Early onset of Chanarin-Dorfman syndrome with severe liver involvement in a patient with a complex rearrangement of ABHD5 promoter

BACKGROUND: \u3b1/\u3b2-hydrolase domain-containing protein 5 (ABHD5) plays an important role in the triacylglycerols (TAG) hydrolysis. Indeed, ABHD5 is the co-activator of adipose triglyceride lipase (ATGL), that catalyses the initial step of TAG hydrolysis. Mutations in ABHD5 gene are associated with the onset of Chanarin-Dorfman syndrome (CDS), a rare autosomal recessive lipid storage disorder, characterized by non-bullous congenital ichthyosiform erythroderma (NCIE), hepatomegaly and liver steatosis. CASE PRESENTATION: We describe here a 5-years-old Brazilian child who presented with NCIE at birth and diffuse micro and macro-vesicular steatosis on liver biopsy since she was 2 years old. Molecular analysis of coding sequence and putative 5' regulatory region of ABHD5 gene was performed. A homozygous novel deletion, affecting the promoter region and the exon 1, was identified, confirming the suspected diagnosis of CDS for this patient. RT-PCR analysis showed that the genomic rearrangement completely abolished the ABHD5 gene expression in the patient, while only a partial loss of expression was detected in her parents. This is the first report describing the identification of a large deletion encompassing the promoter region of ABHD5 gene. The total loss of ABHD5 expression may explain the early onset of CDS and the severe liver involvement. After molecular diagnosis, the patient started a special diet, poor in fatty acids with medium chain triglycerides (MCT), and showed hepatic and dermatologic improvement in spite of severe molecular defect. CONCLUSIONS: This case report extends the spectrum of disease-causing ABHD5 mutations in CDS providing evidence for a novel pathogenic mechanism for this rare disorder. Moreover, our preliminary data show that early diagnosis and prompt treatment of neutral lipid accumulation might be useful for CD patients

Rapidly advancing phenotype consistently identified in five Brazilian MPS VI patients homozygous for the R315Q mutation

HCPA, Porto Alegre, RS, BrazilUniv Fed Rio de Janeiro, IPPGM, Rio de Janeiro, RJ, BrazilHosp Municipal Crianca, Guarulhos, SP, BrazilUniv Fed Minas Gerais, Dept Pediat, Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, Dept Pediat, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Pediat, São Paulo, BrazilWeb of Scienc

Recommendations on Diagnosis, Treatment, and Monitoring for Gaucher Disease

Universidade Federal de São Paulo, Ctr Referencia Erros Inatos, São Paulo, BrazilUniv Fed Minas Gerais, Fac Med, Dept Propedeut Complementar, Belo Horizonte, MG, BrazilUniv Fed Sao Paul, Fac Med, Hosp Clin Inst Crianca, Unidade Hepatol Pediat, São Paulo, BrazilUniv Fed Rio Grande do Sul, Dept Bioquim ICBS, Porto Alegre, RS, BrazilHosp Clin Porto Alegre, Serv Genet, Porto Alegre, RS, BrazilUniv Fed Parana, Dept Pediat, Discipline Hematol & Oncol, BR-80060000 Curitiba, Parana, BrazilHosp Evangel Londrina, Serv Hematol, Londrina, Parana, BrazilClin Dr Ricardo Pires Doencas Metab, Porto Alegre, RS, BrazilFac Serv Med Santa Casa São Paulo, Disciplina Hematol & Oncol, São Paulo, BrazilUniversidade Federal de São Paulo, Ctr Referencia Erros Inatos, São Paulo, BrazilWeb of Scienc

De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females

PURPOSE: Hardikar syndrome (MIM 612726) is a rare multiple congenital anomaly syndrome characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, but with preserved cognition. Only four patients have been reported previously, and none had a molecular diagnosis. Our objective was to identify the genetic basis of Hardikar syndrome (HS) and expand the phenotypic spectrum of this disorder. METHODS: We performed exome sequencing on two previously reported and five unpublished female patients with a clinical diagnosis of HS. X-chromosome inactivation (XCI) studies were also performed. RESULTS: We report clinical features of HS with previously undescribed phenotypes, including a fatal unprovoked intracranial hemorrhage at age 21. We additionally report the discovery of de novo pathogenic nonsense and frameshift variants in MED12 in these seven individuals and evidence of extremely skewed XCI in all patients with informative testing. CONCLUSION: Pathogenic missense variants in the X-chromosome gene MED12 have previously been associated with Opitz-Kaveggia syndrome, Lujan syndrome, Ohdo syndrome, and nonsyndromic intellectual disability, primarily in males. We propose a fifth, female-specific phenotype for MED12, and suggest that nonsense and frameshift loss-of-function MED12 variants in females cause HS. This expands the MED12-associated phenotype in females beyond intellectual disability.status: publishe

Guidelines for the Management of Mucopolysaccharidosis Type I

Universidade Federal de São Paulo, Ctr Referencia Erros Inatos Metab, São Paulo, BrazilUniversidade Federal de São Paulo, Discipline Otorrinolaringol Pediat, São Paulo, BrazilPontificia Univ Catolica Campinas, São Paulo, BrazilUniv Ciencias Saude Alagoas, Maceio, BrazilUniv Fed Minas Gerais, Fac Med, Dept Propedeut Complementar, Belo Horizonte, MG, BrazilUniv São Paulo, Fac Med, Dept Pediat, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, Discipline Med & Biol Sono, São Paulo, BrazilUniv Estacio Sa, Florianopolis, SC, BrazilAPAE, Triagem Neonatal, Salvador, BA, BrazilUniv Fed Rio Grande do Sul, Dept Bioquim ICBS, Porto Alegre, RS, BrazilHosp Clin Porto Alegre, Serv Genet Med, Porto Alegre, RS, BrazilHosp Reabilitacao, Med Lab Rede Sarah, Belo Horizonte, MG, BrazilFundacao Hosp Estado Minas Gerais, Ctr Geral Pediat, Belo Horizonte, MG, BrazilHosp Restauracao Pernambuco, Serv Hepatol Infantil, Recife, PE, BrazilUniv Fed Minas Gerais, Fac Med, Dept Oftalmol, Belo Horizonte, MG, BrazilHosp Clin Porto Alegre, Setor Mucopolissacaridose, Serv Genet Med, Porto Alegre, RS, BrazilHosp Evangel Londrina Parana, Serv Hematol, Londrina, BrazilClin Doencas Metab Dr Ricardo Pires, Porto Alegre, RS, BrazilHosp Socor, Serv Ortopedia Pediat, Belo Horizonte, MG, BrazilUniv Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Ctr Pesquisas, Lab Terapia Genica, Porto Alegre, RS, BrazilUniversidade Federal de São Paulo, Disciplina Disturbios Comunicacao Humana, Dept Fonoaudiol, São Paulo, BrazilUniversidade Federal de São Paulo, Ctr Referencia Erros Inatos Metab, São Paulo, BrazilUniversidade Federal de São Paulo, Discipline Otorrinolaringol Pediat, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psicobiol, Discipline Med & Biol Sono, São Paulo, BrazilUniversidade Federal de São Paulo, Disciplina Disturbios Comunicacao Humana, Dept Fonoaudiol, São Paulo, BrazilWeb of Scienc

Diagnosis and management of classica homocystinuria in Brazil: a summary of 72 late-diagnosed patients

This study described a broad clinical characterization of classical homocystinuria (HCU) in Brazil. This was a cross-sectional, observational study including clinical and biochemical data from 72 patients (60 families) from Brazil (South, n = 13; Southeast, n = 37; Northeast, n = 8; North, n = 1; and Midwest, n = 1). Parental consanguinity was reported in 42% of families. Ocular manifestations were the earliest detected symptom (53% of cases), the main reason for diagnostic suspicion (63% of cases), and the most prevalent manifestation at diagnosis (67% of cases). Pyridoxine responsiveness was observed in 14% of patients. Only 22% of nonresponsive patients on treatment had total homocysteine levels <100 mmol/L. Most commonly used treatment strategies were pyridoxine (93% of patients), folic acid (90%), betaine (74%), vitamin B12 (27%), and low-methionine diet + metabolic formula (17%). Most patients diagnosed with HCU in Brazil are late diagnosed, express a severe phenotype, and poor metabolic control. Milder forms of HCU are likely underrepresented due to underdiagnosis.SILVA, L. C. S. da. Universidade Federal do Par

Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, 01-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI

Diagnosis and Management of Classical Homocystinuria in Brazil

This study described a broad clinical characterization of classical homocystinuria (HCU) in Brazil. This was a cross-sectional, observational study including clinical and biochemical data from 72 patients (60 families) from Brazil (South, n = 13; Southeast, n = 37; Northeast, n = 8; North, n = 1; and Midwest, n = 1). Parental consanguinity was reported in 42% of families. Ocular manifestations were the earliest detected symptom (53% of cases), the main reason for diagnostic suspicion (63% of cases), and the most prevalent manifestation at diagnosis (67% of cases). Pyridoxine responsiveness was observed in 14% of patients. Only 22% of nonresponsive patients on treatment had total homocysteine levels <100 µmol/L. Most commonly used treatment strategies were pyridoxine (93% of patients), folic acid (90%), betaine (74%), vitamin B12 (27%), and low-methionine diet + metabolic formula (17%). Most patients diagnosed with HCU in Brazil are late diagnosed, express a severe phenotype, and poor metabolic control. Milder forms of HCU are likely underrepresented due to underdiagnosis

Recurrent Dominant Mutations Affecting Two Adjacent Residues in the Motor Domain of the Monomeric Kinesin KIF22 Result in Skeletal Dysplasia and Joint Laxity

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (lepto-SEMDJL, aka SEMDJL, Hall type), is an autosomal dominant skeletal disorder that, in spite of being relatively common among skeletal dysplasias, has eluded molecular elucidation so far. We used whole-exome sequencing of five unrelated individuals with lepto-SEMDJL to identify mutations in KIF22 as the cause of this skeletal condition. Missense mutations affecting one of two adjacent amino acids in the motor domain of KIF22 were present in 20 familial cases from eight families and in 12 other sporadic cases. The skeletal and connective tissue phenotype produced by these specific mutations point to functions of KIF22 beyond those previously ascribed functions involving chromosome segregation. Although we have found Kif22 to be strongly upregulated at the growth plate, the precise pathogenetic mechanisms remain to be elucidated