Uso de canabidiol como terapia adjuvante em paciente com síndrome de Zellweger: relato de caso / Cannabidiol as adjuvant therapy in a patient with Zellweger syndrome: a case report

RESUMO: Também denominada síndrome cerebrohepatorenal, a síndrome de Zellweger é uma doença autossômica recessiva rara, pertencente ao espectro de erros inatos do metabolismo que afetam os peroxissomos. São causados principalmente por mutações em qualquer um dos 14 genes PEX diferentes que codificam para proteínas envolvidas na montagem do peroxissoma, sendo a mais comum do PEX1. O quadro clínico geralmente é observado no período neonatal e primeira infância, incluindo alterações faciais, hipotonia profunda e ausência de reflexos neonatais, além de disfagia, disfunção hepática e convulsões. O diagnóstico é feito a partir da clínica e testes bioquímicos e confirmados pela visualização da mutação em um dos 14 genes PEX. Como não há tratamento específico, é feito tratamento sintomático. Nosso paciente masculino de 1 ano e 9 meses apresentou a hipotonia congênita como sintoma marcante, além de crises convulsivas recorrentes logo após o nascimento. Evoluiu com necessidade de gastrostomia e estagnação de marcos neuromotores. O diagnóstico foi confirmado aos seis meses, através da dosagem de ácidos graxos de cadeia longa. Crises convulsivas evoluíram de maneira refratária a diversos anticonvulsivantes e com elevada frequência diária, por isso iniciamos canabidiol (CBD-RSHO GOLD) por via enteral que reduziu significantemente as crises. Não há tratamento definitivo para esta enfermidade, sendo importante tratamento sintomático das crises convulsivas e terapias de reabilitação, nesse caso, o uso de (CBD- RSHO GOLD) provocou uma redução de 92% na frequência de crises diárias do paciente. No entanto, não é possível concluir, ainda, melhoras em outros sinais e sintomas. (AU)

ABSTRACT: Also referred to as "brain-liver-kidney" syndrome, the Zellweger syndrome is a rare autosomal recessive disorder, belonging to the spectrum of inborn errors of metabolism that affect peroxisomes. They are caused mainly by mutations in any of the 14 different PEX genes that code for proteins involved in the assembly of peroxisome, being the most common of PEX1. The clinic is usually observed in the neonatal and early childhood period, including facial changes, deep hypotonia, and absence of neonatal reflexes in childhood, in addition to dysphagia, hepatic dysfunction, and seizures. The diagnosis is made from clinical and biochemical tests and confirmed by the visualization of the mutation in one of the 14 PEX genes. Since there is no specific treatment, symptomatic treatment is done. Our 1-year and 9-month-old male patient presented congenital hypotonia as a striking symptom in addition to recurrent seizures shortly after birth. It evolved with the need for gastrostomy and stagnation of neuromotor frames. The diagnosis was confirmed at six months by the measurement of long-chain fatty acids. Convulsive seizures evolved in a manner that was refractory to several anticonvulsants and with a high daily frequency, so we initiated cannabidiol (CBD-RSHO GOLD) by an enteral route that significantly reduced the seizures. Since there is no avail-able treatment for seizures, in this case, the use of CBD-RSHO GOLD reduced by 92% the daily seizure frequency. However, it is not possible to conclude further improvements in other signs and symptoms. (AU)

Dysmorphic features in a newborn with neurological, liver and kidney involvement by defective peroxisomal biogenesis. case report

ABSTRACT Introduction: Inborn errors of metabolism have significant morbidity and mortality rates in the neonatal period. One of these disorders is defective peroxisomal biogenesis, which causes complex and severe clinical pictures because peroxisomes are present in all nucleated cells of mammals. Case presentation: This is the case of a newborn with dysmorphic features who had seizures at birth and presented with neurological, liver, kidney and heart involvement during her 20 days of life. Necropsy confirmed liver and kidney involvement, which, together with family history of death of a sibling and a cousin, led to suspect a peroxisomal disease that was confirmed by the biochemical alterations observed. Discussion: Dysmorphism and seizures at birth may be an expression of a metabolic disease. The findings of the physical examination and the demonstration of liver, kidney and heart involvement are consistent with the initial description of Zellweger syndrome; the biochemical alterations are conclusive. Conclusions: It is necessary to define if dysmorphism is an isolated finding or if there is involvement of other organ(s) or system(s) to establish a suitable diagnosis of peroxisome biogenesis. Inborn errors of metabolism should be included in the diagnosis of dysmorphic newborns when several organs are involved, since their identification enables genetic counseling.

RESUMEN Introducción. Los errores innatos del metabolismo pueden ocasionar altas tasa de morbimortalidad en el período neonatal. Dentro de estos trastornos se encuentran los desórdenes en la biogénesis del peroxisoma, que originan cuadros clínicos complejos y graves debido a que los peroxisomas están presentes en todas las células nucleadas de los mamíferos. Presentación del caso. Paciente dismórfica recién nacida quien presentó convulsiones al nacer y desarrolló compromiso neurológico, hepático, renal y cardíaco durante sus 20 días de vida; en la necropsia se confirmó compromiso hepático y renal, por lo que se sospechó de una enfermedad peroxisomal. Las alteraciones bioquímicas reportadas en el presente caso fueron compatibles con un trastorno en la biogénesis de los peroxisomas. Como antecedente se registró la muerte neonatal de un hermano y un primo. Discusión. La presencia de dismorfismo y convulsiones al nacer puede indicar la presencia de una enfermedad metabólica. En la paciente reportada, los hallazgos del examen físico y la demostración del compromiso hepático, renal y cardíaco se ajustan a la descripción inicial del síndrome de Zellweger; por su parte, las alteraciones bioquímicas son concluyentes de un trastorno en la biogénesis de los peroxisomas. Conclusiones. Es necesario definir si el dismorfismo es un hallazgo aislado y si existe afectación de otros órganos o sistemas para establecer un posible diagnóstico de biogénesis de los peroxisomas. Asimismo, los errores innatos del metabolismo deben incluirse en el diagnóstico de los recién nacidos dismórficos cuando hay compromiso de varios órganos, pues su identificación posibilita la asesoría genética.

PEX1 gene related Zellweger syndrome: a report of 2 cases and literature review / 中国新生儿科杂志

Objective To study the phenotypic and genotypic characteristics of Zellweger syndrome caused by PEX1 gene mutation.Method The clinical data of 2 neonates with Zellweger syndrome admitted to the Hospital were retrospectively analyzed.The databases of CNKI,Wipp and Wanfang were retrieved with “peroxisomal disease”,“Zellweger syndrome”,“Zellweger pedigree disorder”,and “PEX1 gene” as key words and the human gene mutation database (HGMD) was retrieved with “PEX1” as the gene name.The biomedical literature database (PubMed),Web of Science database and Embase database were retrieved with “Zellweger syndrome”,“Zellweger spectrum disorder PEX1 gene” as key words.All the databases were retrieved up to Nov 8,2018 to summarize the clinical phenotype and genotype characteristics of children with Zellweger syndrome.Result A total of 2 neonates with Zellweger syndrome were admitted to our Hospital,including 1 male and 1 female.Both the newborns presented with hypotonia,feeding difficulties clinically and showed dilated cerebral ventricles in neuroimaging.They were detected compound heterozygous for PEX1 mutations.Case 1 with the variants [NM_000466:exon 12:c.2050C＞T (p.Q684X);NM_000466:exon20:c.3043G＞T(p.E1015X)] have suffered from seizure at 2 months old.Case 2 with the variants [NM_000466.2:exon5:c.892_895dupTATA (p.Asn299IlefsTer2);NM_000466:exon19:c.2927-2delA] died in the neonatal period.No cases of newborn Zellweger syndrome caused by PEX1 gene mutation have been reported in China.There was a total of 6 articles and 13 cases were reported from foreign literature databases.All the cases presented as hypotonia,abnormal liver function,wide sutures (large fontanelle),hypertelorism and broad nasal bridge clinically.2 newborns carrying 2 missense variants were diagnosed as mild Zellweger spectrum disorder and atypical Zellweger syndrome the 10 newborns with 2 variants typed frameshift,nonsense or splice site were diagnosed as Zellweger syndrome.Conclusion Zellweger syndrome caused by defective gene PEX1 manifested as hypotonia,abnormal liver function,wide sutures (large fontanelle),hypertelorism and broad nasal bridge in neonatal period.Newborns with frameshift,nonsense or splice site variants in PEX1 have more severe clinical phenotypical features.

Laboratory Diagnosis of Peroxisomal Disorders in the -Omics Era and the Continued Importance of Biomarkers and Biochemical Studies

Abstract The clinical as well as biochemical and genetic spectrum of peroxisomal diseases has markedly increased over the last few years, thanks to the revolutionary advances in the field of genome analysis and several -omics technologies. This has led to the recognition of novel disease phenotypes linked to mutations in previously identified peroxisomal genes as well as several hitherto unidentified peroxisomal disorders. Correct interpretation of the wealth of data especially coming from genome analysis requires functional studies at the level of metabolites (peroxisomal metabolite biomarkers), enzymes, and the metabolic pathway(s) involved. This strategy is not only required to identify the true defect in each individual patient but also to determine the extent of the deficiency as described in detail in this article.

Abnormal Prenatal Sonographic findings in Two Cases of Zellweger Syndrome / 대한주산의학회잡지

Zellweger syndrome is a lethal autosomal recessive disorder characterized by neonatal hypotonia, neonatal seizure, psychomotor retardation, facial dysmorphism, and hepatomegaly. It is characterized by an absence or marked decrease of the number of peroxisomes. Children with Zellweger syndrome rarely survive their first year of life. Diagnosis depends on demonstration of elevated very long chain fatty acid in plasma and deficient activity of the peroxisomal enzyme. Chorionic villi sampling or the biochemical analysis of amniocytes makes it possible to identify a fetus affected by Zellweger syndrome during the first trimester of pregnancy. We experienced two cases of postnatally diagnosed Zellweger syndrome with mild sonographic abnormalities prenatally and report our cases with a brief review of literature.

Zellweger Syndrome : First Confirmed Neonatal Case in Korea

We describe below a case of Zellweger syndrome case with facial dysmorphism, profound hypotonia, and hepatomegaly. He died at the age of 2 months. Zellweger syndrome is a disease marked by the absence of hepatic and renal peroxisomes. Because peroxisomes have many vital anabolic and catabolic functions within the cell, their absence results in profound cellular dysfunction. A biochemical study of plasma revealed elevation of very long chains of fatty acids and pipecolic acid, consistent with peroxisomal disorder. The cultured skin fibroblasts showed a marked decrease in plasmalogen synthesis enzyme : dihydroxyacetonephosphate acyl transferase(DHAP-AT) The clinical characteristics and biochemical findings led to the diagnosis of Zellweger syndrome. The pattern of inheritance is autosomal recessive, hence genetic counseling can help the families. In infantile hypotonia patients with unknown cause, peroxisomal disorder should be included in the differential diagnosis. We report the first confirmed case of Zellweger syndrome by enzyme assay in Korea.