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Introducción: La alcaptonuria es un error autosómico recesivo del metabolismo de los aminoácidos aromáticos fenilalanina y tirosina. El déficit de actividad del enzima dioxigenasa 1,2- homogentisato (HGO) lleva al aumento de la concentración en sangre y orina de ácido homogentístico (HGA), resultando en el acúmulo lento de sus productos de oxidación en los tejidos conjuntivos (ocronosis). La manifestación clínica más frecuente de ocronosis es la artropatía, mientras que las manifestaciones cardíacas de esta enfermedad son poco habituales. Las válvulas cardíacas, la aorta, el endocardio, pericardio y las arterias coronarias pueden encontrarse afectadas, siendo la válvula aórtica la que se daña con mayor frecuencia. Objetivos: Describir la afectación cardiovascular en la alcaptonuria, realizar una revisión bibliográfica sistemática en relación con las alteraciones morfológicas y funcionales de la válvula aórtica en la alcaptonuria y describir las características clínicas, epidemiológicas y evolutivas de la valvulopatía aórtica ocronótica. Material y métodos: Se llevó a cabo una revisión bibliográfica de la literatura. Para la búsqueda de información se ha utilizado las bases de datos PubMed y Google Scholar combinando las palabras clave. Se examinaron revisiones sistemáticas, metaanálisis, ensayos clínicos y estudios observacionales. Se incluyeron en la revisión inicialmente artículos publicados desde el 1944 hasta el 2018, ampliando las fuentes de información con artículos referenciados en los artículos seleccionados. Se revisaron las Guías Españolas y Europeas de Cardiología, publicadas en 2017 y el libro de semiología médica “Fisiopatología, semiotecnia y propedéutica. Enseñanza-aprendizaje centrada en la persona”. También se recabó información de los portales web The AKU Society y Orphanet. Resultados: La incidencia y prevalencia de la enfermedad cardiovascular en la alcaptonuria es muy baja. No se aprecian diferencias entre sexos pero sí se observa un aumento de, Introdución: A alcaptonuria é un erro autosómico recesivo do metabolismo dos aminoácidos aromáticos fenilalanina e tirosina. O déficit de actividade do enzima dioxigenasa 1,2-homogentisato (HGO) leva ao aumento da concentración en sangue e orina de ácido homogentístico (HGA), resultando na acúmulación lenta dos seus produtos de oxidación nos tecidos conxuntivos (ocronose). A manifestación clínica máis frecuente da ocronose é a artropatía, mentres que as manifestacións cardíacas desta enfermidade son pouco habituais. As válvulas cardíacas, a aorta, o endocardio, pericardio e as arterias coronarias poden encontrarse afectadas, sendo a válvula aórtica a que sofre danos con maior frecuencia. Obxectivos: Describir a afectación cardiovascular na alcaptonuria, realizar unha revisión bibliográfica sistemática en relación coas alteracións morfolóxicas e funcionais da válvula aórtica na alcaptonuria e describir as características clínicas, epidemiolóxicas e evolutivas da valvulopatía aórtica ocronótica. Material e métodos: Levouse a cabo una revisión bibliográfica da literatura. Para a búsqueda de información utilizáronse as bases de datos. PubMed e Google Scholar, combinando as palabras chave. Examináronse revisións sistemáticas, metaanálises, ensaios clínicos e estudos observacionais. Incluíronse na revisión inicialmente artigos publicados dende 1944 ata o 2018, ampliando as fontes de información con artigos referenciados nos artigos seleccionados. Revisáronse as Guías Españolas e Europeas de Cardioloxía, publicadas en 2017 e o libro de semioloxía médica “Fisiopatoloxía, semiotecnia e propedéutica. Ensinanza-aprendizaxe centrada na persoa”. Tamén se recabou información dos portais web The AKU Society e Orphanet. Resultados: A incidencia e prevalencia da enfermidade cardiovascular na alcaptonuria é moi baixa. Non se aprezan diferencias entre sexos, pero si se observa un aumento da incidencia coa idade. Créese que o mecanismo etiopatoxénico encóntrase relacionado cos depósito, Introduction: Alkaptonuria is an autosomal recessive inborn error of metabolism of the aromatic amino acids, fenilalanin and tirosine. Deficiency of activity of the homogentisate1,2-dioxygenase (HGO) leads to an increased blood and urinary concentration of homogentisc acid (HGA) resulting in a slow accumulation of its oxidation products in the connective tissues (ochronosis). The most common clinical manifestation of ochronosis is arthropathy whereas cardiac involvement is very uncommon. The heart valves, aorta, endocardium, pericardium and coronary arteries may be affected, with the aortic valve more frequently involved. Objectives: to describe the cardiovascular system involvement in the context of alcaptonuria, to carry out a review related to the morphologic and functional alterations of the aortic valve in alkaptonuria and to describe the clinical, epidemiological and evolutive characteristics of ochronotic aortic valvulopathy. Material and methods: A review was conducted through literature search using Pubmed and Google Scholar, combining the keywords. Meta-analyses, systematic reviews, clinical trials, cohort studies and cases and controls studies were included. Initially, articles published between 1944 and 2018 were included. Afterward, articles referenced in the initials were included. European and Spanish Cardiology guides, published in 2017, and the book “Fisiopathology, semiotecnia and propaedeutics. Person-centered teaching and learning” were taken into account. Also The AKU Society and Orphanet webs were consulted. Results: Incidence and prevalence in cardiovascular disease related with alcaptonuria is very low. There are no substancial differences between sex, but there is an increase in incidence related with age. It is thought that the etiopathogenic mecanism is related with the ocronotic pigment’s deposits that accumulate in various locations, preferably in conective tissue. Majorly these deposits are extracellular. The most frequent valvulopathy

Ochronosis is a cutaneous disorder caused by the accumulation of phenols, either endogenously as homogentisic acid in patients with alkaptonuria (autosomal recessive disorder with deficiency of the enzyme homogentisic acid oxidase), or exogenously in patients using phenol products such as topical creams containing hydroquinone or the intramuscular application of antimalarial drugs. Exogenous ochronosis (EO) typically affects the face and was reported in patients with dark skin such as Black South Africans or Hispanics who use skin-lightening products containing hydroquinone for extended periods. Recently more cases have been reported worldwide even in patients with lighter skin tones, to include Eastern Indians, Asians, and Europeans. However, just 39 cases of EO have been reported in the US literature from 1983 to 2020. Here we present two cases; a 69 and a 45-year-old female who were seen for melasma, given hydroquinone 4% cream daily and tretinoin 0.05%. Both patients noticed brown spots on their cheeks, which progressively enlarged and darkened in color. The diagnosis of ochronosis was confirmed by characteristic histopathological features on the punch biopsy. Unfortunately, neither patient responded to multiple treatments (to include, tazarotene 0.1% gel and pimecrolimus ointment, topical corticosteroids, and avoidance of hydroquinone containing products). We also present a case of classic (endogenous) ochronosis in a patient with alkaptonuria to picture the histological similarities of these two entities. EO is an important clinical consideration because early diagnosis and treatment may offer the best outcome for this notoriously refractory clinical diagnosis.

Ochronosis is a cutaneous disorder caused by the accumulation of phenols, either endogenously as homogentisic acid in patients with alkaptonuria (autosomal recessive disorder with deficiency of the enzyme homogentisic acid oxidase), or exogenously in patients using phenol products such as topical creams containing hydroquinone or the intramuscular application of antimalarial drugs. Exogenous ochronosis (EO) typically affects the face and was reported in patients with dark skin such as Black South Africans or Hispanics who use skin-lightening products containing hydroquinone for extended periods. Recently more cases have been reported worldwide even in patients with lighter skin tones, to include Eastern Indians, Asians, and Europeans. However, just 39 cases of EO have been reported in the US literature from 1983 to 2020. Here we present two cases; a 69 and a 45-year-old female who were seen for melasma, given hydroquinone 4% cream daily and tretinoin 0.05%. Both patients noticed brown spots on their cheeks, which progressively enlarged and darkened in color. The diagnosis of ochronosis was confirmed by characteristic histopathological features on the punch biopsy. Unfortunately, neither patient responded to multiple treatments (to include, tazarotene 0.1% gel and pimecrolimus ointment, topical corticosteroids, and avoidance of hydroquinone containing products). We also present a case of classic (endogenous) ochronosis in a patient with alkaptonuria to picture the histological similarities of these two entities. EO is an important clinical consideration because early diagnosis and treatment may offer the best outcome for this notoriously refractory clinical diagnosis.

Alkaptonuria is a rare autosomal recessive disorder caused by the absence of homogentisate 1,2 dioxygenase (HGD) in the liver. Ochronosis and arthropathic ochronosis are characteristic sequelae of this metabolic disorder. We report here the clinical and molecular findings in 29 alkaptonuric patients (17 males and 12 females) from mainland France and the Reunion Island. We searched for living members of theses families, 14 to 45 years after their observations were described in the literature, and performed molecular analysis and a clinical evolution of the most relevant organ systems involved by ochronosis. Molecular data from 16 families, revealed the presence of six missense mutations at homozygous (p.Y62C, p.W97G, p.V181F, p.V300G) or heterozygous state (p.D153G, p.V300G and p.M368V), four frameshift mutations at homozygous (p.G152fs and p.T196fs) or heterozygous state (p.F10fs and p.R58fs) and three splice site mutations at heterozygous state (IVS1-1G > A, IVS9-56G > A and IVS13+1G > T). Three patients, natives from La Reunion Island, a French department located in the Indian Ocean, were studied. Molecular analysis revealed in a female a homozygous missense mutation p.V300G and in one male, a compound heterozygous mutations: p.V300G inherited from the caucasian father and p.R58fs from the black mother. The p.R58fs mutation is important for two reasons: it is the first AKU mutation described in a black subject and second it has been described in four other countries (Finland, India, Slovakia and Turkey) sharing the same HGD haplotype, which suggests that it is an old mutation, that probably originated in Africa and spread throughout Eurasia during human migrations

Objectives. – To confirm alkaptonuria and ochronotic arthropathy diagnosis by mutation screening of the homogentisate 1,2-dioxygenase (HGD) gene. Try to establish a genotype-phenotype correlation in the five subjects with a molecular study on HGD gene. Methods. – We report 14 alkaptonuria cases (10 men and four women) in 11 Algerian families. Consanguineous matings were evidenced in only three families (F = 1/16). Molecular analysis was performed by sequencing genomic DNA in order to identify the mutations of the HGD gene. Results. – Alkaptonuria was always confirmed by urinary homogentisic acid determination. Four different mutations of the HGD gene were found: an homozygous missense mutation, Serine189Isoleucine in two sisters with a mild phenotype; an homozygous splice site mutation (IVS1-1G > A) in a man with a severe phenotype (death at 61 years old from renal failure); a silent mutation, Alanine470Alanine at the heterozygous state in a man with a mild phenotype; a 'G' deletion at the position c.819 which causes a frameshift after Gly217(Gly217fs) that runs into a stop codon at c. 850. This mutation is novel and was found in heterozygosis in a woman with a mild phenotype. Conclusions. – The two homozygous mutations were associated, respectively, with a severe and a mild phenotype but no genotype–phenotype correlation could be found

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published