[Sociocultural aspects of albinism in Sub-Saharan Africa: mutilations and ritual murders committed in east Africa (Burundi and Tanzania)]. / Aspects socioculturels des albinos en Afrique Noire: des mutilations et crimes rituels perpétrés en Afrique de l'est (Burundi et Tanzanie).

This report presents an overview of the many sociocultural prejudices confronting albinos and their parents in Sub-Saharan Africa at each stage of life (infancy, adolescence, and adulthood). The birth of an albino child to two black parents has always been an enigma for African peoples. French-speaking and English-speaking populations in Central, East and South African countries have invented numerous myths to account for this event. Albinos are believed to possess good and evil magical powers. On the white magic side, some organs are believed to confer luck, health, and prosperity. For this reason albinos in Tanzania and Burundi are still in 2008 prey to ritual murders and mutilations to obtain various body parts such as arms, legs, and genitals for preparation of amulets. This barbaric and iniquitous practice has been severely condemned by authorities in both countries as well as by the European Parliament. To end these atrocities disseminating accurate medical information explaining the genetic basis of albinism will be necessary to eliminate ignorance and superstition.

[McArdle disease (gycogenosis type V): analysis of clinical, biological and genetic features of five French patients]. / Maladie de McArdle (glycogénose de type V) : étude clinique, biochimique et génétique d'une cohorte de cinq patients français.

INTRODUCTION: McArdle disease (glycogenosis type V) is an autosomal recessive metabolic myopathy. Defect in glycogen breakdown is due to mutations of the gene for myophosphorylase (PYGM). Among patients of the department, we searched for correlations between disease phenotype, biochemistry analysis of muscle samples and PYGM genotype. METHODS: We included five patients whose muscle biopsy showed deposits of glycogen and negative histochemical staining for myophosphorylase. RESULTS: All patients exhibited exercise intolerance and high serum CK levels (mean 4400). Two of them had an acute renal insufficiency caused by rhabdomyolysis. One patient developed moderate late-onset muscle weakness of the proximal part of upper limbs. Muscle glycogen concentration was high (three times the normal). Myophosphorylase activity was undetectable in four muscle samples out of five. Two patients were homozygous and two other heterozygous for the R50X mutation of PYGM. The other one had a novel missense mutation S814N. Patients homozygous for R50X mutation had higher CK levels (8080 versus 1457, p=0.046), but disease severity and muscle glycogen concentrations were equivalent. CONCLUSIONS: Our patients had typical clinical and laboratory features of McArdle disease. Diagnosis was suggested by exercise intolerance with high CK levels. The R50X mutation was the most common (60% of the mutated alleles). We found no relationship between clinical severity, PYGM genotype and biochemistry analysis of muscle samples.

[Oculocutaneous albinism in French overseas territories (Reunion, French Guyana, Martinique) and Mayotte. Study of 21 cases in 16 families]. / L'albinisme oculocutané dans les départements français d'Outre-Mer (Réunion, Guyane, Martinique) et à Mayotte: à propos de 21 observations dans 16 familles.

The dual purpose of this study was to determine the genotype of patients with oculocutaneous albinism type 1 and 2 based on analysis of tyrosinase and P gene mutations and to attempt to establish a correlation between phenotype and genotype. This study included a total of 21 Caucasian, Indian and Black African patients from La Reunion, la Martinique, French Guyana and Mayotte. PCR-sequencing of genomic DNA was performed to detect tyrosinase gene mutations and PCR-separation of PCR products by agarose gel electrophoresis was performed to detect 2.7kb deletion allele of the P gene. Tyrosinase gene mutations were identified in two cases, i.e., on eheterozygous guanine "g" deletion (c.572 delG) with a frameshift (Gly191fs) resulting in apremature termination signal at codon 225 in a Caucasian patient from La Reunion and one homozygous missense mutation, Glycine419Arginine, in an Indian patient from La Reunion. The 2.7-kb deletion allele of the P gene was detected in three Black African patients, i.e. two in the homozygous state in siblings from Mayotte and one in the heterozygous state in a girl from la Martinique. The latter patient whose mother was from la Martinique inherited the mutation from her father who was from Cameroon. This study shows that characterization of tyrosinase and P gene mutations in albinos patients is crucial to (a) differentiate subjects with oculocutaneous albinism types 1 and 2 and establish a correlation between phenotype and genotype, (b) identify healthy heterozygous carriers among the patient's immediate family (parents and siblings) and (c) allow prenatal diagnosis during subsequent pregnancies in couples who have already engendered albino children with severe visual phenotype and documented mutation(s).

[Sporadic porphyria cutanea tarda: a case report in a Moroccan man]. / La porphyrie cutanée tardive, forme sporadique: à propos d'une observation chez un patient marocain.

This report describes a case of sporadic porphyria cutanea tarda involving a 38-year-old Moroccan man. Clinical diagnosis was based on characteristic features, i.e., facial hypertrichosis and bullous lesions lasting four months during the summer of 2000 followed by macular scarring on the dorsal surfaces on the hands. Three well-known precipitating factors were noted, i.e., sun, ethanol and hepatitis C virus infection. Laboratory diagnosis was based on dark red urine and elevated serum and urine uroporphyrin levels. Enhanced uroporphyrin production was due to urodecarboxylase deficiency in the liver. Urodecarboxylase activity in red blood cells and serum ferritin level were normal. The patient is heterozygous for the His63Asp HFE gene mutation associated with hereditary hemochromatosis. The photoprotective effect of melanin in this dark-skinned patient failed to offset uroporphyrin-induced photosensitivity. Avoidance of sun, ethanol and phlebotomy have prevented recurrences.

Simple, reliable and fast spectrofluorometric method for determination of plasma Verteporfin (Visudyne) levels during photodynamic therapy for choroidal neovascularization.

Photodynamic therapy with Verteporfin, a potent photosensitizer dye, is a very effective treatment for age related macular degeneration due to choroidal neovascularization. Photodynamic therapy offers the potential for selective tissue injury in part attributable to preferential localization of Verteporfin, administrated by intravenous infusion, to the choroidal neovascularization complex and irradiation of the complex with non-laser thermal light at 690 nm resulting in at least temporary thrombosis and vessel closure. Verteporfin is a benzoporphyrin derivative monoacid ring A formulated as a unilamellar liposome. In the blood Verteporfin is associated with lipoprotein fractions and is rapidly cleared via a receptor-mediated uptake mechanism due the high expression of LDL receptors in neovascular tissues. Verteporfin was undetectable in plasma 24 hr after infusion of the recommended dose: 6 mg/m2 of body surface area. The main side effect is photosensitivity of skin which is usually short-lived (24-48 hr) with a low incidence (2.3%). As skin photosensitivity depends on circulating rather than tissue drug levels, we investigate the possibility of developing a simple, fast and reliable spectrofluorometric method to measure plasma Verteporfin levels. Fluorescence emission spectrum (550-750 nm) of 1:10 saline diluted plasma with lambda exc=430 nm showed a characteristic emission peak at 692 nm, the height being proportional to the Verteporfin levels. The sensitivity is around 100 ng/ml and the pharmacokinetics of Verteporfin has been studied from 0 to 5 hr after infusion in six patients older than 65 years with age-related macular degeneration.

Porphobilinogen deaminase gene in African and Afro-Caribbean ethnic groups: mutations causing acute intermittent porphyria and specific intragenic polymorphisms.

Acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is a low-penetrant autosomal dominant disorder caused by mutations in the porphobilinogen deaminase (PBGD) or hydroxymethylbilane synthase (HMBS) gene. Although AIP has been identified in all the main ethnic groups, little is known about PBGD gene defects in Africans, Afro-Caribbean and Afro-Americans. We have carried out PBGD gene screening among seven unrelated AIP families and 98 controls belonging to the Afro-Caribbean (French West Indies) and the sub-Saharan African (Morocco, Algeria, Cameroon, Mali, and Burkina Faso) populations. Using denaturing-gradient gel electrophoresis (DGGE) and direct sequencing we characterized six different mutations, including four novel, from the seven AIP families: three splicing defects (IVS 5+2 Ins G; IVS 7+1 G to A in two families; IVS 10-1 G to T); a small deletion (1004 Del G); and two missense mutations (R116 W; A270G). The allele frequencies of the 14 polymorphic sites, previously known in the normal Caucasian population, were similar in Africans and Afro-Caribbean control populations. Interestingly, two common new intragenic polymorphic sites, close to intron/junction boundaries, were identified only in blacks: 1) in intron 2, a single base-pair G deletion at position 3167 (G:0.88; delG:0.12); 2) in intron 10, a A/G dimorphism at position 7052 (A:0.56; G:0.44). These two single nucleotide polymorphisms (SNPs) were never encountered in 750 unrelated Caucasian subjects. The allele frequency distributions of populations within black ethnic groups (Africans and Afro-Caribbean) are similar. This study highlights differences both in PBGD gene mutations causing AIP and in SNPs between white and black peoples; the allele frequencies provided contribute to a better knowledge of the variability of these markers among the major population groups, especially in sub-Saharan West African and Afro-Caribbean populations.

Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO).

We recently showed that alkaptonuria (AKU) is caused by loss-of-function mutations in the homogentisate 1,2 dioxygenase gene (HGO). Herein we describe haplotype and mutational analyses of HGO in seven new AKU pedigrees. These analyses identified two novel single-nucleotide polymorphisms (INV4+31A-->G and INV11+18A-->G) and six novel AKU mutations (INV1-1G-->A, W60G, Y62C, A122D, P230T, and D291E), which further illustrates the remarkable allelic heterogeneity found in AKU. Reexamination of all 29 mutations and polymorphisms thus far described in HGO shows that these nucleotide changes are not randomly distributed; the CCC sequence motif and its inverted complement, GGG, are preferentially mutated. These analyses also demonstrated that the nucleotide substitutions in HGO do not involve CpG dinucleotides, which illustrates important differences between HGO and other genes for the occurrence of mutation at specific short-sequence motifs. Because the CCC sequence motifs comprise a significant proportion (34.5%) of all mutated bases that have been observed in HGO, we conclude that the CCC triplet is a mutational hot spot in HGO.

Tradition of basic and applied pigment cell research in Marseilles.

Melanogenesis, thyroid hormones and catecholamines synthesis share the same amino acid, free L-tyrosine for melanogenesis and catecholamines synthesis, L-tyrosine residues for thyroid hormones synthesis. The author describes basic and applied research on Melanogenesis and thyroid hormones metabolism in Biochemistry laboratory, School of Medicine, Marseilles since his arrival in 1962. He gives a short review of his participation in these two areas during his career in Marseilles, Yaoundé and Boston.

Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients.

Alkaptonuria (AKU), a rare hereditary disorder of phenylalanine and tyrosine catabolism, was the first disease to be interpreted as an inborn error of metabolism. AKU patients are deficient for homogentisate 1,2 dioxygenase (HGO); this deficiency causes homogentisic aciduria, ochronosis, and arthritis. We cloned the human HGO gene and characterized two loss-of-function mutations, P230S and V300G, in the HGO gene in AKU patients. Here we report haplotype and mutational analysis of the HGO gene in 29 novel AKU chromosomes. We identified 12 novel mutations: 8 (E42A, W97G, D153G, S189I, I216T, R225H, F227S, and M368V) missense mutations that result in amino acid substitutions at positions conserved in HGO in different species, 1 (F10fs) frameshift mutation, 2 intronic mutations (IVS9-56G-->A, IVS9-17G-->A), and 1 splice-site mutation (IVS5+1G-->T). We also report characterization of five polymorphic sites in HGO and describe the haplotypic associations of alleles at these sites in normal and AKU chromosomes. One of these sites, HGO-3, is a variable dinucleotide repeat; IVS2+35T/A, IVS5+25T/C, and IVS6+46C/A are intronic sites at which single nucleotide substitutions (dimorphisms) have been detected; and c407T/A is a relatively frequent nucleotide substitution in the coding sequence, exon 4, resulting in an amino acid change (H80Q). These data provide insight into the origin and evolution of the various AKU alleles.

Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP; MIM 177000) is an inherited disorder caused by partial deficiency of ferrochelatase (FECH), the last enzyme in the heme biosynthetic pathway. In EPP patients, the FECH deficiency causes accumulation of free protoporphyrin in the erythron, associated with a painful skin photosensitivity. In rare cases, the massive accumulation of protoporphyrin in hepatocytes may lead to a rapidly progressive liver failure. The mode of inheritance in EPP is complex and can be either autosomal dominant with low clinical penetrance, as it is in most cases, or autosomal recessive. To acquire an in-depth knowledge of the genetic basis of EPP, we conducted a systematic mutation analysis of the FECH gene, following a procedure that combines the exon-by-exon denaturing-gradient-gel-electrophoresis screening of the FECH genomic DNA and direct sequencing. Twenty different mutations, 15 of which are newly described here, have been characterized in 26 of 29 EPP patients of Swiss and French origin. All the EPP patients, including those with liver complications, were heterozygous for the mutations identified in the FECH gene. The deleterious effect of all missense mutations has been assessed by bacterial expression of the respective FECH cDNAs generated by site-directed mutagenesis. Mutations leading to a null allele were a common feature among three EPP pedigrees with liver complications. Our systematic molecular study has resulted in a significant enlargement of the mutation repertoire in the FECH gene and has shed new light on the hereditary behavior of EPP.

Epidemiology and prophylaxis of endemic goitre in the Bwa village of Sirao (Mali).

A study was conducted in Mali, in some villages exposed to iodine deficiency disorders (IDD). To treat and, above all, prevent endemic goitre, Lipiodol UF was dispensed in two ways: by intra-muscular injection (475 mg I) or by oral administration (48 mg I to 240 mg I). In two cases, hormone levels regained normal values and thyroid hypertrophies regressed significantly. Nevertheless, the impact of the treatment on the size of the goitres seems to be in favour of injections; which is probably due to the fact that in the village which received Lipiodol UF per os, many goitres were nodular.

Type 2 oculocutaneous albinism (OCA2) in Zimbabwe and Cameroon: distribution of the 2.7-kb deletion allele of the P gene.

In previous studies, we characterized a 2.7-kb interstitial deletion allele of the P gene associated with tyrosinase-positive oculocutaneous albinism (OCA2) in African Americans and Africans. In this study, we investigated the frequency of this allele among OCA2 subjects in two African countries, Zimbabwe and Cameroon. The deletion allele was most common in Zimbabwe, comprising nearly all (92%) mutant alleles, which is the highest incidence reported so far. In addition, the deletion allele was widespread but less common among OCA2 Cameroonians and accounted for 65% of the mutant alleles.

Acute intermittent porphyria: rapid molecular diagnosis.

Acute intermittent porphyria (AIP) is an autosomal dominant disorder caused by a partial porphobilinogen (PBG) deaminase deficiency. An exon-by-exon denaturing gradient gel electrophoresis (DGGE) analysis followed by direct sequencing of the DNA fragments was performed to investigate molecular defect in 8 unrelated patients living in south of France: one Algerian, two Moroccan and five French patients. We have optimized the DGGE method in order to study at the same time the fifteen exons of the PBG deaminase gene in only one electrophoresis run. Six different mutations were detected by abnormal mobility patterns. After characterization, a C insertion (716 ins C), 2 deletions (589 del 17 bp; 730 del CT), a non-sense mutation (R149X) and 2 missense mutations (A270G; R173W) were found. The R173W missense mutation was found in 3 unrelated patients, and 716 ins C, 589 del 17 bp and A270G were newly described. According to this small AIP samples, sensitivity of the DGGE screening method was 100%.

[Acute intermittent porphyria in 2 Moroccan families. Clinical and biological study]. / La porphyrie aiguë intermittente chez deux familles marocaines. Etude clinique et biologique.

Three patients from Moroccan kindreds with acute intermittent porphyria (AIP) are described. The propositus of family A originating from Mrirt, Morocco, is living in Embrun, France. This 26 year-old woman who experienced an acute attack with visceral manifestations presented an elevated urinary level of 5-ALA and PBG, and a half-normal activity in porphobilinogen deaminase (PBG-D) in red blood cells (RBC). The family's survey was carried out by measuring the PBG-D activity in RBC (normal values = 125 +/- 40 U). Three of the 16 subjects tested, beside the propositus, were found to be asymptomatic carriers (PBG-D < 70 U). The two patients of family B, originating from Tetouan in the Rif area, were living in Bastia, Corsica. The two brothers, respectively 37 and 39 years old, had a long history (6 years) of neuropsychiatric manifestations before the AIP diagnosis was evidenced by elevated urinary level of 5-ALA and PBG, and showed a partial deficiency, approximately, 50%, of PBG-D activity in RBC. The youngest patient also presented a peripheral neuropathy and recently died after surgery from an unknown reason at the age of 45.

[Parkinson disease and alkaptonuria: fortuitous association or striatonigral ochronosis?]. / Maladie de Parkinson et alcaptonurie: association fortuite ou ochronose striato-nigrale?

We report the case of a 64 year old woman treated for 10 years by DOPA for Parkinson's disease and displaying brown urine. Homogentisic acid was found in urine, establishing the diagnosis of alkaptonuria. Clinical and radiological studies demonstrated ochronosis and ochronotic arthropathy, blue pigmentation of ear cartilage and calcification of the intervertebral lumbar disc giving the classical "inverted spine". Interrelation between this metabolic abnormality and Parkinson's disease is discussed. The recent cloning and mapping of the human gene for alkaptonuria to chromosome 3q should bring some clarification among relationships between these two diseases.