate that different mutations impair protein function, promote tau fibrilization, or perturb tau gene splicing, leading to aberrant and distinct tau aggregates. For recognition of these disorders at neuropathological examination, immunohistochemistry is needed, and this may be combined with biochemistry and molecular genetics to properly determine the nosology of a particular case. As reviewed here, the identification of molecular genetic defects and biochemical alterations in cytoskeletal proteins of human neurodegenerative diseases has facilitated experimental studies and will promote the development of assays of molecules which inhibit abnormal neuronal IF and tau protein inclusions.

Neurodegeneration caused by proteins with an aberrant carboxyl-terminus.

In recent years, 2 groups of hereditary neurodegenerative diseases have been recognized in which different genetic defects lead to the accumulation of proteins that contain a carboxyl-terminus that is abnormal in length and primary sequence. In this paper, we review the current knowledge on the molecular basis of diseases from these 2 groups. The first group includes familial British and Danish dementias, in which the molecular genetic defect resides in the BRI2 gene located on chromosome 13. In this group, carboxyl-terminal proteolytic products of the mutant BRI2 proteins aggregate in the extracellular space of the brain and in blood vessels. The second group includes 2 recently described ferritinopathies, in which the molecular genetic defect resides in the ferritin light polypeptide gene located on chromosome 19. In this group, full-length ferritin polypeptides aggregate intracellularly. The study of these conditions has led to the discovery of the BRI2 gene and to the finding of an unsuspected role for ferritin in neurodegeneration. These diseases provide new models in which to study the relationship between abnormal protein aggregation, neuronal cell death, and dementia.

Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes.

To evaluate the molecular genetic defects associated with retinitis punctata albescens (RPA) in 5 patients from 3 families with this disease. We examined 3 probands and 2 clinically affected relatives with RPA. Clinical examinations included best-corrected visual acuity, visual field testing, electroretinography, dilated fundus examination, and fundus photography. Leukocyte DNA was analyzed for mutations in the exons of the genes encoding cellular retinaldehyde-binding protein 1 (RLBP1), 11-cis-retinol dehydrogenase (RDH5), interphotoreceptor retinoid-binding protein (RBP3), and photoreceptor all-trans-retinol dehydrogenase (RDH8). Not all patients were evaluated for mutations in each gene. The exons were individually amplified and screened for mutations by single-stranded conformational polymorphism analysis or direct genomic sequencing. The 3 probands had similar clinical findings, including a history of poor night vision, the presence of punctate white deposits in the retina, and substantially reduced or absent rod responses on electroretinogram testing. One of the probands (patient 2:III:2) had 2 novel mutations in the RLBP1 gene (Arg151Trp and Gly31[2-base pair deletion], [GGA-->G-]). Segregation analysis showed that the 2 mutations were allelic and that the patient was a compound heterozygote. Both parents of the proband manifested round white deposits in the retina. The other 2 probands had no detected pathogenic mutations in RLBP1 or in the other 3 genes evaluated. The identification of novel RLBP1 mutations in 1 of our 3 probands, all with RPA, is further evidence of genetic (nonallelic) heterogeneity in this disease. The presence of round white deposits in the retina may be observed in those heterozygous for RLBP1. Clinical Relevance Patients with a clinical presentation of RPA can have genetically different mutations. Drusen-like lesions may be observed in heterozygotes in families with this disease and a mutation in RLBP1.

Regional ependymal upregulation of vimentin in Chiari II malformation, aqueductal stenosis, and hydromyelia.

Vimentin, glial fibrillary acidic protein (GFAP) and S-100beta protein were studied by immunocytochemistry in the ependyma of patients with Chiari II malformations, congenital aqueductal stenosis, and hydromyelia. Paraffin sections of brains and spinal cords of 16 patients were examined, 14 with Chiari II malformations, most with aqueductal stenosis and/or hydromyelia as associated features, and 2 patients with congenital aqueductal stenosis without Chiari malformation. Patients ranged in age from 20-wk gestation to 48 years. The results demonstrated: 1) in the fetus and young infant with Chiari II malformations, congenital aqueductal stenosis, and hydromyelia, vimentin is focally upregulated in the ependyma only in areas of dysgenesis and not in the ependyma throughout the ventricular system; 2) GFAP and S-100beta protein are not coexpressed, indicating that the selective upregulation of vimentin is not simple maturational delay; 3) vimentin upregulation also is seen in the ependymal remnants of the congenital atretic cerebral aqueduct, not associated with Chiari malformation; 4) in the older child and adult with Chiari II malformation, vimentin overexpression in the ependyma becomes more generalized in the lateral ventricles as well, hence evolves into a nonspecific upregulation. The interpretation from these findings leads to speculation that it is unlikely that ependymal vimentin is directly involved in the pathogenesis of Chiari II malformation, but may reflect a secondary upregulation due to defective expression of another gene. This gene may be one of rhombomeric segmentation that also plays a role in defective programming of the paraxial mesoderm for the basioccipital and supraoccipital bones resulting in a small posterior fossa. This interpretation supports the hypothesis of a molecular genetic defect, rather than a mechanical cause, as the etiology of the Chiari II malformation.

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Congenital myasthenic syndrome due to a novel missense mutation in the gene encoding choline acetyltransferase

Congenital myasthenic syndromes are caused by different genetic defects affecting proteins expressed at the neuromuscular junction. Recently, the first molecular genetic defect resulting in a presynaptic congenital myasthenic syndrome has been reported: Recessive loss-of-function mutations in CHAT, the gene encoding choline acetyltransferase, were described in five congenital myasthenic syndrome families. In this study, we investigated three patients from two independent Turkish kinships. Clinically, all patients presented with moderate myasthenic symptoms including ptosis and muscle weakness with increased fatigability. Multiple episodes of sudden apnea were reported for all patients. One child suffering from a second, unrelated disorder, i.e. hepatocellular carcinoma, showed a severe myasthenic phenotype, requiring permanent ventilation. Genetically, we identified a novel missense mutation (I336T) in the CHAT gene homozygously in all three patients. Haplotype analysis revealed that the mutant allele cosegregates with the clinical phenotype in both families (maximum combined two-point LOD-score of 2.46 for D10S1793). In summary, we confirm that CHAT mutations are responsible for a clinically distinct form of congenital myasthenic syndrome, characterized by episodic apnea. Infections and stress may lead to a life-threatening failure of neuromuscular transmission in congenital myasthenic syndrome with episodic apnea. The observation of the same mutation (I336T) in two independent Turkish kinships may suggest a common origin, i.e. founder.

PAX6 gene mutations and genotype-phenotype correlations in sporadic cases of aniridia from India

In order to understand the underlying molecular genetic defect causing aniridia in India, eight probands from sporadic cases were screened for all 14 exons of the PAX6 gene using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). Direct sequencing of the SSCP variants revealed a nonsense mutation (R317X) in the eleventh exon leading to a premature termination of the PAX6 protein in the proline-serine-threonine (PST)-rich domain in two probands. Another proband exhibited an intronic polymorphism (IVS 9–12 C-T). The mutation resulted in loss of function of the PAX6 protein along with variable phenotypic manifestations in the probands. This is the first report describing a PAX6 gene mutation in aniridia cases from India and highlights the variable expressivity in phenotypes due to haploinsufficiency.

A Syndrome of Joint Laxity and Impaired Tendon Integrity in Lumican- and Fibromodulin-deficient Mice

Lumican and fibromodulin regulate the assembly of collagens into higher order fibrils in connective tissues. Here, we show that mice deficient in both of these proteoglycans manifest several clinical features of Ehlers-Danlos syndrome. The Lum(-/-)Fmod(-/-) mice are smaller than their wild type littermates and display gait abnormality, joint laxity, and age-dependent osteoarthritis. Misaligned knee patella, severe knee dysmorphogenesis, and extreme tendon weakness are the likely causes for joint laxity in the double-nulls. Fibromodulin deficiency alone leads to significant reduction in tendon stiffness in the Lum(+/+)Fmod(-/-) mice, with further loss in stiffness in a Lum gene dose-dependent way. At the protein level, we show marked increase of lumican in Fmod(-/-) tendons, which may partially rescue the tendon phenotype in this genotype. These results establish fibromodulin as a key regulator and lumican as a modulator of tendon strength. A disproportionate increase in small diameter immature collagen fibrils and a lack of progression to mature, large diameter fibrils in the Fmod(-/-) background may constitute the underlying cause of tendon weakness and suggest that fibromodulin aids fibril maturation. This study demonstrates that the collagen fibril-modifying proteoglycans, lumican and fibromodulin, are candidate genes and key players in the pathogenesis of certain types of Ehlers-Danlos syndrome and other connective tissue disorders.

Deletion in the OA1 gene in a family with congenital X linked nystagmus

AIMSTo elucidate the molecular genetic defect of X linked congenital nystagmus associated with macular hypoplasia in three white males of a three generation family with clear features of ocular albinism...

The range of chronic demyelinating neuropathy of infancy: a clinico-pathological and genetic study of 15 unrelated cases.

The concept of Dejerine-Sottas disease, which corresponds to presumed recessive demyelinating neuropathies with onset in infancy, remains controversial. To learn more on the subject, we performed a clinico-pathological and molecular genetic study in 15 unrelated patients with the Dejerine-Sottas phenotype seen over a 16 year period. There were 12 females and 3 males, born to asymptomatic parents. Study of the PMP22, P0 and Egr2 genes was performed in all cases and 14 underwent a nerve biopsy. First manifestations of neuropathy occurred before 3 years of age in all patients. An inherited disorder was suspected in 10 patients, because of their family history and/or disclosure of a molecular genetic defect in 4 of them. One patient had a recessively transmitted homozygous point mutation (Arg157Trp) of the PMP22 gene. A heterozygous duplication of the 17p11.2-12 segment was detected in one offspring of a consanguineous marriage. One patient carried a "de novo" heterozygous Ser72Leu substitution in the PMP22. A heterozygous double mutation of the P0 gene including a "de novo" Val42 deletion and an Ala221Thr substitution, maternally inherited, were found in an apparently sporadic case. No mutation of the Egr2 gene was identified. A neuropathy with focally folded myelin sheaths (CMT4B) was diagnosed in the nerve biopsy specimens of two patients. In five patients, the clinico-pathological findings along with the absence of an identified mutation suggested the diagnosis of chronic inflammatory demyelinating polyneuropathy of infantile onset. Our findings illustrate the genetic heterogeneity of cases with identified mutations, the scarcity of cases with "demonstrated" recessive transmission and the likelihood of early acquired chronic inflammatory demyelinating polyneuropathy in several patients.